Autoimmunity & Autoimmune diseases Lecture-4 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 T-lymphocyte

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 Risk ( approximate) % HLA-Allele Disease 90-100 B27 Ankylosing spondylitis 14 Postgonococcal arthritis 15 Acute anterior uveitis 4 DR4 Rheumatoid arthritis DR3 Autoimmune hepatitis 10 Primary Sjögren syndrome 5 Type I Diabetes mellitus 6 DR3/DR4 BW7 21-hydroxylase deficiency

C) Microbial agents in autoimmunity Included bacteria, mycoplasmas, & viruses mechanisms are: 1-association of microbial antigens & autoantigens forming new immunogenic units & by pass T-cell 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

* They depend on the nature of Ag: 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 self-antigens 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, SS-A, 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) pathogenesis of systemic lupus erythematosus (SLE). The importance of apoptotic cells as the source of self-antigens is speculative. How susceptibility genes promote activation of self-reactive lymphocytes is unknown.

Characteristic morphological finding in SLE: Skin: granular deposition 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 so-called 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(

Antibodies may also contribute to the disease. 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 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 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 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