AUTOIMMUNE AUTOIMMUNE DISEASESDISEASES -E.SRIDURGA

INTRODUCTIONINTRODUCTION

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.

PATHOPHYSIOLOGYPATHOPHYSIOLOGY

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.

contd....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.

PREDISPOSINGPREDISPOSING FACTORSFACTORS

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

CLASSIFICATIONCLASSIFICATION OFOF AUTOIMMUNEAUTOIMMUNE DISEASESDISEASES

ORGAN SPECIFIC:immune response directed against localised antigens.

Grave’s diseaseHashimoto’s thyroiditis

Addison’s diseasePernicious anemia

Type1 DMSympathetic ophthalmoplegia

Goodpasteure’s syndromePemphigus vulgaris

Bullous pemphigoidesIdiopathic thrombocytopenic

purpuraAutoimmune hemolytic anemia

Myasthenia gravis

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MULTI SYSTEM:immune response directed to widespread targeted

antigens

Rheumatoid arthritisDermatomyositis

Primary biliary cirrhosisAutoimmune hepatitisSjogren’s syndrome

systemic sclerosis,mixed connective tissue

disease,SLE.

GEL & COOMB’S CLASSN. GEL & COOMB’S CLASSN. OF HYPERSENSITIVITY OF HYPERSENSITIVITY DISEASESDISEASES

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.

contd...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.

INVESTIGATIONSINVESTIGATIONSAUTOANTIBODIES: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.

contd...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.

contd...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.

CONDITIONS ASSOSIATED WITH ANTIBODIES TO EXTRACTABLE NUCLEAR ANTIGENS

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 syndromeSLE (20-60%).

Mixed connective tissue diseaseSLE, usually in conjunction with anti-Sm antibodies.

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 lupusMaternal anti-Ro antibodies associated with neonatal lupus and congenital heart blockSjögren'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.

contd...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.

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

Contd…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

contd...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.

TREATMENTTREATMENT

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

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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.

Thank you…..