Immune reactions against self-antigens (autoimmunity ) are an important cause of certain diseases in humans. Autoimmune diseases may result from tissue injury caused by T cells or antibodies , that react against self-antigens. If immune response is directed against a single organ or tissue, resulting in organ-specific disease: e.g,o Type I diabetes mellitus: autoreactive T- cells and antibodies are specific for β cells of pancreatic islets.o Multiple sclerosis: autoreactive T- cells react against central nervous system myelin.
generalized or systemic disease: e.g,o SLE : antibodies directed against DNA, platelets, red cells, and protein-phospholipid complexes ; result in wide spread lesions throughout the body. characterized by injury to skin, joints, kidney, and serosal membranes. In middle of spectrum is Goodpasture syndrome in which antibodies to basement membranes of lung and kidney , induce lesions in these organs.
Immunologic Tolerance: Immunologic tolerance is a state in which the individual is incapable of developing immune response to specific antigen. Self-tolerance refers to lack of immune response against self antigen . autoimmunity results from the loss of self-tolerance. Several mechanisms explain the tolerant state; classified into two broad groups: central tolerance and peripheral tolerance.
Central Tolerance: refers to deletion of self-reactive T- and B-lymphocyte during their maturation in central lymphoid organs (thymus for T cells, and bone marrow for B cells). Many self-antigens may not be present in thymus, and hence T- cells bearing receptors for such autoantigens escape into periphery. There is similar "slippage" in B-cell system as well.
Peripheral tolerance: self-reactive T cells that escape central deletion can cause tissue injury unless they are deleted in peripheral tissues. Several mechanisms for peripheral deletion. They include : 1. Anergy :o refers to prolonged or irreversible inactivation of lymphocytes.o activation of T- cells requires two signals:• peptide antigen on surface of antigen-presenting cells.• costimulatory signals ("second signals") provided by antigen-presenting cells.
o If the antigen is presented by cells that do not bear costimulators, a negative signal is delivered, and T- cell becomes anergic.o Anergy affects B- cells as well.2. Suppression by regulatory T cells:o regulatory T cells preventing immune reactions against self-antigens.o The best-defined regulatory T cells are CD4+ T cells that constitutively express CD25 and the α chain of IL-2 receptor.
3. Clonal deletion by activation-induced cell death:o CD4+ T cells that recognize self-antigens may receive signals that promote their death by apoptosis.o One mechanism involves the Fas-Fas ligand system:-• CD4+ T cells express Fas (CD95).• FasL, expressed mainly on activated T lymphocytes.• The engagement of Fas by FasL induces apoptosis of CD4+ T cells.o Self-reactive B cells may also be deleted by FasL on activated T cells engaging Fas on B cells.
4. Antigen sequestration:o Some antigens are hidden from immune system because the tissues in which these antigens are located do not communicate with blood and lymph as in testis, eye, and brain.o If these antigens are released as a consequence of trauma or infection, the result may be an immune response that leads to tissue inflammation and injury.o This is the postulated mechanism for post-traumatic autoimmune orchitis and uveitis.
Autoimmune diseases ( examples ): Systemic Lupus Erythematosus :- SLE is a multisystem disease of autoimmune origin, characterized by prescence of autoantibodies, particularly antinuclear antibodies (ANAs). Anti double strands DNA antibody is the most common ANA. it is a chronic, remitting and relapsing, often febrile illness characterized by injury to skin, joints, kidney, and serosal membranes. SLE is predominantly a disease of women, usually arises in twenties and thirties
Etiology and Pathogenesis:Genetic Factors:o Up to 20% of clinically unaffected first-degree relatives of SLE patients reveal autoantibodies.o Studies of HLA system showed association of SLE with HLA-DQ locus.Environmental Factors:o drugs such as hydralazine, procainamide, and d-penicillamine can induce SLE-like response .o Exposure to ultraviolet light .o Sex hormones exert an important influence on occurrence and manifestations of SLE.
Immunologic Factors:o Polyclonal B-cell activation can be demonstrated in patients with SLE .o Molecular analyses of anti-double-stranded DNA antibodies, strongly suggest that autoantibodies are results from an antigen-specific helper T cell-dependent B-cell response (TH2).
Morphology:• The lesions result from deposition of immune complexes in blood vessels, kidneys, connective tissue, and skin.(Type III hypersensitivity reaction ).• An acute necrotizing vasculitis involving small arteries and arterioles may be present in any tissue.• In chronic stages, vessels undergo fibrous thickening with luminal narrowing
Kidney:(WHO) classification of lupus nephritis, five patterns arerecognized:(1) minimal or no detectable abnormalities (class I)(2) mesangial lupus glomerulonephritis (class II)(3) focal proliferative glomerulonephritis (class III)(4) diffuse proliferative glomerulonephritis (class IV)(5) membranous glomerulonephritis (class V)Skin:Characteristic erythema affects the facial butterfly area(bridge of nose and cheeks) in approximately 50% ofpatients (facial butterfly skin rash ).
Joints:Non-erosive arthritis with little deformity.Central Nervous System:Focal neurologic symptoms.Cardiovascular system:Mainly pericarditis.Myocarditis is less common.Nonbacterial verrucous endocarditis ( Libman-sack’sendocarditis ).Lungs:Pleuritis and pleural effusions .
Rheumatoid Arthritis: chronic inflammatory disease affects primarily joints(erosive arthritis), but may involve extra-articular tissues such as skin, blood vessels, lungs, and heart. About 1% of worlds population is affected. women two to three times more than men. most common in age 40 to 70, but no age is excluded. The autoimmune reaction consists of activated CD4+ T cells, and probably B lymphocytes as well (Type IV, and Type II H.S.R. ). Many patients have serum Rheumatoid factor (IgM antibody reactive with Fc portion of patients own IgG). HLA DRB1 association.
Sjögren Syndrome : chronic disease characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) resulting from immunologically mediated destruction of lacrimal and salivary glands. It occurs as an isolated disorder (primary form) also known as sicca syndrome; or more often in association with another autoimmune disease (secondary form). Among the associated disorders rheumatoid arthritis is the most common, but some patients have SLE, polymyositis, or scleroderma.
About 75% of patients have rheumatoid factor regardless of whether coexisting rheumatoid arthritis is present or not. Most important are antibodies (ANAs)directed against two ribonucleoprotein antigens SS-A (Ro) and SS-B (La) which can be detected in up to 90% of patients. These autoantibodies are also present in patients with SLE and hence are not pathognomonic of Sjögren syndrome. Sjögren syndrome shows association with HLA-B8, HLA-DR3, and DRW52 genetic loci.
Systemic Sclerosis (Scleroderma): chronic disease of unknown etiology, characterized by abnormal accumulation of fibrous tissue in skin and multiple organs. The skin is most commonly affected, but gastrointestinal tract, kidneys, heart, muscles, and lungs also are frequently involved. Death from renal failure, cardiac failure, pulmonary insufficiency, or intestinal malabsorption . Two major categories: (1) Diffuse scleroderma: widespread skin involvement at onset, with rapid progression and early visceral involvement.
(2) Limited scleroderma: skin involvement is often confined to fingers, forearms, and face. Visceral involvement occurs late.Etiology and Pathogenesis: The cause is not known. The trigger for excessive fibrosis is a combination of abnormal immune responses and vascular damage, resulting in local accumulation of growth factors that act on fibroblasts and stimulate collagen production. Although T cell-mediated fibrogenesis and vascular injury are important ( type IV H.S.R) , but activation of humoral immunity is important as well.
Virtually all patients have ANAs. Two ANAs unique to systemic sclerosis :o One directed against DNA topoisomerase I (anti-Scl 70) is highly specific present more in patients with diffuse systemic sclerosis.o The other anti centromere antibody, is found more in patients with limited systemic sclerosis.o The majority of patients with anticentromere antibody have the CREST syndrome.o It is rare to have both antibodies in the same patient.
Inflammatory Myopathies: uncommon, heterogeneous group of disorders characterized by injury and inflammation of skeletal muscles, which are probably immunologically mediated. Three distinct disorders: Dermatomyositis, Polymyositis, and Inclusion-body myositis. These may occur alone or with other immune-mediated diseases, particularly systemic sclerosis. Anti Histidyl-t-RNA synthetase antibody (Jo-1 )which is ANA is common.