Pathogenetic issues of IgG4 related diseases


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presented in kolkata on 24th december 2013

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Pathogenetic issues of IgG4 related diseases

  1. 1. Speaker Dr. Dibbendhu Khanra Chairperson Dr. Debasish Basu
  2. 2. 44 M: Thailand Asthmatic 54 M: Indian Atopic dermatitis 64 M: Japanese Ascites/ Pedal edema Sjogren’s syndrome Lymphoma SSA/B, Bx –ve, CA pancreus CA 19-9 –ve Bx- nonmalignant B/L Hydronephrosis IVC obstruction Retroperitoneal fibrosis What is common?
  3. 3. What is common? Clinically Serologically Pathologically  Male  Asian  Age _ 50  Tumor  Allergy  Serum globin more  Serum IgE more  Serum IgG more  Fibrosis  Lymphoplasmcytosis  No granuloma Outcome Good Response To Steroids Are we chasing a chameleon?
  4. 4. History and evolution N Engl J Med 2012;366:539-51
  5. 5. IgG4 related diseases Atac et al. The rheumatologists 2013
  6. 6. Pathogenetic issues of IgG4 related diseases  what’s wrong with IgG4?  why common in Asians?  autoimmune/ allergic/ infective disease?  constitutional symptoms?  why multifocal fibro-inflammation?
  7. 7. IgG4 Fc-Fc interaction with other IgG4 antibodies Inter-heavy chain disulfide bond formation Half antibody/ (Fab)–arm exchange Asymmetric bi-specific antibody formation  Negligible binding to C1q & Fcγ 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. 8.  Male (60-80%)  Asian  >50 years IgG4 related diseases: Potential Triggers  HLA DRB1*0405 (Japanese)  HLA DQβ1-57 (Korean) Auto-antibodies directed against antigens expressed in various exocrine organs H. Pylori has been linked to AIP (molecular mimicry) N Engl J Med 2012;366:539-51
  9. 9. IgG4 related diseases: IgG4 class switch V/S allergic diseases Allergic association (40%) IgG4 deposits are not pathogenic V/S autoimmune diseases Fibroinflammation N Engl J Med 2012;366:539-51 Lack of constitutional symptoms
  10. 10. IgG4 related diseases: Cellular response Plasma cells (IgG4 +ve) T cells more V/S Malignancy: B cell Lymphoma Tumefactive enlargement of organs or sites It is unclear whether these organ dysfucntion are due to immune complex–mediated tissue damage or are a bystander phenomenon So, not all IgG4 looses bispecificity
  11. 11. IgG4 related diseases A new entity New understanding of an existing disease Multiple diseases under the umbrella of same pathogenesis/ pathology
  12. 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. 13. IgG4 related diseases – chasing a chameleon Mickulitz syndrome AIP Ormond’s disease Retroperitoneal fibrosis Divided by presentation; united by histology
  14. 14. Pathogenetic issues: Demystified  what’s 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. 15. When, in the wrong place, there is something, that’s disorder. When, in the right place, there is nothing, that’s order - Brecht Thank you