Autoimmune Disorders

1. Autoimmune Disorders Dr Shoaib Raza

2. 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 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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)

11. 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.

12. 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

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

14. 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 T-Cells and B-Cells and result in the production of several species of pathologic autoantibodies.

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

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

17. 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)

18. 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.

19. 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

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

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