pathogenetic issues of igg4 related diseases

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Post on 31-May-2015



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presented in kolkata on 24th december 2013


  • 1. Speaker Dr. Dibbendhu KhanraChairperson Dr. Debasish Basu

2. 44 M: Thailand Asthmatic54 M: Indian Atopic dermatitis64 M: Japanese Ascites/ Pedal edemaSjogrens syndrome Lymphoma SSA/B, Bx ve, CA pancreus CA 19-9 ve Bx- nonmalignantB/L Hydronephrosis IVC obstruction Retroperitoneal fibrosisWhat is common? 3. What is common? ClinicallySerologicallyPathologically Male Asian Age _ 50 Tumor Allergy Serum globin more Serum IgE more Serum IgG more Fibrosis Lymphoplasmcytosis No granulomaOutcome Good Response To SteroidsAre we chasing a chameleon? 4. History and evolutionN Engl J Med 2012;366:539-51 5. IgG4 related diseasesAtac et al. The rheumatologists 2013 6. Pathogenetic issues of IgG4 related diseases whats wrong with IgG4? why common in Asians? autoimmune/ allergic/ infective disease? constitutional symptoms? why multifocal fibro-inflammation? 7. IgG4 Fc-Fc interaction with other IgG4 antibodiesInter-heavy chain disulfide bond formationHalf antibody/ (Fab)arm exchange Asymmetric bi-specific antibody formation Negligible binding to C1q & Fc receptors. Does not activate complement pathway. Unable to crosslink antigens, thereby losing the ability to form immune complexes IgG4 is an anti-inflammatory antibody N Engl J Med 2012;366:539-51 8. Male (60-80%) Asian >50 yearsIgG4 related diseases: Potential Triggers HLA DRB1*0405 (Japanese) HLA DQ1-57 (Korean)Auto-antibodies directed against antigens expressed in various exocrine organsH. Pylori has been linked to AIP (molecular mimicry)N Engl J Med 2012;366:539-51 9. IgG4 related diseases: IgG4 class switchV/S allergic diseasesAllergic association (40%) IgG4 deposits are not pathogenicV/S autoimmune diseasesFibroinflammation N Engl J Med 2012;366:539-51Lack of constitutional symptoms 10. IgG4 related diseases: Cellular responsePlasma cells (IgG4 +ve) T cells moreV/S Malignancy: B cell LymphomaTumefactive enlargement of organs or sitesIt is unclear whether these organ dysfucntion are due to immune complexmediated tissue damage or are a bystander phenomenonSo, not all IgG4 looses bispecificity 11. IgG4 related diseases A new entityNew understanding of an existing diseaseMultiple diseases under the umbrella of same pathogenesis/ pathology 12. IgG4 related diseases Asian, male, >50 years multi-organ involvement subacute mass-like with compression lymphadenopathy lack of constitutional symptoms Polyclonal hyper-gammaglobulin serum IgG4 high (70%) tissue IgG4/ serum IgG4>50% Serum IgE may be high (40%) allergic assocaitions (40%) ANA positive (30%)Lymphoplasmacytic infiltaration. IgG4 positive. Neutrophils rare. Patterned Fibrosis: storiform, cartwheel No necrosis, No granuloma often self-limiting; watchful waiting is prudent good response with steroids increased risk of lymphoma and other malignancy 13. IgG4 related diseases chasing a chameleonMickulitz syndromeAIP Ormonds disease Retroperitoneal fibrosisDivided by presentation; united by histology 14. Pathogenetic issues: Demystified whats wrong with IgG4? sine-qua-non but not pathological why common in Asians? HLA associations autoimmune/ allergic/ infective disease? None; fibro inflammatory why no constitutional symptoms? Localized depositions why multifocal fibro-inflammation? most important cell T reg cells most important molecule TGFb most important by-product IgG4 15. When, in the wrong place, there is something, thats disorder. When, in the right place, there is nothing, thats order - BrechtThank you


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