Dr. Frank Pagdunzulan: Diseases of The Immune System

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM

DISEASES OF THE IMMUNE SYSTEM


1.9
1.9

Dr. Frank Pagdunzulan July 5, 2014


OUTLINE III. Rejection of tissue transplants
DISEASES OF THE IMMUNE SYSTEM A. Mechanisms of recognition and rejection of allografts
I. Normal Immune response 1. T cell mediated
A. Innate immunity 2. Ab mediated reactions
B. Adaptive immunity a. Rejection of kidney grafts
C. Components of the immune system b. Morphology
1. Cells 3. Methods if increasing graft survival
a. T lymphocytes a. Transplantation of other solid organs
b. B lymphocytes b. Transplantation of hematopoietic cells
c. Dendritic cells IV. Immunodeficiency syndromes
d. Macrophages A. Primary immunodeficiencies
e. NK cells 1. X-linked agammaglobulinemia
2. Tissues 2. Common variable immunodeficiency
a. Generative lymphoid organs 3. Isolated IgA deficiency
b. Peripheral lymphoid organs 4. Hyper IgM syndrome
c. Lymphocyte recirculation 5. DiGeorge syndrome
3. MHC molecules 6. Severe combined immunodeficiency
a. Classic I 7. Immunodeficiency with thrombocytopenia and eczema
b. Classic II 8. Genetic deficiencies of the complement system
c. HLA and disease association B. Secondary immunodeficiencies
4. Cytokines C. Acquired immunodeficiency syndrome (GIA)
D. Overview of lymphocyte activation and immune responses 1. Epidemiology
1. Display and Recognition of Ag 2. Etiology
2. Cell mediated immunity a. Structure of HIV
3. Humoral immunity 3. Pathogenesis of HIV infection and AIDS
4. Decline of immune responses and immunological memory a. Life cycle of HIV
II. Hypersensitivity and Autoimmune disorders i. Infection of cells by HIV
A. Mechanisms of hypersensitivity reactions ii. Viral replication
1. Type I b. Mechanism of T cell immunodeficiency in HIV
a. Preformed mediators c. HIV infection in non-T cells
b. Lipid mediators d. Pathogenesis of CNS involvement
c. Cytokines 4. Natural history of HIV infection
d. Systemic anaphylaxis a. Primary infection, virus dissemination, and acute retroviral
e. Local immediate hypersensitivity reactions syndrome
2. Type II b. Chronic infection
a. Opsonization and phagocytosis c. AIDS
b. Inflamm i. Clinical features of AIDS
c. Cellular dysfunction d. Opportunistic infections
3. Type III e. Tumors
a. Systemic immune complex disease i. Kaposi sarcoma
i. Formation ii. Lymphomas
ii. Deposition iii. Other tumors
iii. Tissue injury f. CNS disease
iv. Morphology g. Effect of antiretroviral drug therapy
b. Local immune complex disease h. Morphology
4. Type IV V. Amyloidosis
a. Reactions of CD4 T cells A. Properties of amyloid proteins
i. Proliferation and differentiation 1. Physical nature of amyloid
ii. Responses of differentiated effector T cells 2. Chemical nature of amyloid
b. Reactions of CD8 T cells B. Pathogenesis of amyloidosis
B. Autoimmune diseases C. Classification of amyloidosis
1. Immunological tolerance 1. Primary Amyloidosis
a. Central 2. Reactive systemic amyloidosis
b. Peripheral 3. Hemodialyis-associated amyloidosis
2. Mechanisms of autoimmunity 4. Heredofamilial amyloidosis
a. Role of susceptibility genes 5. Localized amyloidosis
b. Role of infections 6. Endocrine amyloid
3. General features of autoimmune diseases 7. Amyloid of aging
4. SLE D. Morphology
a. Spectrum of antibodies in SLE E. Clinical features
b. Etiology and pathogenesis of SLE
i. Genetic I. NORMAL IMMUNE RESPONSE
ii. Immunologic
iii. Environmental
Defense against infectious pathogens
c. A model for the pathogenesis Mechanisms of protection fall into 2 broad categories:
d. Mechanisms of tissue injury o Innate Immunity (Natural / native immunity)
e. Morphology
f. Clinical features
o Adaptive Immunity (Acquired / specific Immunity)
g. Chronic Discoid
h. Subacute cutaneous INNATE IMMUNITY
i. Drug-induced
5. Rheumatoid arthritis
First line of defense
6. Sjogren syndrome Defense mechanisms that are present even before infection
a. Etiology Have evolved to specifically recognize microbes and
b. Pathogenesis protect individuals against infections
c. Morphology
d. Clinical features Two most important cellular reactions:
7. Systemic sclerosis o Inflammation the process in which phagocytic
a. Etiology and pathogenesis leukocytes are recruited and activated to kill microbes
b. Abnormal immune response o Anti-viral defense mediated by dendritic cells and
c. Vascular damage NK cells
d. Fibrosis
e. Morphology
f. Clinical features A. Pathogen associated molecular patterns (PAMPS)
8. Inflammatory myopathies Components of microbes that are shared among related
9. Mixed CT disease microbes and are often essential for infectivity
10. Polyarteritis nodosa and other vasculitides
Cannot be mutated

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
B. Danger-associated molecular patterns (DAMPS) B. Cell-mediated Immunity
Molecules released by injured and necrotic cells o Responsible for defense against intracellular
microbes
C. Pattern Recognition Receptor o Mediated by T (thymus-derived) lymphocytes
Receptors that recognize PAMPS and DAMPS
Example of which are Toll-like receptors located on cell COMPONENTS OF THE IMMUNE SYSTEM
surfaces and in endosomes, so they are able to recognize
CELLS OF THE IMMUNE SYSTEM
and initiate cellular responses to extracellular and ingested
microbes A. Lymphocytes
Other microbial sensors are located in the cytoplasm, Are not fixed in particular tissues (as are cells in most of the
where they recognize bacteria and viruses that may have organs of the body)
colonized cells. Are capable of migrating among lymphoid and other tissues
Recognition of microbes TLRs and other sensors signal and the vascular and lymphatic circulations.
by a common pathway leads to activation of transcription
In lymphoid organs, different classes of lymphocytes are
factors(NF-κB).
anatomically segregated they interact only when
D. Nuclear Factor kB (NF-kB) stimulated to do so by encounter with antigens and other
Turns on the production of cytokines and proteins that stimuli.
stimulate the microbicidal activities of various cells, Naïve lymphocytes Mature lymphocytes that have not
(phagocytes). encountered the antigen for which they are specific
(immunologically inexperienced).
E. Mannose-Binding Lectin
Cellular receptors for mannose residues that bind microbes Effector cells differentiated lymphocytes after they are
for phagocytosis activated by recognition of antigens and other signals which
Mannose residues are typical of microbial but not host perform the function of eliminating microbes
glycoproteins, Memory cells which live in a state of heightened
awareness and are better able to combat the microbe in
F. Opsonins case it returns.
Opsonins such as antibodies and complement proteins coat
microbes for easy recognition and phagocytosis
.
MAJOR COMPONENTS OF INNATE IMMUNITY
A. Epithelial Barrier
Epithelia of skin, GI and respiratory tracts provide
mechanical barriers against entry of microbes
Epithelial cells produce anti-microbial defensins
lymphocytes located in the epithelia combat microbes at
these sites.

B. Phagocytes
Monocytes and Neutrophils can rapidly be recruited to
any site of infection
Macrophages monocytes that enter the tissues and
mature there.
Dendritic cells produce type I interferons (anti-viral
cytokines) that inhibit viral infection and replication, located
under the epithelia and capture antigens
Natural killer cells provide early protection against many The principal classes of lymphocytes and their functions in
viruses and intracellular bacteria and kill a variety of adaptive immunity
infected cells without prior exposure to them
C. Plasma Proteins T-LYMPHOCYTES
Complement System Develop from precursors in the thymus
o In innate immunity it is activated by microbes
Found in T-cell zones of peripheral lymphoid organs and in
using the alternative and lectin pathways
o In adaptive immunity it is activated by antibodies the blood where they constitute 60-70% of lymphocytes
using the classical pathway Each T cell recognizes a specific cell-bound antigen by
mannose-binding lectin and C-reactive protein means of an antigen-specific T-cell receptor (TCR).
o both coat microbes for phagocytosis TCR consists of a disulfide-linked heterodimer made up of
an α and a β polypeptide chain each having a variable
D. Lung Surfactant
(antigen-binding) region and a constant region.
Provide protection against inhaled microbes
The αβ TCR recognizes peptide antigens that are displayed
ADAPTIVE IMMUNITY by major histocompatibility complex (MHC) molecules on
Consists of lymphocytes and their products, including the surfaces of antigen-presenting cells (APCs).
antibodies MHC restriction ensures that T cells only see cell-
Mechanisms that are stimulated by (―adapt to‖) microbes associated antigens (derived from microbes in cells)
and are capable of recognizing microbial and nonmicrobial achieved by limiting the specificity of T cells for peptides
substances
displayed by cell surface MHC molecules
Develops later, after exposure to microbes, and more
powerful than innate immunity
2 types:
A. Humoral Immunity
o Protects against extracellular microbes and their
toxins
o Mediated by B (bone marrow–derived) lymphocytes
and their secreted products antibodies (Igs)

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
o Function as cytokine-secreting helper cells that help
macrophages and B lymphocytes to combat infections
o Bind to Class II MHC molecules
CD8
o Expressed on about 30% of T cells
o Function as cytotoxic (killer) T lymphocytes (CTLs) to
destroy host cells harboring microbes.
o Bind to class I MHC molecules
CD4 and CD8
o Serve as ―coreceptors‖ in T-cell activation work with
the antigen receptor in responses to antigen.
o Antigen receptor of a T cell recognizes antigen CD4
or CD8 coreceptor initiates signals that are necessary
for activation of the T cells

T-cells have to recognize not only antigen-MHC complexes


The T-cell receptor (TCR) complex and other molecules
involved in T-cell activation. The TCR heterodimer, but additional signals provided by Antigen Presenting cells
consisting of an α and a β chain, recognizes antigen (in the (APC).
form of peptide-MHC complexes expressed on antigen-
presenting cells, or APCs) and the linked CD3 complex and ζ B-LYMPHOCYTES
chains initiate activating signals B lymphocytes develop from precursors in the bone marrow.
Constitute 10% to 20% of the circulating peripheral
RAG-1 and RAG-2 (recombination activating genes) lymphocyte population
Present in peripheral lymphoid tissues such as lymph
produce enzymes in developing lymphocytes in the nodes, spleen, and mucosa-associated lymphoid tissues.
thymus that mediates rearrangement of genes Recognize antigen via the B-cell antigen receptor complex.
Membrane-bound antibodies (IgM and IgD)
TCR genes rearrange o Present on the surface of all mature, naive B cells
o Serves as antigen-binding component of the B-cell
form many different combinations that can be transcribed receptor complex
and translated into functional antigen receptors. B-cell receptor has a unique antigen specificity, derived
from RAG-mediated rearrangements of Ig genes.
Inherited defects in RAG proteins result in a failure to After stimulation by antigen and other signals B cells
generate mature lymphocytes. develop into plasma cells secretes antibodies the
Each T cell expresses TCR molecules of one specificity mediators of humoral immunity.
full complement of T cells in an individual is capable of B-cell antigen receptor complex
o Contains a heterodimer of two invariant proteins
recognizing number of antigens. called Igα and Igβ.
Presence of rearranged TCR genes is a marker of T- o Igα and Igβ are essential for signal transduction
lineage cells. through the antigen receptor.
Each TCR is noncovalently linked to five polypeptide chains, Several other molecules that are essential for responses
which form the CD3 complex and the δ chain dimer include:
o Complement receptors,
CD3 and δ proteins are identical in all T cells.
o Fc receptors
o involved in the transduction of signals into the T cell o CD40
after the TCR has bound the antigen. Type 2 complement receptor (CR2, or CD21) is also the
o Together with the TCR, these proteins form the ―TCR receptor for the Epstein-Barr virus (EBV), and hence EBV
complex.‖ readily infects B cells.
Small population of mature T cells expresses another type
of TCR composed of γ and δ polypeptide chains.
γδ TCR
o recognizes peptides, lipids, and small molecules,
without a requirement for display by MHC proteins.
o tend to aggregate at epithelial surfaces, such as the
skin and mucosa of the gastrointestinal and urogenital
tracts,
o are sentinels that protect against microbes that try to
enter through epithelia.

NK-T cells small subset of T cells that express markers


that are found on NK cells
o Express a very limited diversity of TCRs
o Recognize glycolipids that are displayed by the MHC-
like molecule CD1. The B-cell receptor complex is composed of membrane
CD4, CD8, CD2, integrins, and CD28 expressed by T- immunoglobulin M (IgM; or IgD, not shown), which recognize
antigens, and the associated signaling proteins Igα and Igβ.
cells that assist TCR complex in functional responses. CD21 is a receptor for a complement component that also
promotes B-cell activation
CD4
o Expressed on approximately 60% of mature CD3+ T DENDRITIC CELLS
cells Have numerous fine cytoplasmic processes that resemble
dendrites, from which they derive their name.

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
Two Types: o prevent NK cells from killing normal cells.
A. Interdigitating dendritic cells (dendritic cells) Virus infection or neoplastic transformation
o Most important antigen-presenting cells (APCs) for o Induces expression of ligands for activating receptors
o Reduces the expression of class I MHC molecules
initiating primary T-cell responses against protein
o balance is tilted toward activation infected or tumor
antigens. cell is killed.
o Located under the epithelia the common site of NK cells also secrete cytokines, such as interferon-γ which
entry of microbes and foreign antigens, and in the activates macrophages to destroy ingested microbes
interstitia of all tissues where antigens may be IL-2 and IL-15 stimulate proliferation of NK cells
produced. IL-12 activates killing and secretion of IFN-γ.
o Langerhans cells Immature dendritic cells within
the epidermis.
o Express many receptors for capturing and responding
to microbes, including TLRs and mannose receptors.
o In response to microbes, dendritic cells are recruited
to the T-cell zones of lymphoid organs, where they
are ideally located to present antigens to T cells.
o Express high levels of the molecules needed for
presenting antigens to and activating CD4+ T-cells. Healthy cells express self–class I MHC molecules, which
are recognized by inhibitory receptors, thus ensuring that
B. Follicular Dendritic Cells NK cells do not attack normal cells.
o Present in the germinal centers of lymphoid follicles in healthy cells may express ligands for activating receptors
the spleen and lymph nodes or may not express such ligands but they do not activate
o Bear Fc receptors for IgG and receptors for C3b NK cells because they engage the inhibitory receptors
o Can trap antigen bound to antibodies or complement
proteins.
o Play a role in humoral immune responses by
presenting antigens to B cells and selecting the B
cells that have the highest affinity for the antigen

MACROPHAGES
Part of the mononuclear phagocyte system
Macrophages function as APCs in T-cell activation
o Macrophages phagocytose microbes and protein
antigens process the antigens present peptide
fragments to T cells.
Macrophages are key effector cells in certain forms of cell-
mediated immunity In infected and stressed cells, class I MHC expression is
reduced so that the inhibitory receptors are not engaged,
o T cells activate macrophages and enhance their
and ligands for activating receptors are expressed.
ability to kill ingested microbes Results in NK cells that are activated and the infected cells
Also participate in the effector phase of humoral immunity. are killed.
o Macrophages efficiently phagocytose and destroy
microbes that are opsonized (coated) by IgG or C3b. TISSUES OF THE IMMUNE SYSTEM
I. GENERATIVE LYMPHOID ORGANS
NATURAL KILLER CELLS Also called primary, or central lymphoid organs
Approximately 10-15% of peripheral blood lymphocytes. Where T and B lymphocytes mature and become
Do not express TCRs or Ig. competent to respond to antigens
Morphologically:
Principal generative lymphoid organs are:
o Larger than small lymphocytes
o Contain abundant azurophilic granules o Thymus where T cells develop
Also called large granular lymphocytes. o Bone marrow site of production of all blood cells
Has ability to kill a variety of infected and tumor cells and where B lymphocytes mature.
without prior exposure to or activation by these microbes or
tumors makes NK cells an early line of defense against II. PERIPHERAL LYMPHOID ORGANS
viral infections and some tumors. Secondary lymphoid organs in which adaptive immune
CD16 and CD56 responses to microbes are initiated.
o Two cell surface molecules commonly used to identify Organized to concentrate antigens, APCs, and
NK cells. lymphocytes in a way that optimizes interactions among
o CD16 an Fc receptor for IgG, confers on NK cells these cells and the dev’t of adaptive immune responses.
the ability to lyse IgG-coated target cells. (antibody- Within the peripheral lymphoid organs, T lymphocytes and
dependent cell-mediated cytotoxicity-ADCC). B lymphocytes are segregated into different regions
Functional activity of NK cells is regulated by a balance (lymph nodes):
between signals from activating and inhibitory receptors o B cells are concentrated in discrete structures
NKG2D family (follicles) located around the cortex of each node.
o Activating receptor o If the B cells in a follicle have recently responded to
o NKG2D receptors recognize surface molecules that an antigen follicle may contain a central region
are induced by various kinds of stress, such as (germinal center)
infection and DNA damage. o The T-lymphocytes are concentrated in the
Inhibitory Receptors: killer cell Ig-like receptors and the paracortex, adjacent to the follicles.
CD94 family of lectins (carbohydrate-recognizing o The follicles contain the follicular dendritic cells that
proteins) are involved in the activation of B cells
o Recognize self–class I MHC molecules, which are o Paracortex contains the dendritic cells that present
Expressed on all healthy cells. antigens to T lymphocytes.

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
The location of B cells and T cells in the lymphoid follicles This process of lymphocyte recirculation is most
and paracortical areas is dictated by chemokines produced relevant for T cells because effector T cells have to locate
in these anatomic locales. and eliminate microbes at any site of infection.
When lymphocytes are activated by antigens altered Plasma cells remain in lymphoid organs and do not
expression of chemokine receptors B and T cells leave
and migrate toward each other and meet at the edge of need to migrate to sites of infection because they secrete
follicles helper T cells interact with and help B cells to antibodies that are carried to distant tissues.
differentiate into antibody-producing cells.
Peripheral lymphoid organs consist of:
a. Lymph nodes
b. Spleen
c. mucosal and cutaneous lymph nodes

A. LYMPH NODES
Nodular aggregates of lymphoid tissues located along
lymphatic channels throughout the body
APCs in the nodes are able to sample the antigens of
microbes that may enter through epithelia into tissues and
are carried in the lymph.
Dendritic cells pick up and transport antigens of microbes
from epithelia via the lymphatic vessels to the lymph nodes.
Antigens of microbes that enter through epithelia or
colonize tissues become concentrated in draining lymph
nodes.

Naive T lymphocytes exit the thymus

migrate to lymph nodes

enter the T-cell zones through specialized postcapillary


venules (high endothelial venules)

L-selectin and integrin bind to their ligands found on high


The segregation of B cells and T cells in different regions of the endothelial venules (HEVs)
lymph node
B. SPLEEN Chemokines expressed in lymph nodes (CCL19 and CCL21)
An abdominal organ bind to receptors (CCR7) on naive T cells
Serves the same role in immune responses to blood-borne
antigen as that of lymph nodes in responses to lymph- enhanced integrin-dependent adhesion
borne antigens.
Blood enters the spleen flows through a network of Induced migration of the cells through the HEV wall.
sinusoids Blood-borne antigens are trapped by dendritic
cells and macrophages in the spleen.
T lymphocytes are concentrated in periarteriolar lymphoid naive T cell encounter the antigen that it specifically
sheaths surrounding small arterioles, and B cells reside in recognizes on the surface of an APC and is activated
the follicles.
cells alter their expression of adhesion molecules and
C. Mucosal and Cutaneous lymphoid tissues chemokine receptors
cutaneous lymphoid system located under the epithelia
of the skin migration is mediated by E-selectin and P-selectin,
mucosal lymphoid systems located at the integrins, and chemokines secreted at inflammatory
gastrointestinal and respiratory tracts sites (e.g., CXCL10)
respond to antigens that enter by breaches in the
epithelium. recognized by chemokine receptors (e.g., CXCR3) that
Pharyngeal tonsils and Peyer's patches two are expressed on activated T cells.
anatomically defined mucosal lymphoid tissues.
At any time, more than half the body's lymphocytes are in Activated T lymphocytes(including effector and memory
the mucosal tissues and many of these are memory cells. cells) home to sites of infection in peripheral tissues

III. LYMPHOCYTE RECIRCULATION


Lymphocytes constantly recirculate between tissues and MAJOR HISTOCOMPATIBILITY COMPLEX
home to particular sites (MHC MOLECULES)
Naive lymphocytes traverse the peripheral lymphoid organs Fundamental to the recognition of antigens by T cells and
where immune responses are initiated are linked to many autoimmune diseases
Effector lymphocytes migrate to sites of infection and Name derives from the recognition that they are
inflammation responsible for tissue compatibility between individuals

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
Physiologic function of MHC molecules to display This cleft is formed by an interaction of the α1 and β1
peptide fragments of proteins for recognition by antigen- domains it is in this portion that most class II alleles
specific T cells differ.
Genes encoding the major histocompatibility molecules Polymorphism of class II molecules is associated with
clustered on a small segment of chromosome 6 differential binding of antigenic peptides.
o Major histocompatibility complex, or the
human leukocyte antigen (HLA) complex
HLA system is highly polymorphic Class II MHC molecules
present antigens that are
internalized into vesicles, and are
CLASS I
typically derived from extracellular
Display peptides that are derived from proteins such as microbes and soluble proteins.
viral antigens located in the cytoplasm and usually
produced in the cell internalized proteins are
Expressed on all nucleated cells and platelets. proteolytically digested in
Encoded by three closely linked loci, designated HLA-A, endosomes or lysosomes
HLA-B, and HLA-C
Peptides resulting from proteolytic
Each class I MHC molecule is a heterodimer consisting of a cleavage associate with class II
polymorphic α or heavy chain linked noncovalently to a heterodimers in the vesicles
smaller nonpolymorphic peptide called β2-microglobulin
(not encoded within the MHC) stable peptide-MHC complexes are
Extracellular region of the α chain is divided into three transported to the cell surface.
domains α1, α2, and α3.
The class II β2 domain has a
α1 and α2 domains form a cleft, or groove, where peptides
binding site for CD4
bind.
Polymorphic residues line the sides and the base of the class II–peptide complex is
peptide-binding groove variation in this region explains recognized by CD4+ T cells
why different class I alleles bind different peptides. (function as helper cells)
Class I–associated peptides are recognized by CD8+ T
lymphocytes. CD4+ T cells can recognize antigens only in the context of
viral antigens (proteins and peptides) self–class II molecules, referred to as class II MHC–
located in the cytoplasm and usually restricted.
produced in the cell Class II MHC molecules are mainly expressed on cells
that present ingested antigens and respond to T-cell help
proteins are degraded in proteasomes, (macrophages, B lymphocytes, and dendritic cells).
peptides are transported into the Class II locus contains genes that encode proteins
endoplasmic reticulum (ER)
involved in antigen processing and presentation:
the peptides bind to newly synthesized o Components of the proteasome
class I molecules o Peptide transporter
o Class II–like molecule called DM that facilitates
Peptide-loaded MHC molecules peptide binding to class II molecules.
associate with β2-microglobulin to form a Combination of HLA alleles in each individual is called the
stable trimer that is transported to the HLA haplotype.
cell surface
An individual inherits one set of HLA genes from each
α3 domain of class I MHC molecules has parent and expresses two different molecules for every
a binding site for CD8 locus.
Innumerable combinations of molecules exist because of
Recognition by CD8+ cells of the polymorphism of the HLA loci each individual expresses
peptide-class I complex an MHC profile on his/her cell surface that is different
CD8+ T cells recognize peptides only if presented as a from the haplotypes of other individuals.
complex with self–class I MHC molecules No two individuals (other than identical twins) are likely to
CD8+ T cells are said to be class I MHC–restricted. express the same MHC molecules therefore grafts
Because one important function of CD8+ Cytotoxic T- exchanged are recognized as foreign and attacked by
Lymphocyte is to eliminate viruses(may infect any the immune system.
nucleated cell) makes good sense that all nucleated Different antigenic peptides bind to different MHC
cells express class I HLA molecules and can be molecules
surveyed by CD8+ T cells! An individual mounts an immune response against a
. protein antigen only if he/she inherits the gene(s) for
CLASS II those MHC molecule(s) that can bind peptides derived
Are encoded in a region called HLA-D has three from the antigen and present it to T cells.
subregions: HLA-DP, HLA-DQ, and HLA-DR. Ex: an antigenic peptide from ragweed pollen exposure of
Each class II molecule is a heterodimer consisting of a individual who expresses class II molecules capable of
noncovalently associated α chain and β chain, both are binding the antigen mounting of allergic reactions against
polymorphic. pollen.
Extracellular portions of the α and β chains have two By segregating cytoplasmic and internalized
domains each: α1, α2 and β1, β2. antigens MHC molecules ensure that the correct immune
Have peptide-binding clefts facing outward response is mounted against different microbes:
o CTLs against cytoplasmic microbes

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
o Antibodies and macrophages (both of which are differentiate into effector and memory cells,
activated by helper T cells) against extracellular o Elimination of the antigen
microbes. o Decline of the response, with memory cells being the
long-lived survivors
These general principles apply to protective responses
HLA AND DISEASE ASSOCIATION
against microbes as well as pathologic responses that
Variety of diseases are associated with the inheritance of injure the host
certain HLA alleles.
Diseases that show association with the HLA locus can be DISPLAY AND RECOGNITION OF ANTIGENS
broadly grouped into the following categories: CLONAL SELECTION HYPOTHESIS
o Inflammatory diseases including ankylosing Antigen-specific clones of lymphocytes

spondylitis and several postinfectious arthropathies,
Exposure to antigen
all associated with HLA-B27 ↓
o Autoimmune diseases including autoimmune Antigen enters
endocrinopathies, associated mainly with alleles at ↓
the DR locus Selects the specific cells and activates them
o Inherited errors of metabolism such as 21-
hydroxylase deficiency (HLA-BW47) and hereditary Cells constituting each clone have identical antigen
hemochromatosis (HLA-A) receptors (different from the receptors on the cells of all
other clones)
Disease HLA Allele Relative Risk (%) 7 9
About 10 to 10 different specificities in the total pool of
Ankylosing B27 90–100 12
about 10 lymphocytes in an adult
spondylitis Therefore, at least this many antigens can be recognized
Postgonococcal B27 14 by the adaptive immune system
arthritis
Number of lymphocytes specific for any one antigen is very
Acute anterior B27 14 small, probably less than 1 in 100,000 to 1 in 1 million cells.
uveitis
To permit a small number of lymphocytes to find antigen
Rheumatoid DR4 4 anywhere in the body, the immune system has specialized
arthritis mechanisms for
Chronic active DR3 13 o Capturing antigens
hepatitis o Displaying them to lymphocytes
Primary Sjögren DR3 9 Dendritic cells
syndrome o Resident in epithelia and tissues
Type 1 diabetes DR3 5 o Capture microbes and their protein antigens
DR4 6 o Carry their antigenic cargo to draining lymph nodes
DR3/DR4 20

CYTOKINES
Messenger Molecules of the Immune System
Molecularly defined cytokines are called interleukins,
because they mediate communications between
leukocytes.
Colony-stimulating factors stimulate hematopoiesis
o Assayed by their ability to stimulate formation of blood
cell colonies from bone marrow progenitors
o Functions to increase leukocyte numbers during
immune and inflammatory responses
o Functions also to replace leukocytes that are
consumed during such responses.

Cytokines of innate immunity


Produced rapidly in response to microbes and other stimuli
Made principally by macrophages, dendritic cells, and NK
cells
Mediate inflammation and anti-viral defense
Include TNF, IL-1, IL-12, type I IFNs, IFN-γ, and
chemokines
Cytokines of adaptive immune responses
Made principally by CD4+ T lymphocytes in response to
antigen and other signals
Functions to promote:
o lymphocyte proliferation B lymphocytes
o lymphocyte differentiation o Use their antigen receptors (membrane-bound
antibody molecules)
o activate effector cells.
o Recognize antigens of many different chemical
Main ones in this group are IL-2, IL-4, IL-5, IL-17, and IFN- types, including proteins, polysaccharides, and
γ lipids.
o As the antigens of a microbe are recognized by T
OVERVIEW OF LYMPHOCYTE ACTIVATION AND IMMUNE and B lymphocytes
RESPONSE o Microbe elicits an innate immune response in the
All adaptive immune responses develop in steps, consisting case of immunization with a protein antigen
of: o Innate response is induced by the adjuvant given
o Antigen recognition, with the antigen
o Activation of specific lymphocytes to proliferate and o During this innate response

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
Presence of microbe o Secrete IL-2 and express high-affinity receptors for IL-
↓ 2 (a growth factor that acts on these T lymphocytes
Activates APCs and stimulates their proliferation) increase in the
number of antigen-specific lymphocytes
↓ Some progeny of expanded T cells differentiate to
1. Express molecules called costimulators; effector cells that can secrete different cytokines perform
2. Secrete cytokines different functions
(Stimulate the proliferation and differentiation of T
lymphocytes) SUBSETS OF DIFFERENTIATED CD4+ HELPER CELLS
TH1 subset
B7 proteins (CD80 and CD86) o Secrete IFN-γ,which is a potent macrophage activator
o Principal costimulators for T cells o Combination of CD40- and IFN-γ–mediated activation
o Expressed on APCs induction of microbicidal substances in
o recognized by the CD28 receptor on naive T cells macrophages destruction of ingested microbes
o Function cooperatively to activate antigen-specific TH2 subset
lymphocytes o Produce:
Signal 1: antigen IL-4 (stimulates B cells to differentiate into
Signal 2: costimulatory molecules produced IgE-secreting plasma cells)
during innate immune responses to microbes IL-5 (activates eosinophils, which along with
Signal 2 mast cells, bind to IgE-coated microbes, e.g.,
o Required in microbe triggered response helminthic parasites)
ensures that the adaptive immune response is o Function to eliminate helminths
induced by microbes and not by harmless TH17 (recently discovered)
substances o Signature cytokine – IL-17
o In immune responses to tumors and transplants, o Powerful recruiters of neutrophils and
provided by substances released from monocytes
necrotic cells (the ―danger- o Major roles in several inflammatory diseases
associatedmolecular patterns‖ mentioned o Important for defense against some bacterial and
earlier fungal infections (where neutrophilic inflammation is
The reactions and functions of T and B lymphocytes differ prominent
in important ways and are best considered separately.

CELL-MEDIATED IMMUNITY ACTIVATED CD8+ LYMPHOCYTES


Involves:
Differentiate into CTLs that kill cells harboring microbes in
Activation of T lymphocytes the cytoplasm
Elimination of intracellular microbes CTLs eliminate the reservoirs of infection by destroying the
infected cells
T LYMPHOCYTES
NAÏVE T LYMPHOCYTES HUMORAL IMMUNITY
Activated by antigen and costimulators in peripheral Involves:
lymphoid organs Activation of B lymphocytes proliferate and
Proliferate and differentiate into effector cells that migrate to differentiate into plasma cells secrete different classes of
any site where the antigen (microbe) is present antibodies of distinct function
Elimination of extracellular microbes

Figure: Subsets of helper T (TH) cells. In response to stimuli


(mainly cytokines) present at the time of antigen recognition,
naive CD4+ TH cells may differentiate into populations of Figure:. Humoral immunity. Naive B lymphocytes recognize antigens,
effector cells that produce distinct sets of cytokines and and under the influence of TH cells and other stimuli (not shown), the B
perform different functions. The dominant immune reactions cells are activated to proliferate and to differentiate into antibody-
elicited by each subset, and its role in host defense and secreting plasma cells. Some of the activated B cells undergo heavy-
immunological diseases, are summarized. chain class switching and affinity maturation, and some become long-
lived memory cells. Antibodies of different heavy-chain classes
HELPER T CELLS (isotypes) perform different effector functions, shown on the right.

Mediated by the combined actions


Many polysaccharide and lipid antigens:
o CD40-ligand (CD40L)
Have multiple identical antigenic determinants (epitopes)
o Cytokines
that are able to engage many antigen receptor molecules
The CD4+ helper T cells express CD40L when the cells
on each B cell
recognize antigens being displayed by macrophages or B
Initiate the process of B-cell activation
lymphocytes (CD40L engages CD40 on the macrophages
or B cells and activates these cells) Typical globular protein antigens are not able to bind to
many antigen receptors
One of the earliest responses of CD4+ helper T cells:
The full response of B cells to protein antigens requires

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
help from CD4+ T cells o Generation of memory cells is an important goal of
B cells ingest protein antigens into vesicles, degrade them, vaccination
and display peptides bound to MHC molecules for
recognition by helper T cells HYPERSENSITIVITY AND AUTOIMMUNE DISORDERS
Helper T cells express CD40L and secrete cytokines MECHANISMS OF HYPERSENSITIVITY REACTIONS
which work together to activate the B cells Sensitized individuals = previously exposed to an antigen
Each plasma cell secretes antibodies that have the same Repeat exposures to the same antigen trigger a pathologic
antigen binding site as the cell surface antibodies (B-cell reaction HYPERSENSITIVITY (excessive response)
receptors) that first recognized the antigen General features of hypersensitivity disorders
Polysaccharides & lipids stimulate secretion mainly of IgM o BOTH EXOGENOUS & ENDOGENOUS antigens
may elicit hypersensitivity reactions
ISOTYPES AND AFFINITY MATURATION Exogenous antigens = dust, pollens, foods,
Protein antigens, by virtue of CD40L- and cytokine- drugs, microbes, chemicals, and some blood
mediated helper T-cell actions –induce the production of products
antibodies of different classes, or isotypes (IgG, IgA, IgE) Various immune responses against such
Cytokines that induce isotype switching: exogenous antigens: (discomforts) itching of
o IFN-γ the skin, (fatal) bronchial asthma and
o IL-4 anaphylaxis
Helper T cells also stimulate the production of antibodies May also be evoked by endogenous tissue
with high affinities for the antigen (this process is called antigens
affinity maturation –improves the quality of the humoral Autologous (self) antigens = autoimmune
immune response) diseases
Isotype switching and affinity maturation –occur mainly o Development of both allergic and autoimmune
in germinal centers that are formed by proliferating B cells, disorders is associated with particular susceptibility
especially in helper T cell-dependent responses to protein genes (inherited)
antigens HLA and non-HLA genes in different diseases
o Hypersensitivity reflects an imbalance between the
ANTI-MICROBIAL RESPONSE
effector mechanisms and the control mechanisms
Antibodies bind to microbes prevent them from infecting Can be classified on the basis of the immunologic
Cells ―neutralizing‖ the microbes mechanism that mediates the disease
o IgG antibodies coat (―opsonize‖) them for Classification is of value in distinguishing the manner in
phagocytosis (since phagocytes [neutrophils and which the immune response causes tissue injury and
macrophages] express receptors for the Fc tails of disease, and the accompanying pathologic and clinical
IgG) manifestations
o IgG and IgM activate the complement system by
the classical pathway complement products MAIN TYPES OF HYPERSENSITIVITY REACTIONS
promote phagocytosis and destruction of microbes 1. Immediate (type I)
o production of most opsonizing and complement- o Mediated by TH2 cells, IgE antibodies, and mast cells
fixing release of mediators that act on vessels and
IgG antibodies is stimulated by TH1 helper cells (which smooth muscle and of pro-inflammatory cytokines that
drive the protective response to most bacteria and recruit inflammatory cells
viruses) 2. Antibody-mediated disorders (type II hypersensitivity)
Some antibodies serve special roles at particular anatomic o IgG and IgM antibodies participate directly in injury
sites Promoting their phagocytosis or lysis and by
o IgA inducing inflammation
Secreted from mucosal epithelia 3. Immune complex–mediated (type III hypersensitivity)
Neutralizes microbes in the lumens of the o IgG and IgM antibodies bind antigens in the
respiratory and gastrointestinal tracts (and circulation inflammation
other mucosal tissues) o neutrophils and monocytes produce tissue damage by
o IgG release of lysosomal enzymes and generation of toxic
Actively transported across the placenta free radicals.
Protects the newborn until the immune 4. Cell-mediated (type IV hypersensitivity)
system becomes mature o TH1 and TH17 cells and CTLs are the cause of the
o IgE and eosinophils cellular and tissue injury
Cooperate to kill parasites, mainly by o TH2 cells induce lesions (not considered a form of
release of eosinophil granule contents that type IV hypersensitivity)
are toxic to the worms PROTOTYPI IMMUNE
TYPE OF PATHOLOGI
TH2 cells secrete cytokines that stimulate the production of C MECHANISM
REACTION C LESIONS
IgE and activate eosinophils orchestrating response to DISORDER S
helminths Production of
Most circulating IgG antibodies have half-lives of about 3 IgE Ab →
weeks immediate Vascular
o Some antibody-secreting plasma cells: release of dilation,edem
Anaphylaxis;
o Migrate to the bone marrow vasoactive a, smooth
allergies;
o Live for years IMMEDIAT amines and muscle
bronchial
o Continue to produce low levels of antibodies E other contraction,
asthma
Majority of effector lymphocytes induced by an infectious TYPE I mediators mucus
(atopic
pathogen die by apoptosis after the microbe is eliminated from mast production,
forms)
returning the immune system to its basal resting state cells; later tissue injury,
(homeostasis) recruitment of inflammation
Initial activation of lymphocytes also generates long-lived inflammatory
memory cells (may survive for years after the infection) cells
Memory cells Production of Phagocytosis
o Expanded pool of antigen-specific lymphocytes (more Autoimmune IgG, IgM → and lysis of
numerous than the naive cells specific for any antigen AB- haemolytic binds to cells;
that are present before encounter with that antigen) MEDIATED anemia; antigen on inflammation;
o Respond faster and more effectively when re- (TYPE II) Goodpasture target cell or some
exposed to the antigen than do naive cells ’s syndrome tissue → diseases,
phagocytosis functional

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
or lysis of derangement receptors and cytoplasmic granules
target cell by s without cell o They however are not present in tissues normally but
activated or tissue circulate in the blood in small numbers
complement injury TH2 cells play a central role in initiation nd propagation of
or Fc immediate hypersensitivity reactions by stimulating IgE
receptors; production and promoting inflammation
recruitment of
leukocytes Presentation of antigen to naïve CD4 helper T cells by
Deposition of dendritic cells
Ag-Ab ↓
Systemic complexes → Response to antigen and other stimuli (IL-4)
lupus complement ↓
erythematos activation → T cells differentiate into TH2 cells
us; some recruitment of Inflammation, ↓
IMMUNE-
forms of leukocytes by necrotizing Newly minted TH2 cells produce cytokines upon subsequent
COMPLEX
glomerulone complement vasculitis encounters with the antigen (IL-4, IL-5 and IL-13)
MEDIATED
phritis; products and (fibrinoid
(TYPE III)
serum Fc receptors necrosis) IL-4 acts on B-cells to stimulate class switching to IgE and
sickness; → release of promotes additional TH2 cell development
Arthus enzymes and IL-5 is involved in development and activation of
reaction other toxic eosinophils
molecules IL-13 enhances IgE production and acts on epithelial cells
to stimulate mucus secretion
Contact TH2 cells also produce chemokines that attract more Th2
Activated T
dermatitis; cells to the reaction site
lymphocytes:
multiple Mast cells and basophils express a high-affinity receptor,
1. Release
sclerosis; FcεRI
cytokines →
type I o This is specific for the Fc portion of IgE
CELL- inflammation
diabetes;
MEDIATED and
rheumatoid Allergen in system
(TYPE IV) macrophage
arthritis; ↓
activation
inflammatory Allergen binds to IgE antibodies attached to mast cells
2. T-cell
bowel ↓
mediated
disease; Activation of signal transduction pathways
cytotoxicity
tuberculosis ↓
Mast cell degranulation with discharge of primary mediators
IMMEDIATE (TYPE I) HYPERSENSITIVITY stored in granules and de novo synthesis of secondary
Rapid immunologic reaction (within minutes after mediators
antigen-antibody complex) ↓
Often called allergy and the antigens that elicit them are Initial symptoms of immediate hypersensitivity
called allergens
May occur as a systemic disorder or as a local reaction PREFORMED MEDIATORS
o Systemic reactions Three categories
Usually follows injection of an o Vasoactive amines
antigen into a sensitized individual Histamine is the most important mast cell-
Patient may go into shock in a derived amine
matter of few minutes Histamine causes intense smooth muscle
o Local reactions contraction, increased vascular permeability and
Diverse and vary depending on the portal of increased mucus secretion by nasal, bronchial
entry of the allergen and gastric glands
May take the form of localized cutaneous o Enzymes
swellings (skin allergy, hives), nasal and Contained in the granule matrix
conjunctival discharge, hay fever, bronchial Include neutral proteases and acid hydrolases
asthma or allergic gastroenteritis Cause tissue damage and lead to kinin
Have two well defined phases generation and complement activation
Immediate or initial reaction which is o Proteoglycans
characterized by vasodilation, vascular Include heparin and chondroitin sulfate
leakage and smooth muscle spasm or Serve to package and store amines in
glandular secretions (depending on the granules
location)
Late-phase reaction is characterized by
eosinophilic, neutrophilic, basophilic, LIPID MEDIATORS
monocytic and CD4 T-cell infiltration Leukotrienes
with accompanying tissue destruction(in o LTC4 and LTC4 are the most potent vasoactive and
the form of mucosal epithelial cell spasmogenic agents known
damage) o Several thousand more potent than histamine in
Most are mediated by IgE antibody-dependent activation increasing vascular permeability and causing
of mast cells and other leukocytes bronchial smooth muscle contraction
MAST CELLS o LTB4 is highly chemotactic for neutrophils,
o Abundant near blood vessels and nerves and in eosinophils and monocytes
subepithelial tissues Prostaglandin D2
o Have cytoplasmic membrane-bound granules that o Most abundant mediator produced in mast cells by
contain a variety of biologically active mediators the COX pathway
o Activated by the cross-linking of high-affinity IgE Fc o Causes intense bronchospasm and increase mucus
receptors and also by other stimuli such as secretion
complements C5a and C3a (anaphylatoxins) Platelet-activating factor (PAF)
BASOPHILS o Causes platelet aggregation, histamine release,
o Similar to mast cells in that they have IgE Fc surface bronchospasm, increased vascular permeability and

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
vasodulation In either case the hypersensitivity reaction results from the
o Chemotactic for neutrophils, eosinophils and at high binding of antibodies to normal or altered cell surface
concentrations it activated the inflammatory cells, antigens.
causing them to degranulate

CYTOKINES
TNF, IL-1 and chemokines
o Promote leukocyte recruitment (late-phase reaction)
IL-4
o Amplifies the TH2 response

*The development of immediate hypersensitivity reactions if


dependent on the coordinated actions of a variety of
chemotactic, vasoactive and spasmogenic compounds.

ACTION MEDIATORS
Histamine
Vasodilation, PAF
increases LTC4, D4, E4
vascular Neutral proteases that activate
permeability complement and kinins
PGD2
LTC4, D4, E4
Smooth muscle Histamine MECHANISMS OF ANTIBODY-MEDIATED INJURY
spasm PGs A. PHAGOCYTOSIS
PAF Responsible for depletion of cells coated with antibodies
Cytokines cells opsonized by igg antibodies are recognized by
Cellular LTB4 phagocyte fc receptors, which are specific for the fc
infiltration Chemotactic factors for portions of some igg subclasses.
eosinophils and neutrophils When IgM or IgG antibodies are deposited on the surfaces
EOSINOPHILS of cells, they may activate the complement system by the
o Recruited to sites of immediate hypersensitivity classical pathway.
reactions by chemokines such as eotaxin Complement activation generates by-products, mainly C3b
o Survival is favored by IL-3, IL-5 and GM-CSF and C4b, which are deposited on the surfaces of the cells
o IL-5 is the most potent eosinophil-activating cytokine and recognized by phagocytes that express receptors for
o Liberate proteilytic enzymes and two unique proteins these proteins.
called major basic protein and eosinophil cationic The net result : phagocytosis of the opsonized cells and
protein which are toxic to epithelial cells their destruction
Complement activation on cells also leads to the formation
Susceptibility to immediate hypersensitivity reactions is of the membrane attack complex, which disrupts
genetically determined membrane integrity by ―drilling holes‖ through the lipid
Atopy is the predisposition to develop a localized bilayer, thereby causing osmotic lysis of the cells. This
immediate hypersensitivity reaction to a variety of inhaled mechanism of depletion is probably effective only with cells
and ingested allergens that have thin cell walls, such as Neisseria bacteria.
o Atopic individuals have higher serum levels of IgE
and more IL-4 producing TH2 cells. ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY
(ADCC)
SYSTEMIC ANAPHYLAXIS Another process of antibody-mediated destruction of cells
Characterized by vascular shock, widespread edema and Cells that are coated with low concentrations of IgG
DOB antibody are killed by a variety of effector cells, which bind
May occur in sensitized individuals in hospitals after to the target by their receptors for the Fc fragment of IgG,
protein administration, hormones, enzymes, and cell lysis proceeds without phagocytosis.
polysaccharides and drugs ADCC may be mediated by monocytes, neutrophils,
Also occurs in the community setting following exposure to eosinophils, and NK cells.
food allergens or insect toxins The role of ADCC in particular hypersensitivity diseases is
Within minutes of exposure, itching, hives and skin uncertain.
erythema appear, followed by contraction of respiratory
bronchioles and respiratory distress. Clinically, antibody-mediated cell destruction and
phagocytosis occur in the following situations:
LOCAL AND IMMEDIATE HYPERSENSITIVITY 1. Transfusion reactions, in which cells from an incompatible
REACTIONS donor react with and are opsonized by preformed antibody
in the host;
Allergies involving localized reactions to common 2. Hemolytic disease of the newborn (erythroblastosis fetalis),
environmental allergens (pollen, animal dander, house in which there is an antigenic difference between the
dust, foods and the like) mother and the fetus, and antibodies (of the IgG class) from
Cause urticarial, angioedema, allergic rhinitis and the mother cross the placenta and cause destruction of
bronchial asthma. fetal red cells;
3. Autoimmune hemolytic anemia, agranulocytosis, and
ANTIBODY-MEDIATED (TYPE II) HYPERSENSITIVITY thrombocytopenia, in which individuals produce antibodies
Caused by antibodies that react with antigens present on to their own blood cells, which are then destroyed;
cell surfaces or in the extracellular matrix 4. Certain drug reactions, in which a drug acts as a ―hapten‖
Antigenic determinants may: by attaching to surface molecules of red cells and
o Be intrinsic to the cell membrane or matrix antibodies are produced against the drug–membrane
o Take the form of an exogenous antigen, such as a protein complex
drug metabolite, that is adsorbed on a cell surface or
matrix

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
B. INFLAMMATION The pathologic reaction is initiated when antigen combines
Causes the injury that results from the deposition of with antibody within the circulation (circulating immune
antibodies in fixed tissues, such as basement membranes complexes), and these are deposited typically in vessel
and extracellular matrix walls.
The deposited antibodies activate complement, generating Sometimes the complexes are formed at extravascular
by-products, including chemotactic agents (mainly C5a), sites where antigen may have been ―planted‖ previously
which direct the migration of polymorphonuclear leukocytes (called in situ immune complexes).
and monocytes, and anaphylatoxins (C3a and C5a), which The antigens that form immune complexes may be:
increase vascular permeability. o Exogenous, such as a foreign protein that is injected or
The leukocytes are activated by engagement of their C3b produced by an infectious microbe, or
and Fc receptors which results in the release or generation o Endogenous, if the individual produces antibody
of a variety of pro-inflammatory substances, including against self-components (autoimmunity)
prostaglandins, vasodilator peptides, and chemotactic Immune complex–mediated diseases can be systemic, if
substances. immune complexes are formed in the circulation and are
Leukocyte activation production of other substances that deposited in many organs, or localized to particular organs,
damage tissues, such as lysosomal enzymes, including such as the kidney (glomerulonephritis), joints (arthritis), or
proteases capable of digesting basement membrane, the small blood vessels of the skin if the complexes are
collagen, elastin, and cartilage, and reactive oxygen deposited or formed in these tissues.
species.
It is now believed that inflammation in antibody-mediated
(and immune complex–mediated) diseases is due to both
complement- and Fc receptor–dependent reactions.

ANTIBODY-MEDIATED INFLAMMATION
The mechanism responsible for tissue injury in some forms
of glomerulonephritis, vascular rejection in organ grafts,
and other disorders

SYSTEMIC IMMUNE COMPLEX DISEASE


Acute serum sickness is the prototype of a systemic
immune complex disease; it was once a frequent sequela
to the administration of large amounts of foreign serum
(e.g., serum from immunized horses used for protection
against diphtheria).
The pathogenesis of systemic immune complex disease
can be divided into three phases:
1. Formation of antigen-antibody complexes in the
circulation;
2. Deposition of the immune complexes in various
tissues, thus initiating
3. An inflammatory reaction at the sites of immune
complex deposition

C. CELLULAR DYSFUNCTION
Cases in which antibodies directed against cell surface
receptors impair or dysregulate function without causing
cell injury or inflammation
Example:
o In Myasthenia gravis
antibodies reactive with acetylcholine receptors
in the motor end plates of skeletal muscles
block neuromuscular transmission and therefore
cause muscle weakness
o The converse (i.e., antibody-mediated stimulation of
cell function) is the basis of Graves disease
antibodies against the thyroid-stimulating
hormone receptor on thyroid epithelial cells
stimulate the cells, resulting in hyperthyroidism

IMMUNE COMPLEX–MEDIATED (TYPE III)


HYPERSENSITIVITY
Antigen-antibody complexes produce tissue damage mainly
by eliciting inflammation at the sites of deposition.

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
FIGURE. Pathogenesis of systemic immune complex–
mediated disease (type III hypersensitivity)

A. FORMATION OF IMMUNE COMPLEXES


The introduction of a protein antigen triggers an immune
response that results in the formation of antibodies,
typically about a week after the injection of the protein.
These antibodies are secreted into the blood, where they
react with the antigen still present in the circulation and
form antigen-antibody complexes.

B. DEPOSITION OF IMMUNE COMPLEXES


The circulating antigen-antibody complexes are deposited
in various tissues.
The major influences that determine whether immune
complex formation will lead to tissue deposition and FIGURE. Immune complex deposition in systemic lupus
disease seem to be the characteristics of the complexes erythematosus. Immunofluorescence micrograph of a
and local vascular alterations. glomerulus stained with fluorescent anti-IgG from a
In general, the most pathogenic are the complexes that are patient with diffuse proliferative lupus nephritis.
of medium size, formed in slight antigen excess.
Organs where blood is filtered at high pressure to form If the disease results from a single large exposure to
other fluids, like urine and synovial fluid, are favored; antigen (e.g., acute serum sickness and perhaps acute
hence, immune complexes frequently deposit in glomeruli post-streptococcal glomerulonephritis), the lesions tend to
and joints. resolve, as a result of catabolism of the immune complexes.
A chronic form of serum sickness results from repeated or
C. TISSUE INJURY CAUSED BY IMMUNE COMPLEXES prolonged exposure to an antigen which occurs in several
Complexes deposited in the tissue initiate an acute human diseases, such as systemic lupus erythematosus
inflammatory reaction (the third phase). (SLE), associated with persistent antibody responses to
During this phase (approximately 10 days after antigen autoantigens.
administration), clinical features such as fever, urticaria, In many diseases, however, the morphologic changes and
joint pains (arthralgias), lymph node enlargement, and other findings suggest immune complex deposition but the
proteinuria appear. inciting antigens are unknown. Example: membranous
Wherever complexes deposit, the tissue damage is similar. glomerulonephritis, many cases of polyarteritis nodosa,
The resultant inflammatory lesion is termed: vasculitides
o Vasculitis if it occurs in blood vessels,
o Glomerulonephritis if it occurs in renal glomeruli, LOCAL IMMUNE COMPLEX DISEASE (ARTHUS REACTION)
o Arthritis if it occurs in the joints A localized area of tissue necrosis resulting from acute
The important role of complement in the pathogenesis of immune complex vasculitis, usually elicited in the skin.
the tissue injury is supported by the observations that The reaction can be produced experimentally by
during the active phase of the disease, consumption of intracutaneous injection of antigen in a previously
complement leads to a decrease in serum levels of C3. immunized animal that contains circulating antibodies
Serum C3 levels can, in some cases, be used to monitor against the antigen.
disease activity. As the antigen diffuses into the vascular wall, it binds the
preformed antibody, and large immune complexes are
formed locally which precipitate in the vessel walls and
cause fibrinoid necrosis, and superimposed thrombosis
worsens the ischemic injury.

T CELL–MEDIATED (TYPE IV) HYPERSENSITIVITY


Initiated by antigen-activated (sensitized) T lymphocytes,
including CD4+ and CD8+ T cells
CD4+ T cell–mediated hypersensitivity induced by
environmental and self-antigens can be a cause of chronic
inflammatory disease.
In certain forms of T cell –mediated reactions, especially
those that follow viral infections, CD8+ cells may be the
dominant effector cells.

FIGURE.Immune complex vasculitis. The necrotic vessel wall


is replaced by smudgy, pink ―fibrinoid‖ material.

FIGURE. Mechanisms of T cell–mediated (type IV)


hypersensitivity reactions. A, In delayed-type hypersensitivity
reactions, CD4+ TH1 cells (and sometimes CD8+ T cells, not

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
shown) respond to tissue antigens by secreting cytokines that markedly augmented; they express more class II MHC
stimulate inflammation and activate phagocytes, leading to molecules on the surface, thus facilitating further antigen
tissue injury. CD4+ TH17 cells contribute to inflammation by presentation; they secrete TNF, IL-1, and chemokines,
recruiting neutrophils (and, to a lesser extent, monocytes). B, which promote; and they produce more IL-12, thereby
In some diseases, CD8+ cytotoxic T lymphocytes (CTLs) amplifying the TH1 response.
directly kill tissue cells. APC, antigen-presenting cell. Activated macrophages serve to eliminate the offending
antigen; if the activation is sustained, continued
inflammation and tissue injury result.
TH17 cells are activated by some microbial antigens and by
self-antigens in autoimmune diseases.
Activated TH17 cells secrete IL-17, IL-22, chemokines, and
several other cytokines.
Collectively, these cytokines recruit neutrophils and
monocytes to the reaction, thus promoting inflammation.
TH17 cells also produce IL-21, which amplifies the TH17
response.
Classic example of DTH:
o Tuberculin reaction- produced by the intracutaneous
injection of purified protein derivative (PPD, also
called tuberculin), a protein-containing antigen of the
tubercle bacillus. In a previously sensitized individual,
reddening and induration of the site appear in 8 to 12
hours, reach a peak in 24 to 72 hours, and thereafter
REACTIONS OF CD4+ T CELLS: DELAYED-TYPE slowly subside.
HYPERSENSITIVITY AND IMMUNE INFLAMMATION Morphologically, delayed-type hypersensitivity is
Inflammatory reactions caused by CD4+ T cells were characterized by the accumulation of mononuclear cells,
initially characterized on the basis of delayed-type mainly CD4+ T cells and macrophages, around venules,
hypersensitivity (DTH) to exogenously administered producing perivascular ―cuffing‖.
antigens. In fully developed lesions, the venules show marked
Are responsible for chronic inflammatory reactions against endothelial hypertrophy, reflecting cytokine-mediated
self-tissues endothelial activation.
Sometimes referred to as immune inflammation. With certain persistent or nondegradable antigens, such as
Both TH1 and TH17 cells contribute to organ-specific tubercle bacilli colonizing the lungs or other tissues, the
diseases in which inflammation is a prominent aspect of the perivascular infiltrate is dominated by macrophages over a
pathology. period of 2 or 3 weeks.
Inflammatory reaction associated with TH1 cells The activated macrophages often undergo a morphologic
o Dominated by activated macrophages transformation into epithelium-like cells and are then
Inflammatory reaction triggered by TH17 cells referred to as epithelioid cells.
o Has a greater neutrophil component A microscopic aggregation of epithelioid cells, usually
The cellular events in T cell–mediated hypersensitivity surrounded by a collar of lymphocytes, is referred to as a
consist of a series of reactions in which cytokines play granuloma. (Pattern of inflammation is called
important roles divided into the following stages: granulomatous inflammation which is typically associated
with strong T-cell activation with cytokine production.

1. PROLIFERATION AND DIFFERENTIATION OF CD4+ T


CELLS
Naive CD4+ T cells recognize peptides displayed by
dendritic cells and secrete IL-2, which functions as an
autocrine growth factor to stimulate proliferation of the
antigen-responsive T cells.
The subsequent differentiation of antigen-stimulated T cells
to TH1 or TH17 cells is driven by the cytokines produced by
APCs at the time of T-cell activation.
In some situations the APCs (dendritic cells and
macrophages) produce IL-12, which induces differentiation
of CD4+ T cells to the TH1 subset. IFN-γ produced by
these effector cells promotes further TH1 development,
thus amplifying the reaction.
If the APCs produce inflammatory cytokines such as IL-1,
IL-6, and a close relative of IL-12 called IL-23, these work
in collaboration with transforming growth factor-β (TGF-β)
(made by many cell types) to stimulate differentiation of T
cells to the TH17 subset.
Some of the differentiated effector cells enter the circulation
and may remain in the memory pool of T cells for long
periods.

2. RESPONSES OF DIFFERENTIATED EFFECTOR T FIGURE. Mechanisms of granuloma formation


CELLS
Upon repeat exposure to an antigen, previously activated T Contact dermatitis
cells recognize the antigen displayed by APCs and respond. o Common example of tissue injury resulting from DTH
TH1 cells secrete cytokines, mainly IFN-γ, which are reactions. It may be evoked by contact with urushiol,
responsible for many of the manifestations of delayed-type the antigenic component of poison ivy or poison oak,
hypersensitivity. and presents as a vesicular dermatitis
IFN-γ–activated macrophages are altered in several ways:
their ability to phagocytose and kill microorganisms is

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
REACTIONS OF CD8+ T CELLS: CELL-MEDIATED
CYTOTOXICITY The clinical manifestations of autoimmune disorders are
CD8+ CTLs kill antigen-bearing target cells extremely varied.
may be an important component of many T cell–mediated Examples of organ-specific autoimmunity:
diseases, such as type 1 diabetes o Type 1 diabetes mellitus, in which the autoreactive T
CTLs directed against cell surface histocompatibility cells and antibodies are specific for β cells of the
antigens play an important role in graft rejection and in pancreatic islets,
reactions against viruses. o Multiple sclerosis, in which autoreactive T cells react
In a virus-infected cell, viral peptides are displayed by against central nervous system myelin.
class I MHC molecules and the complex is recognized by The best example of systemic autoimmune disease: - SLE,
the TCR of CD8+ T lymphocytes. in which a diversity of antibodies directed against
The killing of infected cells leads to the elimination of the DNA,platelets, red cells, and protein-phospholipid
infection, and is responsible for cell damage that complexes result in widespread lesions throughout the
accompanies the infection (e.g., in viral hepatitis). body.
Tumor-associated antigens are also presented on the cell In the middle of the spectrum falls:
surface, and CTLs are involved in tumor rejection. Goodpasture's syndrome, in which antibodies to basement
The principal mechanism of T cell–mediated killing of membranes of lung and kidney induce lesions in these
targets involves perforins and granzymes, preformed organs.
mediators contained in the lysosome-like granules of CTLs. Autoimmunity results from the loss of self-tolerance, and
CTLs that recognize the target cells secrete a complex the question arises as to how this happens.
consisting of perforin, granzymes, and a protein called
serglycin, which enters target cells by endocytosis. IMMUNOLOGICAL TOLERANCE
In the target cell cytoplasm, perforin facilitates the release The phenomenon of unresponsiveness to an antigen as a
of the granzymes from the complex. result of exposure of lymphocytes to that antigen.
Granzymes are proteases that cleave and activate Self-tolerance refers to lack of responsiveness to an
caspases, which induce apoptosis of the target cells. individual's own antigens, and it underlies our ability to live
Activated CTLs also express Fas ligand, a molecule with in harmony with our cells and tissues.
homology to TNF, which can bind to Fas expressed on Lymphocytes with receptors capable of recognizing self-
target cells and trigger apoptosis. antigens are being generated constantly, and these cells
CD8+ T cells also produce cytokines, notably IFN-γ, and have to be eliminated or inactivated as soon as they
are involved in inflammatory reactions resembling DTH, recognize the antigens, to prevent them from causing harm.
especially following virus infections and exposure to some Can be classified into: central tolerance and peripheral
contact sensitizing agents. tolerance

AUTOIMMUNE DISEASES
Autoimmunity
o An important cause of certain diseases in humans,
estimated to affect at least 1% to 2% of the US
population.
Autoantibodies can be found in the serum of apparently
normal individuals, particularly in older age groups.
Innocuous autoantibodies are also formed after damage to
tissue and may serve a physiologic role in the removal of
tissue breakdown products.
Ideally, at least three requirements should be met before a
disorder is categorized as truly due to autoimmunity:
1. The presence of an immune reaction specific for
some self-antigen or self-tissue;
2. Evidence that such a reaction is not secondary to
tissue damage but is of primary pathogenic
significance; and
3. The absence of another well-defined cause of the
disease.

FIGURE. Mechanisms of immunological tolerance

CENTRAL TOLERANCE
Process in which immature self-reactive T- and B-
lymphocyte clones that recognize self-antigens during their
maturation in the central (or generative) lymphoid organs
(the thymus for T cells and the bone marrow for B cells) are
killed or rendered harmless.
The mechanisms of central tolerance in T and B cells show
some similarities and differences.
In developing T cells, random somatic gene
rearrangements generate diverse TCRs. Such antigen-
independent TCR generation produces many lymphocytes
that express high-affinity receptors for self-antigens.
Negative selection or deletion
o Responsible for eliminating many self-reactive
lymphocytes from the T-cell pool
o When immature lymphocytes encounter the antigens in
the thymus, the cells die by apoptosis.

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
A wide variety of autologous protein antigens, including SUPPRESSION BY REGULATORY T CELLS
antigens thought to be restricted to peripheral tissues, are Regulatory T cells develop mainly in the thymus, as a result
processed and presented by thymic antigen presenting of recognition of self-antigens but they may also be induced
cells in association with self-MHC molecules and can, in peripheral lymphoid tissues.
therefore, be recognized by potentially self-reactive T cells. The best-defined regulatory T cells are CD4+ cells that
AIRE (autoimmune regulator)- stimulates expression of constitutively express CD25, the α chain of the IL- 2
some ―peripheral tissue-restricted‖ self-antigens inthe receptor, and a transcription factor of the forkhead family,
thymus and is thus critical for deletion of immature T cells called Foxp3.
specific for these antigens Both IL-2 and Foxp3 are required for the development and
Mutations in the AIRE gene - cause of an autoimmune maintenance of functional CD4+ regulatory T cells.
polyendocrinopathy Mutations in Foxp3 result in severe autoimmunity in
In the CD4+ T-cell lineage, some of the cells that see self humans and mice; in humans these mutations are the
antigens in the thymus do not die but develop into cause of a systemic autoimmune disease called IPEX (for
regulatory T cells. immune dysregulation, polyendocrinopathy, enteropathy, X-
Receptor editing linked).
o When developing B cells strongly recognize self- In mice knockout of the gene encoding IL-2 or the IL-2
antigens in the bone marrow, many of them reactivate receptor α or β chain also results in severe multiorgan
the machinery of antigen receptor gene rearrangement autoimmunity, because IL-2 is essential for the
and begin to express new antigen receptors, not maintenance of regulatory T cells.
specific for self-antigens. it is estimated that a quarter Recent genome-wide association studies have revealed
to half of all B cells in the body may have undergone that polymorphisms in the CD25 gene are associated with
receptor editing during their maturation. If receptor multiple sclerosis and other autoimmune diseases, raising
editing does not occur, the self-reactive cells undergo the possibility of a regulatory T-cell defect contributing to
apoptosis, thus purging potentially dangerous these diseases.
lymphocytes from the mature pool. The inhibitory activity of these cells may be mediated by the
Not all self-antigens may be present in the thymus, and secretion ofimmunosuppressive cytokines such as IL-10
hence T cells bearing receptors for such autoantigens and TGF-β, which inhibit lymphocyte activation and effector
escape into the periphery. functions.
There is similar ―slippage‖ in the B-cell system. Self-
reactive lymphocytes that escape negative selection can DELETION BY ACTIVATION-INDUCED CELL DEATH:
inflict tissue injury unless they are deleted or muzzled in the CD4+ T cells that recognize self-antigens may receive
peripheral tissues. signals that promote their death by apoptosis.
a consequence of T-cell activation.
PERIPHERAL TOLERANCE Two mechanisms of activation-induced cell death have
Mechanisms silencing potentially autoreactive T and B cells been proposed, based on studies in mice.
in peripheral tissues: o First, it is postulated that if T cells recognize self-
o Anergy: refers to prolonged or irreversible functional antigens, they may express a proapoptotic member of
inactivation of lymphocytes, induced by encounter with the Bcl family, called Bim, without anti-apoptotic
antigens under certain conditions. members of the family like Bcl-2 and Bcl-x (whose
o Activation of antigen-specific T cells requires two induction requires the full set of signals for lymphocyte
signals: recognition of peptide antigen in association activation). Unopposed Bim triggers apoptosis by the
with self-MHC molecules on the surface of APCs and a mitochondrial pathway.
set of costimulatory signals (―second signals‖) from o Second mechanism involves the Fas-Fas ligand
APCs. These second signals are provided by certain T system. Lymphocytes as well as many other cells
cell–associated molecules, such as CD28, that bind to express Fas(CD95), a member of the TNF-receptor
their ligands (the costimulators B7-1 and B7-2) on family. FasL, a membrane protein that is structurally
APCs. homologous to the cytokine TNF, is expressed mainly
o If the antigen is presented by cells that do not bear the on activated Tlymphocytes. The engagement of Fas by
costimulators, a negative signal is delivered, and the FasL induces apoptosis of activated T cells bythe
cell becomes death receptor. It is postulated that if self-antigens
o Because costimulatory molecules are not expressed or engage antigen receptors of self-antigen–specific T
are weakly expressed on resting dendritic cells in cells, Fas and FasL are co-expressed, leading to
normal tissues, the encounter between autoreactive T elimination of the cells via Fas-mediated apoptosis.
cells and their specific self-antigens displayed by these Selfreactive B cells may also be deleted by FasL on T
dendritic cellsmay lead to anergy. cells engaging Fas on the B cells. The importance of
o Two mechanisms of T-cell anergy have been this mechanism in the peripheral deletion of
demonstrated in various experimental systems. autoreactive lymphocytes is highlighted by two strains
o First, the cells lose their ability to trigger of mice that are natural mutants of Fas or FasL. Both
biochemicalsignals from the TCR complex, in part these strains of mice develop an autoimmune disease
because of activation of ubiquitin ligases and resembling human SLE, associated with generalized
proteolytic degradation of receptor-associated lymphoproliferation. In humans a similar disease is
signaling proteins. caused by mutations in the FAS gene; it is called the
o Second, T cells that recognize self-antigens receive an autoimmune lymphoproliferative syndrome.
inhibitory signal from receptors that arestructurally Postulated mechanism for post-traumatic orchitis and
homologous to CD28 but serve the opposite functions. uveitis
Two of these inhibitory receptors are CTLA-4, which o Some antigens are hidden (sequestered) from the
(like CD28) also binds to B7 molecules, and PD-1, immune system, because the tissues in which these
which binds to two ligands that are expressed on a antigens are located do not communicate with the
wide variety of cells. blood and lymph. Thus, self-antigens in these tissues
Polymorphisms in the CTLA4 gene are associated with do not induce tolerance but fail to elicit immune
some autoimmune endocrinediseases in humans. responses and are essentially ignored by the immune
Anergy also affects mature B cells in peripheral tissues. It is system. This is believed to be the case for the testis,
believed that if B cells encounterself-antigen in peripheral eye,
tissues, especially in the absence of specific helper T cells, and brain, all of which are called immune-
the B cellsbecome unable to respond to subsequent privileged sites because it is difficult to induce
antigenic stimulation and may be excluded from lymphoid immune responses to antigens introduced into
follicles, resulting in their death. these sites. If the antigens of these tissues are
released, for example, as a consequence of

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
trauma or infection, the result may be an immune 2. Microbial infections with resultant tissue necrosis and
response that leads to prolonged tissue inflammation can cause up-regulation of costimulatory
inflammation and injury. molecules on resting APCs in tissue thus favoring a
breakdown of T-cell anergy and subsequent T-cell activation.
MECHANISMS OF AUTOIMMUNITY
Autoimmunity arises from a combination of:
o Inheritance of susceptibility genes, which may
contribute to the breakdown of self-tolerance
o Environmental triggers, such as infections and tissue
damage, which promote the activation of self-reactive
lymphocytes

Figure. Postulated role of infection in autoimmunity.

GENERAL FEATURES OF AN AUTOIMMUNE DISEASE


Once induced it tends to be progressive, sometimes with
sporadic relapses and remissions
o Due to many intrinsic amplification loops that allow
small numbers of antigen-specific lymphocytes to
eradicate infections
o Inappropriate direction agains self-tissues
Figure. Pathogenesis of autoimmunity exacerbation of injury
o Epitope spreading
GENETIC FACTORS IN AUTOIMMUNITY Infections and initial immune response damage self
(ROLE OF SUSCEPTIBILITY GENES) and expose epitopes of antigens normally
Autoimmune diseases have a tendency to run in families concelased from immune system
o there is a greater incidence of the same disease in Continuing activation of lymphocytes that recognize
monozygotic than in dizygotic twins. hidden epitopes
o Most are complex multigenic disorders and are not However, these lymphocytes are not tolerant to these
attributable to single gene mutations epitopes since they were not expressed normally
Several autoimmune diseases are linked with the HLA locus, Clinical and pathological manifestations are determined by
especially class II alleles (HLA-DR, -DQ) the nature of the underlying immune response
The frequency of a disease in an individual with a particular o TH1 responses
HLA allele, compared to individuals who do not inherit that Assoc. with destructive macrophage-rich
allele, is called the relative risk inflammation and production of antibodies that cause
It should also be noted that most individuals with a tissue damage by activating complement and
susceptibility-related MHC allele never develop any disease, binding to fc receptors
and, conversely, individuals without the relevant MHC gene o TH17 responses
can develop the disease Underlie inflammatory lesions dominated by
Two genetic polymorphisms have recently been shown to be neutrophils and monocytes
quite strongly associated with certain autoimmune diseases Show substantial clinical, pathologic and serological
o PTPN22 overlaps
Encodes a phosphatase
Particular variants are associated with rheumatoid SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
arthritis and several other autoimmune diseases Prototype of a multisystem disease of autoimmune origin,
o NOD2 characterized by a vast array of autoantibodies, particularly
Encodes an intracellular receptor for microbial peptides, antinuclear antibodies (ANAs).
and certain variants or mutants of this gene are present Acute or insidious in its onset, it is a chronic, remitting and
in as many as 25% of patients with Crohn's disease in relapsing, often febrile illness characterized principally by
some populations injury to the skin, joints, kidney, and serosal membranes.
Presence of particular MHC alleles affects the Prevalence 1:2500; predominantly affects women (1:700
o Negative selection of T cells in the thymus or the childbearing age), with female-to-male ratio of 9:1. But ratio
o Development of regulatory T cells falls to 2:1 for disease developing during childhood or >65
Presence of particular MHC alleles is not, by itself, the y/o
cause of autoimmunity because many normal individuals Criteria for SLE:
inherit the MHC alleles and normal MHC molecules are o 4 or more of the following, serially or simultaneously,
capable of presenting self-antigens during any period of observation
Many non-MHC genetic loci are associated with
autoimmunity in type I DM & SLE (Remember MD SOAP BRAIN)
a) Malar rash g) Blood disorder
ROLE OF INFECTIONS AND TISSUE INJURY b) Discoid rash (Hematologic)
Two mechanisms postulated to explain link between c) Serositis h) Renal disorder
infections and autoimmunity: d) Oral ulcers i) Anti-nuclear antibody
1. Molecular mimicry e) Arthritis j) Immunological
o Viruses and other microbes, particularly certain bacteria f) Photosensitivity disorder
such as streptococci and Klebsiella organisms, may k) Neurologic disorder
share cross-reacting epitopes with self-antigens, such
that responses to the microbial antigen may attack self-
tissues

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
Table 1. 1997 Revised Criteria for Classification of Systemic nor species-specific; others are directed against cell
Lupus Erythematosus. surface antigens of blood cells
CRITERION DEFINITION Apart from their value in the diagnosis and management of
1. Malar Fixed erythema, flat or raised over the patients with SLE, these antibodies are of major
rash malar eminences tending to spare the pathogenetic significance, as, for example, in the immune
nasolabial folds complex–mediated glomerulonephritis so typical of this
disease.
2. Discoid Erythematous raised patches with
rash adherent keratotic scaling and follicular ANTINUCLEAR ANTIBODIES (ANAs)
plugging
Directed against several nuclear antigens and can be
Atrophic scarring may occur in older grouped into four categories:
lesions 1. Antibodies to DNA
3. Photo- Rash as a result of unusual reaction to 2. Antibodies to histones
sensitivity sunlight, by patient history or physician 3. Antibodies to nonhistone proteins bound to RNA
observation 4. Antibodies to nucleolar antigens
4. Oral Oral or nasopharyngeal ulceration, Most commonly used method is indirect
ulcers usually painless, observed by a immunofluorescence, which detects a variety of nuclear
physician antigens, including DNA, RNA, and proteins (collectively
5. Nonerosive arthritis involving two or called generic ANAs)
Arthritis more peripheral joints characterized by Pattern of nuclear fluorescence suggests the type of
tenderness, swelling, or effusion antibody present in the patient's serum
Four basic patterns are recognized:
6. Serositis Pleuritis: convincing history of pleuritic o Homogeneous or diffuse nuclear staining usually
pain or rub heard by a physician or reflects antibodies to chromatin, histones and,
evidence of pleural effusion occasionally, double-stranded DNA
Pericarditis: documented by o Rim or peripheral staining patterns are most
electrocardiogram or rub or evidence of commonly indicative of antibodies to double-stranded
pericardial effusion DNA
7. Renal Persistent proteinuria >0.5gm/dL or o Speckled pattern refers to the presence of uniform or
disorder >3+if quantitation not performed variable-sized speckles. One of the most commonly
or Cellular casts: may be red blood observed therefore the least specific. It reflects the
cell, hemoglobin, granular, tubular, or presence of antibodies to non-DNA nuclear
mixed constituents. Examples include Sm antigen,
8. Seizures: in the absence of offending ribonucleoprotein, and SS-A and SS-B reactive
Neurologic drugs or known metabolic antigens.
disorder derangements (e.g., uremia, o Nucleolar pattern refers to the presence of a few
ketoacidosis, or electrolyte imbalance) discrete spots of fluorescence within the nucleus and
or Psychosis: in the absence of represents antibodies to RNA. Reported most often in
offending drugs or known metabolic patients with systemic sclerosis.
derangements (e.g., uremia, Fluorescence patterns are not absolutely specific for the
ketoacidosis, or electrolyte imbalance) type of antibody; combination patterns are frequent
9. Hemolytic anemia: with reticulocytosis The immunofluorescence test for ANAs is sensitive
Hematologi 9
or Leukopenia: <4.0 ×10 cells per liter because it is positive in virtually every patient with SLE, but
c disorder (4000 cells per mm3) total on two or it is not specific because patients with other autoimmune
more occasion diseases also frequently score positive.
9
or Lymphopenia: <1.5 ×10 cells per Lupus patients have a host of other autoantibodies
liter (1500 cells per mm3) on two or o Antiphospholipid antibodies (in 40-50% of lupus
more occasions patients) – directed against epitopes of plasma
or Thrombocytopenia: <100 ×10 cells
9 proteins. Antibodies against the phospholipid–β2-
per liter (100 ×103 cells per mm3) in the glycoprotein complex also bind to cardiolipin antigen,
used in syphilis serology, and therefore lupus patients
absence of offending drugs
may have a false-positive test result for syphilis.
10. Anti-DNA antibody to native DNA in
o Some antibodies interfere with clotting in vitro – lupus
Immunologi abnormal titer
c disorder anticoagulant
or Anti-Sm: presence of antibody to Sm o But these patients present with complications
nuclear antigen associated with hypercoagulable state
or Positive finding of This constellation of clinical features is called secondary
antiphospholipid antibodies based on: antiphospholipid antibody syndrome
1. An abnormal serum level of IgG or
IgM anticardiolipin antibodies
2. A positive test for lupus
anticoagulant using a standard test
3. A false-positive serologic test for
syphilis known to be positive for at
least 6 months and confirmed by
negative Treponema pallidum
immobilization or fluorescent
treponemal antibody absorption test
11. An abnormal titer of antinuclear
Antinuclear antibody by immunofluorescence or an
antibody equivalent assay at any point in time
and in the absence of drugs known to
be associated with drug-induced lupus
syndrome

SPECTRUM OF AUTOANTIBODIES IN SLE


Hallmark of the disease is the production of antibodies
Some antibodies recognize diverse nuclear and
cytoplasmic components of the cell that are neither organ-

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
Sex hormones: during the reproductive years, the
frequency of SLE is 10 times greater in women than in men
(age: 17-55 y/o), and exacerbation has been noted during
normal menses and pregnancy.

MODEL FOR THE PATHOGENESIS OF SYSTEMIC LUPUS


ERYTHEMATOSUS (SLE)
UV irradiation and other environmental insults lead to the
apoptosis of cells Inadequate clearance of the nuclei of
these cells results in a large burden of nuclear antigens
Underlying abnormality in B and T lymphocytes is
responsible for defective tolerance Self-reactive
lymphocytes survive and remain functional.
Stimulated by self-nuclear antigens Antibodies are
produced against the antigens
Complexes of the antigens and antibodies bind to Fc
receptors on B cells and dendritic cells, and may be
internalized.
The nucleic acid components engage TLRs (1) stimulate
B cells to produce autoantibodies and (2) activate dendritic
cells to produce interferons and other cytokines Further
enhances the immune response and cause more
apoptosis.
The net result is a cycle of antigen release and immune
activation resulting in the production of high-affinity
autoantibodies.

ETIOLOGY AND PATHOGENESIS OF SLE


Etiology remains unknown; existence of seemingly limitless
number of antibodies against self.
Suggests that the fundamental defect in SLE is a failure of
the mechanisms that maintain self-tolerance.
Figure 1. Model for the pathogenesis of systemic lupus
GENETIC FACTORS erythematosus.
Genetically complex disease with contributions from MHC
and multiple non-MHC genes. MECHANISMS OF TISSUE INJURY
Family members of patients have high risk of developing Autoantibodies are clearly the mediators of tissue injury.
SLE Most of the visceral lesions are caused by immune
complexes (Type III hypersensitivity)
IMMUNOLOGICAL FACTORS DNA-anti-DNA complexes can be detected in the
Recent studies reveal several immunological aberrations glomeruli and small blood vessels.
that collectively may result in the persistence and Low levels of serum complement (secondary to
uncontrolled activation of self-reactive lymphocytes. consumption of complement proteins) and granular
Defective elimination of self-reactive B cells in the bone deposits of complement and immunoglobulins in the
marrow or defects in peripheral tolerance mechanisms may glomeruli further support the immune complex nature of
lead to failure of self-tolerance in B cells. the disease.
Evidence that CD4+Helper T cells specific for nucleosomal Autoantibodies specific for RBC, WBC and platelets
antigens also escape tolerance opsonize these cells and promote their phagocytosis and
lysis.
ENVIRONMENTAL FACTORS ANA’s, involved in immune complex formation, cannot
Drugs such as hydralazine, procainamide, and D- penetrate intact cells. However, if cell nuclei are exposed
penicillamine can induce an SLE-like response in humans then ANA’s can bind to them.
Ultraviolet light exacerbates the disease in many In tissues, nuclei of damaged cells react with ANA’s, lose
individuals. their chromatinpattern and become homogenous to
o May induce apoptosis in cells, and alter the DNA in produce the so called LE bodies or hematoxylin bodies.
such a way that it becomes immunogenic by LE Cell is any phagocytic leukocyte (blood neutrophil or
enhanced recognition by TLRs macrophage) that has engulfed the denatured nucleus of
o UVL may modulate the immune response , e.g. by an injured cell.
inducing keratinocytes to produce IL-1, a factor known Presence of LE Cells in vitro was used in the past as a
to influence the immune response test for SLE.

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
Sometimes, LE Cells are found in pericardial or pleural distinction is based solely on the percentage of
effusions in patients. glomerular involvement (<50% for class III vs >50% for
Summary: SLE is a complex disorder of multifactorial class IV). Patients with diffuse glomerulonephritis are
origin resulting from interactions among genetic, usually symptomatic, showing hematuria as well as
immunological and environmental factors that act in proteinuria. Hypertension and mild to severe renal
concert to cause activation of helper T-cells and B cells insufficiency are also common.
and result in the production of several species of
pathogenic antibodies.

MORPHOLOGY
The most characteristic lesions result from immune
complexes depositing in blood vessels, connective tissue,
kidneys and skin.
An acute necrotizing vasculitis involving capillaries, small
arteries and arterioles may be present in any tissue.
Arteritis is characterized by fibrinoid deposits in the
vessel walls. In chronic stages, vessels undergo fibrous
thickening with luminal narrowing.

KIDNEY o Membranous glomerulonephritis (class V) is


Lupus nephritis affects upt o 50% of SLE patients. characterized by diffuse thickening of the capillary
Principal mechanism of injury is immune complex walls, which is similar to idiopathic membranous
deposition in the glomeruli, tubular or peritubular capillary glomerulonephritis, described in Chapter 20 . This
basement membranes, or larger blood vessels. lesion is seen in 10% to 15% of lupus nephritis patients,
Other injuries may include thrombi in glomerular is usually accompanied by severe proteinuria or
capillaries, arterioles, or arteries, often associated with nephrotic syndrome, and may occur concurrently with
antiphospholipid antibodies. focal or diffuse lupus nephritis.
All of the glomerular lesions described below are the o Granular deposits of antibody and complement can be
result of deposition of immune complexes that are detected by immunofluorescence. Electron microscopy
regularly present in the mesangium or along the entire demonstrates electron-dense deposits that represent
basement membrane and sometimes throughout the immune complexes in mesangial, intramembranous,
glomerulus. subepithelial, or subendothelial locations. All classes
The immune complexes consist of DNA and anti-DNA show variable amounts of mesangial deposits. In
antibodies, but other antigens such as histones have also membranous lupus nephritis, the deposits are
been implicated. Both in situ formation and deposition of predominantly subepithelial (between the basement
preformed circulating immune complexes may contribute membrane and visceral epithelial cells). Subendothelial
to the injury, but the reason for the wide spectrum of deposits (between the endothelium and the basement
histopathologic lesions (and clinical manifestations) in membrane) are seen in the proliferative types (classes
lupus nephritis patients remains uncertain. III and IV) but may be encountered rarely in class I, II,
o Mesangial lupus glomerulonephritis (10% to 25% and V lupus nephritis
of patients) o When prominent, subendothelial deposits create a
Characterized by mesangial cell proliferation and homogeneous thickening of the capillary wall, which
immune complex deposition without involvement are seen by light microscopy as a ―wire-loop‖ lesion
of glomerular capillaries. There is no or slight Such wire loops are often found in both focal and
(class I) to moderate (class II) increase in both diffuse proliferative (class III or IV) lupus nephritis,
mesangial matrix and number of mesangial cells. which reflects active disease.
Granular mesangial deposits of o Changes in the interstitium and tubules are
immunoglobulin and complement are always frequently present in lupus nephritis patients. Rarely,
present. Classes III to V nephritis, described tubulointerstitial lesions may be the dominant
below, are usually superimposed on some abnormality. Discrete immune complexes similar to
degree of mesangial changes. those in glomeruli are present in the tubular or
o Focal proliferative glomerulonephritis (class III) peritubular capillary basement membranes in many
20% to 35% of patients, lupus nephritis patients
Defined by fewer than 50% involvement of all
glomeruli. The lesions may be segmental SKIN
(affecting only a portion of the glomerulus) or Characteristic erythema affects the facial butterfly (malar)
global (involving the entire glomerulus). Affected area (bridge of the nose and cheeks) in approximately 50%
glomeruli may exhibit crescent formation, of patients, but a similar rash may also be seen on the
fibrinoid necrosis, proliferation of endothelial and extremities and trunk.
mesangial cells, infiltrating leukocytes, and Urticaria, bullae, maculopapular lesions, and ulcerations
eosinophilic deposits or intracapillary thrombi also occur.
which often correlate with hematuria and Exposure to sunlight incites or accentuates the erythema.
proteinuria. Some patients may progress to Histologically the involved areas show vacuolar
diffuse proliferative glomerulonephritis. The degeneration of the basal layer of the epidermis
active (or proliferative) inflammatory lesions can In the dermis, there is variable edema and perivascular
heal completely or lead to chronic global or inflammation.
segmental glomerular scarring. Vasculitis with fibrinoid necrosis may be prominent.
o Diffuse proliferative glomerulonephritis (class IV) is Immunofluorescence microscopy shows deposition of
the most severe form of lupus nephritis, occurring in 35% immunoglobulin and complement along the
to 60% of patients. Pathologic glomerular changes may dermoepidermal junction which may also be present in
be identical to focal (class III) lupus nephritis, including uninvolved skin. This finding is not diagnostic of SLE and is
proliferation of endothelial, mesangial and, sometimes, sometimes seen in scleroderma or dermatomyositis.
epithelial cells with the latter producing cellular
crescents that fill Bowman's space. The entire JOINTS
glomerulus is frequently affected but segmental lesions
Joint involvement is typically a nonerosive synovitis with
also may occur. Both acutely injured and chronically
little deformity, which contrasts with rheumatoid arthritis
scarred glomeruli in focal or diffuse lupus nephritis are
qualitatively indistinguishable from one another; the

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
CENTRAL NERVOUS SYSTEM o Butterfly rash over the face
The pathologic basis of central nervous system symptoms o Fever
is not entirely clear, but antibodies against a synaptic o Pain but no deformity in one or more peripheral joints
membrane protein have been implicated. Neuropsychiatric (feet, ankles, knees, hips, fingers, wrists, elbows,
symptoms of SLE have often been ascribed to acute shoulders)
vasculitis, but in histologic studies of the nervous system in o Pleuritic chest pain
such patients significant vasculitis is rarely present. Instead, o Photosensitivity
noninflammatory occlusion of small vessels by intimal In many patients, however, the presentation of SLE is
proliferation is sometimes noted, which may be due to subtle and puzzling taking forms such as a febrile illness of
endothelial damage by antiphospholipid antibodies. unknown origin, abnormal urinary findings or joint disease
masquerading as rheumatoid arthritis or rheumatic fever
PERICARDITIS Antinuclear Antibodies (ANAs) – are found in virtually
Inflammation of the serosal lining membrane may be acute, 100% of the patients although ANAs are not specific
subacute or chronic A variety of clinical findings may point toward renal
During acute phases, the mesothelial surfaces are involvement, including hematuria, red cell casts, proteinuria
sometimes covered with fibrinous exudate and in some cases the class nephrotic syndrome
Later, becomes thickened, opaque and coated with a shaggy Laboratory evidence of some hematologic derangement is
fibrous tissue may lead to partial or total obliteration of the seen virtually in every case but in some, anemia or
serosal cavity thrombocytopenia may be presenting manifestation as well
as the dominant problem
Mental aberrations, including psychosis or convulsions, or
CARDIOVASCULAR SYSTEM
coronary artery disease may be prominent clinical problems
Involvement may manifest as damage to any layer of the Patients with SLE are prone to infections due to immune
heart dysfunction and treatment with immunosuppressive
Symptomatic or asymptomatic pericardial involvement drugs
present in up to 50% of patients More often with appropriate therapy, the disease is
Myocarditis or mononuclear cell infiltration, less common characterized by flare-ups and remissions spanning from
and may cause resting tachycardia and ECG changes years to even decades
Valvular abnormalities primarily of the mitral and aortic o During flare-ups, increased formation of immune complexes
valves manifest as diffuse leaflet thickening that may be and the accompanying complement activation often results
associated with dysfunction (stenosis or regurgitation) in hypercomplementemia
Valvular (so-called Libman-Sacks) endocarditis was more Disease exacerbations are treated with corticosteroids and
common prior to the widespread use of steroids immunosuppressive drugs
o This nonbacterial verrucous endocarditis takes the Even without therapy, in some patients, the diease may run
form of single or multiple 1- to 3-mm warty deposits on a benign course with skin manifestations and mild
any heart valve, distinctively on either surface of the hematuria for years
leaflets The most common cause of death are renal failure and
An increasing number of patients have clinical evidence of intercurrent infections
coronary artery disease (angina, myocardial infarction) o Coronary artery disease also becoming an important
owing to coronary atherosclerosis cause of death
o This complication is particularly noted in young patients
with long-standing disease and especially in those who
CHRONIC DISCOID LUPUS ERYTHEMATOSUS
have been treated with corticosteroids
o Coronary atherosclerosis is probably multifactorial A disease in which the skin manifestations may mimic SLE,
including traditional risk factors of hypertension, but systemic manifestations are rare
obesity and hyperlipidemia are more common in SLE Characterized by the presence of skin plaques showing
patients varying degrees of edema, erythema and scaliness,
o Immune complexes and antiphospholipid antibodies follicular plugging, and skin atrophy surround by an
may cause endothelial damage and promote elevated erythematous border
atherosclerosis Face and scalp are usually affected, but widely
disseminated lesions may occasionally occur
SPLEEN Disease is usually confined to the skin, but 5-10% of
patients with discoid lupus erythematosus develop
Splenomegaly, capsular thickening and follicular
multisystem manifestations after many years
hyperplasia are common features
Conversely, some patients with SLE may have prominent
Central penicilliary arteries may show concentric intimal
discoid lesions in the skin
and smooth muscle hyperplasia – producing so-called
Approximately 35% of patients show positive ANA test,
onion skin lesions
but antibodies to double-stranded DNA are rarely
present
LUNGS
Immunofluorescence studies of skin biopsy specimens
Pleuritis and pleural effusions are the most common show deposition of immunoglobulin and C3 at the
manifestation – affecting almost 50% of patients dermoepidermal junction similar to that of SLE
Alveolar injury with edema and hemorrhage is less common
In some cases, there is chronic interstitial fibrosis and SUBACUTE CUTANEOUS LUPUS ERYTHEMATOSUS
secondary pulmonary hypertension
Also presents with predominant skin involvement and can
None of these changes are specific for SLE
be distinguished from chronic discoid by several criteria
The skinrash in this disease tends to be widespread,
OTHER ORGANS AND TISSUES superficial and non-scarring (although can occur in some
LE or Hematoxylin Bodies in the bone marrow or other patients)
organs are strongly indicative of SLE Most patients have mild systemic symptoms consistent with
Lymph nodes may be enlarged with hyperplastic follicles or SLE
even demonstrate necrotizing lymphadenitis There is a strong association with Antibodies to the SS-A
antigen and with the HLA-DR3 genotype
CLINICAL MANIFESTATIONS Thus the term subacute cutaneous LE seems to define a
A multisystem disease with highly variable clinical group intermediatebetween SLE and LE localized only to
presentations skin
Typically the patient is a young woman with some but not
necessarily all of the following features

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
DRUG-INDUCED LUPUS ERYTHEMATOSUS Inflammation in the tendons, ligaments, and occasionally
A LE-like syndrome may develop from patients receiving a the adjacent skeletal muscle frequently accompanies the
variety of drugs including hydralazine, procainamide, arthritis.
isoniazid and D-penicillamine to name a few
Many of these drugs are associated with the development SKIN
of ANAs, but most patients do not have symptoms of LE Rheumatoid nodules are the most common cutaneous
o E.g. 80% of patients receiving procainamide test lesions in RA
positive for ANAs, but only 1/3 of these manifest o Occur in 25% of patients, usually those with severe
clinical symptoms such as arthralgias, fever and disease
serositis o Arise in pressure regions
Although multiple organs are affected, Renal and o Rheumatoid nodules are firm, non-tender, and round
CNSinvolvement is distinctly uncommon to oval
Antibodies specific for double-stranded DNA are rare, but o In the skin, they arise in the subcutaneous tissue
there is an extremely high frequency of antibodies o Microscopically, they have a central zone of fibrinoid
specific for histone necrosis surrounded by a prominent rim of epitheloid
Persons with the HLA-DR4 allele are at a greater risk of histocytes and numerous lymphocytes and plasma
developing LE after administration of hydralazine cells
The disease remits after withdrawal of the offending drug
BLOOD VESSELS
RHEUMATOID ARTHRITIS Patients with severe erosive disease, rheumatoid nodules,
Chronic inflammatory disease/ Chronic systemic and high titers of rheumatoid factor are at risk of
inflammatory disorder developing vasculitic syndromes
Affects primarily the joints but may involve extra-articular Rheumatoid vasculitis is a potentially catastrophic
tissues such as the skin, blood vessels, lungs, and heart complication of RA, particularly when it affects vital organs
Production of nonsuppurative proliferative and Involvement of medium to small arteries is similar to that
inflammatory synovitis that often progresses to destruction occurring in polyarteritis nodosa except that in RA the
of articular cartilage and ankylosis of the joints kidneys are not involved
Abundant evidence supports the autoimmune nature of Frequently, segments of small arteries such as vasa
the disease. nervorum and digital arteries are obstructed by an
obliterating endarteritis, resulting in peripheral neuropathy,
ulcers, and gangrene
Leukocytoclastic venulitis produces purpura, cutaneous
ulcers, and nail bed infarction

PATHOGENESIS
It is believed that RA is an autoimmune disease triggered
by exposure of a genetically susceptible host to an
unknown arthritogenic antigen
This results in a breakdown of immunological self-
tolerance and a chronic inflammatory reaction
It is the continuing autoimmune reaction, with activation of
CD4+ helper T cells and other lymphocytes, and the local
release of inflammatory mediators and cytokines that
ultimately destroys the joint
o Genetic susceptibility – major contributor to the
pathogenesis of RA
Figure. Rheumatoid arthritis
th
(From Robbins and Cotran Pathologic Basis of Disease, 8 Ed) HLA-DRB1 alleles
PTPN22 (encodes tyrosine phosphatase)
MORPHOLOGY o Environmental arthritogen – thought to be the
initiator of the disease; still uncertain
JOINTS
Epstein-Barr virus, retroviruses, parvoviruses,
Site of most severe morphologic alterations mycobacterioa, Borelia, Proteus mirabilis,
Synovium - grossly edematous, thickened, and hyperplastic Mycoplasma
Histologic features: - All have implicated but none has been
1. Infiltration of synovial stroma by a dense proved to be significant
perivascular inflammatory infiltrate of lymphoid Citrullinated proteins (modified by the conversion
aggregates (mostly CD4+helper T cells), B cells, of arginine to citrullin)
plasma cells, dendritic cells and macrophages o Automimmunity – responsible for the chronic
2. Increased vascularity due to VD and angiogenesis destructive nature of RA
w/ superficial hemosiderin deposits T cells play the pivotal role
3. Aggregation of organizing fibrin covering portions Antigen still uncertain – Type 2 collagen and
of the synovium and floating in the joint space as rice glycosaminoglycans
bodies Activated CD4 + effector, Memory T cells
4. Accumulation of neutrophils in the synovial fluid appear
and along the surface but usually not deep in the TH17 – recruitment of neutrophils and monocytes
stroma Interferon-γ-producing T H1 – may also
5. Osteoclastic activity in underlying bone, allowing contribute
the synovium to penetrate into the bone causing Key considerations in the pathogenesis of the disease are
juxta-articular erosions, subchondral cysts, and (from Old Trans : 2A 2016)
osteoporosis 1. The nature of the autoimmune reaction
6. Pannus formation 2. The mediators of tissue injury
o Pannus – a mass of synovium and synovial stroma 3. Genetic susceptibility to the arthritogenic antigen/s
consisting of inflammatory cells, granulation tissue,
and synovial fibroblasts that grows over the articular
cartilage, causing its erosion
In time, after the cartilage has been destroyed, the pannus
bridges the opposing bones to form a fibrous ankylosis,
which eventually ossifies and results in bony ankylosis.

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9

Figure. Sjögren syndrome. A, Enlargement of the salivary gland. B,


Histopathologic findings include intense lymphocytic and plasma cell
infiltration with ductal epithelial hyperplasia.
th
(From Robbins and Cotran Pathologic Basis of Disease, 8 Ed)

ETIOLOGY AND PATHOGENESIS


(From Robbin’s Basic Pathology, 9th Ed)
Caused by CD4+ Tcell reactions against unknown
antigen in the ductal epithelial cells of the exocrine
glands
Systemic B cell hyperactivity – presence of ANAs and
rheumatoid factor (RF)
Autoantibodies to the nucleoprotein (RNP) antigens SS-
A (Ro) and SS-B (La)
Viral trigger also has been suggested
Genetic variables – Class II MHC alleles predisposes to
the development of specific RNP autoantibodies
Figure. Pathogenesis of RA
th
(From Robbin’s Basic Pathology, 9 Ed) (From Robbins and Cotran Pathologic Basis of Disease, 8th Ed)
The characteristic decrease in tears and saliva (sicca
syndrome) is the result of lymphocytic infiltration and
fibrosis of the lacrimal and salivary glands
The infiltrate contains predominantly activated CD4+
helper T cells and some B cells, including plasma cells
About 75% of the patients have rheumatoidfactor (an
antibody reactive with self-IgG) whether or not coexisting
rheumatoid arthritis is present
ANAs are detected in 50-80% of patients
A host of other organ-specific and non-organ-specific
antibodies have also been identified
o Most important, are antibodies directed against two
ribonucleoprotein antigens, SS-A (Ro) and SS-B (La)
which can be detected in as many as 90% of patients
by sensitive techniques
o These antibodies are thus considered serologic
markers of the disease
o Patients with high titers of antibodies to SS-A are
more likely to have early disease onset, longer
disease duration and extraglandular manifestations
such as cutaneous vasculitis and nephritis
o These autoantibodies are also present in a smaller
percentage of patients with SLE and hence are not
diagnostic of Sjögren syndrome
Sjögren syndrome shows some association, although
weak, with certain HLA alleles
o Studies of whites and blacks suggest linkage of the
primary form with HLA-B8, HLA-DR3 and DRW52 as
well as HLA-DQA1 and HLA-DQB1
o In patients with anti-SS-A or anti-SS-B antibodies,
specific alleles of HLA-DQA1 and HLA-DQB1 are
frequent – this suggests that, as in SLE, inheritance of
certain class II molecules predisposes to the
development of particular autoantibodies
Figure. ImmunoPathogenesis of RA
th
(From Robbins and Cotran Pathologic Basis of Disease, 8 Ed) Although the pathogenesis remains obscure, aberrant T-
cell and B-cell activation are both implicated
SJÖGREN SYNDROME The initiating trigger may be a viral infection of the salivary
A chronic disease characterized by dry eyes glands, which causes local cell death and release of tissue
(keratoconjunctivitis sicca) and dry mouth (xerostomia) self-antigens
resulting from immunologically mediated destruction of In genetically susceptible individuals, CD4+ T cells and B
lacrimal and salivary glands cells specific for these self-antigens may have escaped
It occurs as an isolated disorder (primary form), also tolerance and are able to react resulting to inflammation
known as the sicca syndrome, or more often in tissue damage fibrosis
association with another autoimmune disease (secondary The nature of auto-antigens recognized by these
form) lymphocytes is still mysterious although a cytoskeletal
Among associated disorders, rheumatoid arthritis is the protein called α-fodrin is a candidate auto-antigen but its
most common, but some patients have SLE, polymyositis, role has not been established
scleroderma, vasculitis, mixed connective tissue disease
and thyroiditis

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
Viruses that may initiate are also unknown but may tissues that are the focal point of the autoimmune
include the perennial culprit in chronic inflammatory response particularly the salivary and lacrimal glands
disease (Epstein-Barr virus and hepatitis C virus) In the early stages of the disease, this immune infiltrate
A small proportion of individuals infected with the human consists of a mixture of polyclonal T and B cells
retrovirus human T-cell lymphotropic virus type 1 develop Emergence of a dominant B cell clone is usually indicative
a clinical picture and pathologic changes identical to those of the development of a marginal one lymphoma, a
seen in Sjörgren syndrome specific type of B cell malignancy that often arises in the
setting of chronic lymphocytic inflammation
MORPHOLOGY About 5% of Sjögren patients develop lymphoma, an
Lacrimal and salivary glands – major targets of the incidence that is 40-fold greater than normal
disease
Other targets are exocrine glands – respiratory, GI, SYSTEMIC SCLEROSIS (SCLERODERMA)
vagina A chronic disease characterized by:
Earliest histologic finding in both the major and minor 1. Chronic inflammation thought to be the result of
salivary glands is periductal and perivascular autoimmunity
lymphocytic infiltration 2. Widespread damage to small blood vessels
Eventually the lymphocytic infiltrate become extensive and 3. Progressive interstitial and perivascular fibrosis in the
in the larger salivary glands lymphoid follicles with skin and multiple organs
germinal centers may be seen Characterized by excessive fibrosis throughout the body
The ductal lining epithelial cells may show hyperplasia - The skin is commonly affected, but the gastrointestinal
obstructs the ducts tract, kidneys, heart, muscles and lungs also are
Later there is atrophy of acini, fibrosis and hyalinization frequently involved
still later in the course atrophy and replacement of In some patients the disease seems to remain confined to
parenchyma with fat are seen the skin for many years, but in the majority it progresses to
In some cases the lymphoid infiltrate may be so intense as visceral involvement with death from renal and cardiac
to give the appearance of a lymphoma failure, pulmonary insufficiency or intestinal malabsorption
These patients are at a high risk for development of B-cell The clinical heterogeneity of systemic sclerosis has been
recognized by classifying the disease into two major
lymphomas, and molecular assessments of clonality may
be necessary to distinguish intense reactive chronic categories:
inflammation from early involvement by lymphoma o Diffuse scleroderma – characterized by widespread
skin involvement at onset, with rapid progression and
Lack of tears leads to drying of the corneal epithelium
early visceral involvement
becomes inflamed, eroded and ulcerated
o Limited scleroderma – in which the skin involvement
Oral mucosa may atrophy with inflammatory fissuring and
is often confined to fingers, forearms and face;
ulceration
visceral involvement occurs late thus clinical course is
Dryness and crusting of the nose may lead to ulcerations usually benign
and even perforation of the nasal septum
Some patients with the limited disease also develop a
combination of Calcinosis, Raynaud’s phenomenon,
CLINICAL FEATURES
Esophageal dysmotility, Sclerodactyly and Telangiectasia
Sjögren syndrome occurs most commonly in women called the CREST syndrome
between the ages of 50 and 60
Symptoms result from inflammatory destruction of the ETIOLOGY AND PATHOGENESIS
exocrine glands The cause of systemic sclerosis is not known
The keratoconjunctivitis produces blurring of vision,
Autoimmune responses, vascular damage and collagen
burning and itching, and thick secretions accumulate in the deposition all contribute to the ultimate tissue injury
conjunctival sac
The xerostomia results in difficulty in swallowing solid
foods, a decrease in the ability to taste, cracks and
fissures in the mouth and dryness of the buccal mucosa
Parotid gland enlargement is present in half the patients
Dryness of the nasal mucosa, epistaxis, recurrent
bronchitis and pneumonitis are other symptoms
Manifestations of extraglandular disease are seen in one
third of patients and include synovitis, diffuse pulmonary
fibrosis and peripheral neuropathy
o These are more common in patients with high titers of
antibodies specific for SS-A
In contrast to SLE, glomerular lesions are extremely rare
in sjögren syndrome
Defects of tubular function, including renal tubular
acidosis, uricosuria and phosphaturia are often seen and
are associated histologically with tubulointerstitial nephritis
About 60% of patients have another accompanying
autoimmune disorder such as rheumatoid arthritis and
ABNORMAL IMMUNE RESPONSE
these patients also have symptoms and signs of that
disorder It is proposed that CD4+ T cells responding to an
The combination of lacrimal and salivary gland unidentified antigen accumulate in the skin and release
inflammatory involvement was once called Mikulicz cytokines that activate inflammatory cells and fibroblasts
disease Although inflammatory infiltrates are typically sparse in the
o Now, Mikulicz syndrome broadened to include skin of patients with systemic sclerosis, activated CD4+ T
lacrimal and salivary gland enlargement from any cells can be found in many patients and TH2 cells have
cause including sarcoidosis, leukemia, lymphoma and been isolated from the skin
other tumors Several cytokines produced by these T cells, including
Biopsy of the lip (to examine minor salivary glands) is TGF-β and IL-13, can stimulate transcription of genes that
required for the diagnosis of Sjögren syndrome encode collagen and other extracellular matrix proteins
The lymph nodes of patients are often hyperplastic but (e.g. fibronectin) in fibroblasts
the most intense lymphocytic response is seen in the Other cytokines recruit leukocytes and propagate the
chronic inflammation

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
There is also evidence for inappropriate activation of
humoral immunity, and the presence of various
autoantibodies provides diagnostic and prognostic
information
Virtually ALL patients have ANAs that react with a variety
of nuclear antigens
Two ANAs strongly associated with systemic
sclerosis have been described
a. Directed against DNA topoisomerase I (Anti-Scl
70) – highly specific
Figure. A) Normal skin. B) skin biopsy from a patient with systemic
Depending on the ethnic group and assay, it is sclerosis. Note the extensive deposition of dense collagen in the
present in 10-20% of patients with diffuse dermis with virtual absence of appendages (e.g hair follicles) and foci
systemic sclerosis of inflammation (arrow)
Patients who have this antibody are more likely to th
(From Robbins and Cotran Pathologic Basis of Disease, 8 Ed)
have pulmonary fibrosis and peripheral vascular
disease
b. Anticentromere antibody is found in 20-30% of
patients, who tend to have the CREST syndrome or
limited cutaneous systemic sclerosis
Only rarely does the same patient have both
autoantibodies
Role of these ANAs are unclear

VASCULAR DAMAGE
Hallmark feature and the primary inciting pathology
Cause of injury in unknown but it is believed to be either a
consequence of direct immune attack or a by-product of
chronic perivascular inflammation Figure. Advanced systemic sclerosis;
Intimal proliferation is evident in 100% of digital arteries of The extensive subcutaneous fibrosis has virtually immobilized the
patients with systemic sclerosis fingers, creating a clawlike flexion deformity. Loss of blood supply has
Among the genetic loci implicated in the disease are HLA led to cutaneous ulcerations.
th
class II genes, as well as genes that may encode or regulate (From Robbins and Cotran Pathologic Basis of Disease, 8 Ed)
the production of proteins of the extracellular matrix,
including fibrillin-1 INFLAMMATORY MYOPATHIES
Two ANAs more or less unique to systemic sclerosis Comprise an uncommon, heterogenous group of disorders
have been described characterized by injury and inflammation of mainly the
o Directed against DNA topoisomerase I (anti-Scl 70), is skeletal muscles
highly specific. Three distinct disorders:
o An anticentromere antibody a. Dermatomyositis
b. Polymyositis
FIBROSIS c. Inclusion-body myositis
Results not only from the scarring in the setting of ischemic These may occur with other immune-mediated diseases
injury but also as a consequence of fibrogenic cytokine particularly, systemic sclerosis
elaboration and hyperresponsiveness of fibroblasts to the
various growth factors MIXED CONNECTIVE TISSUE DISEASE
This may not be a distinct entity but rather a heterogenous
MORPHOLOGY subgroup of other autoimmune disorders and can, with
Virtually all organs are involved time, evolve into classic SLE or scleroderma
Prominent changes in skin, alimentary tract, musculoskeletal It is characterized by:
system, and kidney, but lesions are also present in the blood o High antibody titer to U1 ribonucleoprotein
vessels, heart, lungs, and peripheral nerves o Modest initial renal involvement
o Good initial response to steroids
SKIN o Serious complications are pulmonary hypertension
Skin grossly exhibits sclerotic atrophy, which usually begins and progressive renal disease
in the fingers and distal regions of the upper extremities and
extends proximally to involve the upper arms, shoulders, POLYYARTERITIS NODOSA AND OTHER VASCULITIDES
neck, and face Polyarteritis nodosa belongs to a group of diseases
In the early stages, affected skin areas are somewhat characterized by necrotizing inflammation of the walls of
edematous and have a doughy consistency blood vessels and showing strong evidence of an
Histologically, there are edema and perivascular infiltrates immunologic pathogenetic mechanism
containing CD4+ T cells, together with swelling and The general term non-infectious necrotizing vasculitis
degeneration of collagen fibers, which become eosinophilic differentiates these conditions from those due to direct
Capillaries and small arteries (150 to 500 µm in diameter) infection of the blood vessel wall (such as occurs in the
may show thickening of the basal lamina, endothelial cell wall of an abscess) and serves to emphasize that any type
damage, and partial occlusion. With progression, the of vessel may be involved—arteries, arterioles, veins, or
edematous phase is replaced by progressive fibrosis of the capillaries
dermis, which becomes tightly bound to the subcutaneous
structures REJECTION OF TISSUE TRANSPLANTS
In advanced stages, the fingers take on a tapered, clawlike Involves several mechanisms of immune-mediated injury
appearance with limitation of motion in the joints, and the Foreign allografts are subject to antibody-mediated injury
face becomes a drawn mask as well as CTL and DTH responses

MECHANISMS OF RECOGNITION AND


REJECTION OF ALLOGRAFTS
Rejection is a complex process in which both cell-
mediated immunity and circulating antibodies play a role
Both mechanisms are reflected in the histologic features of
the rejected organs

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
1. T CELL MEDIATED REACTIONS Figure. Recognition and rejection of organ allografts via the direct
Aka cellular rejection pathway and indirect pathway
Destruction of graft cells by CD8+ CTLs and delayed 2. ANTIBODY-MEDIATED REACTIONS
hypersensitivity reactions triggered by activated CD4+
Aka humoral rejection
helper cells
Hyper-acute rejection
Differences in highly polymorphic HLA alleles: major
When preformed anti-donor antibodies are present in the
antigenic differences between donor and recipient
circulation of the recipient
resulting to rejection of transplants
May be present in:
The recipient’s T cells recognize donor antigens from the
graft by two pathways, called direct and indirect o A recipient who has previously rejected a kidney
transplant
o Multiparous women who develop anti-HLA antibodies
A. DIRECT PATHWAY against paternal antigens shed from the fetus
Major pathway in acute cellular rejection o Prior blood transfusions since platelets and WBCs are
T cells of the transplant recipient recognize the allogeneic rich in HLA antigens
(donor) MHC molecules on the surface of APCs in the With cross-matching (testing recipient’s serum for
graft antibodies against donor’s cells), hyper-acute reaction is
Dendritic cells no longer a significant clinical problem
o Most important APCs in the anti-graft response Recipients not previously sensitized to transplantation
o Express levels of class I and class II MHC antigens, exposure to the class I and class II HLA antigens
molecules of the donor graft evoke antibodies complement-
o With co-stimulatory molecules (eg. B7-1 and B7-2) dependent cytotoxicity, inflammation, antibody-dependent
Host T cells encounter the donor dendritic cells within the cell-mediated cytotoxicity injury
grafted organ or after the dendritic cells migrate to the Graft vasculature: initial target of these antibodies
draining lymph nodes rejection vasculitis
CD8+ T cells recognize class I MHC molecules
differentiate into active CTLs kill graft cells REJECTION OF KIDNEY GRAFTS
CD4+ T cells delayed hypersensitivity reaction
On the basis of morphology and the underlying
vascular permeability, local accumulation of
mechanism, rejection reactions are classified as hyper-
mononuclear cells (lymphocytes and macrophages) and
acute, acute, and chronic.
graft injury d/t the activated macrophages
Similar changes may occur in any other vascularized
May seem paradoxical to the rules of self-MHC restriction
organ transplant.
but probable explanation is that allogeneic MHC
molecules with their bound peptides resemble/mimic the
A. HYPER-ACUTE REJECTION
self MHC-foreign peptide complexes that are recognized
by the self-MHC-restricted T cells: a cross-reaction Occurs within minutes or hours after transplantation
Kidney – rapidly becomes cyanotic, mottled ad flaccid and
may excrete a few drops of bloody urine
B. INDIRECT PATHWAY
Immunoglobulin and complement deposited in the vessel
More important in chronic rejection wall endothelial injury and fibrin-platelet thrombi
Recipient T lymphocytes recognize MHC antigens of the Neutrophils rapidly accumulate within arterioles, glomeruli
graft donor after they are presented by the recipient’s own and peritubular capillaries
APCs
Glomeruli: thrombotic occlusion of the capillaries
Uptake and processing of MHC and other foreign
Fibrinoid necrosis in arterial walls
molecules from the grafted organ by host APCs
Kidney cortex: outright necrosis (infarction)
Similar to the physiological processing and presentation of
Such non-functioning kidneys have to be removed
other foreign antigens
Generates CD4+ T cells: enter the graft and recognize
graft antigens displayed by host APCs that have also
entered the graft →delayed hypersensitivity
CD8+ T cells that may be generated: cannot directly
recognize/kill graft cells because these CTLs recognize
graft antigens presented by the host’s APCs
T-cell cytokine production and delayed hypersensitivity:
principal mechanism of cellular rejection

Figure. Morphology of hyperacute rejection


Hyperacute rejection of a kidney allograft showing endothelial damage,
platelet and thrombin thrombi, and early neutrophil infiltration in a
glomerulus

B. ACUTE REJECTION
Within days of transplantation in the untreated recipient or
may appear suddenly after months/years later after
immunosuppression has been used/terminated
Cellular or humoral immune mechanisms may
predominate
Humoral rejection vasculitis
Cellular rejection interstitial mononuclear cell infiltrate

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
Glomeruli: scarring with duplication of basement
membranes (chronic transplant glomerulopathy)
Chronically rejecting kidneys: interstitial mononuclear cell
infiltrates of plasma cells and ↑eosinophils

Figure. (left) Acute cellular rejection of a kidney allograft with


inflammatory cells in the interstitium and between epithelial cells of the
tubules.(Right) acute humoral rejection of a kidney allograft (rejection
vasculitis) with inflammatory cells and proliferating smooth muscle cells
in the intima
Figure. Chronic rejection of kidney allografts.
i. ACUTE CELLULAR REJECTION Graft arteriosclerosis. The vascular lumen is replaced by an
accumulation of smooth muscle cells and connective tissue in the
Commonly seen within initial months after transplantation vessel intima
Heralded by clinical and biochemical signs of renal failure th
(From Robbins and Cotran Pathologic Basis of Disease, 8 Ed)
Extensive interstitial mononuclear cell infiltration, edema,
mild interstitial hemorrhage 3. METHODS OF INCREASING GRAFT SURVIVAL
CD4+ and CD8+ T lymphocytes which express markers HLA MATCHING (TISSUE TYPING)
of activated T cells such as the α chain of the IL-2 In kidney transplants, matching between donor and
receptor recipient of all the polymorphic HLA alleles (both inherited
Glomerular and peritubular capillaries: large numbers of alleles of HLA-A, -B and DR) gives substantial benefit
mononuclear cells that may also invade the tubules However, HLA matching is not usually done in the liver,
focal tubular necrosis lungs, and heart because anatomic compatibility, severity
CD8+ T cells injure vascular endothelial cells of the underlying illness and the need to ↓ the time of
endothelitis organ storage override the potential benefits of HLA
Swollen endothelial cells and at places lymphocytes can matching
be seen between the endothelium and the vessel wall
Recognition of cellular rejection important because in the
absence of an accompanying humoral rejection, patients
respond well to immunosuppressive therapy
Cyclosporine: a widely used immunosuppressive drug;
also nephrotoxic; histologic changes from cyclosporine
may be superimposed

ii. ACUTE HUMORAL REJECTION (REJECTION


VASCULITIS)
Manifested mainly by damage to the blood vessels
Mediated by antidonor antibodies
May take the form of necrotizing vasculitis with endothelial
cell necrosis, neutrophilic infiltration, deposition of
immunoglobulins, complement, fibrin and thrombosis
extensive necrosis of the renal parenchyma
In many cases, the vasculitis is less acute and is
characterized by thickening of the intima with proliferating
fibroblasts, myocytes and foamy macrophages
narrowing of the arterioles infarction or renal cortical Figure. The MHC genes on chromosome six, with the loci and their
atrophy respective alleles
Cytokines that cause proliferation of vascular smooth
muscle cells proliferative vascular lesions (mimic IMMUNOSUPPRESSIVE THERAPY
arteriosclerotic thickening) A practical necessity except in the case of identical twins
CD4 (a complement breakdown product) who express same histocompatibility antigen
o Produced during activation of the complement system Drugs used in the therapy
by the antibody-dependent classical pathway o Cyclosporine
o Deposition of such in allografts is a strong indicator if Mainstay of immunosuppression
humoral rejection Blocks activation of transcription factor NFAT
o Importance of making this diagnosis is that it provides (nuclear factor of activated T cells) which is
a rationale for treating affected patients with B cell- required for transcription of cytokine genes (IL-2
depleting agents in particular)
o Azathioprine
C. CHRONIC REJECTION inhibits leukocyte development from bone
Acute rejection significantly controlled in the recent years marrow precursors
by immunosuppressive therapy o Steroids
Chronic rejection: important cause of graft failure block inflammation
Progressive renal failure: ↑serum creatinine over 4-6 o Rapamycin and mycophenolatemofetil
months inhibit lymphocyte proliferation
Dominated by vascular changes, interstitial fibrosis and o Monoclonal anti-T-cell antibodies
tubular atrophy with loss of renal parenchyma Monoclonal anti-CD3 and antibodies against
Vascular changes: dense, obliterative intimal fibrosis the IL-2 receptor α chain (CD25): opsonize and
principally in the cortical arteries → renal ischemia → eliminate the cells and may also block T-cell
glomerular loss, interstitial fibrosis, tubular atrophy and activation
shrinkage of the renal parenchyma Interrupting the interaction between the B7 molecules on
the dendritic cells of the graft donor with the CD28

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
receptors on host T cells by administration of proteins treatment of chronic myelogenous leukemia after
that bind to B7 co-stimulators bone marrow transplant relapse
Risks
o ↑ susceptibility to opportunistic infections A. ACUTE GVH DISEASE
o reactivation of latent viral infections → risk of Within days to weeks after allogeneic bone marrow
developing EBV-induced lymphomas, human transplantation
papillomavirus-induced squamous cell carcinomas Involvement of immune system and epithelia of the skin,
and Kaposi sarcoma liver and intestines: major clinical manifestations
Induction of donor-specific tolerance in graft recipients: to Skin: generalized rash → desquamation in severe cases
circumvent the untoward effects of immunosuppression Destruction of small bile ducts → jaundice
o Giving donor cells to graft recipients Mucosal ulceration of the gut → bloody diarrhea
May prevent reactions to the graft perhaps Affected tissues not usually heavily infiltrated by
because the donor inoculums contains cells, lymphocytes
such as immature dendritic cells, that induce Damage due to direct cytotoxicity by CD8+ T cells and
tolerance to the donor alloantigens cytokines released by the sensitized donor T cells
o May result in long-term mixed chimerism: the recipient
lives with the injected donor cells

OTHER STRATEGIES
Injection of regulatory T cells at the time of transplantation
and promoting the death of alloreactive T cells in the
recipient.

TRANSPLANTATION OF OTHER SOLID ORGANS


The liver, heart, lungs and pancreas also transplanted
Rejection reaction against liver transplants not as vigorous
as might be expected from the degree of HLA disparity;
reason not understood

TRANSPLANTATION OF HEMATOPOETIC CELLS


Use of hematopoetic stem cell transplants
For hematologic malignancies, certain non-hematologic
cancers, aplastic anemias, thalassemias and certain
immunodeficiency states
Genetically engineered hematoppoetic stem cells may Figure. The overall acute GVHD cascade. CTL – cytotoxic T
also be useful for somatic cell gene therapy lymphocyte (Retrieved:
Obtained from the bone marrow or from peripheral http://www.nature.com/nri/journal/v12/n6/fig_tab/nri3212_F1.html)
blood after they are mobilized from the bone marrow
by administration of hematopoietic GFs B. CHRONIC GVH DISEASE
The recipient is irradiated to destroy the immune May follow acute syndrome or may occur insidiously
system (and sometimes Ca (cancer) cells) and to create Extensive cutaneous injury: destruction of skin
a graft bed (if bone marrow transplant is indicated) appendages and fibrosis of the dermis (may resemble
Two problems unique to bone marrow transplantation are systemic sclerosis)
graft-versus-host disease and immunodeficiency Sicca syndrome: dry eyes and mouth due to chronic
inflammation of lacrimal and salivary glands
GRAFT-VERSUS-HOST DISEASE (GVHD) Chronic liver disease: cholestatic jaundice
Damage to the GIT: esophageal strictures
Occurs when immunologically competent cells or
their precursors are transplanted into Devastated immune system: involution of the thymus and
immunologically crippled recipients and the transferred depletion of the lymphocytes in the lymph nodes
cells recognize alloantigens in the host Recurrent and life-threatening infections
Most common in bone marrow transplantation Grafted CD4 helper T cells reacting with host B cells and
Occur rarely after transplantation of solid organs rich in stimulating these cells → manifestations of autoimmunity
lymphoid cells (e.g. liver) or transfusion of unirradiated
blood
When immune-compromised recipients receive normal
bone marrow from allogeneic donors, the
immunocompetent T cells present in the donor
marrow recognize the recipient’s HLA antigens as
foreign and react against them
To ↓ GVH disease: HLA matching between donor and
recipient using sensitive DNA sequencing methods for
molecular typing of HLA alleles
Depletion of donor T cells before transfusion virtually
eliminates the disease
o This protocol is a mixed blessing: GVH disease
ameliorated but ↑incidence of graft failures and EBV-
related B-cell lymphoma and ↑ recurrence of disease
in leukemic patients
Aside from mediation of GVH disease, the multifaceted T Figure. Crucial factors in the development of chronic GVHD; Treg –
regulatory T cells, TH – helper T cells.
cells are required for:
(Retrieved:http://www.nature.com/nri/journal/v12/n6/fig_tab/nri3212_F2
o Engraftment of the transplanted marrow stem .html)
cells
o Suppression of EBV-infected B-cell clones
o Control of leukemic cells, a.k.a graft-versus-
leukemia effect, which can be quite dramatic
Deliberate induction of graft-versus-leukemia
effect by infusion of of allogenic T cells used as

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
IMMUNODEFICIENCY SYNDROMES Mild genetic immune deficiency, is in fact, present in many
OVERVIEW OF IMMUNODEFICIENCY individuals
A frequent complication of bone marrow Manifest themselves in infancy, between 6 months and 2
transplantation years of life
May be due to prior treatment, myeloablative preparation Detected because the affected infants are susceptible to
for the graft, a delay in the repopulation of the recipient’s recurrent infections
immune system and attack on the host’s immune cells by
grafted lymphocytes 1. X-LINKED (BRUTON’S) AGAMMAGLOBULINEMIA
Profound immunosuppression and easy prey to (XLA)
infection Common primary immunodeficiency (Robbins and Cotran,
th
Infection with cytomegalovirus is particularly 8 ed)
important Failure of B-cell precursors (pro-B and pre-B) to develop
Cytomegalovirus-induced pneumonitis is a fatal into mature B-cells
complication Normal B-cell maturation:
From activation of previously silent infection
Divided into primary and secondary immunodeficiency Ig heavy chains rearranged in pre-B cells, expressed on cell
disorders surface with associated ―surrogate‖ light chain

A. PRIMARY IMMUNODEFICIENCY Heavy chains induce signals for light chain rearrangement and
Accidents of nature that provide valuable insights into maturation
some molecules of the human immune system
Genetically determined and affect the humoral and/or Ig signals - quality control mechanism to ensure that
cellular arms of adaptive immunity (mediated by B and maturation will proceed only if functiona Ig proteins are
T lymphocytes, respectively) expressed
Also affects the defense mechanisms of innate X-linked Agammaglobulinemia: mutations in cytoplasmic
immunity (NK cells, phagocytes, or complement) Bruton tyrosine kinase (Btk) the gene that encodes it
Often subclassified on the basis of primary component is located in long arm of X chromosome at Xq21.22.
th
involved (Rubins, 5 ed): Btk – associated with Ig receptor complex of pre-B and
o B-cell or humoral defect - subject to recurrent mature B-cell and is needed to transduce signals from the
bacterial infections, a limited number of specific types receptor
of viral infections and subnormal serum o Mutated: pre-B cell receptor cannot deliver signals
concentrations of either all or specific isotypes of Ig and maturation stops.
Various Ig isotype and subclass deficiencies o Light chains are not produced. Complete antigen
include selective deletions of Ig heavy chains and receptor (heavy chain + light chain) can’t be
loss of light-chain expression assembled and transported to cell membrane
Some patients have normal levels of Igs but fail Seen almost entirely in males; sporadic in females
to make antibodies against specific antigens, Onset of symptoms: Not apparent til 6 months - when
usually polysaccharides maternal immunoglobulins are depleted
o T-cell or cellular defect – typically result in recurrent Usually discovered due to recurrent bacterial (usually
or protracted viral and fungal infections respiratory) infections - acute/chronic pharyngitis, sinusitis,
o Phagocytic (Granulocyte) defect bronchitis, pneumonia
o Abnormalities (defect) in complement system o Causative agents: Haemophilus influenzae, Strep.
pneumoniae, Staph. aureus – normally opsonized by
antibodies and phagocytosed
Persons with disease are also susceptible to viral
infections (enteroviruses e.g. echovirus, poliovirus,
coxsackievirus) spreading from GI tract to the nervous
system via the blood
o Live poliovirus immunization may cause paralytic
poliomyelitis; echovirus causes fatal encephalitis
Giardia lamblia – normally resisted by IgA; causes
recurrent infection
In general, an intact T cell-mediated immunity handles
most viral, protozoan and fungal infections well
Characteristics of classical form of the disease:

B cells in circulation Absent or markedly


decreased
Serum Ig (all classes) Depressed
Pre-B cells (expresses the Normal numbers in bone
B-lineage marker CD19 but marrow
not membrane Ig)
Germinal centers of lymph Underdeveloped
nodes, Peyer’s patches,
appendix, tonsils
Plasma cells Absent (throughout the body)
Figure. Simplified scheme of lymphocyte dev’t and sites of block in T-cell mediated reactions Normal
some primary immunodeficiency diseases are shown. The affected
genes indicated in parentheses for some of the disorders. ADA –
adenosine deaminase; AID – activation-induced deaminase; CD40L – Autoimmune diseases: arthritis and dermatomyositis, have
CD40 Ligand (aka CD154); SCID – severe combined increased frequency (considered paradoxic)
immunodeficiency o Caused by (1.) breakdown of self-tolerance resulting
However these distinctions aren’t clear-cut (Robbins & to autoimmunity and (2.) inflammatory reactions
th
Cotran, 8 ed) induced by chronic infections
o T-cells defect almost always lead to impaired antibody Treatment: Replacement therapy of Immunoglobulins
synthesis, hence, isolated deficiencies of T cells are Prophylactic intravenous therapy – improves lifespan,
often indistinguishable clinically from combined allowing patient to reach adulthood.
deficiencies of T and B cells.

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
2. COMMON VARIABLE IMMUNODEFICIENCY (CVID) Some cases have been associated with drug exposures
Represents a heterogenous group of disorders (phenytoin, D-penicillamine) and some with deletions
th
Common feature: Hypogammaglobulinemia – may or defects in chromosome 18 (Rubins, 5 ed)
affect all or only IgG
Diagnosed by exclusion of other well-defined causes of 4. HYPER-IgM SYNDROME
decreased antibody production Patients make IgM antibodies but deficient in making IgG,
Both sporadic and inherited forms of the disease IgA and IgE
occur Affects T helper cell ability to deliver activating signals to B
Relatives of such patients have high incidence of selective cells and macrophages
IgA deficiency, hence, this suggests that selective IgA Normal Mechanism:
deficiency and common variable immunodeficiency may
represent different expressions of genetic defect in CD4+ helper T cells requires engagement of CD40 (in APCs)
antibody synthesis by CD40L on antigen-activated T cells
In contrast with x-linked agammaglobulinemia, normal or ↓
near normal numbers of B cells but B cells cannot Ig class switching and affinity maturation in B cells
differentiate into plasma cells ↓
Antibody deficiency is due to both intrinsic B cell defects Stimulation of microbicidal functions of macrophage
and abnormal B cell activation by T helper cells
Some of reported causes (minority of cases): X-linked form: majority of cases (70%), caused by
o Abnormal receptor for cytokine BAFF – BAFF mutations in gene encoding CD40L located on Xq26
promotes B cell survival and differentiation Autosomal recessive pattern – mutations on CD40 or the
o Abnormal ICOS (inducible costimulator) molecule enzyme called activation-induced deaminase
– homologous to CD28; for T-cell activation and o Activation-induced deaminase – DNA-editing
interaction with B-cells cytosine deaminase required for class switching and
Clinical manifestations are caused by antibody deficiency; affinity maturation
similar to X-linked Agammaglobulinemia Serum Findings:
o Recurrent sinopulmonary pyogenic infections o IgM– normal or elevated
o Recurrent herpes virus infections (20%) o IgA and IgE– none
o Enterovirus infections causing o IgG – extremely low
meningoencephalitis may occur o B and T cells number – normal
o Persistent diarrhea due to G. lamblia IgM reacts with elements of blood causing autoimmune
Affects males and females equally haemolytic anemia, neutropenia and
Onset: Childhood or adolescence (Rubins: mean age thrombocytopenia
at onset of 25 years) Older patients – uncontrolled proliferation of IgM-
Incedence: between 1:50,000 to 1:200,000 producing plasma cells with GI tract infiltrations.
Histological feature: Hyperplastic B-cell areas of Extensive infiltration can lead to death
lymphoid tissues Clinical Manifestations:
o Caused by defective regulation: B-cells proliferate o Recurrent pyogenic infections – due to low
in response to antigen but no antibodies are opsonizing IgG levels
produced → No normal feedback inhibition by IgG o Pneumonia – caused by Pneumocystis jiroveci, in
High risk for autoimmune disorders e.g. haemolytic and patients with CD40L mutations due to defective cell-
pernicious anemia, neutropenia, thrombocytopenia mediated immunity
th
(Rubins, 5 ed) (20%) and increased risk for lymphoid
malignancies and ulcer 5. DiGeorge SYNDROME (THYMIC HYPOPLASIA)
Lymphoma is 300-times more frequent in affected women T-cell deficiency due to undeveloped third and fourth
th
than in affected men (Rubins, 5 ed) pharyngeal pouches
Most severe T lymphocyte immunodeficiency disorder
th
3. ISOLATED (SELECTIVE) IgA DEFICIENCY (Rubins, 5 ed)
Most common primary immunodeficiency (Rubins, 5
th Fourth pharyngeal pouch – gives rise to thymus,
ed) parathyroids, some clear cells of the thyroid and the
Common (1 in 600 individuals with European descent) ultimobranchial body
Less common in BLACKS and Asians Results to:
Extremely low levels of serum and secretory IgA o Variable loss of T cell-mediated immunity
May be familial or acquired (because of thymus absence/hypoplasia)
Acquired deficiency – associated with toxoplasmosis, o Tetany (lack of parathyroids)
measles and other viral infections o Congenital defects of heart and blood vessels
o Appearance of mouth, ears and facies may be
Most are asymptomatic
abnormal
IgA – major Ig in secretions; deficiency causes weak
o Low T lymphocytes in blood and lymphoid tissues
mucosal defences leading to infections in respiratory,
→ poor defense against fungal and viral infections
GI and urogenital tracts
o Histology: Depleted T cell zones of lymphoid
Clinical Manifestations (symptomatic): organs – paracortical areas of lymph nodes and
o Recurrent sinopulmonary infections periarteriolar sheaths of the spleen
o Diarrhea o Ig levels – normal or reduced, depending on T cell
Some patients may also be deficient in IgG2 and IgG4 deficiency
subclasses of IgG → more prone to infection DiGeorge syndrome is considered part of 22q11 deletion
High frequency of respiratory tract allergy and syndrome (as it affects chromosome 22q11) seen in 90%
autoimmune deficiency (SLE and rheumatoid arthritis) in of patients having the disease
which the basis for its ↑ frequency is still unknown Associated with defects in T-box family of transcription
Blood transfusion with IgA – develop severe, even fatal, factors (development of branchial arch and great
anaphylactic reactions (IgA is considered as foreign vessels)
antigen since the patients do not produce it and are
not tolerant to it) 6. CHRONIC MUCOCUTANEOUS CANDIDIASIS
Basic Defect: Impaired differentiation of naïve B (LIFTED FROM RUBINS, 5 TH ED.)
lymphocytes to IgA-producing cells in which the A yeast infection that is a result of a congenital defect in
molecular basis is still unknown T-cell function
In some patients: BAFF (B-cell activating cytokine) defect It is characterized by susceptibility to candidal
infections

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
Associated with an endocrinopathy (hypoparathyroidism, o Common ɣ-chain is a component in IL-15 receptors;
Addison disease, diabetes mellitus) individuals with the disease has NK cell
Although most T-cell functions are intact, there is an deficiency
impaired response to Candida antigens
Normal reaction: type 1 (IL-2/IFN-a) T cells predominate B. SCID – AUTOSOMAL RECESSIVE FORM
and effectively control candida infections Etiology: Deficiency of adenosine deaminas (ADA) – most
Affected patients mount a type 2 (IL-4/IL-6) helper T-cell common cause
response, which is ineffective at resisting the Leads to accumulation of deoxyadenosine and its
organism derivatives (e.g. deoxy-ATP) – toxic to rapidly dividing
immature lymphocytes especially of T-cell lineage
7. SEVERE COMBINED IMMUNODEFICIENCY (SCID) Greater reduction in T than B cells
Both humoral and cell-mediated immune responses are Other causes (less common):
affected o Mutations in recombinase-activating genes –
Clinical Manifestations: prevent somatic gene rearrangements for T cell
o Infants: Prominent thrush (oral candidiasis), extensive assembly and Ig genes
diaper rash and failure to thrive Blocks development of T and B cells
o Morbilliform Rash – maternal T cells travel across o Mutations in Jak3 kinase – essential for signal
the placenta and attack, causing Graft-versus-host transduction through common ɣ-chain (ɣc) subunit
disease (which is mutated in SCID X-linked form)
o Severe recurrent infections from wide range of Same effects as mutation in common ɣ-chain (ɣc)
pathogens subunit
Candida Albicans Classified also in the category T-B + NK – SCID
th
P. jiroveci (Rubins, 5 ed)
Pseudomonas o Mutations in signalling molecules –in kinases with
Cytomegalovirus T-cell antigen receptors; components of calcium
Varicella channels for calcium entry and signal pathway
Without bone marrow transplantation, death will occur activation
in first year of life o Mutations that impair the expression of class II
Underlying defects are quite different in different forms of MHC – prevent development of CD4+ T cells. Results
SCID, and in many cases, the genetic lesion is not in combined immunodeficiency (CD4+ help B cells)
known Bare Lymphocyte Syndrome – mutations in
Defect is often in T cell compartment, humoral defect transcription factors for MHC II gene expression
only secondary Classified in the category T-B + NK + SCID
th
Histologic Findings: depend on underlying defect (Rubins, 5 ed)
o Both ADA deficiency and ɣ-chain: thymus is small
(LIFTED FROM RUBINS, 5 TH ED.)
and devoid of lymphoid cells
o ADA deficiency SCID – remnants of Hassall’s Four categories of disease are recognized:
corpuscles T–B+ NK- SCID - is the most common form of SCID
o X-linked SCID – thymus with lobules of (same description of the mutation and affected cytokines
undifferentiated epithelial cells (resembles fetal in SCID X-linked form and mutation on Jak 3)
thymus) T–B+ NK+ SCID - can result from a dozen molecular
o Other lymphoid tissues are hypoplastic, with marked lesions.
depletion of T cell areas or both T cell and B cell o For instance, mutations in genes (CD3D, CD3E,
zones CD3G) that encode each subunit (delta, epsilon,
Treatment: gamma) of the TCR associated CD3 complex have
o Bone marrow transplantation – mainstay of been described.
treatment o These patients have all shown defects in T-
o Gene therapy – X-linked SCID is the first human lymphocyte function, although the clinical features
disease in which gene therapy has been successful vary.
Using a retroviral vector to express ɣ-chain gene o (Another group is described in the mutations that
in bone marrow stem cells are transplanted back impair expression of class II MHC)
to the patients T–B- NK- SCID - is the result of mutations in the genes
20% of patients have developed acute T cell for adenosine deaminase (ADA) and purine
leukemias due to activation of oncogenes by nucleoside phosphorylase (PNP), enzymes in the purine
the retrovirus nucleotide salvage pathway.
ADA deficiency – also treated with bone marrow o PNP deficiency is very rare.
transplantation and gene therapy to introduce T–B- NK+ SCID - is the outcome of a variety of rare
normal ADA gene to T cell precursors mutations within genes that encode DNA-binding
proteins involved in Ig and TCR gene rearrangement.
A. SCID - X-LINKED FORM o Some of these patients suffer from radiation
Most common form sensitivity in addition to immunodeficiency.
(50-60%) – more common in boys *T-B+/-NK – involvement of T, B, and NK cells
th
Classified in the category T-B + NK – SCID (Rubins 5 ed)
th 8. IMMUNODEFICIENCY WITH THROMBOCYTOPENIA
Etiology: Mutation in IL2RG (Rubins, 5 ed) which
AND ECZEMA (WISKOTT-ALDRICH SYNDROME)
encodes common ɣ-chain (ɣc) subunit of cytokine
receptors X-linked recessive
Common ɣ-chain (ɣc) subunit – transmembrane protein; Etiology: Mutation in gene encoding Wiskott-Aldrich
part of signal-transducing component of IL-2, IL-4, IL-7, IL- syndrome protein (WASP) at Xp11.23
9, IL-11, IL-15 & IL-21 WASP – from family of proteins that link membrane
IL-7 – for survival and proliferation of lymphoid progenitors, receptors (e.g. antigen receptors) to cytoskeletal elements
particularly T cell precursors o Essential functions in lymphocytes and platelets is
o Defect in IL-7 signalling will cause defect in T cell unclear; may be involved in cytoskeleton dependent
development responses (e.g. cell migration, signal transduction)
o T cell number is greatly reduced, antibody synthesis Characterized by thrombocytopenia, eczema and
is severely impaired, even with normal B cell recurrent infection ending in early death
number, due to lack of T cell help Thymus – morphologically normal early in the disease
IL-15 – for maturation and proliferation of NK cells

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
Progressive secondary depletion of T lymphocytes in
peripheral blood and T cell zones of lymph nodes H. MUTATION IN THE COMPLEMENT REGUALATORY
(paracortical) PROTEIN FACTOR H
No antibodies for polysaccharide antigen; poor Lead to microvascular thrombosis in kidneys
response to protein antigen Causes Hemolytic Uremic Syndrome
Serum Findings:
o IgM – low B. SECONDARY IMMUNODEFICIENCIES
o IgG – Normal More common than the disorders of primary genetic origin
o IgA and IgE – elevated (paradoxical) Most common secondary immunodeficiency is AIDS
Prone to develop Non-Hodgkin B cell lymphoma Associated Diseases/Conditions
Treatment: Only bone marrow transplantation o Cancer, chemotherapy, radiation therapy
o Diabetes
9. GENETIC DEFICIENCIES OF THE COMPLEMENT o Metabolic diseases, malnutrition
SYSTEM o Chronic infection
A. C2 DEFICIENCY o Renal disease
C2 occurs at earlier part of pathway o Intake of immunosuppressive drugs to prevent
Most common of all graft/host reaction
Or a deficiency also of the early components of the Causes:
classical pathway (C1-q, r, s; C4) Probable Cause Related Conditon
Results to increased incidence of SLE like auto- Defective lymphocyte Bone marrow is damaged by
immune disease maturation radiation or chemotherapy or
Little or no increased susceptibility to infections since involved by tumors such as
alternative pathway is adequate for control of most leukemias and metastatic cancers
infections Loss of Ig Protenuric renal disease
Inadequate Ig Malnutrition
B. C3 DEFICIENCY synthesis
C3 is essential for both classical and alternative pathways Lymphocyte depletion From drugs or severe infection
Associated with serious, recurrent pyogenic infections
↑ incidence of immune complex-mediated ACQUIRED IMMUNODEFICIENCY SYNDROME
glomerulonephritis Caused by the retrovirus human immunodeficiency virus
In the absence of complement, immune complex- (HIV)
mediated inflammation is presumably caused by Fc Characterized by profound immunosuppression that leads
receptor-dependent leukocyte activation to opportunistic infections, secondary neoplasms, and
neurologic manifestations
C. C5, 6, 7, 8, 9 DEFICIENCY
EPIDEMIOLOGY
C5-9 are required for the assembly of membrane attack
High Risk Groups
complex involved in the lysis of organisms
o Homosexual/ bisexual men
Increased susceptibility to recurrent neisserial
o Intravenous drug abusers
(gonococcal or meningococcal) infections
o Hemophiliacs (factor VIII or IX)
Neisserial bacteria have thin cell walls which are o Recipients of blood and blood components
susceptible to the lytic actions of the complement o Heterosexual contacts
o Children below 13 y/o (2% of cases due to mother-
D. DEFICIENCY OF THE ALTERNATIVE PATHWAY
child transmission)
E.g. Properdin, Factor D deficiency Major Routes of Transmission
Rare, associated with recurrent pyogenic infection o Sexual Transmission
Responsible for 75% of cases of HIV
E. MUTATION IN MANNOSE-BINDING (LECTIN) Virus carried in the semen, enters the recipient's
PATHWAY body through abrasions in rectal or oral mucosa
Associated with increased susceptibility to infections or by direct contact with mucosal lining cells
Lectin component of pathway is not activated Occurs homosexually and heterosexually
Specific mechanisms of Transmission
F. C1 INHIBITOR DEFICIENCY 1. Direct inoculation of virus in blood vessels
C1 inhibitor - a protease inhibitor whose target enzymes breached
are C1r and C1s of the complement cascade, factor XII of 2. Infection of dendritic cells or CD4+ cells
the coagulation pathway, and the kallikrein system within the mucosa
Autosomal dominant disorder Female to male transmission
Leads to excessive vasoactive peptide e.g. bradykinin due - HIV is present in vaginal secretions and
to unregulated activation of the pathways cervical cells of infected women
Causes hereditary angioedema AIDS is aggravated by the presence of other
o Manifests as edema affecting skin and mucosal STD’s especially those causing ulceration
surfaces such as the larynx and the gastrointestinal o Parenteral Transmission
tract Found in IV drug abusers, haemophiliacs
o may result in life-threatening asphyxia or nausea, receiving factor VIII & IX, blood transfusion
vomiting, and diarrhea after minor trauma or Mostly by IV drug users – sharing of needles,
emotional stress syringes with contaminated blood
o can be treated by C1 inhibitor concentrates Blood & clotting factor transmission causes can
prepared from human plasma be eliminated by screening of blood
G. DEFICIENCY OF OTHER COMPLEMENT- o Mother to Infant Transmission
REGULATORY PROTEINS Three routes concerned:
1. In utero by transplacental spread
Mutations in enzymes required for glycophosphatidyl 2. During delivery through an infected birth
inositol linkage → no assembly of CD59 and decay canal
accelerating factor → no regulation of complement 3. After birth by ingestion of breast milk
Unregulated complement activation on RBC surface may During(intrapartum)and post-delivery (peripartum)
lead to : is most common
o Paroxysmal nocturnal hemoglobinuria
o Hemolysis

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
ETIOLOGY: PROPERTIES OF HIV
Human Immunodeficiency Virus (HIV)
o Causes AIDS
o Non-transforming human retrovirus belonging to the
lentivirus family
o Included in this group are feline immunodeficiency
virus, simian immunodeficiency virus, visna virus of
sheep, bovine immunodeficiency virus, and the
equine infectious anemia virus
o Forms
a. HIV 1 - most common type associated with AIDS
in the United States, Europe, and Central Africa
b. HIV 2 – in West Africa and India

HIV Structure
o Spherical
o Contains an electron-dense Cone-shaped core
Surrounded by a matrix protein called p17, which
lies underneath the virion envelope
Contains
- Major capsid protein p24
- Nucleocapsid protein p7/p9
- Two copies of genomic RNA
- Three viral enzymes (protease, reverse
transcriptase, and integrase)
P24 is the most readily detected and is the target
for antibodies
Figure. The HIV genome. Several viral genes and the functions of the
P17 is a matrix protein that surrounds the viral encoded proteins are illustrated. The genes outlined in red are unique
protein to HIV; others are shared by all retroviruses.
o With Lipid bilayer derived from the host cell
Viral glycoproteins outside membranes: PATHOGENESIS OF HIV
- gp120 and gp41 There are two major targets of HIV infection:
- critical for HIV infection of cells o The Immune system
o Variability in envelope glycoproteins poses difficulty in o The Central Nervous System (CNS)
developing single antigen vaccine Hallmark of AIDS: Profound immune deficiency and
severe loss of CD4+ T Cells.
HIV Subgroups Mechanism of Action
a. M (major) – most common form worldwide
HIV envelope protein (gp120) attaches to the CD4
b. O (outlier)
molecule of T cells
c. N (neither M nor O)
1. HIV enters trough mucosal tissues and blood.
2. HIV infects CD4 T cells causing direct cytotoxicity.
3. Infection of non-T cells
can infect monocytes and macrophages in
tissue
can infect dendritic cells in mucosal tissue
(dendritic cells transfer virus to B-cell
germinal follicles)
macrophages and dendritic cells are
reservoirs for virus (loss of cell-mediated
immunity)
4. Reverse transcriptase
converts viral RNA into proviral double-
Figure. Structure of HIV-1 virion stranded DNA
DNA is integrated into the host DNA
HIV-1 RNA Genome 5. Active viral replication→Progression to AIDS
o Contains the gag, pol, and env genes, which are
typical of retroviruses LIFE CYCLE OF HIV
Products of the gag and pol genes are translated
Consists of:
initially into large precursor proteins that are
a. Infection of cells
cleaved by the viral protease to yield the mature
b. Integration of provirus into host cell genome
proteins
c. Activation of viral replication
o Contains several other accessory genes, including tat,
d. Production and release of infectious virus
rev, vif, nef, vpr, and vpu,
Regulate the synthesis and assembly of
infectious viral particles and the pathogenicity of
the virus
o Anti-HIV-1 protease
Inhibitor drugs that prevent viral assembly by
inhibiting the formation of mature viral proteins

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
May be transcribed, with formation of complete
viral particles that bud from the cell membrane
(productive infection)
Extensive viral budding may lead to death of
infected cells
HIV infects memory and activated T cells
Inefficient at productively infecting naive (unactivated) T
cells
o Naive T cells- contain an active enzyme that produces
mutations on HIV genome
o Enzyme name: APOBEC3G (Apolipoprotein B
mRNA-editing enzyme catalytic polypeptide-like
editing complex 3)
A cytidine deaminase
Introduces cytosine-to-uracil mutations in the viral
DNA
Mutations inhibit further DNA replication
In activated T-cells: APOBEC3G is converted to
an inactive, high molecular mass complex,
explains why pwede na magreplicate dito si HIV
But wait! HIV has evolved to counteract this
Figure. The life cycle of HIV, showing the steps from viral entry to cellular defense mechanism! Viral protein Vif
production of infectious virions. binds to APOBEC3G and promotes its
degradation by cellular proteases.
A. INFECTION OF CELLS BY HIV Completion of viral life cycle in latently infected cells
Selective tropism of the virus for CD4+ T cells and other occurs only after cell activation
CD4+ cells, particularly monocytes / macrophages and In most CD4+ cells this results in cell lysis
dendritic cells. Activation of T-cells upregulates several transcription
HIV gp120 also bind to other cell surface molecules factors:
(coreceptors) for entry into the cell through chemokine o NF-kB
receptors, CCR5 and CXCR4. Stimulate transcription of genes encoding
HIV isolates can be distinguished by their use of receptors: cytokines such as IL-2
o Strain R5 uses CCR5 In resting T-cells: found in the cytoplasm
o Strain X4 uses CXCR4 complexed with IkB (inhibitor of kB) protein
o Some strains like R5X4 are dual-tropic Cellular activation induces cytoplasmic kinases
In 90% of cases, the R5 (M-Tropic) typr of HIV is the that phosphorylate IkB and thus release NF-kB
dominant virus found in the blood of acutely infected allowing it to translocate into the nucleus
individuals. In the nucleus, binds to the promoter region of
Over the course of infection, T-tropic viruses gradually several genes
accumulate. Long terminal repeat sequences that flank the
T-tropic viruses can infect a lot of T cells and even thymic HIV genome also contain NF-kB binding sites
T-cell precursor and cause greater T-cell depletion and Summary:
impairment. Latently infected CD4 T cell + environmental antigen
initial step in infection is the binding of the gp120 to CD4 ↓
molecules; leads to a conformational change that results Activated T-cell
in the formation of a new recognition site on gp120 for the ↓
coreceptors CCR5 or CXCR4
next step involves conformational changes in gp41; Activated macrophages
changes result in the insertion of a fusion peptide at the tip produce TNF and cytokines
of gp41 into the cell membrane of the target cells after Upregulated NF-kB
fusion, the virus core containing the HIV genome enters ↓
the cytoplasm of the cell Activates transcription of cDNA (or proviral DNA)
binding of HIV to its coreceptors is important in the ↓
pathogenesis Production of virions
o First, nonlymphoid cells engineered to express human ↓
CD4 cannot be infected with HIV unless one of the Cell lysis
coreceptors is also expressed in these cells. “Subversion from within”
o second, chemokinessterically hinder HIV infection of HIV infected people are at risk for more infections, this
cells in culture by occupying their receptors. leads to increased lymphocyte activation and production of
o third, individuals who inherit two defective copies of pro-inflammatory cytokines. Since HIV thrives in activated
the CCR5 receptor gene are resistant to infection and T-cells, this stimulates more HIV production, loss of CD4+
the development of AIDS associated with R5 HIV cells and more infection. (vicious cycle)
isolates
MECHANISM OF T-CELL IMMUNODEFICIENCY IN HIV
B. VIRAL REPLICATION INFECTION
Once internalized, RNA genome of virus undergoes Loss of CD4+ T cells is mainly because of infection of the cells
reverse transcription and direct cytopathic effects of the replicating virus.
Leads to the synthesis of double stranded complementary
DNA (cDNA; proviral DNA)
In quiescent T cells:
o cDNA remain in cytoplasm in a linear episomal form
In dividing T-cells:
o cDNA circularizes, enters the nucleus and integrated
into the host genome
o After integration
may be silent for months and years (latent
infection)

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
CD4+ T cells, the ―master regulator‖ play a pivotal role in
regulating both cellular and humoral immune responses.
Loss of this cell has effects on virtually every component
of the immune system

ILLUSTRATION: Mechanisms of CD4+ T cell loss in HIV infection

Frequency of infected cells in the circulation is very low


Many infected cells are in mucosal or peripheral lymphoid
organs death of these cells account for relentless and
eventually profound cell loss
Initially, T cell loss can appear deceptively low
o Immune system can replace dying T cells
As disease progresses, immune system cannot cope
Mechanisms that contribute to the loss of T-cells
include:
1. Increased plasma membrane permeability associated
with viral budding
2. Virus replication interfering with protein synthesis
3. HIV causes progressive destruction of architecture HIV INFECTION OF NON-T CELLS
and cellular composition of lymphoid tissues Infection of macrophages and dendritic cells is also
4. Chronic activation of uninfected cells, responding to important in the pathogenesis of HIV infection
HIV or other infections common in AIDS, lead to Majority of infected macrophages are found in the tissue
apoptosis (activation induced cell death) and number of blood monocytes infected may be low
5. Loss of immature precursors of CD4+ T cells In the lungs and the brain as many as 10% to 50% of
6. Fusion of infected and uninfected cell with formation macrophages are infected
of syncytia (giant cells) Several aspects of HIV infection of macrophages:
Gp120 of infected cells bind to CD4 molecules on 1. HIV-1 can infect and multiply in terminally
uninfected T cells followed by cell fusion differentiated nondividing macrophages
Fused cells develop ballooning and die Dependent on the HIV-1-vpr gene
This property is confined to T-tropic X4 type of Vpr protein allows nuclear targeting of the HIV
HIV-1 preintegration complex through the nuclear pore
7. Apoptosis of uninfected CD4+ T cells by binding of 2. Macrophages bud off relatively small amounts of virus
soluble gp120 from infected cells to the CD4 molecule from their surface but inside they contain large
Hallmark of AIDS: marked reduction in CD4+ T cells! amounts of virus in intracellular vacuoles
o Account for most of the immunodeficiency late in the Resistant to cytopathic effects of HIV so may
course of HIV infection become reservoirs of infection
o In asymptomatic HIV infected persons however, In late stages, when the number of CD4+ cells
qualitative defects in T-cells were also detected. This decline, macrophages may be an important site
include: of continued viral replication (talino talaga ng
Reduction in antigen-induced T-cell proliferation virus na to!)
Decrease in Th1-type responses relative to the 3. Act as gatekeepers of infection
Th2 type Most cases of acute HIV infection are
Results in profound deficiency in cell- characterized by predominantly circulating M-
mediated responses tropic strains
Increased susceptibility to infections by Suggest initial infection of macrophages or
viruses and microbes dendritic cells may be important in the
Defects in intracellular signalling pathogenesis of HIV
Selective loss of the memory subset of CD4+ 4. Uninfected monocytes also have functional defects
helper T cells early in the course of the disease Impaired microbicidal activity
Poor recall responses to previously Decreased chemotaxis
encountered antigen Decreased secretion of IL-1
Low-level Chronic or Latent infection of T cells (and Inappropriate secretion of TNF
macrophages) Poor capacity to present antigens to T cells
o Important feature of HIV infection Mucosal and Follicular Dendritic Cells
o Integrated provirus, without virus expression can o Also targets for initiation and maintenance of HIV
remain in cells for months to years infection
o Potent antiviral therapy which practically sterilizes the o Mucosal Dendritic Cells
peripheral blood cannot affect the latent virus found After infection, they transmit the virus to CD4+ T
within CD4+ cells (T cells and macrophages) in the cells in the lymph nodes
lymph nodes Express a lectin-like receptor that specifically
o An estimated 0.05% of resting CD4+ t cells in lymph binds HIV and displays it in an intact, infectious
nodes are latently infected form to T cells
o These cells have a life span of months to years and o Follicular Dendritic Cells
thus provide a persistent reservoir of virus Found in the germinal centers of lymph nodes,
are potential reservoirs of HIV

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
Trap HIV virions coated with anti-HIV antibodies
on their suface
These trapped virions retain their capacity to
infect and thus infect CD4+ T cells passing
through the meshwork formed by dendritic
processes of follicular dendritic cells
Abnormalities of B Cell Function
o Polyclonal activation of B-cells resulting in:
germinal center B-cell hyperplasia
Bone marrow plasmacytosis
Hypergammaglobulinemia
Formation of circulating immune complexes
o Activation may be caused by:
Reinfection with EBV and cytomegalovirus
(polyclonal B-cell activators)
Gp41 can promote B-cell growth and
differentiation
IL-6 from infected macrophages, stimulate
proliferation of B-cells
Despite presence of spontaneously activated B-cells,
AIDS patients are unable to mount antibody responses to
newly encountered antigens.

PATHOGENESIS OF CENTRAL NERVOUS SYSTEM


Nervous System – major target of HIV infection besides
lymphoid system
Macrophages and microglia
o Cells in the CNS that belong to the macrophage
lineage
o Predominant cell types in the brain that are infected ILLUSTRATION: Pathogenesis of HIV-1 infection. The initial infection
with HIV starts in mucosal tissues, involving mainly memory CD4+ T cells and
dendritic cells, and spreads to lymph nodes. Viral replication leads to
Infected Monocytes – carried HIC into the brain viremia and widespread seeding of lymphoid tissue. The viremia is
HIV isolates from the brain almost exclusively M-tropic controlled by the host immune response (not shown), and the patient
Neurons are not infected by HIV then enters a phase of clinical latency. During this phase, viral
Neuropathologic changes = less than expected from the replication in both T cells and macrophages continues unabated, but
severity of neurologic symptom there is some immune containment of virus (not illustrated). There
continues a gradual erosion of CD4+ cells and ultimately, CD4+ T-cell
Neurologic deficit caused indirectly by:
numbers decline, and the patient develops clinical symptoms of full-
o viral products blown AIDS. CTL, cytotoxic T lymphocyte
o soluble factors produced by infected microglia
IL-1, TNF and IL-6
PRIMARY INFECTION, VIRUS DISSEMINATION, AND THE
o Nitric oxide induced in neuronal cells by gp41
ACUTE RETROVIRAL SYNDROME
o Postulate: direct damage of neurons by soluble HIV
gp120

NATURAL HISTORY OF HIV INFECTION


HIV begins with acute infection (only controlled by
adaptive immune response) chronic progressive
infection of peripheral lymphoid tissues
Virus enters through mucosal epithelia
Phases of subsequent pathogenic events and clinical
manifestations:
1. Acute retroviral syndrome
2. Middle, chronic phase (in which most individuals are
asymptomatic) Figure *: Clinical course of HIV infection. A, During the early period
3. Clinical AIDS after primary infection there is dissemination of virus, development of
an immune response to HIV, and often an acute viral syndrome.
During the period of clinical latency, viral replication continues and the
CD4+ T-cell count gradually decreases, until it reaches a critical level
below which there is a substantial risk of AIDS-associated diseases

B, Immune response to HIV infection. A cytotoxic T lymphocyte (CTL)


response to HIV is detectable by 2 to 3 weeks after the initial infection,
and it peaks by 9 to 12 weeks. Marked expansion of virus-specific
CD8+ T-cell clones occurs during this time, and up to 10% of a
patient's CTLs may be HIV specific at 12 weeks. The humoral immune
response to HIV peaks at about 12 weeks.

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
Acute (early) infection o it is useful surrogate marker of HIV progression
o Characterized by infection of memory CD4+ T cells o clinical value in the management of people with HIV
(which express CCR5) in mucosal lymphoid tissues infection
and death of many infected cells Because the loss of immune containment is associated
Mucosal tissues with declining CD4+ T-cell counts, the Centers for Disease
o largest reservoir of T cells in the body Control (CDC) classification of HIV infection stratifies
o major site of residence of memory T cells patients into three categories on the basis of CD4+ cell
o local lost considerable depletion of lymphocytes counts:
few infected cells = detectable in the blood and other CDC Classification Categories of HIV Infection
tissues CD4+ T-cell Categories
mucosal infection dissemination of the virus + 1 2 3
development of host immune response CLINICAL ≥ 500 200–499 200
CATEGORIES cells/ cells/μL cells/
Dendritic cells in epithelia (site of virus entry) captures virus μL μL
A. Asymptomatic, A1 A2 A3
Migrate into the lymph nodes acute (primary)
HIV, or persistent
In lymphoid tissues: dendritic cells pass HIV on to CD4+ T cells generalized
through direct cell-cell contact lymphadenopathy

Symptomatic, not B1 B2 B3
Within days after the first exposure to HIV: B.
Viral replication in the lymph nodes A or C conditions

VIREMIA CC. AIDS indicator


(high number of HIV particles are present in the patient’s conditions:
blood) including
constitutional
Virus disseminates throughout the body disease,
neurologic
disease, or
Infects helper T cells, macrophages and dendritic cells in
neoplasm
peripheral lymphoid tissues
For clinical management: blood CD4+ T-cell counts =
Anti-viral humoral and cell-mediated immune most reliable short-term indicator of disease progression
response Primary clinical measurement used to determine when to
o Mounts as the HIV infection spreads start combination antiretroviral therapy: CD4+ cell count!
o Evidenced by: Not viral load
seroconversion (usually within 3-7 weeks of
presumed exposure) CHRONIC INFECTION: PHASE OF CLINICAL LATENCY
development of virus-specific CD8+ cytotoxic T Lymph nodes and spleen = sites of continuous HIV
cells replication and cell destruction
o Partially control the infection and viral production Few or more clinical manifestation of the HIV infection are
reflected by a drop in viremia to low but present = reason why it is called: CLINICAL LATENCY
detectable levels by about 12 weeks after the PERIOD
primary exposure Destruction of CD4+ T cells in lymphoid tissues and
HIV-specific CD8+ T cells circulation continuous
o Detected in the blood at about the time viral titer begin Host defenses begin to wane
to fall Proportion of the surviving CD4+ cells infected with HIV
o Most likely responsible for the initial containment of increases
HIV infection HIV RNA levels begin to increase
Acute retroviral syndrome How HIV escapes immune control?
o Clinical presentation of the initial spread of the virus
and the host response
o Estimated that 40% to 90% of individuals who Destruction of CD4+ T cells (critical for effective immunity,
antigenic variation and down-modulation of class I MHC
acquired primary infection develop the viral syndrome
o Occurs 3-6 weeks after infection molecules on infected cells)
o Resolves spontaneously in 2-4 weeks
o Clinically: associated with a self-limited acute illness Viral antigens are not recognized by CD8+ CTLs
with nonspecific symptoms including:
Flu like symptoms: Virus may evolved
Sore throat
Myalgias Virus co-receptor switch from relying solely on CCR5 to enter
Fever its target cells to relying on either CXCR4 or both CCR5 and
CXCR4
Weight loss
Fatigue
Greater infection of T cells
Rash
Cervical adenopathy
Diarrhea Destruction of CD4+ T cells (back to the top! )
vomitting During this phase: patients are asymptomatic or develop
Viral load at the end of the acute phase response = minor opportunistic infections:
equilibrium reached between the virus and the host o Oral candidiasis (thrush)
response (may remain fairly stable for several years) o Vaginal candidiasis
Viral “set point” o Herpes zoster
o level of the steady-state viremia o Mycobacterial tuberculosis
o predictor of the rate of decline of CD4+ T cells o Autoimmune thrombocytopenia
progression of the disease
Extent of viremia
o measured as HIV-1 RNA levels

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
CLINICAL AIDS 1. Pneumonia: Pneumocystis jiroveci
Breakdown of host defense Develop in appproximately 15% to 30% of untreated
plasma virus HIV-infected people
Severe, life threatening clinical disease 2. Candidiasis
Clinical manifestation: most common fungal infection in patients with AIDS
o long-lasting fever (>1month), fatigue, weight loss, and common clinical manifestations: infection of the oral
diarrhea cavity, vagina and esophagus
o after a variable period: serious opportunistic infections, oral candidiasis – sign of immunological
2° neoplasma, or clinical neurologic disease decompensation and it often heralds the transition to
Course of disease (in the absence of treatment): HIV AIDS
infection AIDS is 7-10yrs invasive candidiasis – infrequent in patients with AIDS
Exemptions to the typical course of disease: – usually occurs due to drug-induced neutropenia or
1. Rapid progessors use of indwelling catheters
o chronic phase is telescoped to 2-3yrs after 3. Cytomegalovirus
primary infection Affects the eye and GIT
2. Long-term progressors Cytomegalovirus retinitis – occurs almost exclusively
o untreated HIV-1 infected individuals who remain in patients with CD4+ T cell counts below 50 per liter
asymptomatic for 10yrs or more Gastrointestinal disease – manifests as esophagitis
o stable CD4+ T cell counts and colitis later associated with multiple mucosal
o Low levels of plasma viremia ulcerations
3. Elite controllers 4. Atypical mycobacteria (mainly M. avium-intracellulare)
o undetectable plasma virus (50-75 RNA Disseminated bacterial infection
copies/mL) Occurs late, in the setting of severe
immunosuppression
CLINICAL FEATURES OF AIDS 5. M. tuberculosis
manifest early in the course of AIDS
fever
infection may be confined to lungs or may involve
weight loss multiple organs
Diarrhea pattern of expression depends on the degree of
Generalized lymphadenopathy immunosuppression
Multiple opportunistic infections dissemination is more common in patients with very
Neurologic disease low CD4+ T-cell counts
In many cases, secondary neoplasms. 6. Cryptococcosis
meningitis as the major clinical manifestation
TABLE: AIDS-Defining Opportunistic Infections and 7. Toxoplasma gondii
Neoplasms Found in Patients with HIV Infection cause encephalitis
responsible for 50% of all mass lesions in the central
nervous system
8. JC virus
human papovirus
another important cause of central nervous system
infections in HIV-infected patients
causes progressive multifocal leukoencephalopathy
9. Herpes simplex virus infection
mucocutaneous ulcerations involving the mouth,
esophagus, external genitalia, and perianal region
10. Persistent diarrhea
chronic, profuse, watery diarrhea with massive fluid
loss
caused by infection with protozoans such as
Cryptosporidium, Isospora belli, or microsporidia
also result from enteric bacteria, e.g. Salmonalla,
Shigella, M. avium-intracellulare

TUMORS
High incidence of certain tumors, caused by oncogenic
DNA viruses
o Kaposi sarcoma herpesvirus (KSHV) - Kaposi
sarcoma (KS)
o EBV - non-Hodgkin B-cell lymphoma
o Human papillomavirus
cervical cancer in women – squamous cell
OPPORTUNISTIC INFECTIONS carcinoma of the cervix and its precursor lesions,
Account for the majority of deaths in untreated patients cervical dysplasia and carcinoma in situ
with AIDS anal cancer in men
Many of these infections represent reactivation of latent o increased risk of malignancy in AIDS patients exists
infections mainly because of failure to contain the infections and
o Normally kept in check by a robust immune system reactivation of the viruses, as well as decreased
but are not completely eradicated because the immunity against the tumors
infectious agents have evolved to coexist with their
hosts I. KAPOSI’S SARCOMA
Actual frequency of infections varies in different regions of vascular tumor that is otherwise rare in the United States
the world most common neoplasm in patients with AIDS
o markedly reduced by the advent of highly active characteristics of lesions of KS:
antiretroviral therapy (HAART) o proliferation of spindle-shaped cells
express markers of both endothelial cells
(vascular or lymphatic) and smooth muscle cells
o profusion of slitlike vascular spaces

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
suggesting that the lesions may arise from development of neovascular spaces vaguely
primitive mesenchymal precursors of vascular reminiscent of those in KS
channels KSHV infection is not restricted to endothelial cells
o display chronic inflammatory cell infiltrates o related phylogenetically to the lymphotropic sub-
KS = not a malignant tumor family of herpesviruses (γ-herpesvirus);
o Spindle cells in many KS lesions are polycloncal or o its genome is found in B cells of infected subjects.
oligoclonal, but more advance lesions are monoclonal o KSHV infection is also linked to rare B-cell
o Spindle cells in many KS lesions are diploid and are lymphomas in AIDS patients (called body cavity-
dependent on growth factors for their proliferation based primary effusion lymphoma) and to multicentric
o When these cells are implanted subcutaneously in Castleman disease, a B-cell lymphoproliferative
immunodeficient mouse DO NOT FORM TUMORS disorder
instead: ansiently induce slitlike new blood AIDS-associated KS is quite different from the sporadic
vessels and inflammatory infiltrates in the form
surrounding tissue o In HIV-infected individuals the tumor is usually
current model of KS pathogenesis: widespread, affecting the skin, mucous membranes,
gastrointestinal tract, lymph nodes, and lungs.
spindle cells produce pro-inflammatory and angiogenic factors o These tumors also tend to be more aggressive than
classic KS
Recruit the inflammatory and neovascular components of the
lesion II. LYMPHOMAS
AIDS-related lymphomas
Supply signal that aid in spindle cell survival or growth o Can be divided into 3 groups based on their location:
Systemic Lymphomas
Primary Central Nervous System Lymphomas
Body cavity-based Lymphomas

a. SYSTEMIC LYMPHOMAS
Involves lymph nodes as well as extranodal,
visceral sites.
o CNS – most common extranodal site
affected.
Commonly involved by systemic non-
Hodgkin lymphomas.
Primary site of lymphomatous
involvement in 20% of HIV-infected
patients who develop lymphomas.
o GIT
ILLUSTRATION: Postulated pathogenesis of Kaposi sarcoma (KS).
o Other locations – less common
Proposed roles of HIV, KS herpesvirus (KSHV; HHV8), and cytokines
in the development of KS. Cytokines are produced by the Orbit
mesenchymal cells infected by KSHV, or by HIV-infected CD4+ cells. B Salivary glands
cells may also be infected by KSHV; they are the probable cells in Lungs
body cavity lymphomas, also associated with KSHV infection, but their Constitute 80% of all AIDS-related lymphomas.
role in KS is unclear The vast majority of these lymphomas are
aggressive B-cell tumors that present in an
What initiate the cycle of events?? advanced stage.
o HIV is not the cause, but it is the KS herpesvirus
(KSHV, a.k.a. human herpesvirus 8) b. PRIMARY CENTRAL NERVOUS SYSTEM
o KSHV DNA is found in virtually all KS lesions, LYMPHOMAS
including those that occur in HIV-negative populations. 1000 times more common in patients with AIDS
o Proposed models: than in the general population.
HIV-mediated immune suppression allows
widespread dissemination of KSHV in the host, c. BODY CAVITY LYMPHOMAS
allowing it to access more spindle cells and set rare, but they attract attention because of their
them on the path to uncontrolled growth unusual presentation as pleural, peritoneal, or
HIV-infected T cells produce cytokines or other pericardial effusions
proteins that promote spindle cell proliferation
and survival
KSHV establish latent infection (like other herpesvirus) PATHOGENESIS OF AIDS-RELATED B-CELL
o Several proteins are produced with potential roles in LYMPHOMAS
stimulating spindle cell proliferation and preventing Involves sustained polyclonal B-cell activation
apoptosis: emergence of monoclonal or oligoclonal B-cell populations
Viral homologue of cyclin D During the frenzy of proliferation, some clones undergo
Several inhibitor of p53 mutations or chromosomal translocations involving
Small subpopulation of cells in KS undergo lytic viral oncogenes or tumor suppressor genes, and subsequent
replication (cell death and the release of viral progeny) neoplastic transformation.
o Remarkable for its production of numerous paracrine There is morphologic evidence of B-cell activation in
signaling molecules, including: lymph nodes, and it is believed that such triggering of B
A viral homologue of the cytokine IL-6 and cells is multifactorial.
several chemokines Patients with AIDS have high levels of several cytokines
play prominent roles in eliciting the (e.g. IL-6 -growth factors for B cells).
inflammatory infiltrates that are an important EBV (Epstein-Barr Virus) - known to be a polyclonal
feature of KS
mitogen for B cells.
active G protein–coupled receptor o Half of the systemic B-cell lymphomas and virtually all
expression activates the release of vascular lymphomas primary in the central nervous system are
endothelial growth factor (VEGF), which can latently infected with EBV.
promote angiogenesis in the surrounding o Other evidence of EBV infection includes:
tissue oral hairy leukoplakia (white projections on the
expression of the viral G protein–coupled tongue)
receptor in transgenic mice leads to the

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
resulting from EBV-driven squamous cell Prevention, effective public health measures, and
proliferation of the oral mucosa. antiretroviral drugs remain the mainstays in the fight
In cases in which molecular footprints of EBV infection against AIDS
cannot be detected, other viruses and microbes may
initiate polyclonal B-cell proliferation. MORPHOLOGY (AIDS)
There is no evidence that HIV by itself is capable of causing Marked follicular hyperplasia in lymph nodes
neoplastic transformation. B cell areas of the node affected
KSHV (Kaposi sarcoma herpesvirus) o Mantle zones attenuated
o the rare body cavity–based primary effusion o Germinal centers (where HIV particles seen) seem to
lymphomas are uniformly latently infected with this. merge with the interfollicular area
the number of AIDS patients who develop non-Hodgkin In the early phase, viral DNA found in nuclei of CD4+ T
lymphoma has increased steadily. cells (parafollicular region)
approximately 6% of all patients with AIDS develop B cell hyperplasia in bone marrow
lymphoma during their lifetime. o ↑ plasma cells
the risk of developing non-Hodgkin lymphoma is Peripheral blood smears
approximately 120-fold greater than in the general o Rouleaux or stacking because of
population. hypergammaglobulinemia
In contrast to KS, immunodeficiency is firmly implicated as With progression:
the central predisposing factor. o B cell proliferation subsides
patients with CD4+ T-cell counts below 50 per microliter o Severe follicular involution
incur an extremely high risk. o Organized network of follicular dendritic cells is
disrupted
III. OTHER TUMORS o Germinal centers hyalinized
Carcinoma of the uterine cervix and of anal cancer o Due to profound immunosuppression, inflammatory
o Increased occurrence in patients with HIV. response to infections may be sparse or atypical
o Most likely due to reactivation of latent human o Spleen and Thymus appear to be ―wastelands‖
papillomavirus (HPV) infection as a result of
immunosuppression. AMYLOIDOSIS
This virus is believed to be intimately associated Results from abnormal folding of proteins, which are
with squamous cell carcinoma of the cervix and deposited as fibrils in extracellular tissues and disrupt
its precursor lesions, cervical dysplasia and normal function
carcinoma in situ. o Normally, misfolded proteins are degraded by
HPV-associated cervical dysplasia is 10 times proteosomes (intracellularly) and macrophages
more common in HIV-infected women as (extracellularly)
compared with uninfected women attending Amyloid- pathologic proteinaceous substance, deposited
family planning clinics. in the extracellular space in various tissues and organs of
Hence it is recommended that gynecologic the body in a wide variety of clinical settings
examination be part of a routine work-up of HIV- o Produces pressure atrophy of adjacent cells
infected women. o Congo red stain used to differentiate amyloid from
other hyaline deposits
CNS DISEASE o 95% fibril proteins; 5% P component and
Common and important manifestation; patients: glycoproteins
o 90% - neurologic manifestation o 3 most common forms of amyloid proteins:
AL (amyloid light chain)
o 40-60% - neurologic dysfunction
AA (amyloid-associated)
Includes: Aβ (from β amyloid precursor protein
o Meningoencephalitis Not a single disease but rather group of diseases
o Aseptic meningitis having in common deposition of similar-appearing
o Vacuolar myelopathy proteins
o Peripheral neuropathies
o AIDS-dementia complex PATHOGENESIS OF AMYLOIDOSIS
Misfolded proteins that are unstable and self-associate
Progressive encephalopathy
form oligomers and fibrils which are deposited in tissues
The proteins that form amyloid fall into two general
EFFECT OF ANTIRETROVIRAL DRUG THERAPY ON THE
categories:
CLINICAL COURSE OF HIV INFECTION
(1) normal proteins that have an inherent tendency
To reduce the emergence of mutants that develop to fold improperly, associate and form fibrils, and do
resistance to any one so when they are produced in increased amounts
To target the viral reverse transcriptase, protease, and (2) mutant proteins that are prone to misfolding and
integrase subsequent aggregation
HAART - highly active antiretroviral therapy Accumulation of misfolded proteins
o Complication is long-term toxicities o Degraded by either proteosomes (intracellularly) or
Once the virus is suppressed, the progressive loss of macrophages (extracellularly)
CD4+ T cells is halted; Over a period of several years the
peripheral CD4+ T-cell count slowly increases and often Shown in the figure above, SAA proteins are synthesized
returns to a normal level during inflammation; ↑ production of SAA not sufficient
Immune Reconstitution Inflammatory Syndrome for deposition of amyloid. Individuals developing
o Develop paradoxical clinical deterioration despite amyloidosis either:
antiretroviral therapy o have an enzyme defect that results in complete
Major causes of morbidity: breakdown of SAA generating insoluble AA molecules
o Cancer or
o Accelerated CV disease o genetically determined structural abnormality in the
o Kidney disease SAA molecules (rendering itself resistant to
o Liver disease macrophages)
Prognosis remains dismal Familial Amyloidosis
Treated patients (asymptomatic) still carry viral DNA in o TTR deposition does not result to overproduction
lymphoid tissues o TTRs prone to misfolding, aggregation and resistant
to proteolysis

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PATHOLOGY // DISEASES OF THE IMMUNE SYSTEM 1.9
Amyloid consist of AL protein in some cases

6. ENDOCRINE AMYLOID
Amyloid proteins derived from polypeptide hormones
(medullary carcinoma) or unique proteins (islet
amyloid polypeptide)
Also found in pheochromocytomas, undifferentiated
carcinomas of stomach, islet of Langerhans (people with
Type II DM)

7. AMYLOID OF AGING
Senile systemic amyloidosis (previously senile cardiac
amyloidosis because of related dysfunction of the heart)
Present with cardiomyopathy and arrhythmias
Amyloid protein: TTR; mutant TTR (affecting
predominantly the heart)

CLINICAL FEATURES OF AMYLOIDOSIS


CLASSIFICATION OF AMYLOIDOSIS There can be no anatomic change, clinical manifestations
Systemic (generalized) but can cause death
o Primary Amyloidosis Prognosis for generalized amyloidosis is poor (Those
Associated with monoclonal plasma cell with immunocyte- derived amyloidosis (not including
proliferation multiple myeloma) have a median survival of 2 years after
o Secondary Amyloidosis diagnosis
Complication of underlying chronic inflammatory Symptoms directly related to magnitude of deposits
or destructive tissue process Clinical Manifestations:
Localized o Weakness
o Deposits limited to a single organ o Weight loss
o Lightheadedness
1. PRIMARY AMYLOIDOSIS: IMMUNOCYTE o Syncope
DYSCRASIAS WITH AMYLOIDOSIS Renal Involvement
Most common form o Proteinuria -> nephrotic syndrome
Malignant B cells synthesize abnormal amounts of Ig; only o Obliteration of glomeruli - > renal failure (common
the light chains (Bence- Jones protein) found in the cause of death) and uremia
serum (also in the urine) Cardiac Involvement
Bence- Jones protein not enough to produce amyloidosis o May present as insidious congestive heart failure
but other factors, such as the type of light chain o Conduction disturbances and arrhythmias
produced (amyloidogenic potential) and the o Cardiac amyloidosis disguises as chronic constrictive
susceptibility to degradation influence deposition of pericarditis
Bence-Jones protein GI involvement
o May be asymptomatic
2. REACTIVE SYSTEMIC AMYLOIDOSIS o Amyloidosis of the tongue may cause sufficient
Amyloid systemic and composed of AA enlargement and inelasticity thus hampering speech
Previously secondary amyloidosis because of and swallowing
association with chronic inflammation o Stomach and intestine depositon -> malabsorption,
Complicates rheumatoid arthritis and other connective diarrhea, disturbances in digestion
tissue disorders Tests
Chronic skin infections associated with “skin-popping” of o Congo red stain
narcotics responsible for amyloidosis o Scintigraphy with radiolabeled serum amyloid P (SAP)

3. HEMODIALYSIS- ASSOCIATED AMYLOIDOSIS FINALLY! CONGRATULATIONS!


Deposition of β2-microglobulin (cannot be filtered
through dialysis membranes thus retained in circulation)
Patients present with carpal tunnel syndrome
Patients on long-term dialysis (>20 yrs) have amyloid
deposits in synovium, jounts, or tendon sheaths

4. HEREDOFAMILIAL AMYLOIDOSIS
Rare
Familial Mediterranean Fever
o ↑ IL-1
o Fever
o Inflammation of serosal surfaces
o Gene: pyrin
o Major fibril protein: AA
Familial amyloidotic neurophaties
o Autosomal dominant
o Deposition of amyloid predominantly in peripheral and
autonomic nerves
o Mutant TTR

5. LOCALIZED AMYLOIDOSIS
Limited to single organ
Deposits grossly detectable
Nodular deposits (in the lungs, larynx, skin, urinary
bladder, tongue, or eyes)
Are infiltrates of lymphocytes and plasma cells in the
periphery of amyloid masses

Transcribers: Maez, Junic, Jess, Karla, Dy, Anca, Guia, Jap Page 41 of 41

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