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