1. Dr Shoaib Raza

2.   Immune reactions against self antigens  Affects 1% to 2% of US population  Requirements for an autoimmune disorder:  Presence of immune reaction specific for some self- antigen 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

3.   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 Autoimmune Disorders

4.   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 Immunologic Tolerance

5.   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

6.   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 T-Cells

7.   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 Central Tolerance of B-Cells

8.   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 Peripheral Tolerance

9.   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 Mechanism of Autoimmunity

10.   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) Role of Infection in Autoimmune Diseases

11.   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. General Features of Autoimmune Diseases

12.   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 Systemic Lupus Erythematosus (SLE)

13.   Exact cause is unknown  Failure of the mechanisms that maintain self- tolerance  Genetic factors  Immunologic factors  Environmental factors Etiology & Pathogenesis

14.   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 T- Cells and B-Cells and result in the production of several species of pathologic autoantibodies. Mechanism of Tissue Injury

15.   Kidney:  Lupus nephritis  Joints:  Synovitis, arthritis etc  CNS:  Due to acute vasculitis  Heart:  Pericarditis, non-bacterial verrucous endocarditis  Lungs, Spleen, etc.  Splenomegaly, pleuritis Morphology

16.   Variable presentation according to organ involved  Unpredictable presentation and course of the disease  Chronic discoid lupus erythematosus  Subacute cutaneous lupus erythematosus Clinical Features

17.   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) Rheumatoid Arthritis

18.   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. Sjögren Syndrome

19.   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 Systemic sclerosis (Scleroderma)

20.   Clinical features, mixture of  SLE  Systemic sclerosis  Polymyositis  Serologically characterized by:  Autoantibodies to ribonucleotide particle containing U1 ribonucleoprotein. Mixed Connective Tissue Diseases

21.   Necrotizing inflammation of small sized blood vessel wall  Small size blood vessels of lungs and kidneys are usually affected Polyarteritis Nodosa