Autoimmune diseases occur when the immune system attacks the body's own tissues and organs. There are several mechanisms that normally prevent this, including central tolerance in the thymus and bone marrow, and peripheral tolerance by regulatory T cells. A failure of these tolerance mechanisms can result in autoimmune diseases. Genetic and environmental factors also contribute to predisposing individuals. Autoimmune diseases can be organ-specific or affect multiple systems. Diagnosis involves detecting elevated levels of autoantibodies through various tests. Treatment aims to suppress immune induction and restore tolerance, as well as inhibit effector mechanisms causing organ damage.

1. AUTOIMMUNE DISEASES -E.SRIDURGA

2. INTRODUCTION Autoimmunity is defined as the presence of immune responses against self targets. It may be a harmless phenomenon however autoimmune disease can occur if these responses cause significant organ damage.

3. PATHOPHYSIOLOGY IMMUNOLOGICAL TOLERANCE : Central tolerance : Occurs during lymphocyte development &operates in thymus and bone marrow where there is deletion of the lymphocytes that recognise self antigens.This process is most active in fetal life,but continues as immature lymphocytes develop throughout life. Peripheral tolerance : Some autoreactive cells escape into the peripheral circulation, where they are suppressed by regulatory t cells.

4. contd.... This results in development of hyporesponsiveness in lymphocytes that encounter antigen in the absence of co-stimulatory signal that accompany inflammation. “ Immunologically previleged sites ” like eyes are inaccessible to autoreactive cells. Failure of these tolerance mechanisms results in autoimmune diseases.

5. PREDISPOSING FACTORS GENETIC: HLA gene is the most important autoimmune susceptibility gene ,that shapes the lymphocyte response. -Other contributing factors genes determining cytokine activity , co-stimulation & cell death . ENVIRONMENTAL : -women commonly affected. -infection -trauma -drug

6. CLASSIFICATION OF AUTOIMMUNE DISEASES ORGAN SPECIFIC:immune response directed against localised antigens. Grave’s disease Hashimoto’s thyroiditis Addison’s disease Pernicious anemia Type1 DM Sympathetic ophthalmoplegia Goodpasteure’s syndrome Pemphigus vulgaris Bullous pemphigoides Idiopathic thrombocytopenic purpura Autoimmune hemolytic anemia Myasthenia gravis

7. contd... MULTI SYSTEM:immune response directed to widespread targeted antigens Rheumatoid arthritis Dermatomyositis Primary biliary cirrhosis Autoimmune hepatitis Sjogren’s syndrome systemic sclerosis, mixed connective tissue disease, SLE.

8. GEL & COOMB’S CLASSN. OF HYPERSENSITIVITY DISEASES TYPE 1 : (Immediate hypersensitivity ) -IgE binds to mast cells and basophils, causing them to undergo degranulation and release several mediators. -It is not associated with autoimmune diseases,but causes allergy. TYPE 2: ( antibody mediated ) -Involve activation of complement by IgG or IgM binding to an antigenic cell causing cell killing. -It causes transfusion reaction. AU diseases caused are AU haemolytic anemia ,ITP, Goodpasteure’s Syndrome.

9. contd... TYPE 3: ( immune complex mediated ) -Ig G or IgM bind soluble antigen to form immune complexes which trigger classical complement pathway activation. -It causes serum sickness, farmer’s lung. -In AU diseases it causes SLE. TYPE4: ( Delayed type ) -Involves reactions by TD memory cells. First contact sensitizes person & Subsequent contacts elicit a reaction. -It causes acute cellular rejection. AU diseases caused are type 1 DM, Hashimoto’s thyroiditis.

10. INVESTIGATIONS AUTOANTIBODIES: Increased no. of autoantibodies help diagnosis & monitoring AU disease. -Normal range may vary depending on the method used. * A) RHEUMATOID FACTOR : It is the Ab directed against common (fc) region of IgG. -IgM is commonly tested. A titre of >1:40 or unit value >20 is diagnostic. -Conditions ass.with positive rh factor. -rh.arthritis,Sjogren’s syndrome, Mixed essential cryoglobulinemia,Primary biliary cirrhosis,SLE,SABE,TB,elderly. -Thus it has low sensitivity & specificity.

11. contd... B)ANTI-CCP ANTIBODY : -cyclic citrullinated peptide antibody. -It is more specific test for rh arthritis than rh factor. -In undifferentiated arthritis it may predict the likeliness of patient to develop rh arthritis. C)ANTINUCLEAR ANTIBODIES : -ANA are ab that bind to components of nucleus. -Ab titre of>1:80 is positive. -Pattern of immunofluorescence helps find the clinical subgroups. *Peripheral/rim pattern:SLE (100%sensitive) *Nucleolar staining:Diffuse scleroderma.

12. contd... -Specificity is low as it is seen SLE, scleroderma sjogren’s syndrome , dermatomyositis, mixed connective tissue diseases, auto immune hepatitis. ANTI-DNA ANTIBODIES : -Antibodies bind to double stranded DNA. -It is highly specific for SLE . -Very high titre indicates more severe disease involving renal &cns. -Antibodies to single stranded DNA are non specific.

13. CONDITIONS ASSOSIATED WITH ANTIBODIES TO EXTRACTABLE NUCLEAR ANTIGENS

14. Anti-centromere antibody Anti-histone antibody Anti-Jo-1 (anti-histidyl-tRNA synthetase) Anti-La antibody (anti-SS-B) Anti-ribonucleoprotein antibody (anti-RNP) CREST variant of scleroderma (sensitivity 60%, specificity 98%) Also occasionally found in primary Raynaud's syndrome. Drug induced lupus. Polymyositis, dermatomyositis or polymyositis-scleroderma overlap (20-30%). Particularly associated with interstitial lung disease. Sjögren's syndrome SLE (20-60%). Mixed connective tissue disease SLE, usually in conjunction with anti-Sm antibodies.

15. Anti-Ro antibody (anti-SS-A). Anti-RNA polymerase I. Anti-Smith antibody (Anti-Sm). Anti-topoisomerase I antibody (Anti-Scl70) SLE (35-60%): associated with photosensitivity, thrombocytopenia and subacute cutaneous lupus Maternal anti-Ro antibodies associated with neonatal lupus and congenital heart block Sjögren's syndrome (40-80%). Rapidly progressive diffuse scleroderma. Very specific for SLE (15-30%): associated with more benign prognosis. Diffuse scleroderma: associated with more severe organ involvement, including pulmonary fibrosis.

16. contd... ANTIPHOSPHOLIPID ANTIBODIES : - They are associated with development of venous & arterial thrombosis. -Also occur in primary antiphospholipid syndrome or as a complication of SLE(sec.antiphospholipid syndrome) -It can be detected in rhuematic , infetions & malignant conditions . -Commonest kind of antibodies are: *Anti cardiolipin antibody. *Lupus anticoagulant.

17. contd... ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODIES : -These are the IgG antibodies to cytoplasmic constituents of granulocytes. -Two patterns in association with vasculitic syndromes:

18. Contd… Cytoplasmic fluorescence (c-ANCA) -associated with ab to protienase 3 & it occurs in wegener’s granulomatosis. Perinuclear staining ( p-ANCA ) -ass. with ab to other cytoplasmic enzymes (MPO, lactoferrin, elastase ) -p-ANCA with myeloperoxidase ab is ass. with microscopic polyarteritis& churg-strauss vasculitis. -Atypical p-ANCA not ass. with MPO ulcerative colitis, autoimmune liver disease

19. contd... MEASURES OF COMPLEMENT ACTIVATION : -Quantification of complement components is useful in evaluation of immune complex diseases. -Complement pathway activation leads to decreased circulating C3 & C4 levels. -Serial measurement of C3 & C4 is useful in SLE monitoring.

20. TREATMENT Treatment focuses on : *Suppressing the induction of immunity. *Restoring normal regulatory mechanisms. *Inhibiting the effector mechanisms. Elimination of autoreactive cells Immunosuppressive / ablative therapies used. Prevention of immune activation Cytokine blockade

21. contd... Cytokine blockade Targets TNF or IL-1 that limit organ damage in some diseases. Biologicals that interface with T cell activation or delete B cells used to treat rheumatoid arthritis. Major therapeutic approach to AU disease is -Prevent target organ damage, -Support target organ function.

22. Thank you…..