3. Objective
Upon completion of these materials the student will be able to:
⢠Describe contributive factors to autoimmune diseases
⢠Describe about IMMUNOLOGIC TOLERANCE and its mechanisms
⢠Distinguish organ specific and systemic autoimmune diseases with
examples of each
⢠Describe the Cause of autoimmune diseases
⢠Discuss about some of autoimmune diseases
4. Introduction
Autoimmune diseases
â˘Immune reactions against self antigensâAutoimmunity
â˘Autoimmune disease is the faliure in recognizing its own constituent
parts which allows an immune response against its own self and tissues.
â˘A condition that occurs when the immune system mistakenly attacks
and destroys healthy body tissue
â˘Any disease which results in such an aberrant immune response is
termed as autoimmune disease.
5. ⢠The mere presence of autoantibodies does not indicate an
autoimmune disease
ďIdeally, at least three requirements should be met before a
disorder is categorized as truely caused by 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
3. The absence of another well-defined cause of the disease
6. IMMUNOLOGIC TOLERANCE
To function properly, your T and B cells must have two traits:
⢠(1) They must be able to recognize your own major
histocompatibility complex (MHC) proteins, a process known
as self-recognition, and
⢠(2) they must lack reactivity to peptide fragments from your
own proteins, a condition known as self-tolerance.
Loss of self-tolerance leads to the development of autoimmune
diseases
7. ⢠Tolerance to self antigens is a fundamental property of the
immune system, and breakdown of tolerance is the basis of
autoimmune diseases.
⢠Self-tolerance refers to lack of responsiveness to an individualâs
own antigens, and it underlies our ability to live in harmony with
our cells and tissues
8. ⢠Central tolerance: Immature self-reactive lymphocytes
that recognize self antigens in generative (âcentralâ)
lymphoid organs (i.e., in the thymus for T cells and in the
bone marrow for B cells). die by apoptosis; other fates .
⢠Peripheral tolerance: Mature self-reactive lymphocytes
that recognize self antigens in peripheral tissues are
inactivated (anergy), killed (deletion) or suppressed.
9. MECHANISMS OF IMMUNLOGIC
TOLERANCE
ďą Central Tolerance:
ďśNegative selection or deletion
ďśReceptor editing
ďą Peripheral Tolerance:
ďśAnergy
ďśSuppression by regulatory T cells
ďśDeletion by apoptosis
10.
11.
12.
13. MECHANISMS OF AUTOIMMUNITY
⢠Cause of autoimmune diseases is the failure of tolerance
⢠Autoimmunity arises from a combination of the inheritance of
susceptibility genes, which may contribute to the breakdown of
self-tolerance, and environmental triggers, such as infections
and tissue damage, which promote the activation of self-reactive
lymphocytes
14. ⢠It is thought that susceptibility genes and environmental
triggers induce a number of changes that contribute to the
development of autoimmunity
ďśDefective tolerance or regulation
ďśAbnormal display of self antigens
ďśInflammation or an initial innate immune response
15. ďśDefective tolerance or regulation
⢠Failure of the mechanisms that maintain self tolerance
ďśAbnormal display of self antigens
⢠Increased expression and persistence of self antigens
that are normally cleared
⢠Structural changes in these antigens resulting from
enzymatic modifications or from cellular stress or
injury
ďśInflammation or an initial innate immune response
⢠Microbes or cell injury may elicit local inflammatory reactions
resembling innate immune responses, and these may be
critical inducers of the autoimmune disease.
16. ROLE OF SUSCEPTIBILITY GENES
⢠Most autoimmune diseases are complex multigenic disorders
Association of HLA Alleles with Disease
⢠Among the genes known to be associated with autoimmunity, the
greatest contribution is that of HLA genes
Association of Non-MHC Genes with Autoimmune Diseases
⢠Polymorphisms in a gene called PTPN22
⢠Polymorphisms in the gene for NOD2
⢠Polymorphisms in the genes encoding the IL-2 receptor(CD25)
and IL-7 receptor Îą chains
17.
18.
19. ROLE OF INFECTIONS
⢠Autoimmune reactions may be triggered by infections
⢠Two mechanisms have been postulated
1.Induction of costimulators on APCs
ďą Microbial infections with resultant tissue necrosis and
inflammation can stimulate expression of costimulatory
molecules on APCs in the tissue, thus favoring a breakdown
of T cell tolerance and subsequent T cell activation.
20.
21. 2 Molecular mimicry :
ďąViruses and other microbes may share cross- reacting
epitopes with self antigens, such that responses may be
induced by the microbe but may attack self tissues. e.g.
Rheumatic heart disease in which an antibody response
against streptococci cross-targets cardiac antigens.
22.
23.
24. role of inf..
⢠Microbes may induce other abnormalities that promote
autoimmune reactions.
⢠Some viruses, such as Epstein-Barr virus (EBV) and HIV, cause
polyclonal B-cell activation, which may result in production of
autoantibodies
⢠Tissue injury that is common in infections may release self
antigens and structurally alter these antigens so that they are
able to activate T cells that would not be tolerant to these new,
modified antigens.
25. Enviromental factors
ď Ultraviolet (UV) radiation causes cell death and maylead to the
exposure of nuclear antigens, which elicit pathologic immune
responses in lupus.
ď Smoking is a risk factor for rheumatoid arthritis, perhaps
because it leads to chemical modification of self antigens.
26. GENERAL FEATURES
Autoimmune diseases tend to be chronic, sometimes with relapses and
remissions, and the damage is often progressive
The clinical and pathologic manifestations of an autoimmune disease
are determined by the nature of the underlying immune response
The systemic diseases tend to involve blood vessels and connective
tissues, and therefore, they are often called collagen vascular diseases
or connective tissue diseases
24
28. Classification
⢠Depending on the principal
clinico-pathologic features of each
disease Autoimmune diseases can
be broadly divided into
⢠Systemic and
⢠Organ-specific or localised
autoimmune disorders, .
31. Autoimmune disease in which islet destruction is caused
primarily by immune effector cells reacting against endogenous
β-cell antigens
Develops in childhood, becomes manifest at puberty, and
progresses with age
Pathogenesis-
Genetic Susceptibility-
ďąHigher concordance rates for disease in monozygotic vs dizygotic twins
ďągenome-wide association studies have identified multiple genetic susceptibility
loci
ďąthe most important locus is the HLA gene cluster on chromosome
232
32. ďą 90 to 95% have either an HLA-DR3 or HLA-DR4 haplotype
ďą 40% to 50% of patients combined DR3/DR4 heterozygotes
ďą DR3 or DR4 concurrently with a DQ8 haplotype highest inherited
risks for type 1 diabetes
ďą The first disease-associated non-MHC gene to be identified was
insulin, with variable number of tandem repeats (VNTRs) in the
promoter region being associated with disease susceptibility
Environmental Factors-
ďą viral infections have been suggested as triggers
ďą viruses might share epitopes with islet antigens- Molecular
mimicry
233
35. ⢠Chronic inflammatory disorder of autoimmune origin that may
affect many tissues and organs but principally attacks the joints,
producing a nonsuppurative proliferative and inflammatory
synovitis
⢠Progresses to destruction of the articular cartilage and ankylosis of the
joints
⢠Extraarticular lesions may involve skin, heart, blood vessels and lungs
⢠The disease peaks in the second to fourth decades and is three times
more common in women than men.
36. Pathogenesis
⢠Genetic predisposition and environmental factors
⢠The pathologic changes are mediated by antibodies
against self-antigens and cytokine-mediated
inflammation
⢠CD4+ T helper (TH) cells may initiate the
autoimmune response in RA by reacting with an
arthritogenic agent
37. ⢠Antibodies produced in lymphoid organs and in the synovium are
specific for cylic citrullinated peptides (CCPs)
⢠Antigen-antibody complexes containing citrullinated fibrinogen,
type II collagen, Îą-enolase and vimentin deposit in the joints
⢠80% of patients have serum IgM or IgA autoantibodies that bind to
the Fc portions of their own IgG.
⢠These autoantibodies are called rheumatoid factor
⢠Deposit in joints as immune complexes
38. ARTHRITOGEN
⢠Specific HLA-DRB1 alleles are linked to rheumatoid arthritis,
⢠And these alleles share a common sequence of amino acids in a
polymorphic region of the β chain, which is designated the shared
epitope
⢠The environmental arthritogen- uncertain.
⢠CCPs are produced during inflammation (so insults such as
infection and smoking may promote citrullination of self-
proteins,creating new epitopes that trigger autoimmune
reactions)
39. MORPHOLOGY
Joints-
â˘Symmetric arthritis, affecting the small joints of the hand and
feet
â˘The synovium becomes grossly edematous, thickened, and
hyperplastic, transforming its smooth contour to one covered by
delicate and bulbous villi
40. The characteristic histologic features:
â˘Synovial cell hyperplasia and proliferation
â˘Dense inflammatory infiltrates (frequently forming lymphoid
follicles) of CD4+ helper T cells, B cells, plasma cells, dendritic cells,
and macrophages increased vascularity due to angiogenesis
â˘Fibrinopurulent exudate on the synovial and joint surfaces
â˘Osteoclastic activity in underlying bone, allowing the synovium to
penetrate into the bone and cause periarticular erosions and
subchondral cysts
41. ⢠Together, the above changes produce a pannus: a mass of
edematous synovium, inflammatory cells, granulation tissue,
and fibroblasts that grows over the articular cartilage and
causes its erosion
⢠In time, after the cartilage has been destroyed, the pannus
bridges the apposing bones to form a fibrous ankylosis,
which eventually ossifies and results in fusion of the bones,
called bony ankylosis
42.
43. Skin
â˘Rheumatoid subcutaneous nodules- Most common lesions
occur in approximately 25% of affected individuals, usually
those with severe disease
â˘Arise in regions of the skin that are subjected to pressure
44. Blood vessels-
ď§Acute necrotizing vasculitis involves small and large arteries
ď§Segments of small arteries such as vasa nervorum and the
digital arteries are obstructed by an obliterating endarteritis
resulting in peripheral neuropathy, ulcers, and gangrene
ď§Leukocytoclastic vasculitis produces purpura, cutaneous ulcers,
and nail bed infarction
45.
46. The diagnosis of RA is supported by
1.Characteristic radiographic findings
2.Sterile, turbid synovial fluid with decreased viscosity, poor
mucin clot formation, and inclusion-bearing neutrophils,
3.The combination of rheumatoid factor and anti-ccp antibody
(80% of patients)
48. Hashimotoâs Thyroiditis
⢠Autoimmune disease that results in destruction of the
thyroid gland and gradual and progressive thyroid failure
⢠Is characterized by the destruction of thyroid cells by various
cell- and antibody-mediated immune process.
⢠Caused by auto Ab of IgG & IgM type against the constituents
of thyroid gland Hashimotoâs thyroiditis
49. ďAn association of cytotoxic lymphocyte-associated antigen 4
(CTLA4), a T cell regulatory gene, with autoimmune phenomenon in
Hashimotoâs disease has been reported.
ďThere is initial activation of CD4+ T helper cells, which then induce
infiltration of CD8+ T cytotoxic cells in the thyroid parenchyma.
ďIn the process, B cells are also activated to form autoantibodies,
which bring about immune destruction of thyroid parenchyma.
55. GRAVES DISEASE
⢠Graves disease is an autoimmune disease where the thyroid
is overactive, producing an excessive amount of thyroid
hormones
⢠This is caused by thyroid autoantibodies that activate the TSH-
receptor, thereby stimulating thyroid hormone synthesis and
secretion, and thyroid growth (causing a diffusely enlarged
goiter)
60. Myasthenia gravis is an autoimmune disease that is usually
associated with autoantibodies directed against acetylcholine
receptors
Prevalence of 150 to 200 per million and shows a bimodal age
distribution.
About 85% of patients have autoantibodies against postsynaptic
acetylcholine receptors
Remaining patients have antibodies against the sarcolemmal
protein muscle-specific receptor tyrosine kinase
225
61. Anti-acetylcholine receptor antibodies lead to the
aggregation and degradation of the receptors, and
also to damage of the postsynaptic membrane
through complement fixation
Autoantibodies directed against muscle-specific
receptor tyrosine kinase do not fix complement
ďą Antibodies seem to interfere with the trafficking and
clustering of acetylcholine receptor within the sarcolemmal
membrane
226
66. Systemic sclerosis is
characterized by:
1. Chronic inflammation thought to be the result of autoimmunity,
2. Widespread damage to small blood vessels, and
3. Progressive interstitial and perivascular fibrosis in the skin and
multiple
organs
67. The skin is most commonly affected
But the gastrointestinal tract, kidneys, heart, muscles,
and lungs also are frequently involved
Diffuse scleroderma-
ďąwidespread skin involvement at onset, with rapid
progression and early visceral involvement
Limited scleroderma-
ďąskin involvement is often confined to fingers,
forearms, and face
68. Some patients develop
CREST SYNDROME
ďľ Combination of
ďśCalcinosis
ďśRaynaud phenomenon
ďśEsophageal dysmotility
ďśSclerodactyly
ďśTelangiectasia
69. ETIOLOGY AND PATHOGENESIS
Autoimmunity-
ďľ CD4+ T cell responding to an unidentified antigen accumulate in the skin
release cytokines that activate inflammatory cells and fibroblasts.
ďľ Cytokines produced- TGF-β and IL-13, stimulate transcription of genes that
encode collagen and other extracellular matrix proteins (e.G., Fibronectin) in
fibroblasts.
ďľ Other cytokines recruit leukocytes and propagate the chronic inflammation
70. Vascular damage-
ďľ Microvascular disease is consistently present early in the course,may be the
initial lesion.
ďľ Intimal proliferation is evident in the digital arteries.
ďľ Capillary dilation with leaking, as well as destruction
ďľ Nailfold capillary loops are distorted
138
71. Fibrosis
ďľ Characteristic of the disease
ďľ Culmination of multiple abnormalities including
ďąThe accumulation of alternatively activated macrophages,
ďąActions of fibrogenic cytokines produced by infiltrating leukocytes,
ďąHyperresponsiveness of fibroblasts to these cytokines, and
ďąScarring following upon ischemic damage caused by the vascular
lesions
72. MORPHOLOGY
Skin-
ďľ Diffuse, sclerotic atrophy of the skin
ďľ Begins in the fingers and distal regions of the upper extremities and
extends
proximally to involve the upper arms, shoulders, neck, and face
ďľ Histologically, there are edema and perivascular infiltrates containing CD4+
T cells, together with swelling and degeneration of collagen fibers
ďľ Capillaries and small arteries (150 to 500 Îźm in diameter)show thickening
of the
basal lamina, endothelial cell damage, and partial occlusion
73. Progression of the disease, there is increasing fibrosis of the
dermis, which becomes tightly bound to the subcutaneous
structures
There is marked increase of compact collagen in the dermis,
usually with thinning of the epidermis, loss of rete pegs,
atrophy of the dermal appendages, and hyaline thickening
of the walls of dermal arterioles and capillaries
Focal and sometimes diffuse subcutaneous calcifications
may
develop, especially in patients with the CREST syndrome
141
74. The extensive subcutaneous
fibrosis has virtually immobilized
the fingers, creating a clawlike
flexion deformity. Loss of blood
supply has led to cutaneous
ulcerations
143
75. Alimentary tract-
Affected in approximately 90% of patients
Progressive atrophy and collagenous fibrous
replacement of the muscularis develop at any level of
gut- severe in esophagus
The lower two thirds of the esophagus often
develops a rubber- hoseâlike inflexibility
76. The mucosa is thinned and may be ulcerated
There is excessive collagenization of the lamina
propria and submucosa.
Loss of villi and microvilli in the small bowel is the
basis for the malabsorption syndrome
77. Musculoskeletal System-
Inflammation of the synovium, associated with
hypertrophy and hyperplasia of the synovial soft tissues,
later fibrosis
Kidneys-
In 2/3rd of patients
Most prominent are the vascular lesions
Interlobular arteries show intimal thickening as a result
of deposition of mucinous or finely collagenous material
78. Lungs-
In more than 50% of individuals
Manifest as pulmonary hypertension and
interstitial fibrosis
Heart-
Pericarditis with effusion, myocardial fibrosis,
and thickening of intramyocardial arterioles occur
in one third of the patients.
148
79. SUMMARY
ď Autoimmunity - Breakdown in self-tolerance.
ď Muliple causes - genetic, environmental, nutrition, infections,
etc
ď Organ specific or Systemic.
ď Majority are caused by autoAb production
ď Treatment: Immunosuppressive drugs, Abs against TCR,
cytokines, adhesion molecules, etc.
80. Refreance
ďźKumar, V., Abbas, A. K., & Aster, J. C. (2017). Robbins basic pathology
e-book: Elsevier Health Sciences.
ďźRobbins and Cotran Pathologic Basis of Disease 9th edition.
ďźHarsh Mohan Textbook of Pathology, 7th edition.
ďźKuby Immunology 5th edition.