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Hggh

1. AUTOIMMUNITY Moderator: Dr Vidya Pai

2. HISTORY Paul Ehrlich –Horror autotoxicus

3. AUTOIMMUNITY Body’s own immunologically competent cells / antibodies act against its self antigens resulting in structural / functional damage. Failure of host humoral and cellular immune system to distinguish self from non self.

4. IMMUNOLOGICAL TOLERANCE An individual is incapable of developing immune response against his own tissue antigen. 2 types: Central tolerance Peripheral tolerance

5. PERIPHERAL TOLERANCE Back up mechanism to counteract the self reactive T and B cells that escape central tolerance .

6. Peripheral tolerance T-regulatory cells Downregulate self-reactive T cells . Secreting cytokines IL10 and TGF-ß. Killing by direct cell to cell contact Dendritic cells Immature / tolerogenic DCs Downregulate expression of co-stimulation ligands CD40 and B7. Activates T regulatory cells Sequestration of self antigens Evade immune recognition by sequestration in privileged sites. Eg : Corneal protein, testicular antigens, antigens from brain.

7. Mechanisms of autoimmunity Breakdown of T -cell anergy Normal cells without co-stimulatory molecules can be induced (tissue necrosis , local inflammation). MS, RA, Psoriasis.

8. Failure of AICD

9. Loss of T reg cells Autoimmunity results following loss of T reg cell mediated suppression of self reactive lymphocytes .

10. Release of sequestered antigen They are anatomically isolated . Never exposed to tolerance mechanism during development. When released, it can activate both T and B cells .

11. Release of sequestered antigen Eg : Heart muscle Ag following MI S perm associated Ag –post vasectomy orchitis Lens and corneal proteins of eye trauma/infection-post traumatic uveitis .

12. Polyclonal T cell activation

13. Polyclonal B cell activation Viruses and bacteria can induce non specific polyclonal B cell activation. HSV, CMV, EBV , HIV.

14. Molecular mimicry(cross reacting antigens) Viruses and bacteria possess antigenic determinants that are very similar to normal host cell components . Immune response against such microbes would produce Ab that can cross react with self Ag.

15. Classification

16. Features of autoimmune disorder Elevated levels of Ig . Demonstrable autoantibodies . Deposition of Ig or their derivatives at lesion sites. Accumulation of lymphocytes and plasma cells at lesion sites. Genetic predisposition.

17. Features of autoimmune disorder Condition is diminished with corticosteroid or immunosuppressive therapy. Occurrence of more than one type of autoimmune lesion in an individual. Higher incidence among females. Chronicity , usually non-reversible.

18. Diagnosis of autoimmune diseases Clinical pointers : 1)Systemic autoimmune: C hronic illness Multisystem involvement Vague symptomatology Clinical overlap(Pernicious anaemia and autoimmune thyroiditis) 2)Local autoimmune disease : Chronic illness and unexplained organ failure

19. Problems with lab diagnosis of AID Diseases are present in combination. Lab testing is complex and often misunderstood . Clinical complexity of autoimmune disease is proportional to the complexity of test result.

20. Routine investigation Urine examination: Proteinuria and urine sediments _SLE, vasculitis . Hematuria , hemoglobinuria,hemosiderinuria –AIHA (intravascular hemolysis ) Oliguria / anuria_AIHA , lupus nephritis.

21. Hematological investigation Hemoglobin –indicate anaemia RBC indices Normocytic normochromic anaemia Macrocytic anaemia-pernicious anaemia AIHA Autoagglutination Microspherocytes Schistocytes Tear drop cells

22. WBC and Platelet count Eosinophilia - Churg strauss syndrome. PMN leucocytosis-vasculitis Leucopenia / lymphopenia -SLE Platelet count Decreased-ITP, SLE, RA, scleroderma Increased- W egner granulomatosis ESR elevated(indirect measure of inflammatory process)

23. Biochemical test Serum Bilirubin Elevated in AIHA,PBC,PSC Elevated ALP/SGOT/SGPT- A utoimmune hepatitis Elevated GGT/ALP/SGOT/SGPT -PSC/PBC Elevated RFT - Vasculitis , SLE

24. Autoimmune diseases Laboratory diagnosis AIHA Coombs test : Red cells are incubated with an anti- human IgG antiserum. If autoantibodies are present –cells will get agglutinated. Goodpasture syndrome Biopsies from patients are stained with fluorescent labelled anti – IgG and anti C3b Linear deposits of IgG and C3b along the basement membranes.

25. SLE Autoantibody detection using IFA and ELISA . ANA –more sensitive (positive in >90%) Anti – ds DNA-highly specific. Anti- Sm antibodies. Lupus band test :Direct IFA Detect the deposits of Ig and complement proteins in patients skin . Scleroderma Anti Scl 70 antibody is raised Detect by indirect IFA

26. Sjogrens syndrome SS-A(or anti-Ro Ab ) SS-B(or anti-La Ab ) By indirect IFA Rheumatoid arthritis RF and Anti CCP RF are autoantibodies directed against Fc portion of the IgG . Detected (LAT/ Nephlometry /ELISA 80% Sensitivity and specificity. Anti-CCP ELISA 95% Specificity and 70% sensitivity .

27. INDIRECT IMMUNOFLUORESCENT ASSAY

28. ANCA Test Directed against Ag that reside within the primary granules of neutrophils and monocytes . Two types of ANCA are relevant to vasculitis MPO( myeloperoxidase )- pANCA PR3( proteinase 3)- cANCA ANCA titres measured using IIF and ELISA.

29. Major histocompatibility complex(MHC) MHC Class I and II genes are the major genetic determinants of susceptibility to many autoimmune diseases. Detected using gel electrophoresis, PCR, ELISA.

30. References Jones,Owen J Kuby Immunology 8 th edition New York: Macmillian education:2019. Harrison principles of internal medicine 20 th edition. Christine Stevens clinical immunology and serology.Laboratory perspective 4 th edition. Sastry AS, Bhat S. Essentials of medical microbiology. JP Medical Ltd 3 rd edition. Ananthanarayanan and Panikers textbook of microbiology 12 th edition .