Download - Pathogenetic issues of IgG4 related diseases
Pathogenetic issues ofIgG4 related diseases
SpeakerDr. Dibbendhu
Khanra
Chairperson
Dr. Debasish Basu
What is common?
44 M: Thailand Asthmatic 54 M: Indian
Atopic dermatitis 64 M: JapaneseAscites/ Pedal edema
Sjogren’s syndrome
LymphomaSSA/B, Bx –ve,
CA pancreusCA 19-9 –ve
Bx- nonmalignantB/L Hydronephrosis
IVC obstructionRetroperitoneal fibrosis
What is common?
Male Asian Age _ 50 Tumor Allergy
Clinically
Serum globin more Serum IgE more Serum IgG more
Serologically Pathologically
Fibrosis Lymphoplasmcytosis No granuloma
Outcome Good Response To Steroids
Are we chasing a chameleon?
History and evolution
N Engl J Med 2012;366:539-51
IgG4 related diseases
Atac et al. The rheumatologists 2013
Pathogenetic issues ofIgG4 related diseases
what’s wrong with IgG4?
why common in Asians?
autoimmune/ allergic/ infective disease?
constitutional symptoms?
why multifocal fibro-inflammation?
IgG4
Negligible binding to C1q & Fcγ receptors. Does not activate complement pathway.
Unable to crosslink antigens, thereby losing the ability to form immune complexes
Inter-heavy chain disulfide bond formation
Fc-Fc interaction with other IgG4 antibodies
Asymmetric bi-specific antibody formation
N Engl J Med 2012;366:539-51
Half antibody/ (Fab)–arm exchange
IgG4 is an anti-inflammatory antibody
HLA DRB1*0405 (Japanese) HLA DQβ1-57 (Korean)
Male (60-80%) Asian >50 years
H. Pylori has been linked to AIP
(molecular mimicry)
Auto-antibodies directed against antigens expressed
in various exocrine organs
IgG4 related diseases: Potential Triggers
N Engl J Med 2012;366:539-51
IgG4 related diseases: IgG4 class switch
N Engl J Med 2012;366:539-51
Allergic association
(40%)
V/S autoimmune
diseases
V/S allergic diseases
Fibro-inflammation
IgG4 deposits are not
pathogenic
Lack of constitutional symptoms
IgG4 related diseases: Cellular response
Plasma cells(IgG4 +ve)T cells more
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
V/SMalignancy:
B cell Lymphoma
So, not all IgG4 looses bispecificity
IgG4 related diseases
A new entity
New understanding of an existing disease
Multiple diseases under the umbrella of
same pathogenesis/ pathology
Lymphoplasmacytic infiltaration. IgG4 positive. Neutrophils rare. Patterned Fibrosis: “storiform”, “cartwheel” No necrosis, No granuloma
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%)
often self-limiting; watchful waiting is prudent good response with steroids increased risk of lymphoma and other malignancy
IgG4 related diseases
IgG4 related diseases – chasing a chameleon
Divided by presentation; united by histology
Mickulitz syndrome
AIP
Ormond’s diseaseRetroperitoneal fibrosis
Pathogenetic issues:Demystified
what’s wrong with IgG4?
why common in Asians?
autoimmune/ allergic/ infective disease?
why no constitutional symptoms?
why multifocal fibro-inflammation? most important cell – T reg cells
most important molecule – TGFb
most important by-product – IgG4
sine-qua-non but not pathological
HLA associations
None; fibro inflammatory
Localized depositions
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