presented in kolkata on 24th december 2013

1. Speaker
Dr. Dibbendhu
Khanra
Chairperson
Dr. Debasish
Basu

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. 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. History and evolution
N Engl J Med 2012;366:539-51

5. IgG4 related
diseases
Atac et al. The rheumatologists 2013

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. 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.  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. 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. 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. IgG4 related diseases
A new
entity
New understanding of
an existing disease
Multiple 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 chameleon
Mickulitz
syndrome
AIP
Ormond’s disease
Retroperitoneal fibrosis
Divided by presentation; united by histology

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

16. 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