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