Analysis of IgG4 class switch-related molecules in IgG4-related disease

Tsuboi, Hiroto; Matsuo, Naomi; Iizuka, Mana; Tsuzuki, Sayaka; Kondo, Yuya; Tanaka, Akihiko; Moriyama, Masafumi; Matsumoto, Isao; Nakamura, Seiji; Sumida, Takayuki

doi:10.1186/ar3924

Cited by 95 publications

(87 citation statements)

References 21 publications

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“…IgG4 antibodies are supposed to be produced after long-term antigen exposure in response to interleukin (IL)-4 and IL-10 [61], but the molecular mechanisms that drive the IgG4 classswitch are not fully understood. Indeed, part of these mechanisms (e.g.…”

Section: The Role Of Igg4 Antibodiesmentioning

confidence: 99%

Immunology of IgG4-related disease

Della‐Torre

Lanzillotta

Doglioni

2015

Clinical and Experimental Immunology

187

215

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SummaryImmunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory condition that derives its name from the characteristic finding of abundant IgG4 1 plasma cells in affected tissues, as well as the presence of elevated serum IgG4 concentrations in many patients. In contrast to fibrotic disorders, such as systemic sclerosis or idiopathic pulmonary fibrosis in which the tissues fibrosis has remained largely intractable to treatment, many IgG4-RD patients appear to have a condition in which the collagen deposition is reversible. The mechanisms underlying this peculiar feature remain unknown, but the remarkable efficacy of B cell depletion in these patients supports an important pathogenic role of B cell/T cell collaboration. In particular, aberrant T helper type 2 (Th2)/ regulatory T cells sustained by putative autoreactive B cells have been proposed to drive collagen deposition through the production of profibrotic cytokines, but definitive demonstrations of this hypothesis are lacking. Indeed, a number of unsolved questions need to be addressed in order to fully understand the pathogenesis of IgG4-RD. These include the identification of an antigenic trigger(s), the implications (if any) of IgG4 antibodies for pathophysiology and the precise immunological mechanisms leading to fibrosis. Recent investigations have also raised the possibility that innate immunity might precede adaptive immunity, thus further complicating the pathological scenario. Here, we aim to review the most recent insights on the immunology of IgG4-RD, focusing on the relative contribution of innate and adaptive immune responses to the full pathological phenotype of this fibrotic condition. Clinical, histological and therapeutic features are also addressed.

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Section: The Role Of Igg4 Antibodiesmentioning

confidence: 99%

Immunology of IgG4-related disease

Della‐Torre

Lanzillotta

Doglioni

2015

Clinical and Experimental Immunology

187

215

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“…Th2 induces an allergic immune response with eosinophilia and increased serum IgE (8,9). Activated mast cells, strongly positive for IgE, promote the differentiation of naïve T cells to Treg cells (10).…”

Section: Pathogenesis Of Igg4-related Diseasementioning

confidence: 99%

“…The responsiveness to immunosuppressive therapy supports an autoimmune or other chronic inflammatory etiology. About 30-50% of patients have a history of allergies, eosinophilia and/or elevated serum IgE levels (5, 6).In contrast to patients with autoimmune diseases supported by T helper 1 (Th1) or Th17-mediated immunity and production of inflammatory cytokines interleukin-2 (IL-2), interferon gamma, and tumor necrosis factor alpha, the patients with IgG4-RD have mainly up-regulated responses of Th2 (cytokines IL-4, IL-5, IL-13, and IL-21) and regulatory T (Treg) cells (IL-10 and transforming growth factor beta 1 (TGF-β1)) (7).Th2 induces an allergic immune response with eosinophilia and increased serum IgE (8,9). Activated mast cells, strongly positive for IgE, promote the differentiation of naïve T cells to Treg cells (10).…”

mentioning

confidence: 99%

IgG4-related disease: A relatively new concept for clinicians

Vasaitis

2016

European Journal of Internal Medicine

105

129

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IgG4-related disease (IgG4-RD) is a recently recognized chronic fibrotic inflammation, which can affect almost every organ, and may come to clinical attention first due to visible organ swelling or organ dysfunction, or is identified incidentally by imaging and specific biopsy.The disorder has an allergic background and is immune-mediated. Up-regulated responses of T helper 2 and T regulatory cells and their cytokines play a major role in disease progression.About 30-50% of patients are atopic or have mild eosinophilia. IgG4-RD predominantly affects middle-aged male patients. The cornerstones of diagnosis of the disease are compatible clinical features and typical histopathology. Swelling of salivary and lacrimal glands, lymphadenopathy, and type 1 autoimmune pancreatitis (AIP) are the most common manifestations of the disease. However, other tissues and organs, such as retroperitoneum, lung, kidney, aorta, upper airways, thyroid gland, meninges, heart, mesenterium and skin may be involved. Typical histopathology is lymphoplasmacytic infiltration abundant in IgG4-positive plasma cells, storiform-type fibrosis, and obliterative phlebitis. Elevated serum IgG4 concentration supports the diagnosis. Characteristic imaging features such as a "capsule-like rim" surrounding the pancreatic lesions is highly specific to type 1 AIP. 18F-fluorodeoxyglucose positron emission tomography/computed tomography enables mapping the sites of inflammation, permits evaluation of the extent of the disease, helps in guiding biopsy decision, and may be used in monitoring response to treatment. Glucocorticoids alone or in combination with B-cell depletion with rituximab induces prompt clinical response to IgG4-RD.This article reviews the current understanding, different clinical manifestations, and approaches to diagnosis and treatment of IgG4-RD. 3Highlights Ø IgG4-related disease is a chronic fibrotic inflammation.Ø The disease affects multiple organs, is progressive, and impairs function.Ø The disorder has an allergic background and is immune-mediated.Ø Compatible clinical signs and typical pathology are the basis for the diagnosis.Ø Glucocorticoids and/or B-cell depletion induces prompt clinical response.Immunoglobulin G4-related disease (IgG4-RD) is a chronic fibrotic inflammation, characterized by tissue infiltration by lymphocytes, IgG4-positive plasma cells, simultaneous development of fibrosis, and often, but not always, elevated serum levels of IgG4 (1, 2). The disease can affect multiple organs. Early diagnosis of IgG4-RD is not easy because of the indolent course of the disease with vague, nonspecific symptoms. It may first come to clinical attention as visible organ swelling or detected organ dysfunction due to fibrosis, or is identified incidentally by imaging and specific biopsy when the patient undergoes investigation of suspected tumor disease. Most forms of organ involvement in IgG4-RD, even in the advanced fibrotic stages, respond well to glucocorticoids (3, 4). 4A comprehensive search for all articles in E...

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“…Activation-induced cytidine deaminase (AID) is required for both CSR and SHM [14,15]. AID is expressed not only in secondary lymphoid organs but also in local tissues in salivary glands of Sjögren syndrome (SS) [16][17][18], nasal mucosa of allergic rhinitis [19,20] and bronchial asthma [21].…”

Section: Introductionmentioning

confidence: 99%

Analysis of IgG4-positive clones in affected organs of IgG4-related disease

Kakuchi

Yamada

Ito

et al. 2016

Modern Rheumatology

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Objective. We investigated class switch reaction (CSR) in affected organs and evaluated whether the same or genetically related clones exist in IgG4-RD.Methods. We studied three patients with IgG4-RD. Total cellular RNA was extracted from salivary glands and peripheral blood, and lung tissue. Activation-induced cytidine deaminase (AID) and immunoglobulin heavy chain third complementarity determining region (IgVH-CDR3) of IgM and IgG4 were detected by reverse transcription polymerase chain reaction. We analyzed the clonal relationship of infiltrating IgG4-positive cells, as compared with IgM. We determined the existence of common clones among organs and patients.Result. AID was expressed in salivary glands of all patients and lung tissue in one. Closely Conclusion. Our results demonstrate the existence of common antigen(s) shared by patients with IgG4-RD.

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Analysis of IgG4 class switch-related molecules in IgG4-related disease

Cited by 95 publications

References 21 publications

Immunology of IgG4-related disease

Immunology of IgG4-related disease

IgG4-related disease: A relatively new concept for clinicians

Analysis of IgG4-positive clones in affected organs of IgG4-related disease

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