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IgG4 related disorders of the eye

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Text of IgG4 related disorders of the eye

  • 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


  • 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


  • T Lymphocytes

    Dense fibrotic tissue and abundant IgG4+

    plasma cells suggest an underlying Modified

    Th2 immune response

    IL-13 & TGF- : Deposition of extracellular

    matrix by activated fibroblasts.

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

    switch in nave B Lymphocytes.

  • IHC and molecular studies have showed

    variable amounts of Th1, Th2 and T regulatory


    Altered IL-21 expression by follicular T helper

    cells has been associated with autoantibody


  • Macrophages

    Activated macrophages

    contribute to angiogenesis,


    wound-healing and fibrosis

    TGF- and PDGF

    CD163+ macrophages correlate with tissue


  • Ophthalmic IgG4-RD

    Orbital or periorbital:

    Orbital inflammatory pseudotumor

    Lacrymal Gland:

    Mikuliczs Disease

  • Clinical Features


    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,


  • 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


    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


    B lymphocytes tend to be organized in

    germinal centers.

  • Tissue Eosinophilia and


    Eosinophils are positive in 50% of cases.

    Granulomas argue strongly against IgG4 RD.

    Neutrophils and Necrosis are classically


  • Treatment



  • 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

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