IgG4 Related

DiseasesDr. Akshay Agarwal

Moderator: Dr. Ujwala M.

Introduction

IgG4-related disease is a newly recognized

fibro-inflammatory condition

Tumefactive lesions in multiple sites

Elevated serum IgG4 concentrations

Initially recognized in pancreas

Known as Autoimmune Pancreatitis in 2001.

Two types: Type 1 is now renamed as IgG4 RD

Organs involved are:

Biliary tree, salivary glands, periorbital tissues,

kidneys, lungs, lymph nodes, meninges, aorta,

breast, prostate, thyroid, pericardium and skin.

The histopathological features bear strikingly

similar and unique histopathological

appearance.

2.2 cases per 100,000

Middle aged to elderly men with sporadic

reports of paediatric cases

Multi-organ systemic disorder

Immunopathology of IgG4-RD

IgG4 antibodies are produced after long-term

antigen exposure in response to IL-4 & IL-10.

Complement activation

Activate CD4+ T cells

Pathogenesis

FAB Arm Exchange

Putative autoantigens have been proposed as

targets of antibody response in a proportion of

patients with IgG4 RD.

Molecular mimicry of H. pylori and pancreatic

self-proteins has been proposed.

B Lymphocytes

IgG4 RD has been associated with an increased risk of malignant lymphoid transformation, FISH and IHC has failed to identify monoclonality.

There is oligoclonal expansion of somatically hypermutated IgG4+ B cell clones supporting antigen-specific affinity maturation.

CD19, CD27 & CD38 positive; CD20-

Activated IgG4+ B cells and plasmablasts

indirectly activate CD4+ T cells surving as

effective antigen presenting cells.

Extensive T helper cell dependent activation

leads to sustained myofibroblast activation &

production of profibrotic cytokines.

B cell depletion

Treatment with anti-CD20 monoclonal

antibody induces a prompt clinical response

with drastic reduction in plasmablasts.

B cell depletion abrogates the secretion of

profibrotic cytokins by pathogenic T cell

populations.

T Lymphocytes

Dense fibrotic tissue and abundant IgG4+

plasma cells suggest an underlying Modified

Th2 immune response

IL-13 & TGF-β : Deposition of extracellular

matrix by activated fibroblasts.

IL-4 & IL-10 : Major inducer of IgG4 class

switch in naïve B Lymphocytes.

IHC and molecular studies have showed

variable amounts of Th1, Th2 and T regulatory

cytokines.

Altered IL-21 expression by follicular T helper

cells has been associated with autoantibody

production.

Macrophages

Activated macrophages

contribute to angiogenesis,

immunomodulation,

wound-healing and fibrosis

TGF-β and PDGF

CD163+ macrophages correlate with tissue

fibrosis.

Ophthalmic IgG4-RD

Orbital or periorbital:

Orbital inflammatory pseudotumor

Lacrymal Gland:

Mikulicz’s Disease

Clinical Features

indolent

High spiking fevers absent

Weight loss

Long standing history of allergies in 40% of pt.

Pseudotumor-like lesions

Mechanical compression, fibrotic masses

Exophthalmos

haemianopsia

Ptosis

Headache

Scleritis

Xerophthalmia

Johann von Mikulicz-Radeck,

1888

Mikulicz Disease

idiopathic, bilateral, painless, and symmetrical swelling of the lacrimal, parotid, and submandibular glands.

considered as a subtype of SjogrenSyndrome.

The enlargement of lacrimal and salivary glands is persistent and secretory dysfunction is either not detectable or slight.

Laboratory Diagnosis

Based solely on Histopathological

examination and clinical features

Serological and radiological lack sensitivity

and specificity

Serology:

Increase serum C-Reactive Protein

Increase ESR

Eosinophilia

Increased IgE in 30%

Increased IgG4 in 60-70% patients

Low titer antinuclear antibody

Positive for anti-sjogren syndrome and ANCA implicate other autoimmune disorders.

Radiology

Edema with sausage shaped pancreas

PET scan identifies active inflammation

Histopathological Findings

Dense storiform fibrosis

Obliterative phlebitis

Lymphoplasmacytic infiltrate

Mild to moderate eosinophilic infiltrate

Storiform Fibrosis

Irregularly whorled organization of collagen

bundles due to activation of myofibroblasts

following profibrotic stimuli provided by

inflammatory infiltrate

Storiform Fibrosis

Obliterative Phlebitis

Parital / complete occlusionof the lumina of

small and medium sized veins by

lymphoplasmacytic infiltrate

Extrinsic compression

Lymphoplasmacytic Infiltrate

Polyclonal or oligoclonal B and T

lymphocytes.

B lymphocytes tend to be organized in

germinal centers.

Tissue Eosinophilia and

Macrophages

Eosinophils are positive in 50% of cases.

Granulomas argue strongly against IgG4 RD.

Neutrophils and Necrosis are classically

absent.

Treatment

Corticosteroids

plasmapheresis

Conclusion

IgG4-related disease is a recently recognized multiorgan system condition with pathological features that are largely consistent across a wide range of organ systems.

Its presence in tissue in association with plasma cells provides a robust biomarker for diagnosis when interpreted in the proper histopathological and clinical contexts.

The diagnosis of IgG4-related disease requires

collaboration between the pathologist and the

treating physician.

The diagnosis of IgG4-related disease rests on

the combined presence of the characteristic

histopathological appearance and increased

numbers of IgG4 plasma cells.

Tissue IgG4 counts and IgG4:IgG ratios are

secondary in importance.

Thank You