IgG4-related disease and systemic vasculitis - is there any connection? Choroba IgG4-zależna a układowe zapalenie naczyń - czy istnieje jakiś związek?
01 Jan 2014-
TL;DR: The aim of this study is to draw attention to the fact that in some cases, both clinical presentation and histopathological findings in IgG4-related diseases and systemic vasculitis may be similar.
Abstract: Summary IgG4-related disease is a relatively new group of diseases of still unknown etiology. It is characterized by elevated serum levels of subclass IgG4 immunoglobulin and by abundant infiltration of IgG4+ plasma cells with typical fibrosis of the affected organs. Elevated concentration of IgG4 may be present in many other conditions associated with chronic inflammation. In recent years, it is noted that this may also apply to patients with systemic vasculitis, in particular antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. The aim of this study is to draw attention to the fact that in some cases, both clinical presentation and histopathological findings in IgG4-related diseases and systemic vasculitis may be similar. The importance of elevated serum IgG4 immunoglobulin in patients with ANCA-associated vasculitis (AAV) is unclear and requires further research.
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Vikram Deshpande1, Yoh Zen2, John Kc Chan, Eunhee E Yi3, Yasuharu Sato4, Tadashi Yoshino4, Günter Klöppel5, J. Godfrey Heathcote6, Arezou Khosroshahi1, Judith A. Ferry1, Rob C. Aalberse7, Daniel Bloch1, William R. Brugge1, Adrian C Bateman8, Mollie N. Carruthers1, Suresh T. Chari3, Wah Cheuk, Lynn D. Cornell3, Carlos Fernandez-del Castillo1, David G. Forcione1, Daniel L. Hamilos1, Terumi Kamisawa9, Satomi Kasashima, Shigeyuki Kawa10, Mitsuhiro Kawano11, Gregory Y. Lauwers1, Yasufumi Masaki12, Yasuni Nakanuma11, Kenji Notohara, Kazuichi Okazaki13, Ji Kon Ryu14, Takako Saeki, Dushyant V. Sahani1, Thomas C. Smyrk3, James Robert Stone1, Masayuki Takahira11, George Webster15, Motohisa Yamamoto16, Giuseppe Zamboni17, Hisanori Umehara12, John H. Stone1 •
Harvard University1, University of Cambridge2, Mayo Clinic3, Okayama University4, Technische Universität München5, Dalhousie University6, University of Amsterdam7, Southampton General Hospital8, Tokyo Metropolitan Komagome Hospital9, Shinshu University10, Kanazawa University11, Kanazawa Medical University12, Kansai Medical University13, Seoul National University14, University College London15, Sapporo Medical University16, University of Verona17
TL;DR: This statement proposes a terminology scheme for the diagnosis of IgG4-related disease that is based primarily on the morphological appearance on biopsy, and advocates the use of strict criteria for accepting newly proposed entities or sites as components of the IgG 4- related disease spectrum.
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Hisanori Umehara1, Kazuichi Okazaki2, Yasufumi Masaki1, Mitsuhiro Kawano3, Motohisa Yamamoto4, Takako Saeki, Shoko Matsui5, Tadashi Yoshino6, Shigeo Nakamura7, Shigeyuki Kawa8, Hideaki Hamano8, Terumi Kamisawa9, Toru Shimosegawa10, Akira Shimatsu, Seiji Nakamura11, Tetsuhide Ito11, Kenji Notohara1, Takayuki Sumida12, Yoshiya Tanaka, Tsuneyo Mimori13, Tsutomu Chiba13, Michiaki Mishima13, Toshifumi Hibi14, Hirohito Tsubouchi15, Kazuo Inui16, Hirotaka Ohara17 •
Kanazawa Medical University1, Kansai Medical University2, Kanazawa University3, Sapporo Medical University4, University of Toyama5, Okayama University6, Nagoya University7, Shinshu University8, Tokyo Metropolitan Komagome Hospital9, Tohoku University10, Kyushu University11, University of Tsukuba12, Kyoto University13, Keio University14, Kagoshima University15, Fujita Health University16, Nagoya City University17
TL;DR: The comprehensive diagnostic criteria for IgG4-RD are practically useful for general physicians and nonspecialists and have increased the sensitivity of diagnosis to 100% for Igg4-related MD, KD, and AIP.
Abstract: IgG4-related disease (IgG4-RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4+ plasma cells Although IgG4-RD is not rare and is clinically important, its clinical diagnostic criteria have not been established Comprehensive diagnostic criteria for IgG4-RD, including the involvement of various organs, are intended for the practical use of general physicians and nonspecialists Two IgG4-RD study groups, the Umehara and Okazaki teams, were organized by the Ministry of Health, Labor and Welfare Japan As IgG4-RD comprises a wide variety of diseases, these groups consist of physicians and researchers in various disciplines, including rheumatology, hematology, gastroenterology, nephrology, pulmonology, ophthalmology, odontology, pathology, statistics, and basic and molecular immunology throughout Japan, with 66 and 56 members of the Umehara and Okazaki teams, respectively Collaborations of the two study groups involved detailed analyses of clinical symptoms, laboratory results, and biopsy specimens of patients with IgG4-RD, resulting in the establishment of comprehensive diagnostic criteria for IgG4-RD Although many patients with IgG4-RD have lesions in several organs, either synchronously or metachronously, and the pathological features of each organ differ, consensus has been reached on two diagnostic criteria for IgG4RD: (1) serum IgG4 concentration >135 mg/dl, and (2) >40% of IgG+ plasma cells being IgG4+ and >10 cells/high powered field of biopsy sample Although the comprehensive diagnostic criteria are not sufficiently sensitive for the diagnosis of type 1 IgG4-related autoimmune pancreatitis (IgG4-related AIP), they are adequately sensitive for IgG4-related Mikulicz’s disease (MD) and kidney disease (KD) In addition, the comprehensive diagnostic criteria, combined with organ-specific diagnostic criteria, have increased the sensitivity of diagnosis to 100% for IgG4-related MD, KD, and AIP Our comprehensive diagnostic criteria for IgG4-RD are practically useful for general physicians and nonspecialists
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TL;DR: IgG4 by itself is unlikely to be a cause of allergic symptoms, but the presence of allergen‐specific IgG4 indicates that anti‐inflammatory, tolerance‐inducing mechanisms have been activated.
Abstract: Despite its well-known association with IgE-mediated allergy, IgG4 antibodies still have several poorly understood characteristics. IgG4 is a very dynamic antibody: the antibody is involved in a continuous process of half-molecules (i.e. a heavy and attached light-chain) exchange. This process, also referred to as 'Fab-arm exchange', results usually in asymmetric antibodies with two different antigen-combining sites. While these antibodies are hetero- bivalent, they will behave as monovalent antibodies in most situations. Another aspect of IgG4, still poorly understood, is its tendency to mimic IgG rheumatoid factor (RF) activity by interacting with IgG on a solid support. In contrast to conventional RF, which binds via its variable domains, the activity of IgG4 is located in its constant domains. This is potentially a source of false positives in IgG4 antibody assay results. Because regulation of IgG4 production is dependent on help by T-helper type 2 (Th2) cells, the IgG4 response is largely restricted to non-microbial antigens. This Th2-dependency associates the IgG4 and IgE responses. Another typical feature in the immune regulation of IgG4 is its tendency to appear only after prolonged immunization. In the context of IgE-mediated allergy, the appearance of IgG4 antibodies is usually associated with a decrease in symptoms. This is likely to be due, at least in part, to an allergen-blocking effect at the mast cell level and/or at the level of the antigen-presenting cell (preventing IgE-facilitated activation of T cells). In addition, the favourable association reflects the enhanced production of IL-10 and other anti-inflammatory cytokines, which drive the production of IgG4. While in general, IgG4 is being associated with non-activating characteristics, in some situations IgG4 antibodies have an association with pathology. Two striking examples are pemphigoid diseases and sclerosing diseases such as autoimmune pancreatitis. The mechanistic basis for the association of IgG4 with these diseases is still enigmatic. However, the association with sclerosing diseases may reflect an excessive production of anti-inflammatory cytokines triggering an overwhelming expansion of IgG4-producing plasma cells. The bottom line for allergy diagnosis: IgG4 by itself is unlikely to be a cause of allergic symptoms. In general, the presence of allergen-specific IgG4 indicates that anti-inflammatory, tolerance-inducing mechanisms have been activated. The existence of the IgG4 subclass, its up-regulation by anti-inflammatory factors and its own anti-inflammatory characteristics may help the immune system to dampen inappropriate inflammatory reactions.
697 citations