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Dr Shoaib Raza Autoimmune Disorders Immune reactions against self antigens Affects 1% to 2% of US population Requirements for an autoimmune disorder: Presence of immune reaction specific for some selfantigen or self-tissue Evidence that the reaction is not secondary to tissue damage Absence of another well defined cause of disease DIAGNOSIS OF EXCLUSION Autoimmune Disorders Clinical manifestations are varied Organ specific disease Type 1 diabetes mellitus Multiple sclerosis Systemic or generalized diseases Systemic lupus erythematosus Middle of the spectrum Goodpasture’s syndrome Immunologic Tolerance The phenomenon of unresponsiveness to an antigen as a result of exposure to lymphocytes to that antigen. Self tolerance refers to lack of responsiveness to an individual’s own antigen Central tolerance Peripheral tolerance Central Tolerance Immature self reactive T or B-Cell clones that recognize self-antigens during their maturation in the central lymphoid organs (Thymus or Bone marrow) are killed or rendered harmless. Central tolerance is however far from PERFECT Self reactive T or B-cells may skip the central tolerance and enter the circulation Central Tolerance of T-Cells In the thymus Negative selection: Self reactive T-Cells die by apoptosis AIRE protein stimulates expression of “peripheral tissue restricted” self-antigens in the thymus Some self reactive CD4+ T-Cells in the thymus do not die, but later on develop into regulatory cells Central Tolerance of B-Cells In the bone marrow: Receptor editing: Some self-reactive B-Cells reactivate the machinery of antigen receptor gene and begin to express new antigens receptors If receptor editing does not occur, self-reactive B-Cells undergo apoptosis Peripheral Tolerance Several mechanisms Anergy Prolonged or irreversible inactivation of lymphocytes Absence of co-stimulatory signals induce apoptosis Suppression by regulatory T-Cells Mainly developed in thymus May be developed in peripheral tissues ? immunosuppressive cytokines are released (IL-10) Deletion by activation-induced cell death Self-reactive CD4+ T-Cells undergo apoptosis Mechanism of Autoimmunity Autoimmunity arises from a combination of Inheritance of susceptibility genes may lead to breach in self-tolerance Environmental triggers e.g. infections and tissue damage Role of Infection in Autoimmune Diseases Many autoimmune diseases are: Associated with infections Up-regulation of expression of co-stimulators on APC Molecular mimicry (e.g. rheumatic heart disease) Polyclonal B-Cell activation (e.g. EBV infection) General Features of Autoimmune Diseases Autoimmune diseases are PROGRESSIVE, with relapses and remissions Clinical and pathological manifestations are determined by nature of underlying immune response Different autoimmune diseases show substantial clinical, serological and pathological overlap. Systemic Lupus Erythematosus (SLE) Prototype of multisystem disease of autoimmune origin Antinuclear antibodies (ANAs) are usually present Acute or insidious in onset Chronic, remitting and relapsing, often febrile illness characterized principally by injury to the skin, joints, kidney and serosal membranes Complex set of criteria for establishing the diagnosis Etiology & Pathogenesis Exact cause is unknown Failure of the mechanisms that maintain selftolerance Genetic factors Immunologic factors Environmental factors Mechanism of Tissue Injury Most of the visceral lesions are caused by Type III Hypersensitivity reaction DNA-AntiDNA complexes are formed Immune complex nature of the disease Autoantibodies specific for RBC, WBC and platelets, opsonize these cells for phagocytosis SLE is a complex disorder of multifactorial origin resulting from genetic, immunologic and environmental factors that act in concert to cause activation of helper TCells and B-Cells and result in the production of several species of pathologic autoantibodies. Morphology Kidney: Lupus nephritis Joints: Synovitis, arthritis etc CNS: Due to acute vasculitis Heart: Pericarditis, non-bacterial verrucous endocarditis Lungs, Spleen, etc. Splenomegaly, pleuritis Clinical Features Variable presentation according to organ involved Unpredictable presentation and course of the disease Chronic discoid lupus erythematosus Subacute cutaneous lupus erythematosus Rheumatoid Arthritis Chronic systemic inflammatory disease that principally affects joints Non-suppurative proliferative and inflammatory synovitis Often progress to ankylosis Genetic susceptibility Arthritogenic antigen Autoimmunity Anti IgG antibody (Fc portion) Sjögren Syndrome Chronic disease, characterized by: Keratoconjunctivitis sicca (Dry Eyes) Xerostomia (Dry mouth) Immunlogically mediated destruction of the lacrimal and salivary glands May be associated with other autoimmune disorders SLE, RA, polymyositis, scelroderma, vasculitis, thyroiditis, MCTD, etc. Systemic sclerosis (Scleroderma) Chronic disease characterized by: Chronic inflammation as a result of autoimmunity Widespread damage to small blood vessels Progressive interstitial and perivascular fibrosis CREST syndrome Calcinosis Raynaud’s disease Esophageal dysmotility Sclerodactyly Telangiectasia Mixed Connective Tissue Diseases Clinical features, mixture of SLE Systemic sclerosis Polymyositis Serologically characterized by: Autoantibodies to ribonucleotide particle containing U1 ribonucleoprotein. Polyarteritis Nodosa Necrotizing inflammation of small sized blood vessel wall Small size blood vessels of lungs and kidneys are usually affected
