AUTOIMMUNITY- II Dr. Ashraf Abdelfatah Deyab Assistant Professor of Pathology Collage of Medicine, Majmaah University-

Autoimmunity: Part 2 At the end of the session the student should be able to: a. List the Genetic factors in autoimmunity b. Discuss the Role of infections and tissue injury. Suggested readings: Robbins basic pathology, 8th edition. Page:138 – 139

Role of Genes Susceptibility-1 III. The mechanism of autoimmunity- Loss of self-tolerance= breakdown of tolerance Most of Autoimmune diseases due to complex multigenic disorders predisposed by : a) Single gene mutation : few number of autoimmune diseases caused by single gene defect (Fas, AIRE= Defect in central tolerance). b) HLA genes “disease-associated alleles”: have greatest contribution in AD (HLA: B27, DR2,DR3,DR3\4)- mechanism remain obscure. c) Non-HLA gene mutation

Role of Genes Susceptibility- 2. III. The mechanism of autoimmunity- Loss of self-tolerance= breakdown of tolerance b) HLA genes “disease-associated alleles”: Mechanism: remain obscure but postulated that presence of MHC alleles defects are lead to C) Non-HLA genes: recent Family & Twins studies- reveals multiple disorders specially gene defect proved to be among monozygotic greater than > 4 times in dizygotic twins. – three recent examples cont.) 1) Affects the negative selection of T cells in the thymus. 2) Affect the development of regulatory T cells.

Role of Genes Susceptibility. III. The mechanism of autoimmunity- Loss of self-tolerance= breakdown of tolerance -Recent examples: 1- Polymorphisms in a gene called PTPN-22 (most frequently implicated with AD, a\w RA & type 1 DM. 2- Polymorphisms in the gene for NOD-2 ( NOD-2 is a cytoplasmic sensor of microbes), a\w Crohn disease. Mechanism : defect in encoded phosphatase > defect in control of tyrosine kinases activity>defect of lymphocyte responses>> excessive activation Mechanism : NOD-2 defect>> ineffective at sensing intestinal microbes>> entry of microbes>> chronic inflammatory responses against well-tolerated commensal bacteria

Role of Genes Susceptibility 3- The genes encoding the IL-2 receptor (CD25) and IL-7 receptor α chains are associated with multiple sclerosis and other autoimmune diseases OUTCOME> These cytokines may control the maintenance of regulatory T cells

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