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Immunopathology
Autoimmunity & Autoimmune
diseases
Lecture-4
Autoimmune Diseases
• These are diseases caused by an immune reaction against self-Ag.
• * They may involve
– single organ
– multisystemic.
• *Affecting mainly female.
Self- Tolerance
• Self- Tolerance refers to a lack of immune
responsiveness to the individual own tissue
antigens
• The mechanisms of self tolerance are:
– Clonal deletion ( Central tolerance )
– Clonal anergy
– peripheral suppression by suppressor Tlymphocyte
The principal
mechanisms
of central &
peripheral
self-tolerance
in CD4+ T
cells .
1- Clonal deletion:
• Loss or deletion of self reactive clones of T or
B-lymphocytes or both during their maturation
• Many self antigens expressed in the thymus in
associated with MHC, the developing T cells
that express high affinity receptors for such self
antigens are deleted by apoptosis
• Self reactive B-cells also affected but to less
extend than T cells
2- Clonal anergy:
• Those cells that escape clonal deletion in thymus,
become inactive outside the thymus by clonal
anergy
• It is a functional inactivation of lymphocytes
induced by failure of expression of co-stimulators
(e.g., B7-1 & B7-2) in the APC & parenchymal
tissue, so negative signal is delivered make the
cell anergic
• Affect both T & B cells
• It is the major mechanism for B cell tolerance
3- Peripheral suppression by T cells:
• Presence of CD8 suppressor T cells make this
mechanism
• they inactivate both helper T cells & B cells
• they act through secretion of inhibitory cytokines
such as IL-10 & TGF-β
(TGF-β=Transforming growth factor- β )
Mechanisms of
autoimmune disease
A) Loss of self – tolerance
B) Genetic factors in autoimmunity
A) Loss of self - tolerance
1- Bypass of helper T- cell tolerance: by
• A /modification of molecule: if self antigen is
modified as due to drugs or microorganisms, this
recognized by T cells as a foreign antigen so cooperate
with B cells leading to formation of autoantibodies as in
autoimmune hemolytic anemia
• B /Expressions of costimulatory molecules: as in
infection which can activate macrophages to express
costimulatory molecules and present self antigens
2- Molecular mimicry:
• Some infectious agent share epitopes with self
antigens so cross reaction with self antigen is
result as in rheumatic heart disease
3- Polyclonal lymphocyte activation:
• Some of autoreactive lymphocytes that were not
deleted during development may become
stimulated by antigen-independent mechanisms
as in endotoxins of bacteria induced polyclonal
antibody against self antigens
4- Imbalance of suppressor-Helper T-cell
function:
• loss of suppressor T cell function or
• excessive helper T cell function result in B cell
activation
• 5- Emergence of sequestered antigens:
• Some antigen are anatomically segregated from the
developing immune system special clonal deletion
or anergy fails to occur, if they release into
circulation they induced an immune response e.g.,
ocular antigens
B) Genetic factors in autoimmunity
• They play significant role in the predisposition to
autoimmune diseases.
• The evidence for that are:
1-Familial clustering of several human autoimmune
diseases e.g., SLE, autoimmune hemolytic anemia, &
autoimmune thyroiditis
2-Linkage of several autoimmune diseases with HLA
especially class II
3-Induction of autoimmune diseases in transgenic rats by
introduce certain human HLA e.g., HLA-B27
Association of HLA with diseases
Disease
HLA-Allele
Risk ( approximate) %
Ankylosing spondylitis
B27
90-100
Postgonococcal arthritis
B27
14
Acute anterior uveitis
B27
15
Rheumatoid arthritis
DR4
4
Autoimmune hepatitis
DR3
14
Primary Sjögren syndrome DR3
10
Type I Diabetes mellitus
DR3
5
DR4
6
DR3/DR4
15
21-hydroxylase deficiency BW7
15
C) Microbial agents in autoimmunity
• Included bacteria, mycoplasmas, & viruses
• mechanisms are:
1-association of microbial antigens & autoantigens
forming new immunogenic units & by pass Tcell tolerance
2-Induction of nonspecific polyclonal B-cell
mitogens & formation of Autoantibodies
3-loss of suppressor T cell function
4-Cross reaction with self antigens
• Why does some autoimmune disease
affecting single organ while other are
systemic?
* They depend on the nature of Ag:
(1) If Ag restricted in its expression to single organ e.g.,
Grave’s disease the autoimmune disease will be limited
to the cells of that organ only.
(2) If more organs express the same Ag, so more wide
spread diseases occur.
SUMMARY :Immunological Tolerance and Autoimmunity
• Tolerance (unresponsiveness) to self-antigens is a fundamental
property of the immune system, and breakdown of tolerance is the
basis of autoimmune diseases.
*Central tolerance:
• immature lymphocytes that recognize self-antigens in the central
(generative) lymphoid organs are killed by apoptosis;
• in the B-cell lineage, some of the self-reactive lymphocytes switch
to new antigen receptors that are not self-reactive.
*Peripheral tolerance :
• mature lymphocytes that recognize self-antigens in peripheral
tissues become functionally inactive (anergic), or are
suppressed by regulatory T lymphocytes, or die by apoptosis.
• The variables that lead to a failure of self-tolerance and the
development of autoimmunity include (1) inheritance of
susceptibility genes that may disrupt different tolerance pathways,
and (2) infections and tissue alterations that may expose selfantigens and activate APCs and lymphocytes in the tissues .
Systemic Lupus Erythromatosus
Definition: -
• multisystem disease of autoimmune origin,
acute or gradual in onset, chronic, remitting &
relapsing febrile illness characterized principally
by injury to the skin, joint, kidney & serosal
membranes.
• * Female: male ratio 9:1.
• * Age group 20-40 years.
Systemic Lupus Erythromatosus
Four out of 11 clinical or laboratory criteria must be present
for diagnosis of SLE:
(1) Malar rash.
(2) Discoid rash.
(3) Photosensitivity.
(4) Oral ulcers.
(5) Arthritis.
(6) Serositis.
(7) Renal disorders.
(8) Neurological disorders (seizures, psychosis).
(9) Hematological disorders (cytopenia, hemolytic anemia).
(10) Immunological disorder (Ab to DNA or anti-Sm,
antiphospholipid Ab).
(11) Antinuclear Ab.
Etiology & pathogenesis
1- Immunologic Factors:
• Autoantibodies result from hyperactivity of B cell
which occur as a result of
• A/ intrinsic defect in B cells
• B/ excessive stimulation by helper T cells
• C/ Defect in suppressor T cell function
• ANA are directed against several nuclear
Antigens & categorized into:
(1) Ab against DNA.
(2) Ab to histones.
(3) Ab to nonhistone proteins bound to RNA (smith Ag, SSA, SS-D).
(4) Ab to nucleolar Ag.
2- Genetic factors:
• high rate of concordance (30%) in
monozygotic twins
• family members have an increased risk of
developing SLE
• Association between SLE & HLA-DQ locus
3- Non genetic factors:
• occurrence of SLE in patients received
certain drugs as procainamide & hydralazine
• Sex hormones esp. estrogen
• Ultraviolet light exposure
pathogenesis of
systemic lupus
erythematosus
(SLE). The
importance of
apoptotic cells as
the source of selfantigens is
speculative. How
susceptibility
genes promote
activation of selfreactive
lymphocytes is
unknown.
Characteristic morphological finding in SLE:
* granular deposition
Skin:
of immune complex along
the epidermal-dermal
basement membrane
producing maculopapular
eruption over the malar
eminencies & bridge of
the nose producing
butterfly pattern
immunofluorescence staining pattern with antibody to
IgG showing evidence for immune complexes at the
dermal-epidermal junction
• *Appearance of LE
bodies (hemotoxylin
bodies), nuclei of
damaged cells react
with ANAs loss their
chromatin pattern and
become homogenous.
*LE cells positive in 70 %
of patients
Kidney: deposition of immune complex in
glomerular blood vessels & tubules.
granular pattern of
immunofluorescence in the
glomerulus
Glomerulus with thickened
pink capillary loops, the socalled wire loop in a patient
with lupus nephritis
* Kidney: deposition of immune complex in
glomerular blood vessels & tubules.
*joint involvement: swelling & inflammation
* Heart: immune complex deposition on the
value especially mitral value.
* spleen: marked perivascular fibrosis giving
onion-skin lesion
Cardiac pathology of SLE:
• * Pericarditis (most common).
• * Endocarditis (Libman-Sacks).
• * Non specific myocarditis.
• * Accelerated coronary atherosclerosis
Summary
• SLE is a systemic autoimmune disease caused by
autoantibodies produced against numerous self-antigens and
the formation of immune complexes.
• The major autoantibodies, and the ones responsible for the
formation of circulating immune complexes, are directed
against nuclear antigens.
• Other autoantibodies react with erythrocytes, platelets, and
various complexes of phospholipids with proteins.
• Disease manifestations include nephritis, skin lesions and
arthritis (caused by the deposition of immune complexes),
and hematologic and neurologic abnormalities.
• The underlying cause of the breakdown in self-tolerance in
SLE is unknown; it may include excess or persistence of
nuclear antigens, multiple inherited susceptibility genes, and
environmental triggers (e.g., UV irradiation, which results in
cellular apoptosis & release of nuclear proteins(
• Rheumatoid Arthritis
• RA is a chronic inflammatory disease that affects
mainly the joints, especially small joints, but can
affect multiple tissues.
• The disease is caused by an autoimmune
response against an unknown self antigen(s),
which leads to T-cell reactions in the joint with
production of cytokines that activate phagocytes
that damage tissues & stimulate proliferation of
synovial cells (synovitis).
• The cytokine TNF plays a central role, &
antagonists against TNF are of great benefit.
• Antibodies may also contribute to the disease .
Rheumatoid arthritis .
A ,A joint lesion .
B ,Low magnification reveals marked synovial
hypertrophy with formation of villi .dense lymphoid
aggregates are seen in the synovium
C ,higher magnification,
Figure 5-25
Model for the
pathogenesis
of
rheumatoid
arthritis.
CD4+ T cells
reacting
against an
unknown
arthritogenic
antigen are
believed to
stimulate
autoantibody
production &
to activate
macrophages
& other cells
in the joint
synovium.
• Sjögren Syndrome
• Sjögren syndrome is an inflammatory disease
that affects primarily the salivary and lacrimal
glands, causing dryness of the mouth & eyes.
• The disease is believed to be caused by an
autoimmune T-cell reaction against an unknown
self antigen(s) expressed in these glands, or
immune reactions against the antigens of a virus
that infects the tissues .
Sjögren syndrome .
A ,Enlargement of the salivary gland .
B ,The histologic view shows intense lymphocytic and
plasma cell infiltration with ductal epithelial hyperplasia
SUMMARY
• Systemic Sclerosis
• Systemic sclerosis (commonly called scleroderma (is
characterized by progressive fibrosis involving the skin,
gastrointestinal tract, and other tissues.
• Fibrosis may be the result of activation of fibroblasts by
cytokines produced by T cells, but what triggers T-cell
responses is unknown.
• Endothelial injury and microvascular disease are
commonly present in the lesions of systemic sclerosis,
perhaps causing chronic ischemia, but the pathogenesis
of vascular injury is not known .
Figure 5-27 Systemic
sclerosis
A ,Normal skin .
B ,Extensive
deposition of dense
collagen in the
dermis .C ,The
extensive
subcutaneous fibrosis
has virtually
immobilized the
fingers, creating a
clawlike flexion
deformity. Loss of
blood supply has led to
cutaneous ulcerations
Autoantibodies
used in the
diagnosis of
disease