Serum levels of IgG and IgG4 in Hashimoto thyroiditis.

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Kawashima, Sachiko-Tsukamoto; Tagami, Tetsuya; Nakao, Kanako; Nanba, Kazutaka; Tamanaha, Tamiko; Usui, Takeshi; Naruse, Mitsuhide; Minamiguchi, Sachiko; Mori, Yusuke; Tsuji, Jun; Tanaka, Issei; Shimatsu, Akira

2014-03-01

Although IgG4-related disease is characterized by extensive infiltration of IgG4-positive plasma cells and lymphocytes of various organs, the details of this systemic disease are still unclear. We screened serum total IgG levels in the patients with Hashimoto thyroiditis (HT) to illustrate the prevalence of IgG4-related thyroiditis in HT. Twenty-four of 94 patients with HT (25.5%) had elevated serum IgG levels and their serum IgG4 was measured. Five of the 24 cases had more than 135 mg/dL of IgG4, which is the serum criterion of IgG4-related disease. One was a female patient who was initially treated as Graves' disease and rapidly developed a firm goiter and hypothyroidism. The biopsy of her thyroid gland revealed that follicular cells were atrophic with squamous metaplasia, replaced with fibrosis, which was compatible with the fibrous variant of HT. Immunohistochemical examination revealed diffuse infiltration of IgG4-positive plasma cells, and the serum IgG4 level was 179 mg/dL. The levels of IgG and IgG4 were positively correlated with the titers of anti-thyroglobulin antibody or anti-thyroid peroxidase antibody. In conclusion, at least a small portion of patients with HT with high titers of anti-thyroid antibodies may overlap the IgG4-related thyroiditis.

Histopathologie der IgG4-RD

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Detlefsen, S; Klöppel, G

2016-01-01

infiltrate, 2) storiform fibrosis and 3) obliterative phlebitis. The diagnosis is further supported by immunohistochemical demonstration of an increased infiltration of IgG4-positive plasma cells and an elevated IgG4/IgG ratio. The morphological criteria of IgG4-RD are in most cases detectable in biopsies...

Cholangiocarcinoma with respect to IgG4 Reaction

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Kenichi Harada

2014-01-01

Full Text Available IgG4 reactions marked by infiltration of IgG4-positive plasma cells in affected organs occur in cancer patients and in patients with IgG4-related diseases. Extrahepatic cholangiocarcinomas including gall bladder cancer are often accompanied by significant IgG4 reactions; these reactions show a negative correlation with CD8-positive cytotoxic T cells, suggesting that the evasion of immune surveillance is associated with cytotoxic T cells. The regulatory cytokine IL-10 may induce IgG4-positive plasma cell differentiation or promote B cell switching to IgG4 in the presence of IL-4. Cholangiocarcinoma cells may function as nonprofessional antigen presenting cells that indirectly induce IgG4 reactions via the IL-10-producing cells and/or these may act as Foxp3-positive and IL-10-producing cells that directly induce IgG4 reactions. Moreover, IgG4-related disease is a high-risk factor for cancer development; IgG4-related sclerosing cholangitis (IgG4-SC cases associated with cholangiocarcinoma or its precursor lesion biliary intraepithelial neoplasia (BilIN have been reported. IgG4-positive cell infiltration is an important finding of IgG4-SC but is not a histological hallmark of IgG4-SC. For the diagnosis of IgG4-SC, its differentiation from cholangiocarcinoma remains important.

Increased IgG4-Positive Plasma Cells in Granulomatosis with Polyangiitis: A Diagnostic Pitfall of IgG4-Related Disease

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Sing Yun Chang

2012-01-01

Full Text Available Granulomatosis with polyangiitis (Wegener’s (GPA may mimic IgG4-related disease (IgG4-RD on histologic examination of some biopsies, especially those from head and neck sites. IgG4 immunostain is often performed in this context for differential diagnosis with IgG4-RD. However, the prevalence of IgG4+ cells in GPA has not been explored. We examined the IgG4+ cells in 26 cases confirmed as GPA by a thorough clinical and pathologic assessment. Twenty-six biopsies consisted of 14 sinonasal/oral cavity/nasopharynx, 7 orbit/periorbital, 3 lung/pleura, 1 iliac fossa/kidney, and 1 dura specimens. Eight of 26 (31% biopsies revealed increased IgG4+ cells (>30/HPF and >40% in IgG4+/IgG+ ratio. The IgG4+ cells and IgG4+/IgG+ ratio ranged 37–137/hpf and 44–83%, respectively. Eight biopsies with increased IgG4+ cells were from sinonasal (n=4 or orbital/periorbital (n=4 sites. In conclusion, increased IgG4+ cells are not uncommonly seen in sinonasal or orbital/periorbital biopsies of GPA, which could pose as a diagnostic pitfall.

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

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Kakuchi, Yasushi; Yamada, Kazunori; Ito, Kiyoaki; Hara, Satoshi; Fujii, Hiroshi; Yamagishi, Masakazu; Kawano, Mitsuhiro

2016-11-01

We investigated class switch reaction (CSR) in affected organs and evaluated whether the same or genetically related clones exist in IgG4-RD. 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 (RT-PCR). 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. AID was expressed in salivary glands of all patients and lung tissue in one. Closely related IgVH-CDR3 sequences in infiltrating IgG4-positive cells were detected in salivary glands and lung tissue. Identical IgVH-CDR3 sequence between IgM and IgG4 in salivary glands was detected in one patient, indicating CSR in salivary glands. Identical IgVH-CDR3 sequences of IgG4-positive cells were detected between salivary glands and peripheral blood in two patients. Four identical sequences of IgVH-CDR3 existed between patients. Interestingly, one of the four sequences was detected in all patients. Our results demonstrate the existence of common antigen(s) shared by patients with IgG4-RD.

Clinicopathological Analysis of Ocular Adnexal Extranodal Marginal Zone B-Cell Lymphoma with IgG4-Positive Cells

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Lee, Min Joung; Kim, Namju; Choe, Ji-Young; Khwarg, Sang In; Jeon, Yoon Kyung

2015-01-01

This study aims to analyze clinical and pathological characteristics of ocular adnexal extranodal marginal zone B-cell lymphoma (EMZL) accompanying IgG4-positive cells. Fifty patients with a diagnosis of primary non-conjunctival ocular adnexal EMZL were enrolled in this study. The number of IgG4-positive cells and the ratio of IgG/IgG4 were evaluated by immunohistochemistry in the biopsy specimens. The patients were divided into two groups based on the absolute number and the ratio of IgG4-positive cells (IgG4-posivite vs IgG4-negative groups). The demographic data, clinical staging at diagnosis, histopathological characteristics, and response to initial treatment were comparatively analyzed between the 2 groups. Five (10%) of 50 patients were defined as IgG4-positive group, and all the cases showed characteristic histological features such as extensive plasma cell infiltration and dense fibrosis. Most of these patients (4 of 5 patients) had lymphoma of the lacrimal gland. The patients from the IgG4-positive group showed a lower response rate to initial treatment (87.5 vs 33%, p = 0.03) than IgG4-negative group with a median follow-up period of 38 months. A part of the ocular adnexal EMZLs were accompanied with IgG4-positive cells. Significantly, most IgG4-positive ocular adnexal EMZLs occurred in the lacrimal gland, and can be related with a more frequent treatment failure. PMID:26111022

Histopathology of IgG4-Related Autoimmune Hepatitis and IgG4-Related Hepatopathy in IgG4-Related Disease.

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Nakanuma, Yasuni; Ishizu, Yoji; Zen, Yoh; Harada, Kenichi; Umemura, Takeji

2016-08-01

Immunoglobulin G4-related disease (IgG4-RD) is a systemic disease involving many organs; it includes IgG4-related sclerosing cholangitis and inflammatory pseudotumor in the hepatobiliary system. Two types of hepatic parenchymal involvement have been reported in IgG4-RD: IgG4-related autoimmune hepatitis (AIH) and IgG4-hepatopathy. Moreover, only three cases of IgG4-related AIH have been reported. Immunoglobulin G4-related AIH is clinicopathologically similar to AIH, except for an elevated serum IgG4 level and heavy infiltration of IgG4-positive plasma cells in the liver tissue. Interestingly, IgG4-related AIH can be complicated by well-known IgG4-RD(s). Immunoglobulin G4-hepatopathy, which includes various histopathological lesions encountered in the liver of patients with type I autoimmune pancreatitis, is classified into five histological categories: portal inflammation, large bile duct damage, portal sclerosis, lobular hepatitis, and cholestasis. Immunoglobulin G4-hepatopathy is currently a collective term covering hepatic lesions primarily or secondarily related to IgG4-related sclerosing cholangitis and type 1 autoimmune pancreatitis. In conclusion, the liver is not immune to IgG4-RD, and at least two types of hepatic involvement in IgG4-RD have been reported: IgG4-related AIH and IgG4-hepatopathy. Additional studies are required to clarify their precise clinical significance with respect to IgG4-RD and inherent liver diseases. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Are Classification Criteria for IgG4-RD Now Possible? The Concept of IgG4-Related Disease and Proposal of Comprehensive Diagnostic Criteria in Japan

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Kazuichi Okazaki

2012-01-01

Full Text Available Recent studies suggest simultaneous or metachronous lesions in multiorgans characterized by elevated serum levels of IgG4 and abundant infiltration of IgG4-positive plasma cells with various degrees of fibrosis. Two Japanese research committees for IgG4-RD, one from fibrosclerosis (Okazaki team and the other from lymph proliferation (Umehara team supported by the “Research Program for Intractable Disease” of the Ministry of Health, Labor, and Welfare of Japan, have agreed with the unified nomenclature as “IgG4-RD” and proposed the comprehensive diagnostic criteria (CDC for IgG4-RD. Validation of the CDC demonstrated satisfactory sensitivity for the practical use of general physicians and nonspecialists but low sensitivity in the organs to be difficult in taking biopsy specimens such as type1 autoimmune pancreatitis (IgG4-related AIP, compared with IgG4-related sialadenitis/dacryoadenitis (Mikulicz's disease and IgG4-related kidney disease. Although the diagnostic criteria covering all IgG4-RD are hard to be established, combination with the CDC and organ-specific diagnostic criteria should improve sensitivity.

IgG4-related disease

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Detlefsen, Sönke; Klöppel, Günter

2018-01-01

disease (IgG4-RD). The histologic key findings are lymphoplasmacytic infiltration rich in IgG4-positive plasma cells combined with storiform fibrosis and obliterative phlebitis. Among the organs mainly affected by IgG4-RD are the pancreas and the extrahepatic bile ducts. The pancreatic and biliary...... alterations have been described under the terms autoimmune pancreatitis (AIP) and sclerosing cholangitis, respectively. These diseases are currently more precisely called IgG4-related pancreatitis (or type 1 AIP to distinguish it from type 2 AIP that is unrelated to IgG4-RD) and IgG4-related sclerosing...... cholangitis (IgG4-related SC). Clinically and grossly, both diseases commonly imitate pancreatic and biliary adenocarcinoma, tumors that are well known for their dismal prognosis. As IgG4-RD responds to steroid treatment, making a resection of a suspected tumor unnecessary, a biopsy is often required...

IgG4 and IgE co-positive group found in idiopathic orbital inflammatory disease

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Peng-Xiang Zhao

2018-01-01

Full Text Available AIM: To reveal the cytokines involved in idiopathic orbital inflammatory disease (IOID and the relationship between Th17 cells, IgE and IOID pathogenesis. METHODS: Whole blood samples were processed immediately after collection and serological IgG4, IgG, and IgE antibodies were tested using ELISA. IOID and orbital cavernous hemangioma (CH tissue samples underwent Bio-Plex multiplex cytokine detection. Hematoxylin-Eosin (HE staining of all paraffin samples suggested the histological features of IOIDs, and expressions of IgG4 and IL-17A in affected tissues were detected by immunohistochemistry. RESULTS: Among 40 IOID plasma samples, 52.5% (21/40 were positive for IgG4 and 25% (10/40 were positive for IgE. Overlapped IgG4 or IgE positive samples accounted for 22.5% (9/40. Therefore, IOID samples were separated into three groups. The IgE+/IgG4+ group had a relevantly lower level of pro-inflammatory cytokine expression. IL-4 (Th2 cell related, IL-10 and TGF-β1 (Treg cell immunity related were elevated in all three groups. Some of the Th17 cell related cytokines (i.e. IL-17A/F, IL-25, IL-23, and IL-33 displayed higher expression levels in the IgE-/IgG4- group compared to the other two groups. CONCLUSION: We discovered an IgG4-IgE co-positive group as well as Th17 cell immune involvement in IgG4-IgE co-negative subgtroup in IOID for the first time. The pathogenesis of IOID could differ from different subgroups according to the IgG4 and IgE detection. Therefore, we recommend that, Treatment stratagy should be made according to the clinical assessment of IgG4-IgE and Th17 profile detection.

IgG4 Aortitis: A Case Report.

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Marketkar, Shivali; LeGolvan, Mark

2017-04-03

IgG4 aortitis is one of the entities seen in the spectrum of IgG4-related disease (IgG4-RD). It is characterized by serologic (elevated serum IgG4) and histologic features including a lymphoplasmacytic infiltrate with increased numbers of IgG4-positive plasma cells, storiform fibrosis and obliterative phlebitis. Some studies have described a correlation between infections and IgG4 aortitis. We describe a patient with an aneurysm of the infrarenal descending abdominal aorta with features of IgG4-RD, as well as culture evidence of Streptococcus sanguis. [Full article available at http://rimed.org/rimedicaljournal-2017-04.asp].

The autoimmune IgG4 -associated endocrine pathology

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Marina Yu. Yukina

2017-11-01

Full Text Available Immunoglobulin G4-associated diseases (IgG4-AD arethe group of chronic progressive autoimmune fibro-inflammatory pathology of various organs and tissues, characterized by their enlargement and abundant infiltration of immunoglobulin G4-positive plasma cells, as well as an increase in the level of serum immunoglobulin G4 (IgG4.In most patients, the disease is characterized by a mild course.However, there is evidence of a high incidence of malignancies in patients with IgG4-AD.Among endocrine IgG4-associated pathologies, pancreatitis with outcome in diabetes mellitus, hypophysitis and thyroiditis are described. Laboratory examination usually reveals an increased level of IgG4. However, the concentration of IgG4 could not be used as the only diagnostic criterion.The possibility of plasmablastsdetermining as a marker of the disease is discussed.Among the imaging techniques CT, MRI and 18F-FDG-PET/CT are used.However, the most informative method of diagnosis is biopsy. Randomized clinical trials to determine clear recommendations for the treatment of IgG4-AD were not conducted.In most cases, glucocorticoids are prescribed, and immunosuppressive therapy is sometimes used.According to the results of recent studies, the genetically engineered drug rituximab is relatively effective in inducing remission of the disease.Given the high recurrence rate and the risk of malignancy, patients with IgG4-AD require careful long-term follow-up. Thus, the review describes the clinical manifestations of IgG4-AD, examines the possibilities of their diagnosis and presents the existing methods of treatment.However, given the fact that IgG4-AD became a separate group of autoimmune pathology less than 20 years ago, there are insufficient data on these diseases. Researches related to epidemiology, pathophysiology, diagnosis and effective treatment of IgG4-AD are actual.

Immunohistochemical analysis of IgA expression differentiates IgG4-related disease from plasma cell-type Castleman disease.

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Manabe, Akihiro; Igawa, Takuro; Takeuchi, Mai; Gion, Yuka; Yoshino, Tadashi; Sato, Yasuharu

2017-03-01

Plasma cell-type Castleman disease (PCD) is often encountered when differentiating IgG4-related disease (IgG4-RD). Given that serum IgA is often elevated in Castleman disease, we investigated whether IgA expression levels in histological specimens can be used to differentiate between the two diseases. Lymph node lesions obtained from 12 IgG4-RD and 11 PCD patients were analysed by immunohistochemistry with anti-IgG, -IgG4, and -IgA antibodies. In addition to all 12 cases of IgG4-RD, 8/11 cases (72.7 %) of PCD also met the diagnostic criteria of IgG4-RD (serum IgG4 ≥135 mg/dl and IgG4/IgG-positive cells ≥40 %). IgA-positive cells were sparsely and densely distributed in IgG4-RD and PCD cases, respectively. The median number of IgA-positive cells ± SD in all 12 cases of IgG4-RD was 31 ± 37 cells per three high-powered fields (3HPFs) (range 4-118 cells/3HPFs). In contrast, the median number of IgA-positive cells, which was significantly higher in all 11 cases of PCD, was 303 ± 238 cells/3HPFs (range 74-737 cells/3HPFs) (P IgG4-RD.

Clinical features of IgG4-related rhinosinusitis.

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Hanaoka, Machiko; Kammisawa, Terumi; Koizumi, Satomi; Kuruma, Sawako; Chiba, Kazuro; Kikuyama, Masataka; Shirakura, Satoshi; Sugimoto, Taro; Hishima, Tsunekazu

2017-09-01

IgG4-related disease is a systemic disease that affects various organs of the body. Aim of this study is to elucidate the clinical characteristics of IgG4-related rhinosinusitis. Clinical features, laboratory findings, radiological and endoscopic findings, associated disease, treatment and prognosis were retrospectively examined in 10 patients with IgG4-related rhinosinusitis. The age was 59.1±11.3 years old and male-to-female ratio was 1:1. The chief nasal complaints were hyposmia (n=4), nasal obstruction (n=3), and nothing (n=3). Serum IgG4 levels were elevated in all patients and the value was 740.4±472.4mg/dl. Other IgG4-related diseases were associated in all 10 patients, including IgG4-related sialadenitis (n=6), IgG4-related dacryoadenitis (n=5), and autoimmune pancreatitis (n=5). Imaging findings on CT/MRI were obstruction of the way of elimination (n=10), thickening of the sinus mucous membrane (n=10), and fluid in the sinus (n=6). All of the cases had bilateral findings. Nasal endoscopic findings were chiefly deviated nasal septum (n=5), polyps (n=4), edema of the mucous membrane (n=3). Histologically, abundant infiltration of IgG4 positive plasma cell and lymphocyte and an elevated IgG4+/IgG+ cell ration was detected in all 8 patients and 5 patients, respectively. Endoscopic sinus surgery was performed in 8 patients. Eight patients were treated with steroid therapy for other associated IgG4-related diseases. Symptoms improved in all 6 patients after an initial treatment (endoscopic surgery (n=5) and steroids (n=1)), but one patient suffered relapse. IgG4-related rhinosinusitis is a distinct entity of IgG4-related disease, and is associated in patients with multiple IgG4-related diseases. Copyright © 2017 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.

IgG4-related retroperitoneal fibrosis: a newly characterized disease.

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Lian, Linjuan; Wang, Cong; Tian, Jian-Li

2016-11-01

Retroperitoneal fibrosis (RPF) is a rare disease characterized by chronic, nonspecific inflammatory and sclerotic or fibrotic tissue in the periaortic or periiliac retroperitoneum that encases adjacent structures. There will be a series of clinical manifestations once the proliferated fibrous tissues encase the abdominal aorta, iliac arteries and urinary duct. RPF is generally divided into two types: idiopathic retroperitoneal fibrosis (IRPF) without identified pathogenesis, making up about two-thirds of cases, and secondary retroperitoneal fibrosis. Recent studies on Immunoglobulin G4-related disease (IgG4-RD) reveal that abundant infiltration of IgG4 positive plasma cells is found in biopsies on the mass of RPF of some IRPF patients, which is identified as one spectrum of IgG4-RD and is named IgG4-related RPF. IgG4-related RPF is often misdiagnosed as retroperitoneal visceral malignancy and is treated with surgery. In addition, because of its good response to glucocorticoid, early detection and treatment is important. We review the definition, epidemiology, clinical features, diagnostic criteria, treatment and prognosis of IgG4-related RPF in this article to raise awareness of this newly characterized disease. © 2016 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

IgG4-related nephropathy.

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Quattrocchio, Giacomo; Roccatello, Dario

2016-08-01

IgG4-related disease (IgG4-RD) is a recently recognized disorder, often with multiple organ involvement, characterized by dense tissue infiltration of IgG4-positive plasma cells, storiform fibrosis, obliterative phlebitis and frequently elevated serum IgG4 concentration. The kidney can be involved either directly or indirectly. The most frequent direct renal manifestations of IgG4-RD are IgG4-related tubulointerstitial nephritis (TIN) and membranous glomerulonephropathy. Retroperitoneal fibrosis (RPF) is another condition that is frequently IgG4-related and that can indirectly affect the kidney causing ureteral obstruction and hydronephrosis. Contrast-enhanced computerized tomography, magnetic resonance imaging and (18)F-fluorodeoxyglucose positron emission tomography/computed tomography show different imaging findings and are useful tools for monitoring therapeutic response. Steroid treatment is the first line of therapy, but relapsing or refractory forms of the disease are frequently observed and require more aggressive therapeutic approaches. At our centre, we treated three cases of aggressive IgG4-related TIN and two cases of IgG4-related RPF with an intensified, immune suppressive protocol, obtaining good results without severe adverse effects.

Prognostic significance of IgG4+ plasma cell infiltrates following neoadjuvant chemoradiation therapy for esophageal adenocarcinoma.

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Yakirevich, Evgeny; Lu, Shaolei; Allen, Danisha; Mangray, Shamlal; Fanion, Jacqueline R; Lombardo, Kara A; Safran, Howard; Resnick, Murray B

2017-08-01

Lymphoplasmacytic infiltrates in esophageal adenocarcinoma (EAC) tissue following chemoradiotherapy (CRT) reflect alterations in the tumor immunoenvironment. The presence and role of plasma cells in this process are poorly understood. Our aim was to characterize the IgG4+ plasma cell population in EAC following CRT. Seventy-one esophagectomy specimens post-CRT were compared with a surgery-only group of 31 EACs. The distribution, density, and ratio of IgG4+ and IgG+ plasma cells were evaluated by immunohistochemistry and correlated with clinicopathologic features, treatment response, and survival. In the CRT group, the presence of higher numbers of IgG4+ (≥ median of 94/high-power field) and IgG+ (≥ median of 225/high-power field) plasma cells and increased IgG4+/IgG+ ratio (≥ median of 41%) within ulcers was associated with complete or near-complete treatment response (P = .0077, P = .0503, and P = .0063, respectively). Lower tumor grade, smaller tumor size, and higher levels of IgG4+ plasma cells in posttherapy ulcers significantly correlated with better overall survival, whereas pretherapy clinical stage, posttherapy pathologic stage, smaller tumor size, and lower tumor grade were associated with longer recurrence-free survival. Multivariate analysis revealed that both posttherapy pathologic stage and high IgG4+ plasma cells in ulcers were independent predictors of overall survival (P = .05 and P = .01), whereas only posttherapy pathologic stage was associated with recurrence-free survival (P IgG4+ plasma cell infiltrate in EAC following CRT. The presence of increased IgG4+ plasma cells may be a novel reliable factor to predict prognosis of EAC patients following CRT. Copyright © 2017 Elsevier Inc. All rights reserved.

IgG4-related Disease of the Genitourinary Tract

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Mukul K. Divatia

2014-02-01

Full Text Available IgG4-related disease (IgG4-RD is a recently established albeit well recognized fibro-inflammatory condition with distinctive features including a characteristic histopathological appearance; a propensity to develop tumefactive lesions in multiple body sites; and oft elevated serum IgG4 levels. The consensus statement on IgG-4 RD equips practicing pathologists with a set of working guidelines for the diagnosis of pathologic lesions identified in a host of different organ system affected with this disease. The diagnosis of IgG4-RD requires the combined presence of the characteristic histopathological appearance and increased numbers of IgG4-positive plasma cells. The essential histopathological features include a dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis. Tissue IgG4-positive plasma cell counts and IgG4: IgG ratios are significant ancillary aids in establishing the diagnosis. The spectrum of IgG4-RD continues to expand and involve multiple body sites. The genitourinary system comprising of the kidneys, ureters, urinary bladder, urethra, prostate gland, testes and penis is one of the multiple organ systems to be affected by IgG4-RD. This review describes the clinical and histopathologic patterns of involvement of the genitourinary system by IgG4-RD, in association with serologic and radiological features. [J Interdiscipl Histopathol 2014; 2(1.000: 3-18

Diagnosis and Treatment of IgG4-Related Disease.

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Kamisawa, Terumi; Okazaki, Kazuichi

2017-01-01

It is critical to differentiate IgG4-related disease (IgG4-RD) from malignant tumor and similar disease of the affected organ to apply appropriate therapy and avoid unnecessary surgery. IgG4-RD is diagnosed on combination of typical radiological findings; elevation of serum IgG4 levels; histopathological findings of abundant infiltration of IgG4-positive plasma cells and lymphocytes, storiform fibrosis , and obliterative phlebitis ; association with other IgG4-related diseases; and response to steroids. Histopathological approach is particularly recommended. Systemic glucocorticoids are currently the first-line approach for IgG4-RD, and the indications are symptoms. The initial recommended dose of oral prednisolone for induction of remission is 0.6 mg/kg/day, administered for 2-4 weeks. This dose is gradually tapered to a maintenance dose of 2.5-5 mg/day over a period of 2-3 months. As IgG4-RD sometimes relapses after steroids, maintenance therapy is usually performed in Japan. However, as IgG4-RD patients are typically elderly and are at high risk of developing steroid-related complications, cessation of the medication should be attempted at least within 3 years. For relapsed IgG4-RD, re-administration or dose up of steroid is effective, but the addition of immunomodulatory drugs such as azathioprine has been considered to be appropriate. B cell depletion with rituximab (an anti-CD20 antibody) is effective, even in many patients in whom treatment with immunomodulatory drugs was unsuccessful. The short-term clinical, morphological, and functional outcomes of most IgG4-RD patients treated with steroid therapy are good, but the long-term outcomes are less clear due to several unknown factors such as relapse, developed fibrosis, and associated malignancy.

The role of IgG4 (+) plasma cells in the association of Hashimoto's thyroiditis with papillary carcinoma.

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Taşli, Funda; Ozkök, Güliz; Argon, Asuman; Ersöz, Didem; Yağci, Ayşe; Uslu, Adam; Erkan, Nazif; Salman, Tarik; Vardar, Enver

2014-12-01

Hashimoto's thyroiditis (HT) is considered to be a risk factor for the formation of papillary carcinoma. The association of IgG4-related sclerosing disease with tumor is reported to be as sporadic cases in many organs. In this study, it was intended to re-classify the HT diagnosed cases on the basis of the existence of IgG4 (+) plasma cells; to investigate the clinicopathologic and histopathologic features of the both groups; and in addition, to evaluate the papillary carcinoma prevalence in IgG4 (+) and IgG4 (-) HT cases as well as the prognostic parameters between these groups. Totally 59 cases between the years 2008-2013, 29 of which contain Hashimoto thyroiditis diagnosis in total thyroidectomy materials, and 30 of which contain the diagnosis of HT+papillary carcinoma, were included in the study. The materials were immunohistochemically applied IgG and IgG4; and the cases were classified in two groups as IgG4-positive HT and IgG4-negative HT containing cases, on the basis of IgG4/IgG rate. All histopathologic and clinicopathologic parameters between these two groups, as well as their association with papillary carcinoma were investigated. Thirty eight (64.4%) of total 59 cases were NonIgG4 thyroiditis, and 21 (35.5%) were IgG4 thyroiditis. Tumors were detected in 14 (36.8%) of the NonIgG4 thyroiditis cases, and in 16 (76.1%) of the IgG4 thyroiditis cases. The association of IgG4 thyroiditis with tumor is statistically significant (p thyroiditis cases. Perithyroidal extension was detected in six of the cases with tumor, and five of the six cases were IgG4 thyroiditis cases. The association of IgG4 (+) HT cases with increased papillary carcinoma prevalence is suggestive of that IgG4 (+) plasma cells can play a role in carcinogenesis in papillary carcinomas developed in HTs, without a chronic sclerosing ground. In addition, although the number of cases is limited, the high-association of IgG4 (+) plasma cells with adverse prognostic parameters such as

Pathomorphological characteristic of IgG4-related diseases

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O. O. Dyadyk

2016-08-01

Full Text Available IgG4-related diseases are a relatively new group of diseases of unknown etiology which are characterized by the development of fibrosis of organs with the presence of big amounts of IgG4-positive plasma-cells in the area of the lesions and increased levels of IgG4 in serum. The organs that may be affected are pancreas, salivary gland, and others, clinical cases of kidney damage are described as well. Renal involvement in IgG4-related diseases most often occurs on the type of tubulointerstitial nephritis, with the further development of acute or chronic kidney injury. The clinic may be represented by the pseudotumor of kidney, renal tissue heterogeneity on the results of CT-studies; acute or chronic renal disease; combination with other organ damage (autoimmune pancreatitis, sclerosing cholangitis, sclerosing lymphoplasmacytic cholecystitis, colitis, sialadenitis, retroperitoneal fibrosis, etc.. Laboratory findings include an increased level of IgG4 in the blood serum, hypocomplementemia, eosinophilia. Histologically, there is interstitial inflammation with many plasma cells, interstitial fibrosis, tubular atrophy, thickening of the tubular basement membrane, some cases are a type of membranous glomerulonephritis. The aim of the study is to identify the patients with IgG4-related diseases with renal impairment and widening the pathological database of such patients with renal impairment to determine the classification criteria of this pathological condition. Materials and methods will include the deceased kidney screening, screening of patients with autoimmune and allergic diseases, nephrological patients screening with the lifetime biopsy (in some cases – repeat biopsy with chronic or acute kidney impairment. There will be clinical and pathological comparison in kidney damage and other diseases with the development of criteria for the classification of lesions in the presence of IgG4-positive substrates and further development of practical

Recurrent Mastoiditis Mimics IgG4 Related Disease: A Potential Diagnostic Pitfall.

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Deshpande, Vikram; Zane, Nicolas A; Kraft, Stefan; Stone, John H; Faquin, William C

2016-09-01

IgG4-related disease (IgG4-RD) is a recently recognized entity that causes progressive fibrosis and formation of mass lesions. IgG4-RD can be diagnosed histologically by its hallmarks of storiform fibrosis, prominent lymphoplasmacytic infiltrate, and obliterative phlebitis, accompanied by the infiltration of excessive numbers of IgG4-positive plasma cells as well as elevations in serum IgG4 concentrations. A recent publication reported a case of IgG4-RD in the mastoid sinus, representing a new anatomic location for this disease. We report two additional cases of IgG4-RD occurring in the mastoid and causing clinical mastoiditis. The presenting symptoms were varied-tinnitus, hearing loss, and cranial nerve palsies. All three cases showed a dense lymphoplasmacytic infiltrate, storiform type fibrosis as well as elevated numbers of IgG4 positive plasma cells. The three patients responded to immunosuppressive therapy that included steroids and Rituximab. We further investigated 162 consecutive mastoiditis cases at our institution in order to determine the frequency of IgG4-RD as a previously unrecognized cause of mastoiditis. Within this latter cohort we identified nine cases of mastoiditis that had two of the histologic features of IgG4-RD, specifically storiform fibrosis and a dense lymphoplasmacytic infiltrate. Two of these cases showed >50 IgG4-positive plasma cells per high-power field with IgG4-IgG ratio of >40 %, thus fulfilling histological criteria for IgG4-RD. However, both were due to severe acute or chronic infection. In conclusion, we reaffirm IgG4 related mastoiditis as a distinct but uncommon cause of recurrent mastoiditis. The diagnosis of IgG4-related mastoiditis should be rendered with caution, and only after the exclusion of potential mimickers, particularly infection.

Clinical pathology observation on orbit IgG4 related disease

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Ji-Hua Guo

2015-09-01

Full Text Available AIM:To discuss clinical pathological features of orbit IgG4 related disease(IgG4-RD. METHODS: The clinical pathological materials of 23 patients(35 eyeswith orbit IgG4-RD were collected. They were observed in terms of histology and immunohistochemistry, and its clinical and pathologic characteristics were summarized. RESULTS: There were 23 patients(35 eyeswith orbit IgG4-RD(8 male patients, 9 eyes; 15 female patients, 26 eyes, with an average age of 52.1 year-old(from age 28 to 72. 19 patients(30 eyesoccured in lacrimal gland and 4 cases(5 eyesin other places, and they went to hospital for lacrimal gland cyst or exophthalmos. There were 11 cases in one side and 12 cases in both sides. The disease lasted from 1mo to 10a, averaging 27mo. It recureded in one patient(1 eyeafter 1mo. In general inspection: Gray nodular goiter, thin fibrous coat wrapping around the lacrimal gland could be observed. Histologic characteristics: lacrimal gland bubble and catheter group shrinked or even disappeared, substituted by lymphocyte, plasma cells and lymphoid follicle and accompanied with fibrosis. Immunohistochemical staining: IgG4 positive plasma cells of 23 cases(35 eyeswas >50/HPF, and IgG4/IgG ratio of positive plasma cells was >40%. CONCLUSION: Orbit IgG4-RD mainly occures in lacrimal gland tissue, and expression of IgG4 can be detected through histologic characteristics and immunohistochemical staining. IgG4-RD should be screened, prevented and treated in the early phase.

[IgG4 immunohistochemistry in Riedle thyroiditis].

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Wang, S; Luo, Y F; Cao, J L; Zhang, H; Shi, X H; Liang, Z Y; Feng, R E

2017-03-08

Objective: To observe the histopathological changes and immunohistochemical expression of IgG4 in Riedle thyroiditis (RT) and to study the relationship between RT and IgG4-related diseases (IgG4-RD). Methods: A total of 5 RT patients were collected from the Department of Pathology, Peking Union Medical College Hospital during April 2012 to August 2014. The clinical and immunohistochemical features were analyzed in the 5 patients. Histopathologic analysis was performed on hematoxylin and eosin-stained sections. Results: There were one male and four female patients, aged 52 to 78 years (median 59 years). Five cases were characterized by multiple nodules of thyroid, which increased year by year. All patients were found to have surrounding tissue compression symptoms and signs. Two female patients were found to have hypothyroidism. The serum concentration of IgG was elevated in 2 cases, and the serum concentration of IgG was not tested before operation in the remaining patients. By ultrasound, all presented as low echo or medium low echo. Strong echo occasionally appeared in hypoechoic nodules. Microscopically, fibrous tissue hyperplasia was infiltrated with varying numbers of lymphocytes and plasma cells. The occlusion of phlebitis was found in 4 cases and eosinophils were found in 3 cases. IgG4 counts and IgG4/IgG ratios in 5 cases were 20/HPF, 16%; 60/HPF, 82%; 22/HPF, 28%; 400/HPF, 266% and 33/HPF, 71%, respectively. Conclusions: With the similar pathological manifestations between RT and IgG4-RD, immunohistochemical staining shows that the number of IgG4 positive plasma cells and IgG4/IgG ratio of RT are increased in varying degrees. Some cases meet the diagnostic criteria of IgG4-RD, and speculate that some cases of RT belong to IgG4-RD.

IgG4-related disease in thymus. A very rare case of chronic fibrosis mimicking sarcoidosis.

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Simonetti, Sara; Pérez Muñoz, Noelia; López Vivancos, Josefa; Sanchez Sitjes, Lluís; Herranz Pérez, Javier Cesar; Leal Bohorquez, Nelson; Maestre Alcacer, José Antonio; de García, Inessa Koptseva; Carrasco García, Miguel Ángel

2017-11-15

IgG4-related disease (IgG4-RD) is a multi-organ immune-mediated chronic fibroinflammatory condition, with unclear certain etiology. It is morphologically characterized by storiform fibrosis, dense IgG4-positive lymphoplasmacytic infiltrate, and obliterative phlebitis. It was recognized as a systemic condition as recently as 2003. IgG4-RD has been described in virtually every organ, forming sclerosing masses, and often mimicking tumors. Clinically, patients present unspecific symptoms and this condition is often recognized incidentally. The epidemiology remains poorly studied, but it has been noted that in the majority of recorded instances, patients are middle-aged men. IgG4-RD could mimic conditions other than tumors, such as infection, inflammation, or other systemic disorders. To ensure accuracy of diagnosis, an exhaustive histopathological analysis is required, together with clinical, radiological, and serological data. Thymic fibrosis in the absence of other primary thymic lesions is a very rare occurrence; in English literature only 1 case has been reported with scattered IgG4 plasma cells infiltrate and focal obliterative phlebitis. We will describe, for the first time, the case of a 49-year-old man displaying an anterior mediastinic, hilar, and intramyocardial mass simulating a sarcoidosis, with a definitive diagnosis of IgG4-related thymic fibrosis extending to the mediastinum and the heart. At the histological examination, we found many features of IgG4-RD in the thymic tissue, such as diffused storiform fibrosis, dense lymphoplasmacytic infiltrate with abundant plasma cells IgG4 positive (ratio IgG/IgG4: 40%), obliterative phlebitis, eosinophilic infiltrate, and Castleman-like lymphoid follicles. We discussed the differential diagnosis and reviewed the literature and the other cases of IgG4-related diseases that had been diagnosed in our department.

IgG4-Related Disease Combined with Autoimmune Hemolytic Anemia and Steroid-Responsive Transient Hypercalcemia

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Sho Hasegawa

2015-01-01

Full Text Available A 67-year-old man with elevated serum immunoglobulin G4 (IgG4 levels, systemic lymphadenopathy infiltrated by IgG4-positive plasma cells, and Coombs-positive autoimmune hemolytic anemia (AIHA showed marked hypercalcemia. Although the intact parathyroid hormone (PTH level was elevated, 99mTc-MIBI scintigraphy and thyroid ultrasonography revealed no evidence of primary hyperparathyroidism. Liver biopsy showed marked infiltration of IgG4-positive plasma cells, which confirmed the diagnosis of IgG4-related disease (IgG4-RD. Corticosteroid therapy was initiated, and subsequently, intact PTH and serum calcium levels gradually normalized. Transient hypercalcemia in a patient with AIHA may therefore be associated with IgG4-RD.

Jugular Foramen Collision Tumor (Schwannoma and Plasma Cell Pseudotumor), a Probable IgG4-Related Disease.

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Bakhit, Mudathir S; Fujii, Masazumi; Jinguji, Shinya; Sato, Taku; Sakuma, Jun; Saito, Kiyoshi

2017-06-01

Lower cranial nerve sheath tumors are relatively rare. Cases of schwannoma collision tumors have rarely been reported, with most of the reported cases describing schwannoma and meningioma collision tumors. We report a very rare case of a cerebellopontine angle collision tumor of the ninth cranial nerve schwannoma with an IgG4 plasma cell pseudotumor. IgG4 plasma cell pseudotumors comprise a group of diseases called IgG4-related diseases (IgG4-RDs). These diseases usually affect organs such as the pancreas and salivary gland. Few cases of nervous system IgG4-RDs have been reported. Under intraoperative microscopy, the tumor in our case did not appear different from usual cases of schwannoma, but histopathology showed significant infiltration of IgG4 plasma cells. IgG4-RDs have a distinctive histopathologic pattern; however, their pathophysiology remains unclear. Special attention must be paid to the diagnosis of such diseases because they mimic other diseases and can be missed. Copyright © 2017 Elsevier Inc. All rights reserved.

Some histopathological aspects of the disease related to IgG-4

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Minerva Lazos-Ochoa

2015-04-01

Full Text Available The IgG4-related disease (IgG4-RD is a recurrent chronic fibroinflammatory disease, probably of autoimmune origin, recently recognised. Its diagnosis is based on a combination of clinical, radiological, serological, histopathological and immunohistochemical data. However, the histopathology is considered as the golden “standard” for diagnosis. In most of the cases, the sum of lymphoplasmacytic inflammatory infiltrate with abundant IgG4+ plasma cells, storiform fibrosis and obliterative phlebitis makes a reliable diagnosis. Patients usually show elevated serum IgG4 concentrations and respond well to steroid therapy. Nowadays, IgG4-RD has been described in almost every organ: pancreatobiliary tract, liver, salivary glands, nasopharynx, bone marrow, lacrimal gland, extra-ocular muscles and retrobulbar space, kidney, lung, lymph nodes, meninges, aorta, skin, breast, prostate, thyroid gland and pericardium.

Current Concept of IgG4-Related Disease.

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Okazaki, Kazuichi; Umehara, Hisanori

2017-01-01

IgG4-related disease (IgG4-RD) is a fibroinflammatory disease of unknown etiology, which is characterized by a tendency to form tumefactive lesions, increased serum levels of IgG4, and massive infiltration of IgG4-positive plasma cells with storiform fibrosis and/or obliterative phlebitis. Patients with IgG4-RD have frequently multiorgan involvements such as the pancreas, biliary tree, salivary glands, periorbital tissues, kidneys, lungs, lymph nodes, and retroperitoneum. IgG4-RD mainly affects middle-aged to elderly men except for involvement in lachrymal and salivary glands, so-called Mikulicz's disease. The clinical manifestations of IgG4-RD depend on individually involved organs and respond well to steroid, but the prognosis still remains unclear. Some patients develop serious complications such as obstructive jaundice due to hepatic, gallbladder, or pancreatic lesions; hydronephrosis due to retroperitoneal fibrosis; or respiratory symptoms due to pulmonary lesions. Nomenclatures of individual organ manifestation of IgG4-RD have been internationally consented.

IgG4 Cholangiopathy

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Yoh Zen

2012-01-01

Full Text Available IgG4 cholangiopathy can involve any level of the biliary tree which exhibits sclerosing cholangitis or pseudotumorous hilar lesions. Most cases are associated with autoimmune pancreatitis, an important diagnostic clue. Without autoimmune pancreatitis, however, the diagnosis of IgG4-cholangiopathy is challenging. Indeed such cases have been treated surgically. IgG4-cholangiopathy should be diagnosed based on serological examinations including serum IgG4 concentrations, radiological features, and histological evidence of IgG4+ plasma cell infiltration. Steroid therapy is very effective even at disease relapse. A Th2-dominant immune response or the activation of regulatory T cells seems to be involved in the underlying immune reaction. It is still unknown why IgG4 levels are specifically elevated in patients with this disease. IgG4 might be secondarily overexpressed by Th2 or regulatory cytokines given the lack of evidence that IgG4 is an autoantibody.

IgG4-Related Autoimmune Prostatitis: Is It an Unusual or Underdiagnosed Manifestation of IgG4-Related Disease?

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María T. Bourlon

2013-01-01

Full Text Available IgG4-related disease (IgG4-RD encompasses a wide range of extrapancreatic manifestations. Albeit some are relatively well known, others such as autoimmune prostatitis remain poorly described. We present a 61-year-old Latin-American male with autoimmune pancreatitis (AIP who presented with lower urinary tract symptoms (LUTS, normal prostate specific antigen (PSA test, and prostate enlargement attributed to benign prostatic hyperplasia (BPH. He underwent a transurethral resection of the prostate (TURP after which symptoms were resolved. On histopathology, prostatic stroma had a dense inflammatory infiltrate rich in plasma cells and lymphocytes; immunohistochemical morphometric assessment showed >10 IgG4-positive plasma cells/high power field (HPF. The diagnosis of IgG4-related prostatitis was postoperatively. We compared the patient characteristics with those of previous reports on Asian patients. Shared findings included prostate enlargement, LUTS (symptoms that can be confused with BPH, and PSA within normal limits or mild elevations. IgG4-related prostatitis is rarely considered as a preprocedural diagnosis, even in patients with evidence of IgG4-RD. Involved prostate zones include mainly central and transitional zones and less frequently the peripheral. Currently, there is insufficient data about the natural history and outcome. Whether steroids, transurethral resection, or both are the treatment of choice needs to be elucidated.

Orbital Pseudotumor: Uncommon Initial Presentation of IgG4-Related Disease

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Teresa Carbone

2015-01-01

Full Text Available IgG4-related disease (IgG4-RD encompasses a group of fibroinflammatory conditions recognized in recent times. The main clinical features include variable degrees of tissue fibrosis, tumorlike expansions, perivascular lymphocytic infiltration rich in IgG4-positive plasma cells, and elevated serum IgG4. A case has been reported of an elderly patient with an unexplained unilateral exophthalmia; biopsy was performed and revealed lymphocytic infiltration, suggesting IgG4-RD. High serum levels of IgG4, in association with a good response to steroid therapy and to the exclusion of other diagnoses, confirmed the hypothesis of orbital pseudotumor by IgG4-RD.

Clinicopathological features of Riedel's thyroiditis associated with IgG4-related disease in Japan.

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Takeshima, Ken; Inaba, Hidefumi; Ariyasu, Hiroyuki; Furukawa, Yasushi; Doi, Asako; Nishi, Masahiro; Hirokawa, Mitsuyoshi; Yoshida, Akira; Imai, Ryoukichi; Akamizu, Takashi

2015-01-01

Riedel's thyroiditis (RT) is a rare chronic fibrosing disorder characterized by a hard, infiltrative lesion in the thyroid gland, which is often associated with multifocal fibrosclerosis. Immunoglobulin G4-related disease (IgG4-RD) is typified by infiltration of IgG4-positive plasma cells into multiple organs, resulting in tissue fibrosis and organ dysfunction. In order to evaluate the clinicopathological features of RT and its relationship with IgG4-RD, we performed a Japanese literature search using the keywords "Riedel" and "Riedel's thyroiditis." We used the electronic databases Medline and Igaku Chuo Zasshi, the latter of which is the largest medical literature database in Japan. The diagnosis of RT was based on the presence of a fibroinflammatory process with extension into surrounding tissues. Only 10 patients in Japan fulfilled RT diagnostic criteria during the 25-year period between 1988 and 2012. Two patients with confirmed IgG4/IgG immunohistochemical findings demonstrated 43 and 13 IgG4-positive plasma cells per high-power field, respectively, and the IgG4-positive/IgG-positive plasma cell ratios of 20% and less than 5%. Of the 10 patients with RT, two received glucocorticoids, one of whom experienced marked shrinkage of the thyroid lesion. One patient had extra-thyroid involvement in the form of retroperitoneal fibrosis. Although the clinicopathological features of RT suggest that IgG4-RD may be the underlying condition in some cases, further investigation is needed to clarify the etiology of RT in relation to IgG4-RD.

IgG4-Related Disease: A Multispecialty Condition

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Iuri Usêda Santana

2014-01-01

Full Text Available IgG4-related disease (IgG4-RD is a recently recognized group of conditions, characterized by tumor-like swelling of involved organs, lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, variable degrees of fibrosis, and elevated serum IgG4 concentrations. Currently IgG4-RD is recognized as a systemic condition that can affect several organs and tissues. Herein we report the case of a 34-year-old male patient who was admitted to our hospital with diffuse abdominal pain, weight loss, and painful stiffness in his neck. He had a history of tumoral mass of the left maxillary region, right palpebral ptosis with protrusion of the eyeball, and chronic dry cough for about 6 years. Laboratory tests revealed polyclonal hypergammaglobulinemia and increased serum IgG4 levels. Immunohistochemical staining of the maxillary biopsy was compatible with IgG4-RD. He had an excellent response to corticosteroid therapy. This case highlights that IgG4-RD should be included in the differential diagnosis with multisystem diseases.

Severe IgG4-Related Disease in a Young Child: A Diagnosis Challenge

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Susana Corujeira

2015-01-01

Full Text Available Immunoglobulin G4-related disease (IgG4-RD is an increasingly recognized syndrome that can appear with multiple organ involvement, typically with tumor-like swelling, lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, and elevated serum IgG4 concentrations. We report the case of a 22-month-old female child with failure to thrive and recurrent respiratory tract infections since 8 months of age. Physical examination was normal except for pulmonary auscultation with bilateral crackles and wheezes. Laboratory tests revealed elevated erythrocyte sedimentation rate, and elevated serum IgG and IgG4 with polyclonal hypergammaglobulinemia. Thoracic CT and MRI showed multiple mediastinal lymphadenopathies and a nodular posterior mediastinal mass in right paratracheal location with bronchial compression. Initial fine needle aspiration biopsy was compatible with reactive lymphadenopathy but after clinical worsening a thoracoscopic partial resection of the mass was performed and tissue biopsy revealed lymphoplasmacytic infiltrate and increased number of IgG4-positive plasma cells and a ratio of IgG4/IgG positive cells above 40%. Glucocorticoids therapy was started with symptomatic improvement, reduction in the size of the mass, and decrease of serum IgG4 levels after 6 weeks. There are very few reports of IgG4-RD in children. Long-term follow-up is necessary to monitor relapses and additional organ involvement.

Isolated Mass-Forming IgG4-Related Cholangitis as an Initial Clinical Presentation of Systemic IgG4-Related Disease

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Seokhwi Kim

2016-07-01

Full Text Available IgG4-related disease (IgG4-RD may involve multiple organs. Although it usually presents as diffuse organ involvement, localized mass-forming lesions have been occasionally encountered in pancreas. However, the same pattern has been seldom reported in biliary tract. A 61-year-old male showed a hilar bile duct mass with multiple enlarged lymph nodes in imaging studies and he underwent trisectionectomy under impression of cholangiocarcinoma. Gross examination revealed a mass-like lesion around hilar bile duct. Histopathologically, dense lymphoplasmacytic infiltration and storiform fibrosis were identified without evidence of malignancy. Immunohistochemical stain demonstrated rich IgG4-positive plasma cell infiltration. Follow-up imaging studies disclosed multiple enlarged lymph nodes with involvement of pancreas and perisplenic soft tissue. The lesions have been significantly reduced after steroid treatment, which suggests multi-organ involvement of systemic IgG4-RD. Here, we report an unusual localized mass-forming IgG4-related cholangitis as an initial presentation of IgG4-RD, which was biliary manifestation of systemic IgG4-related autoimmune disease.

A small subgroup of Hashimoto's thyroiditis is associated with IgG4-related disease.

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Jokisch, Friedrich; Kleinlein, Irene; Haller, Bernhard; Seehaus, Tanja; Fuerst, Heinrich; Kremer, Marcus

2016-03-01

IgG4-related disease is a newly identified syndrome characterized by high serum IgG4 levels and increased IgG4-positive plasma cells in involved organs. The incidence of IgG4-related thyroiditis in the Caucasian population of Europe is unknown. We investigated formalin-fixed thyroid gland samples of 216 patients (191 Hashimoto's thyroiditis, 5 Riedel's thyroiditis, and 20 goiters, as controls), morphologically, and immunohistochemically. Cases were divided into two groups: IgG4-related Hashimoto's thyroiditis (24 cases) together with Riedel thyroiditis (1 case) and 171 non-IgG4-related thyroiditis. Compared to the non-IgG4-related cases, IgG4-related thyroiditis showed a higher IgG4/IgG ratio (0.6 vs. 0.1, p thyroiditis was diagnosed in 23 of the 24 IgG4-related cases (96 %) and in 13 of 167 (18 %, p > 0.001) non-IgG4-related cases. The single case of IgG4-related Riedel's thyroiditis also showed a higher median IgG4 plasma cell count (56.3 vs. 14.3) and a higher IgG4/IgG ratio (0.5 vs. 0.2) than the four cases of non-IgG4-related Riedel's thyroiditis. Our data suggests the incidence of IgG4-related disease (IgG4-RD) of the thyroid gland in Europe is considerably lower than that observed in other studies. A significant elevation of IgG4-positive plasma cells was only found in a small group of Hashimoto's thyroiditis and then accompanied by intense fibrosis, indicating an association with IgG4-RD. Morphologically, IgG4-RD of the thyroid gland differs from that in other organ systems, exhibiting a dense fibrosis without intense eosinophilia or obliterative phlebitis.

Histopathologic Overlap between Fibrosing Mediastinitis and IgG4-Related Disease

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Tobias Peikert

2012-01-01

Full Text Available Fibrosing mediastinitis (FM and IgG4-related disease (IgG4-RD are two fibroinflammatory disorders with potentially overlapping clinical and radiological features. In this paper, we looked for histopathologic features of IgG4-RD and enumerated infiltrating IgG4-positive plasma cells within mediastinal tissue biopsies from FM patients. We identified 15 consecutive FM surgical mediastinal tissue biopsies between 1985 and 2006. All patients satisfied the clinical and radiological diagnostic criteria for FM. All patients had either serological or radiological evidence of prior histoplasmosis or granulomatous disease, respectively. Formalin-fixed paraffin-embedded tissue sections of all patients were stained for H&E, IgG, and IgG4. Three samples met the predefined diagnostic criteria for IgG4-RD. In addition, characteristic histopathologic changes of IgG4-RD in the absence of diagnostic numbers of tissue infiltrating IgG4-positive plasma cells were seen in a number of additional cases (storiform cell-rich fibrosis in 11 cases, lymphoplasmacytic infiltrate in 7 cases, and obliterative phlebitis/arteritis in 2 cases. We conclude that up to one-third of histoplasmosis or granulomatous-disease-associated FM cases demonstrate histopathological features of IgG4-RD spectrum. Whether these changes occur as the host immune response against Histoplasma or represent a manifestation of IgG4-RD remains to be determined. Studies to prospectively identify these cases and evaluate their therapeutic responses to glucocorticoids and/or other immunosuppressive agents such as rituximab are warranted.

[IgG4-related disease - a case report].

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Milczarek-Banach, Justyna; Brodzińska, Kinga; Jankowska, Anna; Ambroziak, Urszula; Szczepankiewicz, Benedykt; Nałęcz-Janik, Jolanta; Miśkiewicz, Piotr

2017-09-29

Immunoglobulin G4-related disease (IgG4-RD) is a comparatively new condition that may involve more than one organ. The lack of characteristic, pathognomonic clinical symptoms may delay the diagnosis of this disease. The diagnosis is based upon clinical manifestation, elevated serum levels of IgG4 and histopathologic examination with immunohistochemical staining to reveal infiltration of IgG4-positive plasma cells. The first line treatment is oral glucocorticoids. 38-year-old woman with Hashimoto disease, chronic sinusitis and chronic hepatitis of unknown etiology was admitted to the Department of Endocrinology because of moderate eyelids swelling accompanied by redness for 3 years. Graves' orbitopathy and systemic vasculitis were suspected, however both were excluded (negative antibodies results: anty-TSHR, ANCA, ANA). Serologic investigation of Sjögren's syndrome was also negative. In Magnetic Resonance Imaging (MRI) of orbits there were described bilateral mild extension of lateral rectus muscles, normal signal of adipose tissue and bilateral lacrimal glands enlargement. Moreover, increased IgG4 serum levels were detected. The material derived from perinasal sinuses surgery was analyzed in histopathology examination with immunohistochemical staining, which revealed characteristic features of chronic inflammatory process and increased numbers of IgG4 - positive plasma cells (>50 in a large field of view). The diagnosis of IgG4-RD was established. Because of non-effective oral methylprednisolone therapy in the past, the patient was referred to Clinic of Rheumatology for further treatment. After the therapy with methylprednisolone and azathioprine there were observed the significant reduction of symptoms. Because of lack of characteristic symptoms of IgG4- RD, it should be always considered in differential diagnosis of chronic inflammatory diseases of various organs.

Does the Intensity of IGG4 Immunostaining Have a Correlation with the Clinical Presentation of Riedel’s Thyroiditis?

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C. A. Simões

2018-01-01

Full Text Available Riedel’s thyroiditis (RT represents one type of IgG4-related thyroid disease (IgG4RTD and the diagnosis involves quantitative immunohistochemistry showing dense lymphoplasmacellular inflammatory infiltrate consisting of IgG4-positive plasma cells with storiform fibrosis and obliterative phlebitis. We report a case of RT with progressive enlargement of the anterior neck, severe dysphagia, odynophagia, and dyspnea. The patient underwent surgical decompression of the airway, protection tracheotomy, and gastrostomy for nutritional intake 6 months after first symptoms. Complete resolution occurred after surgical treatment combined with prednisolone. Immunostaining revealed IgG4-positive plasma cells 12/HPF (high-power field and the IgG4/IgG ratio 25%, values that were disproportionate to the intensity of the patient’s symptoms. As to this case and the few cases described and analyzed in the literature, our impression is that there is no relation between the intensity of symptoms in RT with the total number of IgG4-positive plasma cells and the IgG4/IgG ratio, but more studies are needed.

Immunology of IgG4-related disease

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Della-Torre, E; Lanzillotta, M; Doglioni, C

2015-01-01

Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory condition that derives its name from the characteristic finding of abundant IgG4+ 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. PMID:25865251

IgG4-positive cell infiltration in various cardiovascular disorders - results from histopathological analysis of surgical samples.

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Hourai, Ryoto; Kasashima, Satomi; Sohmiya, Koichi; Yamauchi, Yohei; Ozawa, Hideki; Hirose, Yoshinobu; Ogino, Yasuhiro; Katsumata, Takahiro; Daimon, Masahiro; Fujita, Shu-Ichi; Hoshiga, Masaaki; Ishizaka, Nobukazu

2017-02-03

The diagnosis of Immunoglobulin G4 (IgG4)-related disease (IgG4-RD), in general, depends on serum IgG4 concentrations and histopathological findings; therefore, diagnosis of IgG4-RD in cardiovascular organs/tissues is often difficult owing to the risk of tissue sampling. Prevalence of IgG4-positive lymphoplasmacytic infiltration in 103 consecutive cardiovascular surgical samples from 98 patients with various cardiovascular diseases was analyzed immunohistochemically. The diagnoses of the enrolled patients included aortic aneurysm (abdominal, n = 8; thoracic, n = 9); aortic dissection (n = 20); aortic stenosis (n = 24), aortic regurgitation (n = 10), and mitral stenosis/regurgitation (n = 17). In total, 10 (9.7%) of the 103 specimens showed IgG4-positive cell infiltration with various intensities; five of these were aortic valve specimens from aortic stenosis, and IgG4-positive cell infiltration was present at >10 /HPF in three of them. In one aortic wall sample from an abdominal aortic aneurysm, various histopathological features of IgG4-RD, such as IgG4-positive cell infiltration, obliterating phlebitis, and storiform fibrosis, were observed. IgG4-positive cell infiltration was observed in 9.7% of the surgical cardiovascular specimens, mainly in the aortic valve from aortic stenosis and in the aortic wall from aortic aneurysm. Whether IgG4-positive cell infiltration has pathophysiological importance in the development or progression of cardiovascular diseases should be investigated in future studies.

The Histopathology of IgG4-Related Disease.

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Avincsal, Mehmet Ozgur; Zen, Yoh

2017-01-01

IgG4-related disease is a multi-organ immune-mediated chronic fibroinflammatory condition characterized by elevated serum IgG4 concentrations, tumefaction, and tissue infiltration by IgG4-positive plasma cells. The exact etiology of IgG4-related disease remains unclear with no known role of the IgG4 molecule itself being identified. Although the pancreas and salivary glands are the main organs affected, the involvement of other organs has also been reported. This multi-organ disease mimics a large number of malignant, infectious, and inflammatory disorders; therefore, a prompt differential diagnosis is important for selecting the right therapeutic strategy. Early steroid therapy assists in preventing tissue fibrosis, parenchymal extinction, and severe functional impairments in the affected organs. The definitive and prompt diagnosis of IgG4-related disease requires both histopathological confirmation and clinicopathological correlations. A histopathological examination is mandatory to exclude neoplastic or inflammatory conditions that mimic IgG4-related disease. The histological changes that occur are basically similar in any organ manifestation, with several site-specific findings being recognized. This chapter summarizes general rules for the pathological examination of IgG4-related disease, as well as the histopathological features and differential diagnoses of major organ manifestations.

Characteristic tubulointerstitial nephritis in IgG4-related disease.

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Yamaguchi, Yutaka; Kanetsuna, Yukiko; Honda, Kazuho; Yamanaka, Nobuaki; Kawano, Mitsuhiro; Nagata, Michio

2012-04-01

Nephropathy associated with IgG4-related disease is characterized by tubulointerstitial nephritis. To better identify its pathology, the present study analyzed clinicopathologic features of IgG4-related tubulointerstitial nephritis cases from across Japan. Sixteen cases were identified as IgG4-related nephropathy using the criterion of high serum IgG4 levels (>135 mg/dL) with abnormal kidney computed tomography or elevated serum creatinine levels. Male predominance (75%) and advanced age (average, 62.0 years) were noted. Eight cases displayed no autoimmune pancreatitis. Renal computed tomography abnormalities were found in 12 of 13 cases examined. Renal dysfunction was found in 15 of 16 cases at biopsy. Distinctive features of tubulointerstitial lesions included (1) well-demarcated borders between involved and uninvolved areas; (2) involvement of the cortex and medulla, often extending beyond the renal capsule and with occasional extension to retroperitoneal fibrosis; (3) interstitial inflammatory cells comprising predominantly plasma cells and lymphocytes, with a high prevalence of IgG4-positive cells often admixed with fibrosis; (4) peculiar features of interstitial fibrosis resembling a "bird's-eye" pattern comprising fibrosis among inter-plasma cell spaces; and (5) deposits visible by light and immunofluorescent microscopy in the tubular basement membrane, Bowman capsule, and interstitium that are restricted to the involved portion, sparing normal parts. Ultrastructural analysis revealed the presence of myofibroblasts with intracellular/pericellular collagen accompanied by plasma cell accumulation from an early stage. Histology could not discriminate between IgG4-related tubulointerstitial nephritis with and without autoimmune pancreatitis. In conclusion, the distinctive histologic features of IgG4-related tubulointerstitial nephritis can facilitate the differential diagnosis of tubulointerstitial nephritis, even without autoimmune pancreatitis or an abnormal

[IgG4-related lung disease: analysis of 8 cases and literature review].

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Han, G J; Hu, H; Mao, D; Bai, X; She, D Y; Zhao, S F; Wen, Z L; Gao, J

2017-03-12

Objective: To improve the understanding and treatment of IgG4-related lung disease (IgG4-RLD). Methods: The clinical characteristics, serum IgG4 levels, pathological features, chest CT, therapy and prognosis of 8 patients with IgG4-RLD were retrospectively analyzed. These patients were admitted to the People's Liberation Army General Hospital and the pathological diagnosis was made between December 2005 and March 2016. Relevant literatures were reviewed. Results: The 8 patients with IgG4-RLD included 4 men and 4 women, with an average age of (59±4) years (range, 37-74). The respiratory symptoms included shortness of breath, cough, and expectoration. Extra-pulmonary symptoms included abdominal pain, facial edema, and fever. Extrapulmonary organs were involved in 7 cases. Serum IgG4 levels were elevated in 8 cases, with an average concentration of(17±6)g/L. Chest CT showed solid lung nodules in 6, alveolar-interstitial infiltration in 5, bronchovascular lesions in 3 and ground glass shadows in 2 cases. PET/CT was performed in 2 cases and it showed multiple organ involvement with higher radioactivity uptake(SUVmax2.9-4.2). The pathological examination found lymphocyte and plasma cell infiltration in 7, fibrous tissue hyperplasia in 5, and occlusive vasculitis in 2 cases. On immunohistochemical staining, the ratio of IgG4-positive plasma cells to IgG-positive plasma cells was higher than 40%in 3 cases. The number of IgG4-positive plasma cells was 10-50/HP in 8 cases. The misdiagnosis rate was 100% before the final diagnosis was made. Three cases received glucocorticoids with immunosuppressant therapy, 2 received surgery combined with glucocorticoid therapy, 2 received glucocorticoid therapy alone, and 1 only received surgery. The follow-up time was 4-132 months, with remission in 7 cases, and disease progression in 1 case, but no death. A total of 195 cases of IgG4-RLD were reviewed from the literature, among whom 111 cases were admitted with respiratory symptoms

IgG4-Related Tubulointerstitial Nephritis.

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Zhang, Pingchuan; Cornell, Lynn D

2017-03-01

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a fibroinflammatory disorder that can involve nearly any organ. The disorder has increasingly become known as a distinct clinical entity during the last decade. IgG4-related tubulointerstitial nephritis (IgG4-TIN) is the most common manifestation of IgG4-RD in the kidney. Many patients with IgG4-TIN are diagnosed after IgG4-RD has been recognized in other organ systems, but the kidney may also be the first or only site involved. The presenting clinical features of IgG4-TIN are most commonly kidney insufficiency, kidney mass lesion(s), or both. On biopsy, IgG4-TIN shows a dense lymphoplasmacytic infiltrate, increased IgG4+ plasma cells, storiform fibrosis, and often tubular basement membrane immune complex deposits. Elevation of serum IgG4 often accompanies IgG4-RD; however, it is not specific in reaching the diagnosis. Like IgG4-RD in other organs, IgG4-TIN characteristically responds promptly to steroids, although there is a high relapse rate on discontinuation of immunosuppression. The pathogenesis of IgG4-RD is not understood. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Riedel's thyroiditis and multifocal fibrosclerosis are part of the IgG4-related systemic disease spectrum.

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Dahlgren, Mollie; Khosroshahi, Arezou; Nielsen, G Petur; Deshpande, Vikram; Stone, John H

2010-09-01

Riedel's thyroiditis is a chronic fibrosing disorder of unknown etiology often associated with "multifocal fibrosclerosis." IgG4-related systemic disease is characterized by IgG4+ plasma cell infiltration and fibrosis throughout many organs. We hypothesized that Riedel's thyroiditis is part of the IgG4-related systemic disease spectrum. We searched our institution's pathology database using the terms "Riedel's," "struma," "thyroid," and "fibrosis," and identified 3 cases of Riedel's thyroiditis. Riedel's thyroiditis was diagnosed if there was a fibroinflammatory process involving all or a portion of the thyroid gland, with evidence of extension of the process into surrounding tissues. Immunohistochemical stains for IgG4 and IgG were performed. The histopathologic and immunohistochemical features of each involved organ were evaluated. The clinical features of one patient with multiple organ system disease were described. All 3 thyroidectomy samples stained positively for IgG4-bearing plasma cells. One patient had extensive extrathyroidal involvement diagnostic of IgG4-related systemic disease, including cholangitis, pseudotumors of both the lung and lacrimal gland, and a lymph node contiguous to the thyroid that stained intensely for IgG4+ plasma cells. The histologic features of all organs involved were consistent with IgG4-related systemic disease. Patient 3 had 10 IgG4+ plasma cells per high-power field initially, but rebiopsy 2 years later demonstrated no IgG4+ plasma cells. That patient's second biopsy, characterized by fibrosis and minimal residual inflammation, further solidifies the link between IgG4-bearing plasma cells in tissue and the histologic evolution to Riedel's thyroiditis. Riedel's thyroiditis is part of the IgG4-related systemic disease spectrum. In many cases, multifocal fibrosclerosis and IgG4-related systemic disease are probably the same entity.

Riedel's thyroiditis association with IgG4-related disease.

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Stan, Marius N; Sonawane, Vikram; Sebo, Thomas J; Thapa, Prabin; Bahn, Rebecca S

2017-03-01

IgG4-positive (+) plasma cells have been reported in both Riedel's thyroiditis (RT) and Hashimoto's thyroiditis (HT). These cells are the hallmark of IgG4-related disease (IgG4-RD). We sought to determine whether RT is part of IgG4-RD spectrum. This was a case-control study performed at a tertiary medical centre. We included RT cases from the period 1958 to 2008 that had sufficient paraffin-embedded tissue for IgG4 immunostaining. Controls were patients with HT, age and gender matched, with similar pathology criteria. The main outcome measures were the intensity of the IgG4 staining and the clinical and histological correlates with IgG4-RD. Six pairs of RT and HT were analysed. The mean age was 44·7 years. In both groups, 5/6 cases had positive IgG4 staining. The mean number of IgG4 + cells/ HPF, normalized to the degree of inflammation, was 3·2 ± 3·0 SD (RT) vs 0·9 ± 0·7 (HT), P = 0·15, for fibrotic areas and 2·1 ± 2·3 SD vs 1·0 ± 0·8 (P = 0·39) for areas with lymphoid aggregates. We found the number of IgG4 +  cells in RT to be inversely correlated with the duration of disease (P = 0·046). Three RT cases had associated comorbidities from the IgG4-RD spectrum while none of the HT cases had such conditions. Riedel's thyroiditis is a component of IgG4-RD with the density of the IgG4 +  lymphocytic infiltrate being time dependent. In this small study, we did not identify differences in IgG4 infiltration between RT and HT, minimizing the utility of this marker in RT diagnosis. © 2016 John Wiley & Sons Ltd.

IgG4-related disease with cavernous sinus and intra-orbital lesions diagnosed by nasal mucosa biopsy.

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Nakata, Ruka; Yoshimura, Shunsuke; Motomura, Masakatsu; Tsujino, Akira; Hayashi, Tomayoshi; Hara, Minoru

2016-09-29

IgG4-related disease is a systemic disease characterized by lesions with IgG4 positive plasma cell infiltration in the involved organs and a raised serum IgG4 level. We report a patient of 70-year-old male presented orbital inflammation of IgG4-related disease. The patient developed right eye pain, double vision, and reduced eye sight. MRI image revealed mild right ocular proptosis and swelling of right carvenous sinus, bilateral intraorbital extraocular muscles and right optic nerve. Right optic nerve showed ring-like enhancement. IgG4-related disease was suspected with increased serum IgG4 level of 355 mg/dl, mediastinal lymphadenopathy and prostate enlargement. Transbronchial lung biopsy and prostate needle biopsy were administered with negative results. The eye related symptoms resolved with time, but serum IgG4 continuously increased. IgG4-related disease was diagnosed by nasal mucosa biopsy, which showed IgG4 positive plasma cells within the inflammatory infiltrate. This report emphasizes the usefulness of nasal mucosa biopsy for the diagnosis of IgG4 related disease with lesions difficult to approach.

IgG4-Associated Cholangitis--A Mimic of PSC

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Beuers, Ulrich; Hubers, Lowiek M.; Doorenspleet, Marieke; Maillette de Buy Wenniger, Lucas; Klarenbeek, Paul L.; Boonstra, Kirsten; Ponsioen, Cyriel; Rauws, Erik; de Vries, Niek

2015-01-01

IgG4-associated cholangitis (IAC) is an inflammatory disorder of the biliary tract representing a major manifestation of IgG4-related disease (IgG4-RD) often with elevation of serum IgG4 levels, infiltration of IgG4+ plasma cells in the affected tissue and good response to immunosuppressive

IgG4-Related Disease of Bilateral Temporal Bones.

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Li, Lilun; Ward, Bryan; Cocks, Margaret; Kheradmand, Amir; Francis, Howard W

2017-03-01

IgG4-related disease (IgG4-RD) is an idiopathic inflammatory condition that causes pseudotumor formation in single or multiple organs, including those of the head and neck. Temporal bone involvement is rare, with only 3 cases of unilateral temporal bone IgG4-RD described in the literature. We report the first known case of IgG4-RD of bilateral temporal bones and describe its clinical presentation, diagnosis, and treatment. The patient was a 52-year-old man with latent tuberculosis (TB) who presented with a 10-year history of bilateral profound hearing loss and vestibular dysfunction. Computed tomography and magnetic resonance imaging demonstrated bilateral labyrinthine destruction with invasion of the posterior fossa. Immunoglobulin level testing showed elevated total serum IgG levels with normal IgG4 levels. Bilateral mastoidectomies were performed, with biopsy samples demonstrating IgG4 staining with IgG4-positive plasma cells up to 40/HPF (high power field) on the right and 20/HPF on the left, consistent with bilateral IgG4-RD. IgG4-RD of bilateral temporal bones presents with chronic and progressive bilateral hearing loss and vestibular dysfunction. Clinical presentation and radiologic findings are nonspecific, and definitive diagnosis must be made with histopathology and immunostaining. Corticosteroids are therapeutic, but surgical resection may be necessary for temporal bone IgG4-RD to improve long-term remission.

Unusual IgG4-related hypophysitis: one case report and analysis of clinicopathological characteristics

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Zhen-qi LI

2014-10-01

Full Text Available Background Immunoglobulin G4 (IgG4-related disease is a recently characterized autoimmune disease entity marked by elevated serum IgG4 levels and tissue infiltration by IgG4-positive plasma cells in multiple involved organs. Hypophysitis is a rare inflammatory disorder and IgG4-related sclerosing disease involving the ituitary alone is especially rare. Imaging studies may reveal a mass lesion in the sellar area or a thickening of pituitary stalk, mimicking a pituitary tumor. Due to its rarity and non-specific appearance in radiological examination, it is a diagnostic challenge for clinicians and histopathologists to differentiate solitary IgG4-related hypophysitis from other pituitary lesions. The aim of this study is to summarize the clinicopathological features of unusual IgG4-related hypophysitis and discuss the differential diagnosis of histologically similar inflammatory lesions in pituitary. Methods The clinical manifestation of a patient with solitary IgG4-related hypophysitis was presented retrospectively. Resected mass was routinely paraffin-embedded and stained with Hematoxylin and Eosin. Dako EnVision immunohistochemical staining system was used to detect the tumor antigen expressions, including vimentin (Vim, S-100 protein (S-100, pan cytokeratin (PCK, epithelial membrane antigen (EMA, CD3, CD20, CD68, CD1a, κ-light chain, λ-light chain and progestrone receptor (PR.  Results A 47-year-old male patient presented with 1-year history of mild limb weakness and hyposexuality. Laboratory examination revealed hypopituitarism with low levels of serum testosterone, cortisol, luteinizing hormone (LH and follicle stimulating hormone (FSH, although his serum IgG4 level was high. MRI of the pituitary gland revealed a mass lesion in the sellar area with T1WI mild hyperintense and homogeneous enhancement after gadolinium administration. The patient underwent a transsphenoidal mass resection of the pituitary gland. Histological examination

Enterocolic lymphocytic phlebitis as a newly recognized manifestation of IgG4-related disease.

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Laco, Jan; Örhalmi, Július; Bártová, Jolana; Zimandlová, Dana

2015-04-01

Herein we present a case of a 65-year-old woman with enterocolic lymphocytic phlebitis (ELP) who presented with anemic syndrome and in whom severe stenosis of the right flexure of large bowel was detected. The microscopic examination revealed fibrosis of the submucosa and lymphoplasmacytic phlebitis of small veins and venules, whereas arteries were spared. There were 110 IgG4-positive and 160 IgG-positive plasma cells in 1 high-power field, respectively, with corresponding IgG4/IgG ratio of 0.69. The IgG4 serum level was 2.42 g/L. According to the currently proposed criteria, this ELP case is the first that may be diagnosed as definite IgG4-related disease (IgG4-RD). Although based on the sole case description, taken together with a recent review and a case report, we presume that a subset of ELPs is a manifestation of IgG4-RD. © The Author(s) 2014.

IgG4-related disease simulating Hodgkin lymphoma in a child

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D. Eric Ewing, MD

2016-06-01

Full Text Available Immunoglobulin (Ig G4-related disease is a recently described syndrome characterized by mass forming lymphoplasmacytic tissue infiltration and elevated serum IgG4 concentrations usually affecting middle-aged or older individuals. Lymphadenopathy is frequently observed and is sometimes the first or only manifestation of the disease. We report a case of IgG4-related disease mimicking Hodgkin lymphoma in a 13-year-old girl. The patient presented with progressive unilateral cervical lymphadenopathy of several months duration. Biopsy showed follicular hyperplasia with progressive transformation of germinal centers. Interfollicular areas were expanded by small lymphocytes, histiocytes, eosinophils and fibrosis with occasional CD30 positive cells initially concerning for interfollicular Hodgkin lymphoma. Immunohistochemical analysis revealed an intrafollicular plasmacytosis with an IgG4-positive/IgG-positive plasma cell ratio of 50% supporting a diagnosis of IgG4-related lymphadenopathy, progressively transformed germinal centers type. Laboratory studies were supportive with elevated serum IgG4 (178 mg/dL and IgE (30.40 kU/L levels along with an elevated serum IgG4/IgG ratio (0.16. Very few cases of IgG4-related disease have been described in children. Within this age group, there is considerable clinical overlap between IgG4-related disease associated lymphadenopathy and Hodgkin lymphoma. In addition, lymphadenopathy secondary to IgG4-related disease demonstrates substantial histologic diversity with the potential to simulate the inflammatory background and fibrosis of Hodgkin lymphoma. The importance of accurate diagnosis is underscored by the prognostic implications considering the marked response of the syndrome to steroid therapy. In addition, appropriate follow up is critical to monitor for relapse and additional organ involvement.

Tubulointerstitial fibrosis in patients with IgG4-related kidney disease: pathological findings on repeat renal biopsy

NARCIS (Netherlands)

Arai, Haruna; Hayashi, Hiroki; Takahashi, Kazuo; Koide, Shigehisa; Sato, Waichi; Hasegawa, Midori; Yamaguchi, Yutaka; Aten, Jan; Ito, Yasuhiko; Yuzawa, Yukio

2015-01-01

Renal parenchymal lesions in patients with IgG4-related kidney disease (IgG4-RKD) are characterized by tubulointerstitial nephritis with storiform fibrosis and infiltration by high numbers of IgG4-positive plasma cells. The aim of this study was to evaluate the clinical and pathological effects of

IgG4-related disease: with emphasis on the biopsy diagnosis of autoimmune pancreatitis and sclerosing cholangitis.

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Detlefsen, Sönke; Klöppel, Günter

2018-04-01

In 2011, chronic fibroinflammatory processes occurring simultaneously or metachronously in various organs and associated with elevated IgG4 serum levels and/or tissue infiltration with IgG4-positive plasma cells have been recognized as manifestations of a systemic disorder called IgG4-related disease (IgG4-RD). The histologic key findings are lymphoplasmacytic infiltration rich in IgG4-positive plasma cells combined with storiform fibrosis and obliterative phlebitis. Among the organs mainly affected by IgG4-RD are the pancreas and the extrahepatic bile ducts. The pancreatic and biliary alterations have been described under the terms autoimmune pancreatitis (AIP) and sclerosing cholangitis, respectively. These diseases are currently more precisely called IgG4-related pancreatitis (or type 1 AIP to distinguish it from type 2 AIP that is unrelated to IgG4-RD) and IgG4-related sclerosing cholangitis (IgG4-related SC). Clinically and grossly, both diseases commonly imitate pancreatic and biliary adenocarcinoma, tumors that are well known for their dismal prognosis. As IgG4-RD responds to steroid treatment, making a resection of a suspected tumor unnecessary, a biopsy is often required to establish the preoperative diagnosis. This review discusses the morphologic spectrum of IgG4-related pancreatitis and IgG4-related SC and focuses on the biopsy relevant histologic features for the diagnosis and differential diagnosis of these diseases.

Clinical and imaging diagnosis of IgG4-related disease in the head and neck

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Yu Changliang; Liu Bin; Yu Yongqiang

2013-01-01

IgG4-related disease in the head and neck is a newly recognized multi-organ system disease characterized by elevated serum IgG4, infiltration of numerous IgG4-positive plasma cells, tissue fibrosis, and dramatic response to corticosteroid treatment. IgG4-related disease of the head and neck has some relative characteristics on CT and MRI, which can provide valuable information for the diagnosis and differential diagnosis, and are helpful for the clinical treatment, evaluation of therapeutic effects and prediction of prognosis. (authors)

IgG4-related pleural disease presenting as a massive bilateral effusion.

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Ishida, Atsuko; Furuya, Naoki; Nishisaka, Takashi; Mineshita, Masamichi; Miyazawa, Teruomi

2014-07-01

A 74-year-old woman with massive bilateral pleural effusion, which was exudative in nature, and with mononuclear cell predominance underwent a pleuroscopy. Parietal pleura were thickened and partly reddish in color. Biopsy specimens taken from the parietal pleura revealed lymphoplasmacytic inflammation with fibrosis. As her performance status rapidly worsened with thoracentesis, we performed bilateral pleurodesis using talc. Pathologic evaluation of the pleural biopsy specimen with immunohistochemical staining revealed 91 IgG4-positive plasma cells per high-power field and an IgG4/IgG ratio of 91%. Thus, the diagnosis of pleuritis from IgG4-related disease was established. Our case suggests that IgG4-related disease is one of the causes of pleural effusion, and it should be included in the differential diagnosis of unexplained pleuritis.

TREATMENT OF IgG4-RELATED DISEASE

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E. V. Sokol

2016-01-01

Full Text Available IgG4-related disease (IgG4-RD is a fibroinflammatory condition characterized by the occurrence of tumor-like foci in different organs with a unique histological pattern (moirо-like fibrosis, obvious lymphoplasmacytic infiltration with large numbers of IgG4+ plasma cells, and obliterating phlebitis and elevated serum IgG4 levels in the majority of patients. Its first-line therapy is glucocorticoids at a starting dose of 0.6 mg/kg/day (equivalent to prednisolone; however, this treatment entails a great number of adverse events and high recurrence rates. The paper provides a review of today's literature on the treatment of IgG4-RD; particular emphasis is laid on the description of therapy with glucocorticoids and rituximab.

Pathogenicity of IgG in patients with IgG4-related disease.

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Shiokawa, Masahiro; Kodama, Yuzo; Kuriyama, Katsutoshi; Yoshimura, Kenichi; Tomono, Teruko; Morita, Toshihiro; Kakiuchi, Nobuyuki; Matsumori, Tomoaki; Mima, Atsushi; Nishikawa, Yoshihiro; Ueda, Tatsuki; Tsuda, Motoyuki; Yamauchi, Yuki; Minami, Ryuki; Sakuma, Yojiro; Ota, Yuji; Maruno, Takahisa; Kurita, Akira; Sawai, Yugo; Tsuji, Yoshihisa; Uza, Norimitsu; Matsumura, Kazuyoshi; Watanabe, Tomohiro; Notohara, Kenji; Tsuruyama, Tatsuaki; Seno, Hiroshi; Chiba, Tsutomu

2016-08-01

IgG4-related disease (IgG4-RD) is a systemic disease characterised by elevated serum IgG4 and IgG4-positive lymphoplasmacytic infiltration in the affected tissues. The pathogenic role of IgGs, including IgG4, in patients with IgG4-RD, however, is unknown. We examined the pathogenic activity of circulating IgGs in patients with IgG4-RD by injecting their IgGs into neonatal male Balb/c mice. Binding of patient IgGs to pancreatic tissue was also analysed in an ex vivo mouse organ culture model and in tissue samples from patients with autoimmune pancreatitis (AIP). Subcutaneous injection of patient IgG, but not control IgG, resulted in pancreatic and salivary gland injuries. Pancreatic injury was also induced by injecting patient IgG1 or IgG4, with more destructive changes induced by IgG1 than by IgG4. The potent pathogenic activity of patient IgG1 was significantly inhibited by simultaneous injection of patient IgG4. Binding of patient IgG, especially IgG1 and IgG4, to pancreatic tissue was confirmed in both the mouse model and AIP tissue samples. IgG1 and IgG4 from patients with IgG4-RD have pathogenic activities through binding affected tissues in neonatal mice. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Ectopic Germinal Centers and IgG4-Producing Plasmacytes Observed in Synovia of HLA-B27+ Ankylosing Spondylitis Patients with Advanced Hip Involvement

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Xiugao Feng

2015-01-01

Full Text Available Introduction. Ectopic lymphoid neogenesis and the presence of IgG4-positive plasmacytes have been confirmed in chronic inflammatory sclerosing diseases. This study aims to investigate hip synovial tissues of ankylosing spondylitis (AS patients for IgG4-positive plasma cells and ectopic lymphoid tissues with germinal centers (GCs. Methods. Synovial samples were collected from 7 AS patients who received total hip replacement and were evaluated using immunohistochemistry for the presence of CD20+ B-cells, CD3+ T-cells, CD21+ follicular dendritic cells (FDC, and CD38+ plasma cells. Furthermore, immunoglobulin G (IgG and IgG4, IgA, IgM, and complement components C3d and C4d in synovia were evaluated. Both synovial CD21+ FDCs and IgG4-producing plasmacytes were analyzed. Results. All seven patients had severe fibrosis. Massive infiltrations of lymphocytes were found in 5 out of 7 patients’ synovia. Ectopic lymphoid tissues with CD21+ FDC networks and IgG4-positive plasma cells were observed coincidentally in two patients’ synovia. Conclusion. The pathophysiological mechanism of AS patients’ hip damage might be related to the coincidental presence of ectopic lymphoid tissue with FDCs network and IgG4-positive plasma cells identified here for the first time in AS patients’ inflamed synovial tissue.

IgG4-Related Disease in a Urachal Tumor

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Travis W. Dum

2014-01-01

Full Text Available IgG4-related disease is a newly recognized fibroinflammatory disorder that has the ability to affect nearly every organ system. It is characterized by tumefactive lesions and fibrosis and closely mimics neoplasms. Only one case of IgG4-related bladder mass has been reported in the literature, but there are no reports of IgG4-related disease in a urachal mass. Herein, we report a 26-year-old male who initially presented with symptoms of recurrent UTI. Work-up revealed a 6 cm urachal tumor, a 1.4 cm pulmonary lesion, and mediastinal lymphadenopathy; all metabolically active on PET scan and suspicious for urachal adenocarcinoma. Lung lesion fine needle aspiration and TURBT pathology revealed inflammation but no evidence of malignancy. The patient underwent a partial cystectomy and umbilectomy with pathology demonstrating dense plasmacytic cells, a high rate of immunohistochemistry staining positive for IgG4 plasma cells, a storiform pattern of fibrosis, and an obliterative phlebitis. Furthermore, the patient had an elevated serum IgG4 level of 227 mg/dL (range 2.4–121 mg/dL. IgG4-related disease is a newly recognized fibroinflammatory disorder that can mimic neoplastic processes and a high index of suspicion and accurate tissue pathology is necessary for an accurate diagnosis.

IgG4-related sialadenitis and Sjögren's syndrome.

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Fragoulis, G E; Zampeli, E; Moutsopoulos, H M

2017-03-01

IgG4-related disease (IgG4-RD) has emerged as a new entity in the last decade. It comprises numerous conditions previously thought to be unrelated. Macroscopically, these diseases cause diffuse organ swelling and formation of pseudotumorous masses. Histopathologically, they are characterized by a lymphoplasmacytic infiltrate with increased IgG4+ plasma cells and storiform fibrosis. Despite rapid progress within the last years, our knowledge on these conditions is still fragmented. To date, more than forty organs have been reported to be included in IgG4-RD, and salivary gland involvement is amongst the most common organs affected [IgG4-related sialadenitis (IgG4-RS)]. Interestingly, IgG4-RS shares commonalities with Sjögren's syndrome (SS), like glandular enlargement, sicca symptoms, arthralgias, hypergammaglobulinemia, hypocomplementemia, and circulating antinuclear antibodies. Nonetheless, they differ in that the incidence of anti-Ro and anti-La reactivity is not frequently found in patients with IgG4-RS, their salivary glands are infiltrated by a large number of IgG4+ plasma cells and IgG4-RS symptoms respond promptly to steroids. The aim of this review was to describe the clinical, serological, histopathological and pathophysiological aspects of IgG4-RS in the context of IgG4-RD and highlight the differences between IgG4-RS and SS. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Anti-pituitary antibodies against corticotrophs in IgG4-related hypophysitis.

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Iwata, Naoko; Iwama, Shintaro; Sugimura, Yoshihisa; Yasuda, Yoshinori; Nakashima, Kohtaro; Takeuchi, Seiji; Hagiwara, Daisuke; Ito, Yoshihiro; Suga, Hidetaka; Goto, Motomitsu; Banno, Ryoichi; Caturegli, Patrizio; Koike, Teruhiko; Oshida, Yoshiharu; Arima, Hiroshi

2017-06-01

IgG4-related disease is a systemic inflammatory disease characterized by infiltration of IgG4-positive plasma cells into multiple organs, including the pituitary gland. Autoimmunity is thought to be involved in the pathogenesis of IgG4-related disease. The diagnosis of IgG4-related hypophysitis (IgG4-RH) is difficult because its clinical features, such as pituitary swelling and hypopituitarism, are similar to those of other pituitary diseases, including lymphocytic hypophysitis and sellar/suprasellar tumors. The presence and significance of anti-pituitary antibodies (APA) in IgG4-RH is unclear. In this case-control study, we used single indirect immunofluorescence on human pituitary substrates to assess the prevalence of serum APA in 17 patients with IgG4-RH, 8 control patients with other pituitary diseases (lymphocytic infundibulo-neurohypophysitis, 3; craniopharyngioma, 2; germinoma, 3), and 9 healthy subjects. We further analyzed the endocrine cells targeted by the antibodies using double indirect immunofluorescence. APA were found in 5 of 17 patients with IgG4-RH (29%), and in none of the pituitary controls or healthy subjects. The endocrine cells targeted by the antibodies in the 5 IgG4-RH cases were exclusively corticotrophs. Antibodies were of the IgG1 subclass, rather than IgG4, in all 5 cases, suggesting that IgG4 is not directly involved in the pathogenesis. Finally, antibodies recognized pro-opiomelanocortin in 2 of the cases. Our study suggests that autoimmunity is involved in the pathogenesis of IgG4-RH and that corticotrophs are the main antigenic target, highlighting a possible new diagnostic marker for this condition.

Atypical IgG4+ Plasmacytic Proliferations and Lymphomas: Characterization of 11 Cases.

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Bledsoe, Jacob R; Wallace, Zachary S; Deshpande, Vikram; Richter, Joshua R; Klapman, Jason; Cowan, Andrew; Stone, John H; Ferry, Judith A

2017-09-01

To report the clinicopathologic features of monotypic immunoglobulin G4+ (IgG4+) lymphoid and plasmacytic proliferations. Cases were identified from the pathology files. Pathology and clinical materials were reviewed. Eleven cases of monotypic IgG4+ proliferations were identified at nodal, orbital, or salivary sites. Six cases (three men, three women; age, 57-94 years) met criteria for lymphoma or plasma cell neoplasia. Most contained frequent Mott cells. Five cases (three men, two women; age, 40-80 years) had restricted proliferations of atypical/monotypic IgG4+ plasma cells in a background of reactive lymphoid hyperplasia or inflammation. Monotypic IgG4+ proliferations include lymphomas, plasmacytic neoplasms, and a previously uncharacterized group of proliferations not meeting criteria for conventional hematolymphoid neoplasia. Distinct features included prominent Mott cells and/or monotypic plasma cells within follicles. The proliferations were infrequently associated with IgG4-related disease (IgG4-RD). Our findings raise questions regarding the relationship between clonal IgG4+ proliferations, reactive/inflammatory processes, and IgG4-RD. © American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Graves' Disease Patients with Persistent Hyperthyroidism and Diffuse Lymphoplasmacytic Infiltration in the Thyroid Show No Histopathological Compatibility with IgG4-Related Disease.

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Eijun Nishihara

Full Text Available IgG4-related disease is a novel disease entity characterized by diffuse lymphoplasmacytic infiltration rich in IgG4-positive plasma cells and fibrosis into multiple organs. There is still controversy over whether some thyroid diseases are actually IgG4-related disease. The objective of this study was to elucidate the clinicopathological features of Graves' disease with diffuse lymphoplasmacytic infiltration in the thyroid.Among 1,484 Graves' disease patients who underwent thyroidectomy, we examined their histopathological findings including the degree of lymphoplasmacytic and fibrotic infiltration and levels of IgG4-positive plasma cells in the thyroid. Their clinical pictures were defined by laboratory and ultrasonographic evaluation.A total of 11 patients (0.74% showed diffuse lymphoplasmacytic infiltration in the stroma of the thyroid gland. Meanwhile, other patients showed variable lymphoid infiltration ranging from absent to focally dense but no aggregation of plasma cells in the thyroid gland. Based on the diagnostic criteria of IgG4-related disease, 5 of the 11 subjects had specifically increased levels of IgG4-positive plasma cells in the thyroid. Fibrotic infiltration was present in only 1 patient developing hypothyroidism after anti-thyroid drug treatment for 4 years, but not in the other 10 patients with persistent hyperthyroidism. Obliterative phlebitis was not identified in any of the 11 subjects. Thyroid ultrasound examination showed 1 patient developing hypothyroidism who had diffuse hypoechogenicity, but the other hyperthyroid patients had a coarse echo texture.In our study, Graves' disease patients with persistent hyperthyroidism who had diffuse lymphoplasmacytic infiltration rich in IgG4-positive plasma cells in the thyroid showed no concomitant fibrosis or obliterative phlebitis.

IgG4-Related Perineural Disease

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Dai Inoue

2012-01-01

Full Text Available Aims. To elucidate characteristics of IgG4-related disease involving the peripheral nervous system. Methods. Retrospective review of 106 patients with IgG4-related disease identified 21 peripheral nerve lesions in 7 patients. Clinicopathological and radiological features were examined. Results. Peripheral nerve lesions were commonly identified in orbital or paravertebral area, involving orbital (=9, optic (=4, spinal (=7, and great auricular nerves (=1. The predominant radiological feature was a distinct perineural soft tissue mass, ranging 8 to 30 mm in diameter. Histologically, the epineurium was preferentially involved by massive lymphoplasmacytic infiltration rich in IgG4+ plasma cells. All lesions were neurologically asymptomatic and steroid-responsive at the first presentation, but one recurrent lesion around the optic nerve caused failing vision. Conclusion. IgG4-related disease of the peripheral nervous system is characterized by orbital or paravertebral localization, perineural mass formation, and rare neurologic symptoms. The term “IgG4-related perineural disease” seems appropriate to describe this entity.

Detection of Serum IgG4 Levels in Patients with IgG4-Related Disease and Other Disorders

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Wang, Chenqiong; Wu, Xuefen; Miao, Ye; Xiong, Hui; Bai, Lin; Dong, Lingli

2015-01-01

Objective Elevated serum IgG4 levels are an important hallmark for diagnosing IgG4-related disease (IgG4-RD), but can also be observed in other diseases. This study aimed to compare two different testing methods for IgG4: ELISA and nephelometric assay. Both assays were used to measure serum IgG4 concentrations, and to assess the prevalence of high serum IgG4 levels in both IgG4-RD and non-IgG4-RD diseases. Methods A total of 80 serum samples were tested using the nephelometric assay and ELISA method that we established. Serum IgG4 concentrations were determined by ELISA for 957 patients with distinct diseases, including 12 cases of IgG4-RD and 945 cases of non-IgG4-RD. Results IgG4 levels from 80 selected serum samples examined by ELISA were in agreement with those detected using the nephelometry assay. Meanwhile, the serum IgG4 concentrations measured by ELISA were also consistent with the clinical diagnoses of patients with IgG4-RD during the course of disease. The Elevated levels of serum IgG4 (>1.35 g/L) were detected in all IgG4-RD (12/12) patients, and the prevalence of high IgG4 serum levels was 3.39% in non-IgG4-RD cases. Among them, the positive rates of serum IgG4 were 2.06% in patients with carcinoma and 6.3% in patients with other non-IgG4 autoimmune diseases. Conclusion Our established ELISA method is a reliable and convenient technique, which could be extensively used in the clinic to measure serum IgG4 levels. High levels of IgG4 were observed in IgG4-RD. However, this phenomenon could also be observed in other diseases, such as carcinomas and other autoimmune diseases. Thus, a diagnosis of IgG4 disease cannot only be dependent on the detection of elevated serum IgG4 levels. PMID:25885536

IgG4-related Hashimoto’s thyroiditis – A new variant of a well known disease

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Luiz, Henrique Vara; Gonçalves, Diogo; Silva, Tiago Nunes da; Nascimento, Isabel; Ribeiro, Ana; Mafra, Manuela; Manita, Isabel; Portugal, Jorge

2014-01-01

Hashimoto’s thyroiditis (HT) has been characterized for many years as a well-defined clinicopathologic entity, but is now considered a heterogeneous disease. IgG4-related HT is a new subtype characterized by thyroid inflammation rich in IgG4-positive plasma cells and marked fibrosis. It may be part of the systemic IgG4-related disease. We report a case of a 56-year-old Portuguese man who presented with a one-month history of progressive neck swelling and dysphagia. Laboratory testing revealed...

Fibrosing variant of Hashimoto thyroiditis is an IgG4 related disease.

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Deshpande, Vikram; Huck, Amelia; Ooi, Esther; Stone, John H; Faquin, William C; Nielsen, G Petur

2012-08-01

Hashimoto thyroiditis (HT) and the fibrosing variant of Hashimoto thyroiditis (FVHT) are immune-mediated tumefactive lesions of the thyroid. Immunoglobulin G4-related disease (IgG4-RD) is now a widely recognised multi-organ system disease characterised by elevated serum and tissue concentrations of IgG4. In this study, the authors address several unresolved questions pertaining to the relationship between HT and FVHT, and the association of each of these diseases with IgG4-RD. The authors evaluated 28 consecutive cases of HT and nine cases of FVHT. The clinical, demographic and serological data were recorded. The slides were stained immunohistochemically using antibodies to IgG4 and IgG and the quantitative analysis was recorded. Data on thyroid function tests were available on seven cases of FVHT and 14 cases of HT. Based on the availability of data, hypothyroidism was noted in 62% (9/14) of HT and 86% of FVHT (6/7). FVHT demonstrated an exaggerated lobular pattern with lobules separated by cellular storiform-type fibrosis, resembling fibrosis seen in other forms of IgG-RD. The median IgG4 counts per high power field (×40) in HT and FVHT were 2.3 and 22, respectively. The median IgG4:IgG ratios in HT and FVHT were 0.11 and 0.58, respectively. The authors propose that FVHT belongs to the spectrum of IgG4-RD. Although a proportion of cases of HT show elevated numbers of IgG4 positive plasma cells, these cases lack the histological features typically associated with IgG4-RD, and thus the relationship between HT and IgG4-RD remains unproven.

IgG4 immunostaining and its implications in orbital inflammatory disease.

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Amanda J Wong

Full Text Available OBJECTIVE: IgG4-related disease is an emerging clinical entity which frequently involves tissue within the orbit. In order to appreciate the implications of IgG4 immunostaining, we analyzed gene expression and the prevalence of IgG4- immunostaining among subjects with orbital inflammatory diseases. METHODS: We organized an international consortium to collect orbital biopsies from 108 subjects including 22 with no known orbital disease, 42 with nonspecific orbital inflammatory disease (NSOI, 26 with thyroid eye disease (TED, 12 with sarcoidosis, and 6 with granulomatosis with polyangiitis (GPA. Lacrimal gland and orbital adipose tissue biopsies were immunostained for IgG4 or IgG secreting plasma cells. RNA transcripts were quantified by Affymetrix arrays. RESULTS: None of the healthy controls or subjects with TED had substantial IgG4 staining. Among the 63 others, the prevalence of significant IgG4-immunostaining ranged from 11 to 39% depending on the definition for significant. IgG4 staining was detectable in the majority of tissues from subjects with GPA and less commonly in tissue from subjects with sarcoidosis or NSOI. The detection of IgG4+ cells correlated with inflammation in the lacrimal gland based on histology. IgG4 staining tissue expressed an increase in transcripts associated with inflammation, especially B cell-related genes. Functional annotation analysis confirmed this. CONCLUSION: IgG4+ plasma cells are common in orbital tissue from patients with sarcoidosis, GPA, or NSOI. Even using the low threshold of 10 IgG4+ cells/high powered field, IgG4 staining correlates with increased inflammation in the lacrimal gland based on histology and gene expression.

IgG4 Immunostaining and Its Implications in Orbital Inflammatory Disease

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Wong, Amanda J.; Planck, Stephen R.; Choi, Dongseok; Harrington, Christina A.; Troxell, Megan L.; Houghton, Donald C.; Stauffer, Patrick; Wilson, David J.; Grossniklaus, Hans E.; Dailey, Roger A.; Ng, John D.; Steele, Eric A.; Harris, Gerald J.; Czyz, Craig; Foster, Jill A.; White, Valerie A.; Dolman, Peter J.; Kazim, Michael; Patel, Payal J.; Edward, Deepak P.; Katan, Hind al; Hussain, Hailah al; Selva, Dinesh; Yeatts, R. Patrick; Korn, Bobby S.; Kikkawa, Don O.; Rosenbaum, James T.

2014-01-01

Objective IgG4-related disease is an emerging clinical entity which frequently involves tissue within the orbit. In order to appreciate the implications of IgG4 immunostaining, we analyzed gene expression and the prevalence of IgG4- immunostaining among subjects with orbital inflammatory diseases. Methods We organized an international consortium to collect orbital biopsies from 108 subjects including 22 with no known orbital disease, 42 with nonspecific orbital inflammatory disease (NSOI), 26 with thyroid eye disease (TED), 12 with sarcoidosis, and 6 with granulomatosis with polyangiitis (GPA). Lacrimal gland and orbital adipose tissue biopsies were immunostained for IgG4 or IgG secreting plasma cells. RNA transcripts were quantified by Affymetrix arrays. Results None of the healthy controls or subjects with TED had substantial IgG4 staining. Among the 63 others, the prevalence of significant IgG4-immunostaining ranged from 11 to 39% depending on the definition for significant. IgG4 staining was detectable in the majority of tissues from subjects with GPA and less commonly in tissue from subjects with sarcoidosis or NSOI. The detection of IgG4+ cells correlated with inflammation in the lacrimal gland based on histology. IgG4 staining tissue expressed an increase in transcripts associated with inflammation, especially B cell-related genes. Functional annotation analysis confirmed this. Conclusion IgG4+ plasma cells are common in orbital tissue from patients with sarcoidosis, GPA, or NSOI. Even using the low threshold of 10 IgG4+ cells/high powered field, IgG4 staining correlates with increased inflammation in the lacrimal gland based on histology and gene expression. PMID:25303270

Overlapping Morphologic and Immunohistochemical Features of Hashimoto Thyroiditis and IgG4-Related Thyroid Disease.

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Raess, Philipp W; Habashi, Arlette; El Rassi, Edward; Milas, Mira; Sauer, David A; Troxell, Megan L

2015-05-01

Immunoglobulin G4-related disease (IgG4-RD) is an emerging clinicopathologic entity characterized by both IgG4+ plasma cell infiltration and fibrosis in one or more organs, prototypically pancreas or salivary/lacrimal glands. IgG4-RD in the thyroid (IgG4-RTD) is an area of active study, and the relationship between IgG4-RTD and Hashimoto thyroiditis is not fully delineated due to their overlapping histologic features. Retrospective review was performed of all thyroidectomy cases demonstrating lymphocytic inflammation at a single institution over a 4-year period. Approximately half (23/38) of patients had a clinical diagnosis of Hashimoto thyroiditis (HT). Nine of the 38 patients had increased absolute and relative numbers of IgG4+ plasma cells. Patients with a clinical diagnosis of HT had increased lymphoplasmacytic inflammation, but the relative proportion of IgG4+ plasma cells was not increased compared to patients without HT. There was no correlation between IgG4 levels and the amount of fibrosis in patients with or without HT. Patients identified as having the fibrosing variant of HT were not more likely to have increased levels of IgG4+ plasma cells than those without. There is significant morphologic and immunohistochemical overlap between HT and IgG4-RTD. Future studies to identify specific characteristics of IgG4-RTD involving the thyroid are necessary to accurately define this entity.

Utility of FDG PET/CT in IgG4-related systemic disease

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Nakatani, K., E-mail: koyakn@kuhp.kyoto-u.ac.jp [Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto (Japan); Nakamoto, Y.; Togashi, K. [Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto (Japan)

2012-04-15

IgG4-related systemic disease (IgG4-RSD) is an emerging clinical entity about which much remains to be elucidated, in terms of its aetiology, pathogenesis, diagnosis, treatment and outcome. Autoimmune pancreatitis (AIP) and Mikulicz disease (MD) are the two major, well-studied constituents of IgG4-RSD. AIP and MD have common characteristics of forming tumour-mimicking lesions that consist of lymphoplasmacytic infiltrates and fibrosclerosis with numerous immunoglobulin G4 (IgG4)-positive plasma cells, as well as various multi-organ manifestations of IgG4-RSD. 2-[{sup 18}F]-fluoro-2-deoxy-D-glucose positron-emission tomography/ computed tomography (FDG PET/CT) enables the acquisition of whole-body images and provides functional information about disease activity; as such it has a valuable role in staging extent of disease, guiding biopsy, and monitoring response to treatment. However, FDG PET/CT is likely to be only one component of the management strategy, and clinical, laboratory, imaging and histological findings are crucial in the overall diagnosis of the condition. At present FDG PET/CT does not have a well-established role in the assessment of patients with IgG4-RSD and future prospective studies are required to define the cost-effectiveness and clinical impact in this patient group more accurately.

Utility of FDG PET/CT in IgG4-related systemic disease

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Nakatani, K.; Nakamoto, Y.; Togashi, K.

2012-01-01

IgG4-related systemic disease (IgG4-RSD) is an emerging clinical entity about which much remains to be elucidated, in terms of its aetiology, pathogenesis, diagnosis, treatment and outcome. Autoimmune pancreatitis (AIP) and Mikulicz disease (MD) are the two major, well-studied constituents of IgG4-RSD. AIP and MD have common characteristics of forming tumour-mimicking lesions that consist of lymphoplasmacytic infiltrates and fibrosclerosis with numerous immunoglobulin G4 (IgG4)-positive plasma cells, as well as various multi-organ manifestations of IgG4-RSD. 2-[ 18 F]-fluoro-2-deoxy-D-glucose positron-emission tomography/ computed tomography (FDG PET/CT) enables the acquisition of whole-body images and provides functional information about disease activity; as such it has a valuable role in staging extent of disease, guiding biopsy, and monitoring response to treatment. However, FDG PET/CT is likely to be only one component of the management strategy, and clinical, laboratory, imaging and histological findings are crucial in the overall diagnosis of the condition. At present FDG PET/CT does not have a well-established role in the assessment of patients with IgG4-RSD and future prospective studies are required to define the cost-effectiveness and clinical impact in this patient group more accurately.

Multifocal fibrosclerosis and IgG4-related disease involving the cardiovascular system

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Ishizaka, Nobukazu; Terasaki, Fumio; Sakamoto, Aiko; Imai, Yasushi; Nagai, Ryozo

2012-01-01

The cardiovascular system may be involved as a target organ of multifocal fibrosclerosis, which may manifest as idiopathic retroperitoneal fibrosis, inflammatory aortic aneurysm, inflammatory periarteritis, and inflammatory pericarditis. These pathological conditions can sometimes occur concomitantly. Idiopathic retroperitoneal fibrosis and inflammatory abdominal aortic aneurysm are both characterized by the presence of fibro-inflammatory tissue around the abdominal aorta expanding into the surrounding retroperitoneal structures, and together they may be termed 'chronic periaortitis'. Cardiovascular fibrosclerosis has become non-uncommonly encountered condition since imaging modalities have made its diagnosis more feasible. In addition, recent studies have demonstrated that a certain fraction, but not all, of cardiovascular fibrosclerosis may have a link with immunoglobulin-G4 (IgG4)-related sclerosing disease (IgG4-SD). IgG4-SD is histologically characterized by dense fibrosclerosis and infiltration of lymphocytes and IgG4-positive plasma cells, and these histopathologic findings seem to be essentially similar regardless of the organs involved. In this mini review, we summarize what is known so far about multifocal fibrosclerosis of the cardiovascular system and its association with IgG4-SD, and what remains to be clarified in future investigations. (author)

Diagnostic Performance of Serum IgG4 Levels in Patients With IgG4-Related Disease

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Yu, Kuang-Hui; Chan, Tien-Ming; Tsai, Ping-Han; Chen, Ching-Hui; Chang, Pi-Yueh

2015-01-01

Abstract The aim of this study is to study the clinical features and diagnostic performance of IgG4 in Chinese populations with IgG4-related diseases (IgG4-RDs). The medical records of 2901 adult subjects who underwent serum IgG4 level tests conducted between December 2007 and May 2014 were reviewed. Serum concentrations of IgG4 were measured in 2901 cases, including 161 (5.6%) patients with IgG4-RD and 2740 (94.4%) patients without IgG4-RD (non-IgG4-RD group). The mean age of the IgG4-RD patients was 58.4 ± 16.1 years (range: 21–87), and 48 (29.8%) were women. The mean serum IgG4 level was significantly much higher in IgG4-RD patients than in non-IgG4-RD (1062.6 vs 104.3 mg/dL, P IgG4 >135 mg/dL, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), likelihood ratio (LR)+, and LR− were 86%, 77%, 18%, 99%, 3.70, and 0.19, respectively. When the upper limit of normal was doubled for an IgG4 >270 mg/dL, the corresponding data were 75%, 94%, 43%, 98%, 12.79, and 0.26, respectively. For IgG4 >405 mg/dL (tripling the upper limit of normal), the corresponding data were 62%, 98%, 68%, 98%, 37.00, and 0.39, respectively. When calculated according to the manufacturer's package insert cutoff (>201 mg/dL) for the diagnosis of IgG4-RD, the corresponding sensitivity, specificity, PPV, NPV, LR+, and LR− were 80%, 89%, 29%, 99%, 7.00, and 0.23, respectively. For IgG4 >402 mg/dL (>2× the upper limit of the normal range), the corresponding data were 62%, 98%, 68%, 98%, 36.21, and 0.39, respectively. For IgG4 >603 mg/dL (>3× the upper limit of the normal range), the corresponding data were 50%, 99%, 84%, 97%, 90.77 and 0.51, respectively. The optimal cutoff value of serum IgG4 (measured by nephelometry using a Siemens BN ProSpec instrument and Siemens reagent) for the diagnosis of IgG4-RD was 248 mg/dL, the sensitivity and specificity were 77.6% and 92.8%, respectively. The present study demonstrated that 2 or

IgG4-related spinal pachymeningitis.

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Lu, Zhang; Tongxi, Liu; Jie, Luo; Yujuan, Jiao; Wei, Jiang; Xia, Liu; Yumin, Zheng; Xin, Lu

2016-06-01

The aim of this study is to study the clinical, laboratory, imaging pathology, and prognosis features of IgG4-related spinal pachymeningitis. We worked with a 55-year-old man suffering from IgG4-related spinal pachymeningitis who had the most widespread lesion in his dura mater. We also review previous related studies and discuss the clinical characteristics of this rare disease. In total, eight IgG4-related spinal pachymeningitis patients have been reported in the literature since 2009. They were mostly male patients, 51.7 ± 11.9 years old on average. Cervical and thoracic vertebrae were the most common sites for lesions. The most prominent symptom was varying numbness and weakness of the limbs and/or body associated with spinal cord compression. There was one patient (1/5) with elevated serum IgG4 levels and three patients (3/3) with increased cerebrospinal fluid (CSF) IgG4 index. Positive histopathologic findings are the strongest basis for a diagnosis. All the patients with IgG4-related spinal pachymeningitis responded well to glucocorticoid therapy. IgG4-related spinal pachymeningitis is an orphan disease that mainly occurs in cervical and thoracic vertebrae. Older males are the most susceptible group. Serum IgG4 levels were consistently normal in these cases, so analysis of CSF for IgG4 production (IgG4 index) could become a useful tool. Pathological findings remain the gold standard for diagnosis. Most patients responded favorably to glucocorticoid treatment.

Thoracic Paravertebral Mass as an Infrequent Manifestation of IgG4-Related Disease

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Melissa Matzumura Kuan

2017-01-01

Full Text Available Case. A 50-year-old African American male presented with abdominal pain and significant weight loss. On physical examination, he had parotid and submandibular gland enlargement associated with right eye proptosis. Computed tomography showed a thoracic paravertebral soft tissue mass, enlarged lymph nodes, and ascending aortic aneurysm. Laboratory results were remarkable for elevated total IgG and IgG4 subclass. The submandibular gland pathology revealed chronic sclerosing sialadenitis, with a large subset of inflammatory cells positively staining for IgG4. The histology of the paravertebral mass demonstrated fibrosclerosis with increased lymphocytic infiltrate, associated with increased IgG4 plasma cells. He was diagnosed with immunoglobulin G4-related disease (IgG4-RD. Steroid therapy initially yielded improvement; however, after steroids were stopped, there was disease recurrence. Prednisone was restarted, and the plan was to start him on rituximab. Interestingly, the patient’s brother also had IgG4-RD. Conclusion. IgG4-RD can present as a paravertebral mass which is usually responsive to steroids; however, recurrent and resistant disease can be seen for which steroid-sparing agents such as rituximab should be considered. In addition, to the best of our knowledge, this is the first reported case of IgG4-RD in two family members presenting as a paravertebral mass, highlighting an exciting area for more research in the future.

Deconstructing IgG4-related disease involvement of midline structures: Comparison to common mimickers.

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Lanzillotta, Marco; Campochiaro, Corrado; Trimarchi, Matteo; Arrigoni, Gianluigi; Gerevini, Simonetta; Milani, Raffaella; Bozzolo, Enrica; Biafora, Matteo; Venturini, Elena; Cicalese, Maria Pia; Stone, John H; Sabbadini, Maria Grazia; Della-Torre, Emanuel

2017-07-01

A series of destructive and tumefactive lesions of the midline structures have been recently added to the spectrum of IgG4-related disease (IgG4-RD). We examined the clinical, serological, endoscopic, radiological, and histological features that might be of utility in distinguishing IgG4-RD from other forms of inflammatory conditions with the potential to involve the sinonasal area and the oral cavity. We studied 11 consecutive patients with erosive and/or tumefactive lesions of the midline structures referred to our tertiary care center. All patients underwent serum IgG4 measurement, flow cytometry for circulating plasmablast counts, nasal endoscopy, radiological studies, and histological evaluation of tissue specimens. The histological studies included immunostaining studies to assess the number of IgG4 + plasma cells/HPF for calculation of the IgG4+/IgG + plasma cell ratio. Five patients with granulomatosis with polyangiitis (GPA), three with cocaine-induced midline destructive lesions (CIMDL), and three with IgG4-RD were studied. We found no clinical, endoscopic, or radiological findings specific for IgG4-RD. Increased serum IgG4 and plasmablasts levels were not specific for IgG4-RD. Rather, all 11 patients had elevated blood plasmablast concentrations, and several patients with GPA and CIMDL had elevated serum IgG4 levels. Storiform fibrosis and an IgG4+/IgG + plasma cell ratio >20% on histological examination, however, were observed only in patients with IgG4-RD. Histological examination of bioptic samples from the sinonasal area and oral cavity represents the mainstay for the diagnosis of IgG4-RD involvement of the midline structures.

Elevated Serum IgG4 Defines Specific Clinical Phenotype of Rheumatoid Arthritis

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Le-Feng Chen

2014-01-01

Full Text Available Objectives. To explore the correlation of serum IgG4 (sIgG4 with clinical manifestations or therapeutic response in rheumatoid arthritis (RA. Methods. Consecutive 136 RA patients were recruited and followed up at regular interval. SIgG4 was detected by immunonephelometry. Serial synovial tissue sections from 46 RA patients were stained immunohistochemically for IgG4. Results. Forty-six percent of 136 RA patients had elevated sIgG4. Patients with elevated sIgG4 had higher sIgG4/sIgG ratio, C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor, and anticyclic citrullinated peptide antibodies than those with normal sIgG4 (all P<0.05. Among 45 patients who received methotrexate and leflunomide therapy, 50% (9/18 of patients with elevated sIgG4 and 85% (23/27 of patients with normal sIgG4 reached therapeutic target (disease activity score of 28 joints < 3.2 at 6-month visit (χ2=6.508, P=0.011. IgG4-positive plasma cell count correlated positively with sIgG4, total synovitis score, and CD3-, CD20-, and CD38-positive cell counts (all P<0.05. Conclusions. Our results showed that elevated sIgG4 in RA is common and disproportional to total IgG and RA with elevated sIgG4 may be a specific clinical phenotype with higher disease activity, higher level of autoantibodies, and poor response to methotrexate and leflunomide therapy.

Case report: A female case of isolated IgG4-related sclerosing cholangitis mimicking cholangiocarcinoma.

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Xiao, Jianchun; Li, Guanqiao; Yang, Gang; Jia, Congwei; Li, Binglu

2017-04-01

IgG4-related disease is a newly recognized fibroinflammatory disorder, characterized by tumefactive lesions, storiform fibrosis and IgG4-positive plasma cells infiltration. IgG4-related sclerosing cholangitis (IgG4-SC) is the most common extrapancreatic manifestation of IgG4-related disease, but it is frequently associated with autoimmune pancreatitis(AIP). Only few case was reported to be diagnosed with IgG4-SC in the absence of AIP, with a striking male preponderance. Here we report a female case of isolated IgG4 related sclerosing cholangitis mimicking cholangiocarcinoma. A 58-year-old woman complaint of one-month history of jaundice and right upper quadrant discomfort, and the biliary reconstruction showed full-length wall thickening and segmental stenosis. Cholangiocarcinoma was then diagnosed. Choledochoplasty was performed, followed by Roux-en-Y anastomosis. However, pathological examination revealed IgG4-related sclerosing cholangitis (IgG4-SC) and the retrospective measurement of serum IgG4 was 346 mg/dL post-operatively. The patient was followed for another nine monthswithout recurrence. The differential diagnosis between cholangiocarcinoma and IgG4-SC is challenging due to significant overlap of clinical manifestations, lab tests and imaging characteristics. However, as an afterthought of this case, typical cholangiocarcinoma rarely presents full-length wall thickening. What the case taught us was pre-operative IgG4 measurement for patients with long bile duct involvement was highly recommended in order to rule out IgG4-SC.

Value of serum IgG4 in the diagnosis of IgG4-related disease and in differentiation from rheumatic diseases and other diseases.

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Yamamoto, Motohisa; Tabeya, Tetsuya; Naishiro, Yasuyoshi; Yajima, Hidetaka; Ishigami, Keisuke; Shimizu, Yui; Obara, Mikiko; Suzuki, Chisako; Yamashita, Kentaro; Yamamoto, Hiroyuki; Hayashi, Toshiaki; Sasaki, Shigeru; Sugaya, Toshiaki; Ishida, Tadao; Takano, Ken-Ichi; Himi, Tetsuo; Suzuki, Yasuo; Nishimoto, Norihiro; Honda, Saho; Takahashi, Hiroki; Imai, Kohzoh; Shinomura, Yasuhisa

2012-06-01

IgG4-related disease (IgG4-RD) is a novel disease entity that includes Mikulicz's disease, autoimmune pancreatitis (AIP), and many other conditions. It is characterized by elevated serum IgG4 levels and abundant IgG4-bearing plasmacyte infiltration of involved organs. We postulated that high levels of serum IgG4 would comprise a useful diagnostic tool, but little information is available about IgG4 in conditions other than IgG4-RD, including rheumatic diseases. Several reports have described cutoff values for serum IgG4 when diagnosing IgG4-RD, but these studies mostly used 135 mg/dL in AIP to differentiate from pancreatic cancer instead of rheumatic and other common diseases. There is no evidence for a cutoff serum IgG4 level of 135 mg/dL for rheumatic diseases and common diseases that are often complicated with rheumatic diseases. The aim of this work was to re-evaluate the usual cutoff serum IgG4 value in AIP (135 mg/dL) that is used to diagnose whole IgG4-RD in the setting of a rheumatic clinic by measuring serum IgG4 levels in IgG4-RD and various disorders. We therefore constructed ROC curves of serum IgG4 levels in 418 patients who attended Sapporo Medical University Hospital due to IgG4-RD and various rheumatic and common disorders. The optimal cut-off value of serum IgG4 for a diagnosis of IgG4-RD was 144 mg/dL, and the sensitivity and specificity were 95.10 and 90.76%, respectively. Levels of serum IgG4 were elevated in IgG4-RD, Churg-Strauss syndrome, multicentric Castleman's disease, eosinophilic disorders, and in some patients with rheumatoid arthritis, systemic sclerosis, chronic hepatitis, and liver cirrhosis. The usual cut-off value of 135 mg/dL in AIP is useful for diagnosing whole IgG4-RD, but high levels of serum IgG4 are sometimes observed in not only IgG4-RD but also other rheumatic and common diseases.

Overview of IgG4 - Related Disease.

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Opriţă, R; Opriţă, B; Berceanu, D; Diaconescu, I B

2017-01-01

Rationale (hypothesis): IgG4-related disease (IgG4-RD) is a pathological entity recently recognized by the medical world that can affect any organ or system. However, there is insufficient data about this disease in medical literature. Aim (objective): A more extensive clarification of the IgG4 molecule, the diversified aspects of IgG4-related disease, and the response of this disease to treatment, will provide a crucial understanding of the immune system and other diseases now known to be associated with IgG4. The MEDLINE online medical database was used, and, after a comprehensive review of medical articles regarding IgG4-RD, published after 2003, using the search words "IgG4- related disease" and "IgG4 molecule", we have described the clinical, pathological and therapeutic features of IgG4-RD, as well as the presence of the IgG4 molecule in the evolution, diagnosis and management of this syndrome. We characterized the potential disease mechanisms and discussed early observations related to treatment. Given the response to immunosuppressive therapy, it is hypothesized that IgG4-related disease is most likely an autoimmune disease. Therefore, IgG4-related disease is a fibro-inflammatory condition that can affect any organ and can lead to the formation of pseudotumoral lesions requiring differential diagnosis with various malignancies. Positive diagnostic criteria are histopathological and require at least two features out of the following three: dense limphoplasmocitary infiltrate, storiform fibrosis, obliterative phlebitis.

Histopathological Diagnostic Value of the IgG4+/IgG+ Ratio of Plasmacytic Infiltration for IgG4-Related Diseases

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Deng, Chuiwen; Li, Wenli; Chen, Si; Zhang, Wen; Li, Jing; Hu, Chaojun; Wen, Xiaoting; Zhang, Fengchun; Li, Yongzhe

2015-01-01

Abstract This article aims to perform a meta-analysis to evaluate the diagnostic value of the immunoglobulin G (IgG)4+/IgG+ ratio of plasmacytic infiltration for IgG4-related diseases. Four databases—EMBASE, ISI Web of Knowledge, PubMed, and the Cochrane Library—were systematically searched. Approximately 200 participants from several studies were included in this research. STATA 11.2 software (Stata Corporation, College Station, TX) and Meta-DiSc 1.4 (Unit of Clinical Biostatistics, Ramon y Cajal Hospital, Madrid, Spain) were used to perform the meta-analysis. Nine studies were included in the meta-analysis. The pooled diagnostic odds ratio was 18.94 [95% confidence interval (CI), 2.89–124.30]. The sensitivity was 58.80% (95% CI, 50.90–66.30) and the specificity was 90.20% (95% CI, 81.20–95.80). The positive and negative likelihood ratios were 3.12 (95% CI, 1.07–9.16) and 0.26 (95% CI, 0.09–0.70), respectively. The area under the curve of the summary receiver-operating characteristic was 0.88. To conclude, the IgG4+/IgG+ ratio of plasmacytic infiltration is modestly effective in diagnosing IgG-related disease. PMID:25738476

IgG4-related disease in the eye and ocular adnexa.

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Derzko-Dzulynsky, Larissa

2017-11-01

IgG4-related disease is a multi-organ fibro-inflammatory disease with characteristic histopathology showing lymphoplasmacytic infiltration, increased IgG4+ plasma cells and elevated IgG4/IgG ratios (>40%). The lacrimal gland is the most common ocular site of involvement. Scleritis and intraocular involvement in IgG4-related ophthalmic disease (IgG4-ROD) have recently been reported. The purpose of this review is to describe orbital and intraocular IgG4-ROD with a focus on publications since 2016. Case reports of scleritis and uveitis in IgG4-ROD have been described since 2012. Systemic prednisone is recommended as the first-line treatment, but immunosuppressive therapy may be required for steroid-sparing or in steroid-resistant cases. High rates of systemic IgG4-RD involvement exist in patients with bilateral IgG4-ROD or if the lacrimal gland is involved. Rituximab is the most specific immune targeted therapy available with high rates of remission. IgG4-ROD is an emerging cause of scleritis and uveitis and should be considered in any patient with multisystem inflammatory disease. New targeted immune therapies may improve outcomes and lead to clinical remission.

Multi-organ IgG4-related disease: Demystifying the diagnostic enigma

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S Bhardwaj

2018-01-01

Full Text Available IgG4-related disease (IgG4-RD is a multisystemic mass forming immune-mediated disease entity, commonly creating confusion and diagnostic challenges. We present a case of a 25-year-old female who presented with bilateral orbital masses, lymphadenopathy, paraspinal and renal masses, which clinicoradiologically simulated lymphoma. The lymph node biopsy revealed interfollicular sheets of plasma cells creating confusion with Castleman's disease and marginal zone lymphoma. The orbital biopsy revealed ductular destruction, periductular plasma cells, and fibrosis, mimicking Sjogren's syndrome and Castleman's disease. However, the correlation of the clinical features with histopathological findings, IgG4 immunopositivity, and serum studies helped in clinching the diagnosis. This case presents an uncommon combination of clinical features infrequently reported in literature. Furthermore, and more importantly, it highlights the need to keep a differential of IgG4-RD in mind, to aid early and correct treatment of the disease.

Recent advances in knowledge regarding the head and neck manifestations of IgG4-related disease.

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Takano, Kenichi; Yamamoto, Motohisa; Takahashi, Hiroki; Himi, Tetsuo

2017-02-01

IgG4-related disease (IgG4-RD) is a chronic inflammatory disorder, characterized by elevated serum IgG4 levels as well as abundant infiltration of IgG4-positive plasmacytes and fibrosis in various organs, including the head and neck region. In particular, the salivary glands, orbit, and thyroid are common sites of disease involvement. IgG4-RD is diagnosed based on various clinical, serological, and histopathological findings, none of which are pathognomonic. Hence, various differential diagnoses, which exhibit elevated serum IgG4 levels and infiltration of IgG4-postive cells into tissues, need to be excluded, especially malignant diseases and mimicking disorders. Systemic corticosteroids are generally effective in inducing IgG4-RD remission; however, recurrent or refractory cases are common. In addition, although the pathogenic mechanisms of IgG4-RD remain unclear, an antigen-driven inflammatory condition is believed to be involved. Recent studies have indicated the important pathogenic role of B cell/T cell collaboration and innate immunity in this disease. Nevertheless, additional research and discussions are needed to resolve many remaining questions. In this review, we provide an overview of the recent insights on the history, clinical features, diagnosis, and treatment of IgG4-RD in the head and neck region. Furthermore, we have also addressed the pathogenesis of this disease. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

IgG4-related prostatitis progressed from localized IgG4-related lymphadenopathy.

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Li, Dujuan; Kan, Yunzhen; Fu, Fangfang; Wang, Shuhuan; Shi, Ligang; Liu, Jie; Kong, Lingfei

2015-01-01

Immunoglobulin G4-related disease (IgG4-RD) is a recently described inflammatory disease involving multiple organs. Prostate involvement with IgG4-RD is very rare. In this report, we describe a case of IgG4-related prostatitis progressed from localized IgG4-related lymphadenopathy. This patient was present with urine retention symptoms. MRI and CT examination revealed the prostatic enlargement and the multiple lymphadenopathy. Serum IgG4 levels were elevated. Prostatic tissue samples resected both this time and less than 1 year earlier showed the same histological type of prostatitis with histopathologic and immunohistochemical findings characteristic of IgG4-RD. The right submandibular lymph nodes excised 2 years earlier were eventually proven to be follicular hyperplasia-type IgG4-related lymphadenopathy. This is the first case of IgG4-RD that began as localized IgG4-related lymphadenopathy and progressed into a systemic disease involving prostate and multiple lymph nodes. This patient showed a good response to steroid therapy. This leads us to advocate a novel pathogenesis of prostatitis, and a novel therapeutic approach against prostatitis. Pathologists and urologists should consider this disease entity in the patients with elevated serum IgG4 levels and the symptoms of prostatic hyperplasia to avoid ineffective medical or unnecessary surgical treatment.

IgG4- related disease: an orphan disease with many faces

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2014-01-01

Immunoglobulin G4- related disease (IgG4-RD) is a rare systemic fibro-inflammatory disorder (ORPHA284264). Although patients have been described more than 100 years ago, the systemic nature of this disease has been recognized in the 21st century only. Type 1 autoimmune pancreatitis is the most frequent manifestation of IgG4-RD. However, IgG4-RD can affect any organ such as salivary glands, orbits, retroperitoneum and many others. Recent research enabled a clear clinical and histopathological description of IgG4-RD. Typically, lymphoplasmacellular inflammation, storiform fibrosis and obliterative phlebitis are found in IgG4-RD biopsies and the tissue invading plasma cells largely produce IgG4. Elevated serum IgG4 levels are found in many but not all patients. Consequently, diagnostic criteria for IgG4-RD have been proposed recently. Treatment is largely based on clinical experience and retrospective case series. Glucocorticoids are the mainstay of therapy, although adjunctive immunosuppressive agents are used in relapsing patients. This review summarizes current knowledge on clinical manifestations, pathophysiology and treatment of IgG4-RD. PMID:25026959

IgG4-related cardiovascular disease. The emerging role of cardiovascular imaging.

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Mavrogeni, Sophie; Markousis-Mavrogenis, George; Kolovou, Genovefa

2017-01-01

Immunoglobulin 4-related disease (IgG4-related disease) is a systemic inflammatory disease that presents with increases of serum IgG4. It may affect various systems, including the cardiovascular (CV) system. Assessment of serum IgG4 levels and involved organ biopsy are necessary for diagnosis. IgG4-related disease is characterized by fibrosclerosis, lymphocytic infiltration and presence of IgG4-positive plasma cells. The disease usually responds to treatment with corticosteroids and/or immunosuppressive medication. CV involvement may manifest as cardiac pseudotumors, inflammatory periaortitis, coronary arteritis and/or pericarditis. IgG4-related cardiovascular disorders can severely affect patient prognosis. Various imaging techniques, including echocardiography, Computed Tomography (CT), 18FDG-PET, Cardiovascular Magnetic Resonance (CMR) and cardiac catheterisation, have been successfully used for early disease detection and follow-up. Echocardiography and vascular ultrasound are the most commonly used non-invasive, non-radiating imaging techniques for the evaluation of IgG4-related CV disease. Periaortitis/periarteritis can be also assessed by CT, showing a soft tissue thickening around arteries. Coronary artery aneurysms can be easily diagnosed by coronary CT. In case of active periarterial or coronary artery inflammation, 18FDG-PET will show FDG uptake at the area of the lesion. CMR, due to its capability to perform function and tissue characterisation, can offer an integrated imaging of aorta, coronary arteries and the heart, assessment of disease acuity, extent of fibrosis and guide further treatment. However, multimodality imaging may be necessary for assessment of disease activity and fibrosis extent in those cases with multifocal CV involvement. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

IgG4-related Hypophysitis with Subtle Hypopituitarism in an Elderly Diabetic Patient: Is Treatment or Observation Preferable?

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Kawasaki, Motoki; Tsujino, Motoyoshi; Sato, Fuminori; Sakurada, Maya; Nishida, Kenji; Kise, Takayasu; Hijioka, Yuko; Ishizawa, Mitsugu; Enatsu, Kazuaki; Ogawa, Yoshihiro

2017-10-15

A 70-year-old man with diabetes mellitus presented with an enlarged pituitary stalk in 2014. IgG4-related parotitis and submandibular sialoadenitis were diagnosed in 2012. He denied any symptoms related to a pituitary mass. His visual field was intact, and his hypopituitarism was subtle. The serum IgG4 level was elevated. A lip biopsy revealed strong fibrosis and hyper-infiltration of IgG4-positive plasma cells. Based on these findings, IgG4-related hypophysitis was diagnosed. The patient was carefully followed without specific intervention. His clinical condition showed no change until December 2016, suggesting a stable, natural course. Care should be taken when considering glucocorticoid therapy, especially for elderly diabetic patients, given possible side effects.

IgG4-related lung disease presenting as interstitial lung disease with bronchiolitis: A case report.

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Chen, Chiu-Fan; Chu, Kuo-An; Tseng, Yen-Chiang; Wu, Chang-Che; Lai, Ruay-Sheng

2017-12-01

IgG4-related disease is a rare and novel disease entity that tends to involve multiple organs. The pulmonary manifestation of this disease is highly variable and may mimic lung cancer, pneumonia, interstitial lung disease (ILD), sarcoidosis, and so forth. Small airway disease is rarely reported in IgG4-related lung disease (IgG4-RLD). In the current study, we describe a rare case of IgG4-RLD with patterns of ILD and bronchiolitis. A 43-year-old man had chronic cough and dyspnea on exertion for 4 years. Initial chest radiography showed diffuse interstitial infiltration. Follow-up chest computed tomography 4 years later revealed bilateral diffuse centrilobular nodules with tree-in-bud pattern, bronchial wall thickening, and mediastinal lymph nodes. Bilateral diffuse multifocal ground-glass opacities and mosaic attenuation were also observed. Pulmonary function test revealed mixed restrictive and obstructive ventilatory impairment. Video-assisted thoracoscopic surgery (VATS) lung biopsy showed interstitial fibrosis with lymphoplasmacytic infiltration rich in IgG4-positive plasma cells. Serum IgG4 level also showed remarkable elevation. Therefore, IgG4-RLD is confirmed. VATS wedge resection of right upper lobe and mediastinal lymph node. The patient responded well to steroid and immunosuppression therapy, and was regular followed-up in outpatient clinic. IgG4-RLD should be considered not only in ILD, but also in small airway disease. Serum IgG4 level may be a useful tool for screening.

LatY136F knock-in mouse model for human IgG4-related disease.

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Yamada, Kazunori; Zuka, Masahiko; Ito, Kiyoaki; Mizuguchi, Keishi; Kakuchi, Yasushi; Onoe, Tamehito; Suzuki, Yasunori; Yamagishi, Masakazu; Izui, Shozo; Malissen, Marie; Malissen, Bernard; Kawano, Mitsuhiro

2018-01-01

The adaptor protein Linker for activation of T cell (LAT) is a key signaling hub used by the T cell antigen receptor. Mutant mice expressing loss-of-function mutations affecting LAT and including a mutation in which tyrosine 136 is replaced by a phenylalanine (LatY136F) develop lymphoproliferative disorder involving T helper type 2 effector cells capable of triggering a massive polyclonal B cell activation that leads to hypergammaglobulinemia G1 and E and to non-resolving inflammation and autoimmunity. The purpose of this study was to evaluate whether the phenotypes of LatY136F knock-in mice resemble the immunohistopathological features of immunoglobulin G4-related disease (IgG4-RD). LatY136F knock-in mice were sacrificed at 4-20 weeks of age, and pancreas, kidney, salivary gland and lung were obtained. All organs were stained with hematoxylin-eosin and with Azan for estimation of collagen in fibrosis, and the severity scores of inflammation and fibrosis were evaluated. Immunostainings were performed to analyze the types of infiltrating cells. In addition, the effects of corticosteroid treatment on the development of tissue lesions and serum levels of IgG1 were assessed. Tissue lesions characterized by inflammatory mononuclear cell infiltration and fibrosis were detected in pancreas, kidney, and salivary gland starting from 6 weeks of age. Immunostainings showed pronounced infiltration of plasma cells, CD4-positive T cells, and macrophages. Infiltrating plasma cells predominantly expressed IgG1. The extent of inflammation in pancreas and salivary glands was markedly reduced by corticosteroid treatment. LatY136F knock-in mice displayed increased production of Th2-type IgG1 (a homologue of human IgG4) and developed multiple organ tissue lesions reminiscent of those seen in patients with IgG4-RD. Moreover, the development of these tissue lesions was highly sensitive to corticosteroid treatment like in IgG4-RD. For these reasons we consider the LatY136F knock-in mouse

Human IgG4 binds to IgG4 and conformationally altered IgG1 via Fc-Fc interactions

NARCIS (Netherlands)

Rispens, Theo; Ooievaar-de Heer, Pleuni; Vermeulen, Ellen; Schuurman, Janine; van der Neut Kolfschoten, Marijn; Aalberse, Rob C.

2009-01-01

The Fc fragment of IgG4 can interact with the Fc fragment of another IgG molecule. This interaction is a confounding factor when measuring IgG4 rheumatoid factor levels. Recently, we demonstrated that half-molecules of IgG4 can exchange to form a bispecific Ab. We expected these two phenomena to be

Fine needle aspiration cytology of IgG4-related disease: A potential diagnostic pitfall?

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Kaur, Rajwant; Mitra, Suvradeep; Rajwanshi, Arvind; Das, Ashim; Nahar Saikia, Uma; Dey, Pranab

2017-01-01

IgG4-related disease (IgG4-RD) is a tumefactive fibro-inflammatory lesion that can affect any organ system in the body. Till date, no cytological data on IgG4-RD are available and this is the first study depicting the cytopathology features of IgG4-RD. To describe the cytopathological features and potential diagnostic errors of IgG4-RD. The cytological features of 10 histopathology proven IgG4-RD cases (11 samples) were retrospectively reviewed along with corresponding histopathology. The cellularity of the cytology smears was low (36.4%) to moderate (45.4%) to high (18.1%). The low cellularity correlated well with the pattern C in histopathology (predominant fibrosis pattern). The non-epithelial background showed a preponderance of lymphocytes along with polymorphs and spindle-shaped fibroblasts. Most of these cases showed the presence of plasma cells and eosinophils. Epithelial atypia was seen in 18.2% cases. The causes of misdiagnosis were low cellularity, epithelial atypia, and non-representative background. The important diagnostic clues to suspect a diagnosis of IgG4-RD include low cellularity despite adequate effort, inflammatory background rich in lymphocytes and spindle cells admixed with a few plasma cells and eosinophils along with radiological features and raised serum IgG4 Diagn. Cytopathol. 2017;45:14-21. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Lesional CD4+ IFN-γ+ cytotoxic T lymphocytes in IgG4-related dacryoadenitis and sialoadenitis

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Maehara, Takashi; Mattoo, Hamid; Ohta, Miho; Mahajan, Vinay S; Moriyama, Masafumi; Yamauchi, Masaki; Drijvers, Jefte; Nakamura, Seiji; Stone, John H; Pillai, Shiv S

2017-01-01

Objectives IgG4-related disease (IgG4-RD) is a chronic, systemic, inflammatory condition of unknown aetiology. We have recently described clonally expanded circulating CD4+ cytotoxic T lymphocytes (CTLs) in IgG4-RD that infiltrate affected tissues where they secrete interleukin (IL)-1β and transforming growth factor -β1 (TGF-β1). In this study, we sought to examine the role of CD4+ CTLs in the pathogenesis of IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS) and to determine whether these cells secrete interferon-gamma (IFN-γ) at lesional sites. Methods Salivary glands of 25 patients with IgG4-DS, 22 patients with Sjögren’s syndrome (SS), 12 patients with chronic sialoadenitis (CS) and 12 healthy controls were analysed in this study. Gene expression analysis was performed on submandibular glands (SMGs) from five patients with IgG4-DS, three with CS and three healthy controls. Infiltrating CD4+ CTLs were examined by quantitative multicolour imaging in tissue samples from 20 patients with IgG4-DS, 22 patients with SS, 9 patients with CS and 9 healthy controls. Results In IgG4-DS tissues, nine genes associated with CD4+ CTLs were overexpressed. The expression of granzyme A (GZMA) mRNA was significantly higher in samples from patients with IgG4-RD compared with corresponding tissues from SS and healthy controls. Quantitative imaging showed that infiltrating CD4+ GZMA+ CTLs were more abundant in patients with IgG4-DS than in the other groups. The ratio of CD4+GZMA+ CTLs in SMGs from patients with IgG4-DS correlated with serum IgG4 concentrations and the number of affected organs. A large fraction of CD4+GZMA+ CTLs in SMGs from patients with IgG4-DS secreted IFN-γ. Conclusions The pathogenesis of IgG4-DS is associated with tissue infiltration by CD4+GZMA+ CTLs that secrete IFN-γ. PMID:27358392

IgG4-related disease -Mechanistic insights from both clinical and immunologic understanding of this condition.

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Maehara, Takashi

2017-01-01

IgG4-related disease (IgG4-RD) is a chronic inflammatory disease characterized by tumescent lesions with characteristic storiform fibrosis, obliterative phlebitis and a marked lymphoplasmacytic infiltrate that includes a large number of IgG4 positive plasma cells. It's widely accepted that rituximab-mediated B cell depletion therapy is effective for this disease. Important mechanistic insights correlated with the pathogenesis of IgG4-RD have been gradually disclosed from studies of patients treated by B cell depletion. 1) IgG4-RD patients have the large clonal expansion of activated plasmablasts and CD4 + CTLs, so this disease might be antigen-driven. 2) CD4 + CTLs are the dominant population in affected tissues, on the other hands direct examination of T H1 and T H2 cells in tissues reveal that these subsets are sparse. 3) CD4 + CTLs into affected lesions secret cytotoxic, inflammatory, and pro-fibrotic cytokines, indicating reactivation by antigen in tissue sites. 4) The decline in CD4 + CTLs number by B cell depletion is associated with clinical remission of IgG4-RD patients. 5) CD4 + CXCR5 + T FH cells that express IL-4 are located outside germinal centers and specialized T FH cells that expanded dramatically in conditions with polarized class switching to IgG4. These results suggested that the disease pathogenesis might be based on orchestrating of activated plasmablasts, CD4 + CTLs, and T FH cells.

IgG4-Related Sclerosing Disease, an Emerging Entity: A Review of a Multi-System Disease

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Divatia, Mukul; Kim, Sun A

2012-01-01

Immunoglobulin G4-related systemic disease (IgG4-RSD) is a recently defined emerging entity characterized by a diffuse or mass forming inflammatory reaction rich in IgG4-positive plasma cells associated with fibrosclerosis and obliterative phlebitis. IgG4-RSD usually affects middle aged and elderly patients, with a male predominance. It is associated with an elevated serum titer of IgG4, which acts as a marker for this recently characterized entity. The prototype is IgG4-related sclerosing pancreatitis or autoimmune pancreatitis (AIP). Other common sites of involvement are the hepatobiliary tract, salivary gland, orbit, and lymph node, however practically any organ can be involved, including upper aerodigestive tract, lung, aorta, mediastinum, retroperitoneum, soft tissue, skin, central nervous system, breast, kidney, and prostate. Fever or constitutional symptoms usually do not comprise part of the clinical picture. Laboratory findings detected include raised serum globulin, IgG and IgG4. An association with autoantibody detection (such as antinuclear antibodies and rheumatoid factor) is seen in some cases. Steroid therapy comprises the mainstay of treatment. Disease progression with involvement of multiple organ-sites may be encountered in a subset of cases and may follow a relapsing-remitting course. The principal histopathologic findings in several extranodal sites include lymphoplasmacytic infiltration, lymphoid follicle formation, sclerosis and obliterative phlebitis, along with atrophy and destruction of tissues. Immunohistochemical staining shows increased IgG4+ cells in the involved tissues (>50 per high-power field, with IgG4/IgG ratio >40%). IgG4-RSD may potentially be rarely associated with the development of lymphoma and carcinoma. However, the nature and pathogenesis of IgG4-RSD are yet to be fully elucidated and provide immense scope for further studies. PMID:22187229

IgG4-related cardiovascular disease. The emerging role of cardiovascular imaging

Energy Technology Data Exchange (ETDEWEB)

Mavrogeni, Sophie, E-mail: soma13@otenet.gr; Markousis-Mavrogenis, George; Kolovou, Genovefa

2017-01-15

Highlights: • Assessment of serum IgG4 levels and involved organ biopsy are necessary for diagnosis of IgG4-related disease. • CV involvement may manifest as cardiac pseudotumors, inflammatory periaortitis, coronary arteritis and/or pericarditis. • Echocardiography and vascular ultrasound are the most commonly used non-invasive, non-radiating imaging techniques. • CT can assess periarteritis and coronary artery aneurysms, while 18FDG-PET shows FDG uptake at the area of the lesion. • CMR offers an integrated imaging of CV system, including assessment of disease acuity, extent of fibrosis and can guide further treatment. - Abstract: Immunoglobulin 4-related disease (IgG4-related disease) is a systemic inflammatory disease that presents with increases of serum IgG4. It may affect various systems, including the cardiovascular (CV) system. Assessment of serum IgG4 levels and involved organ biopsy are necessary for diagnosis. IgG4-related disease is characterized by fibrosclerosis, lymphocytic infiltration and presence of IgG4-positive plasma cells. The disease usually responds to treatment with corticosteroids and/or immunosuppressive medication. CV involvement may manifest as cardiac pseudotumors, inflammatory periaortitis, coronary arteritis and/or pericarditis. IgG4-related cardiovascular disorders can severely affect patient prognosis. Various imaging techniques, including echocardiography, Computed Tomography (CT), 18FDG-PET, Cardiovascular Magnetic Resonance (CMR) and cardiac catheterisation, have been successfully used for early disease detection and follow-up. Echocardiography and vascular ultrasound are the most commonly used non-invasive, non-radiating imaging techniques for the evaluation of IgG4-related CV disease. Periaortitis/periarteritis can be also assessed by CT, showing a soft tissue thickening around arteries. Coronary artery aneurysms can be easily diagnosed by coronary CT. In case of active periarterial or coronary artery inflammation, 18

IgG4-related cardiovascular disease. The emerging role of cardiovascular imaging

International Nuclear Information System (INIS)

Mavrogeni, Sophie; Markousis-Mavrogenis, George; Kolovou, Genovefa

2017-01-01

Highlights: • Assessment of serum IgG4 levels and involved organ biopsy are necessary for diagnosis of IgG4-related disease. • CV involvement may manifest as cardiac pseudotumors, inflammatory periaortitis, coronary arteritis and/or pericarditis. • Echocardiography and vascular ultrasound are the most commonly used non-invasive, non-radiating imaging techniques. • CT can assess periarteritis and coronary artery aneurysms, while 18FDG-PET shows FDG uptake at the area of the lesion. • CMR offers an integrated imaging of CV system, including assessment of disease acuity, extent of fibrosis and can guide further treatment. - Abstract: Immunoglobulin 4-related disease (IgG4-related disease) is a systemic inflammatory disease that presents with increases of serum IgG4. It may affect various systems, including the cardiovascular (CV) system. Assessment of serum IgG4 levels and involved organ biopsy are necessary for diagnosis. IgG4-related disease is characterized by fibrosclerosis, lymphocytic infiltration and presence of IgG4-positive plasma cells. The disease usually responds to treatment with corticosteroids and/or immunosuppressive medication. CV involvement may manifest as cardiac pseudotumors, inflammatory periaortitis, coronary arteritis and/or pericarditis. IgG4-related cardiovascular disorders can severely affect patient prognosis. Various imaging techniques, including echocardiography, Computed Tomography (CT), 18FDG-PET, Cardiovascular Magnetic Resonance (CMR) and cardiac catheterisation, have been successfully used for early disease detection and follow-up. Echocardiography and vascular ultrasound are the most commonly used non-invasive, non-radiating imaging techniques for the evaluation of IgG4-related CV disease. Periaortitis/periarteritis can be also assessed by CT, showing a soft tissue thickening around arteries. Coronary artery aneurysms can be easily diagnosed by coronary CT. In case of active periarterial or coronary artery inflammation, 18

Mitochondrial-dependent Autoimmunity in Membranous Nephropathy of IgG4-related Disease

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Buelli, Simona; Perico, Luca; Galbusera, Miriam; Abbate, Mauro; Morigi, Marina; Novelli, Rubina; Gagliardini, Elena; Tentori, Chiara; Rottoli, Daniela; Sabadini, Ettore; Saito, Takao; Kawano, Mitsuhiro; Saeki, Takako; Zoja, Carlamaria; Remuzzi, Giuseppe; Benigni, Ariela

2015-01-01

The pathophysiology of glomerular lesions of membranous nephropathy (MN), including seldom-reported IgG4-related disease, is still elusive. Unlike in idiopathic MN where IgG4 prevails, in this patient IgG3 was predominant in glomerular deposits in the absence of circulating anti-phospholipase A2 receptor antibodies, suggesting a distinct pathologic process. Here we documented that IgG4 retrieved from the serum of our propositus reacted against carbonic anhydrase II (CAII) at the podocyte surface. In patient's biopsy, glomerular CAII staining increased and co-localized with subepithelial IgG4 deposits along the capillary walls. Patient's IgG4 caused a drop in cell pH followed by mitochondrial dysfunction, excessive ROS production and cytoskeletal reorganization in cultured podocytes. These events promoted mitochondrial superoxide-dismutase-2 (SOD2) externalization on the plasma membrane, becoming recognizable by complement-binding IgG3 anti-SOD2. Among patients with IgG4-related disease only sera of those with IgG4 anti-CAII antibodies caused low intracellular pH and mitochondrial alterations underlying SOD2 externalization. Circulating IgG4 anti-CAII can cause podocyte injury through processes of intracellular acidification, mitochondrial oxidative stress and neoantigen induction in patients with IgG4 related disease. The onset of MN in a subset of patients could be due to IgG4 antibodies recognizing CAII with consequent exposure of mitochondrial neoantigen in the context of multifactorial pathogenesis of disease. PMID:26137589

IgG4-related disease and its pathogenesis—cross-talk between innate and acquired immunity

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Nakajima, Akio; Nakamura, Takuji; Kawanami, Takafumi; Tanaka, Masao; Dong, Lingli; Kawano, Mitsuhiro

2014-01-01

IgG4-related disease (IgG4-RD) is a novel clinical entity proposed in Japan in the 21th century and is attracting strong attention over the world. The characteristic manifestations of IgG4-RD are increased serum IgG4 concentration and tumefaction by IgG4+ plasma cells. Although the clinical manifestations in various organs have been established, the pathogenesis of IgG4-RD is still unknown. Recently, many reports of aberrant acquired immunity such as Th2-diminated immune responses have been published. However, many questions still remain, including questions about the pathogenesis of IgG4-RD and the roles of IgG4. In this review, we discuss the pathogenesis of IgG4-RD by focusing on the cross-talk between innate and acquired immunity. PMID:25024397

Serum total IgG and IgG4 levels in thyroid eye disease

Directory of Open Access Journals (Sweden)

Sy A

2016-10-01

Full Text Available Aileen Sy, Rona Z Silkiss Department of Ophthalmology, California Pacific Medical Center, San Francisco, CA, USA Purpose: To investigate the relationship between immunoglobulin G (IgG4-related disease (IgG4-RD and thyroid eye disease (TED with respect to IgG levels. Patients and methods: A retrospective review of total IgG, IgG subclass, and thyroid stimulating immunoglobulin (TSI levels in 24 patients with TED. Results: Five patients (20.8% demonstrated serum IgG4 levels consistent with IgG4-RD without any additional systemic disease. Total IgG and IgG subclass levels were found to be an inadequate proxy for TSI elevation. Conclusion: There may be a subtype of TED patients with elevated IgG4 in the absence of IgG4-RD systemic findings. Keywords: thyroid eye disease, IgG subclass, IgG4, Graves’ disease, Graves’ ophthalmopathy, IgG4-RD

IgG4-related disease.

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Bozzalla Cassione, Emanuele; Stone, John H

2017-05-01

Remarkable insights have been gleaned recently with regard to the pathophysiology of IgG4-related disease (IgG4-RD). These findings have direct implications for the development of targeted strategies for the treatment of this condition. Oligoclonal expansions of cells of both the B and T lymphocyte lineages are present in the blood of patients with IgG4-RD. Oligoclonal expansions of plasmablasts are a good biomarker for disease activity. An oligoclonally expanded population of CD4+ cytotoxic T lymphocytes is found not only in the peripheral blood but also at tissue sites of active disease. This cell elaborates cytokines that may drive the fibrosis characteristic of IgG4-RD. T follicular helper cells (Tfhc), particularly the Tfhc2 subset, appear to play a major role in driving the class switch to IgG4 that typifies this disease. The relationship between malignancy and IgG4-RD remains an area of interest. Advances in understanding the pathophysiology of IgG4-RD have proceeded swiftly, leading to the identification of a number of potential targeted treatment strategies. The completion of classification criteria for IgG4-RD, an effort supported jointly by the American College of Rheumatology and the European League Against Rheumatism, will further facilitate studies on this disease.

Falsely low immunoglobulin (Ig)G4 in routine analysis: how not to miss IgG4 disease.

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Egner, W; Swallow, K; Lock, R J; Patel, D

2016-10-01

Immunoglobulin (Ig)G4 disease can have apparently 'normal' levels of IgG4 due to antigen excess conditions. IgG4 measurement therefore appears falsely low. UK National External Quality Assurance Scheme (UK NEQAS) data and other reports have suggested that this problem occurred despite pre-existing antigen excess detection steps. To determine the clinical relevance of the problem, we examined the prevalence and characteristics of prozoning in our laboratory and patient cohorts. We establish that the prevalence of raised IgG4 in routine IgG4 analysis is low (IgG4 samples in our patients. This may explain the previous reports of low sensitivity of raised IgG4 for IgG4RD, and predictive values should be re-evaluated in this disease using modified prozone-resistant protocols. All laboratories providing IgG4 measurements should verify that their assays are fit for the clinical quality requirement of detection raised IgG4 levels and must verify the upper limit of their reference ranges and freedom from prozoning. © 2016 British Society for Immunology.

IgG4-producing lymphoma arising in a patient with IgG4-related disease.

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Igawa, Takuro; Hayashi, Toshiaki; Ishiguro, Kazuya; Maruyama, Yumiko; Takeuchi, Mai; Takata, Katsuyoshi; Yoshino, Tadashi; Sato, Yasuharu

2016-12-01

We herein report a case in which an IgG4-producing lymphoma arose in a patient with a previous diagnosis consistent with an IgG4-related disease. A 43-year-old man presented with enlarged cervical lymph nodes and was treated with steroids and radiation for what was initially assumed to be Kimura's disease, although the lesions were later histologically re-diagnosed as IgG4-related lymphadenopathy. Fourteen years later, when the patient was 58-years-old, he presented with retroperitoneal fibrosis and swollen lymph nodes. The suspicious lesions were not histologically examined as the patient did not give consent. However, the serum IgG4 concentration was high (1400 mg/dL) and he was clinically diagnosed with systemic IgG4-related disease. Although steroid administration reduced the size of the lesions, tapering the dose finally resulted in systemic, prominently enlarged lymph nodes. Analysis of the biopsy specimen revealed that these multiple lymph node lesions were marginal zone B cell lymphomas that themselves expressed IgG4. Complete remission was achieved after a total of six courses of chemotherapy including rituximab. This case suggests that the infiltrating IgG4-expressing cells observed in IgG4-related disease can clonally expand to malignant lymphomas.

IgG4-Related Sclerosing Cholangitis.

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Nakazawa, Takahiro; Shimizu, Shuya; Naitoh, Itaru

2016-08-01

More men than women develop immunoglobulin G4-related sclerosing cholangitis (IgG4-SC). Age at clinical onset is significantly older in patients with IgG4-SC. Patients with IgG4-SC appear similar to those with cholangiocarcinoma and primary sclerosing cholangitis (PSC). The association between IgG4-SC and autoimmune pancreatitis (AIP) is useful for the diagnosis of IgG4-SC. However, some IgG4-SC cases are isolated from AIP and are difficult to diagnose. The authors focus on three distinct features of IgG4-SC. First, diffuse inflammation induces a longer stenosis on cholangiography in contrast to the short stenosis of patients with PSC. Second, fibroinflammatory involvement is observed mainly in the stroma of the bile duct wall, whereas the bile duct epithelium is intact. Third, steroid therapy results in remarkable improvement. Although the prognosis of patients with IgG4-SC is good, some cases have developed portal hypertension and liver cirrhosis during their clinical course. Further study is needed to elucidate the long-term outcomes and mechanism of IgG4-SC. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Epstein-Barr virus in the enlarged salivary tissues of patients with IgG4-related disease.

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Furukawa, Takatoshi; Shimotai, Yoshitaka; Ohta, Nobuo; Ishida, Akihiro; Kurakami, Kazuya; Suzuki, Hitoshi; Yamakawa, Mitsunori; Hongo, Seiji; Kakehata, Seiji

2015-09-01

Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized disease entity characterized by high-serum IgG4 concentration and IgG4-producing plasma cell production with fibrotic or sclerotic changes in affected organs. We aimed to clarify the roles of Epstein-Barr virus (EBV) in patients with IgG4-RDs. A retrospective clinical study at the Yamagata University School of Medicine, Yamagata, Japan. The patient group consisted of four males and four females with an average age of 62 years (range: 48-73). Expression of IgG4, latent member protein 1, EBV nuclear antigens-2, and EBV-encoded RNA in affected salivary glands from patients with IgG4-RD was examined by using immunohistochemistry and in situ hybridization. The copy number of EBV DNA in the salivary glands was also investigated by real-time polymerase chain reaction. All patients had hard masses in the salivary or lacrimal glands, or both, bilaterally. Serum concentrations of IgG4 were elevated in all cases (mean 589.1, range 129-1750), and IgG4-positive plasmacytes were observed in the involved salivary glands. Four patients developed potentially life-threatening systemic involvement after initial salivary gland swelling. EBV-associated molecules (EBNA and EBER) were overexpressed in the affected salivary glands. The copy number of EBV DNA was significantly higher in patients with potentially life-threatening systemic involvement than in patients without systemic involvement (P < 0.05). These results suggest that the copy number of EBV DNA could be useful as diagnostic findings in IgG4-RD to predict potentially life-threatening systemic involvement. 4. © 2015 The American Laryngological, Rhinological and Otological Society, Inc.

On the role of IgG4 in inflammatory conditions: lessons for IgG4-related disease

NARCIS (Netherlands)

Trampert, David C.; Hubers, Lowiek M.; van de Graaf, Stan F. J.; Beuers, Ulrich

2017-01-01

The pathophysiology of immunoglobulin G4-related disease (IgG4-RD) and its most common manifestations, IgG4-associated (sclerosing) cholangitis and autoimmune pancreatitis, remains largely unknown, but IgG4 is presumably involved. IgG4 is a promiscuous antibody, which could be directly pathogenic,

Clonally expanded cytotoxic CD4+ T cells and the pathogenesis of IgG4-related disease.

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Mattoo, Hamid; Stone, John H; Pillai, Shiv

2017-02-01

IgG4-related disease (IgG4-RD) is a systemic condition of unknown cause characterized by highly fibrotic lesions, with dense lymphoplasmacytic infiltrates containing a preponderance of IgG4-expressing plasma cells. CD4 + T cells and B cells constitute the major inflammatory cell populations in IgG4-RD lesions. IgG4-RD patients with active, untreated disease show a marked expansion of plasmablasts in the circulation. Although the therapeutic depletion of B cells suggests a role for these cells in the disease, a direct role for B cells or IgG4 in the pathogenesis of IgG4-RD is yet to be demonstrated. Among the CD4 + T-cell subsets, Th2 cells were initially thought to contribute to IgG4-RD pathogenesis, but many previous studies were confounded by the concomitant history of allergic diseases in the patients studied and the failure to use multi-color staining to definitively identify T-cell subsets in tissue samples. More recently, using an unbiased approach to characterize CD4 + T-cell subsets in patients with IgG4-RD - based on their clonal expansion and ability to infiltrate affected tissue sites - CD4 + CTLs have been identified as the major CD4 + T-cell subset in disease lesions as well as in the circulation. CD4 + CTLs in affected tissues secrete pro-fibrotic cytokines including IL-1β, TGF-β1, and IFN-γ as well as cytolytic molecules such as perforin and granzymes A and B. In this review, we examine possible mechanisms by which activated B cells and plasmablasts may collaborate with the expanded CD4 + CTLs in driving the fibrotic pathology of the disease and describe the lacunae in the field and in our understanding of IgG4-RD pathogenesis.

A Comparative Analysis of Serum IgG4 Levels in Patients With IgG4-Related Disease and Other Disorders.

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Wang, Li; Chu, Xinmin; Ma, Yan; Zhang, Min; Wang, Xue; Jin, Li; Tan, Zhen; Li, Xiangpei; Li, Xiaomei

2017-09-01

Elevated serum IgG4 levels are an important hallmark for diagnosing IgG4-related disease (IgG4-RD) but can also be found and reported in other diseases. The present study intended to compare the serum IgG4 levels in both IgG4-RD and non-IgG4-RD and determine the serum IgG4 levels in patients with IgG4-RD before and after glucocorticoid therapy. The study included 323 patients from Anhui Medical University Affiliated Provincial Hospital (China) and was conducted from July 2014-January 2016. A total of 25 patients were eventually diagnosed as having IgG4-RD, according to the IgG4-RD diagnostic criteria. Our study also included 108 patients with connective tissue disease, 94 patients with pancreatic lesions, 66 patients with bile duct lesions, 13 patients with carcinoma of the duodenal papilla and 20 control participants. The assay for serum IgG4 detection was peformed using the nephelometric method. Elevated levels of serum IgG4 (>1.35g/L) were detected in all patients with IgG4-RD, and reduced levels of serum IgG4 (IgG4-RD. The serum IgG4 level in patients with IgG4-RD after glucocorticoid therapy was significantly lower than that before glucocorticoid therapy (t = 2.426, P = 0.04). High levels of IgG4 were observed in IgG4-RD. However, a diagnosis of IgG4 disease can not only be dependent on the detection of elevated serum IgG4 levels but also may need clinical manifestations, serology, histopathology and other comprehensive information for verification. Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

IgG4-related Pleuritis with Elevated Adenosine Deaminase in Pleural Effusion: A Case Report.

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Nagayasu, Atsushi; Kubo, Satoshi; Nakano, Kazuhisa; Nakayamada, Shingo; Iwata, Shigeru; Miyagawa, Ippei; Fukuyo, Shunsuke; Saito, Kazuyoshi; Tanaka, Yoshiya

2018-03-09

An 81-year-old man was admitted with bilateral pleural effusion. A clinical examination showed lymphocytic pleura effusion and elevated serum IgG4 levels, so that IgG4-related disease was suggested, whereas tuberculous pleurisy was suspected because of high adenosine deaminase (ADA) levels in the pleural effusion. A surgical pleural biopsy revealed that there were large numbers of IgG4-positive cells and IgG4/IgG positive cell ratio exceeded 40% in several sites. Accordingly, we diagnosed IgG4-related pleuritis and treated with the patient with glucocorticoid therapy. The ADA levels in pleural effusion can increase in IgG4-related pleuritis, and it is therefore important to perform a pleural biopsy.

Serological blind spots for variants of human IgG3 and IgG4 by a commonly used anti-immunoglobulin reagent.

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Howie, Heather L; Delaney, Meghan; Wang, Xiaohong; Er, Lay See; Vidarsson, Gestur; Stegmann, Tamara C; Kapp, Linda; Lebedev, Jenna N; Wu, Yanyun; AuBuchon, James P; Zimring, James C

2016-12-01

Human immunoglobulin G (IgG) includes four different subtypes (IgG1, IgG2, IgG3, and IgG4), and it is also now appreciated that there are genetic variations within IgG subtypes (called isoallotypes). Twenty-nine different isoallotypes have been described, with 7, 4, 15, and 3 isoallotypes described for IgG1, IgG2, IgG3, and IgG4, respectively. The reactivity of anti-IgG with different isoallotypes has not been characterized. A novel monoclonal anti-K antibody (PugetSound Monoclonal Antibody 1 [PUMA1]) was isolated and sequenced, and a panel of PUMA1 variants was expressed, consisting of the 29 known IgG isoallotypes. The resulting panel of antibodies was preincubated with K-positive red blood cells (RBCs) and then subjected to testing with currently approved anti-IgG by flow cytometry, solid phase systems, gel cards, and tube testing. A US Food and Drug Administration (FDA)-approved monoclonal anti-IgG (gamma-clone) failed to recognize 2 of 15 IgG3 isoallotypes (IgG3-03 and IgG3-13) and 3 of 3 IgG4 isoallotypes (IgG4-01, IgG4-02, and IgG4-03). In contrast, an FDA-approved rabbit polyclonal anti-IgG recognized each of the known human IgG isoallotypes. These findings demonstrate "blind spots" in isoalloantibody detection by a monoclonal anti-IgG. If a patient has anti-RBC antibodies predominantly of an IgG3 subtype (the IgG3-03 and/or IgG3-13 variety), then it is possible that a clinically significant alloantibody would be missed. IgG-03 and IgG-13 have an estimated frequency of 1% to 3% in Caucasian populations and 20% to 30% in certain African populations. Nonreactivity with IgG4 is a known characteristic of this monoclonal anti-IgG, but IgG4 isoallotypes have not been previously reported. © 2016 AABB.

IgG4-related disease-experience of 100 consecutive cases from a specialist centre.

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Bateman, Adrian C; Culver, Emma L

2017-04-01

To describe the features of 100 consecutive cases referred to a single UK institution in which a diagnosis of IgG4-related disease (IgG4-RD) was under consideration. The histological features were reviewed by a single histopathologist, and cases were categorized according to the 2012 Boston criteria: Category 1-histologically highly suggestive of IgG4-RD; Category 2-probable histopathological features of IgG4-RD; and Category 3-insufficient histopathological evidence of IgG4-RD. A 'global assessment' was performed with the available clinical information: Assessment group 1-'definite/very likely IgG4-RD'; Assessment group 2-'possible IgG4-RD'; Assessment group 3-'not IgG4-RD'; and Assessment group 4-insufficient information. The mean IgG4+ plasma cell count and IgG4+/IgG+ ratio were highest in Category 1 [134/high-power field (HPF); 57%] and Assessment group 1 (113/HPF; 52%), and lowest in Category 3 (11/HPF; 18%) and Assessment group 3 (43/HPF; 31%) (Category comparison of IgG4+ count and ratio, both P IgG4+ count, P IgG4-RD diagnosis was rare in Category 1 (7%) but common in Category 2 (60%) and Category 3 (47%). Stromal reactions to neoplasia and chronic oral ulceration were simulants of IgG4-RD. The Boston criteria are linked to the likelihood of IgG4-RD. Other conditions may show some histological features of IgG4-RD. The likelihood of IgG4-RD is much greater when the histological features reach the threshold for Category 1 than when they reach the thresholds for Categories 2 and 3. Despite the utility of the Boston criteria, this study highlights the crucial importance of careful clinicopathological correlation when a diagnosis of IgG4-RD is under consideration. © 2016 John Wiley & Sons Ltd.

IgG4-related disease involving polyserous effusions with elevated serum interleukin-6 levels: a case report and literature review.

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Tong, Xiang; Bai, Min; Wang, Weiya; Han, Qingbing; Tian, Panwen; Fan, Hong

2017-08-01

Immunoglobulin G4-related disease (IgG4-RD) is a recently described immune-mediated fibroinflammatory disease with a characteristic histopathologic appearance that can affect various organs. We report a 43-year-old Chinese female patient with IgG4-RD involving polyserous effusions with reports of worsening exertional dyspnea for 3 months. Laboratory blood tests revealed that serum interleukin (IL)-6, carbohydrate antigens (CA-199 and CA-125), and alpha-fetoprotein levels were significantly increased, but serum IgG4 levels were normal. Repeat pleural effusion and ascite analysis showed lymphocyte-predominant exudates. In addition, computed tomography scan showed massive pleural effusion in the right pleural cavity, abdominal effusion, and some pericardial effusion with a partial compression atelectasis. Further, medical thoracoscopy was performed to examine the pleural cavity and found multiple nodules on the pleura and partly thickened pleura with a reddish color. Histopathologic and immunohistochemical examination revealed marked lymphocytes and IgG4-positive plasma cell infiltration. The patient was finally diagnosed with IgG4-RD according to the comprehensive diagnostic criteria, although the patient presented similar serological and pathological manifestations of Castleman disease (CD). Our case suggests that IgG4-RD may be one of the causes of polyserous effusions and shows the difficulties in differentiating between IgG4-RD and CD.

IgG4 breaking the rules

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Aalberse, Rob C.; Schuurman, Janine

2002-01-01

Immunoglobulin G4 (IgG4) antibodies have been known for some time to be functionally monovalent. Recently, the structural basis for this monovalency has been elucidated: the in vivo exchange of IgG half-molecules (one H-plus one L-chain) among IgG4. This process results in bispecific antibodies that

Human IgG4: a structural perspective.

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Davies, Anna M; Sutton, Brian J

2015-11-01

IgG4, the least represented human IgG subclass in serum, is an intriguing antibody with unique biological properties, such as the ability to undergo Fab-arm exchange and limit immune complex formation. The lack of effector functions, such as antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity, is desirable for therapeutic purposes. IgG4 plays a protective role in allergy by acting as a blocking antibody, and inhibiting mast cell degranulation, but a deleterious role in malignant melanoma, by impeding IgG1-mediated anti-tumor immunity. These findings highlight the importance of understanding the interaction between IgG4 and Fcγ receptors. Despite a wealth of structural information for the IgG1 subclass, including complexes with Fcγ receptors, and structures for intact antibodies, high-resolution crystal structures were not reported for IgG4-Fc until recently. Here, we highlight some of the biological properties of human IgG4, and review the recent crystal structures of IgG4-Fc. We discuss the unexpected conformations adopted by functionally important Cγ2 domain loops, and speculate about potential implications for the interaction between IgG4 and FcγRs. © 2015 The Authors. Immunological Reviews Published by John Wiley & Sons Ltd.

IgG4-related hypophysitis is highly prevalent among cases of histologically confirmed hypophysitis.

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Bernreuther, Christian; Illies, Christopher; Flitsch, Jörg; Buchfelder, Michael; Buslei, Rolf; Glatzel, Markus; Saeger, Wolfgang

2017-11-01

IgG4-related disease is an immune-mediated disease with manifestations in most organ systems among them the pituitary gland. To date, few cases of histologically confirmed cases of IgG-related hypophysitis have been reported. The aim of this study was to retrospectively determine the prevalence of IgG4-related hypophysitis among cases previously diagnosed as primary hypophysitis (lymphocytic hypophysitis, granulomatous hypophysitis and hypophysitis not otherwise specified). Histological and immunohistochemical analysis revealed that 12 of 29 cases (41.4%) previously diagnosed as primary hypophysitis fulfilled the criteria for IgG4-related disease and, thus, IgG4-related hypophysitis should always be considered in the differential diagnosis of primary hypophysitis. All cases of IgG4-related hypophysitis showed a dense lymphoplasmacytic infiltrate with more than 10 IgG4-positive cells per high power field and a ratio of IgG4/IgG-positive cells of more than 40%, whereas storiform fibrosis was an inconsistent histological feature and was also seen in few cases of non-IgG-related hypophysitis, thus lacking sensitivity and specificity. Obliterative phlebitis was not seen in any case. Thus, histological criteria defined for IgG4-related disease in other organs should be modified for IgG4-related hypophysitis, accordingly. © 2016 International Society of Neuropathology.

Large vessel involvement by IgG4-related disease

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Perugino, Cory A.; Wallace, Zachary S.; Meyersohn, Nandini; Oliveira, George; Stone, James R.; Stone, John H.

2016-01-01

rituximab, a majority responded positively. Conclusions: IgG4-RD is a distinctive, unique, and treatable cause of large-vessel vasculitis. It can also involve blood vessels secondary to perivascular tumefactive lesions. The most common manifestation of IgG4-related vasculitis is aortitis with aneurysm formation. The most common secondary vascular manifestation is periaortitis with relative sparing of the aortic wall. Both primary vasculitis and secondary vascular involvement respond well to B cell depletion therapy. PMID:27428181

Immunochemical characteristics of IgG4 antibodies

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van der Zee, J. S.; Aalberse, R. C.

1988-01-01

Although a small part of the IgG4 subclass probably can bind to basophils (and mast cells), IgG4 antibodies usually do not behave as anaphylactic antibodies. Therefore, detection of IgG4 antibodies in serum is not a suitable in vitro assay for IgG-S-TS activity. Furthermore, differences between IgG4

A subset of ocular adnexal marginal zone lymphomas may arise in association with IgG4-related disease

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Ohno, Kyotaro; Sato, Yasuharu; Ohshima, Koh-ichi; Takata, Katsuyoshi; Miyata-Takata, Tomoko; Takeuchi, Mai; Gion, Yuka; Tachibana, Tomoyasu; Orita, Yorihisa; Ito, Toshihiro; Swerdlow, Steven H.; Yoshino, Tadashi

2015-01-01

We previously suggested a relationship between ocular immunoglobulin (Ig)G4-related disease (IgG4-RD) and marginal zone lymphomas (MZLs). However, the cytokine background associated with these disorders and whether it differs between ocular adnexal MZLs with (IgG4-associated MZL) and without (IgG4-negative MZL) numerous IgG4+ plasma cells are unknown. In this study, we identified the mRNA expression pattern of Th2 and regulatory T-cell (Treg) cytokines in IgG4-RD and in IgG4-associated MZL and IgG4-negative MZL using real-time polymerase chain reaction analysis. Ocular IgG4-RD and IgG4-associated MZL exhibited significantly higher expression ratios of interleukin (IL)-4/β-actin, IL-10/β-actin, IL-13/β-actin, transforming growth factor (TGF) β1/β-actin, and FOXP3/β-actin than did IgG4-negative MZL (p IgG4-RD. Furthermore, the presence of a different inflammatory background in IgG4-negative MZLs suggests that IgG4-associated MZLs may have a different pathogenesis. PMID:26311608

Solely lung-involved IgG4-related disease : a case report and review of the literature.

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Zhang, Xiao-Qin; Chen, Guo-Ping; Wu, Sheng-Chang; Yu, Sa; Wang, Hong; Chen, Xuan-Yi; Ren, Zhuo-Chao

2016-12-23

By analyzing the clinical data of 1 case of IgG4-related lung disease(IgG4-RLD) and the review of literature, the author investigated the clinical characteristics of IgG4-RLD. IgG4-RLD is a rare disease characterized by significant elevation of serum IgG4 and infiltration of a large number of IgG4+ plasma cells. The clinical manifestations of the disease were nonspecific, and the imaging features were mixed with several types. The disease can only be involved in the lung, but also multiple organ involvement. Solely lung-involved IgG4-RD is not only extremely rare but also easily misdiagnosed as tuberculosis, lung cancer, lymphoma and other common pulmonary diseases. Histopathological examination is the key to the diagnosis of the disease. Corticosteroids are the first choice of treatment, and the overall prognosis is good.

Epstein-Barr virus-infected cells in IgG4-related lymphadenopathy with comparison with extranodal IgG4-related disease.

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Takeuchi, Mai; Sato, Yasuharu; Yasui, Hiroshi; Ozawa, Hiroaki; Ohno, Kyotaro; Takata, Katsuyoshi; Gion, Yuka; Orita, Yorihisa; Tachibana, Tomoyasu; Itoh, Tomoo; Asano, Naoko; Nakamura, Shigeo; Swerdlow, Steven H; Yoshino, Tadashi

2014-07-01

IgG4-related lymphadenopathy with increased numbers of Epstein-Barr virus (EBV)-infected cells has been reported but not fully described. We analyzed 31 cases of IgG4-related lymphadenopathy and 24 cases of extranodal IgG4-related diseases for their possible relationship with EBV. Other types of reactive lymph nodes (22) and angioimmunoblastic T-cell lymphoma (AITL) (10) were also studied for comparison. EBV-encoded RNA (EBER) in situ hybridization revealed EBER(+) cells in 18 of 31 cases (58%) of IgG4-related lymphadenopathy. Increased EBER(+) cells were found in only 4 of 22 (18.1%) non-IgG4-related reactive lymphoid hyperplasia in patients of a similar age (P=0.002) and in only 5 of 24 (21%) extranodal IgG4-related biopsies (P=0.006). Interestingly, all patients with EBER(+) progressively transformed germinal center-type IgG4-related lymphadenopathy had systemic lymphadenopathy and/or extranodal involvement. AITL also is associated with EBV, and IgG4-related lymphadenopathy sometimes mimics the morphology of AITL; however, the number of IgG4(+) cells in AITL was significantly less than that in IgG4-related lymphadenopathy (Pdisease; however, there was not a significant difference between the EBER(+) and EBER(-) cases. In conclusion, the presence of increased numbers of EBV-infected cells in IgG4-related lymphadenopathy, compared with other reactive lymphadenopathy or extranodal IgG4-related disease, suggests that there may be a relationship at least between nodal IgG4-related disease and EBV. It is important to avoid overdiagnosing these cases as malignant lymphomas or EBV-related lymphoproliferative disorders.

IgG4-gerelateerde ziekte

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Maillette de Buy Wenniger, Lucas J.; Doorenspleet, Marieke E.; Verheij, Joanne; de Vries, Niek; Beuers, Ulrich

2013-01-01

The diagnosis IgG4-related disease (IgG4-RD) is often difficult to make. The clinical spectrum is diverse, with a variety of organ systems that may be affected simultaneously or sequentially. Patients often present with symptoms that mimic a malignant disease, for example, symptoms compatible with a

Acute tubulointerstitial nephritis with severe renal impairment associated with multisystem IgG4-related disease

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Rafael Coimbra Ferreira Beltrame

Full Text Available Abstract The IgG4-related disease has a wide clinical spectrum where multiple organs can be affected, and the diagnosis depends on typical histopathological findings and an elevated IgG4 expression in plasma cells in the affected tissue. We describe the clinical presentation and evolution of a patient with acute tubulointerstitial nephritis, severe kidney failure and systemic manifestations such as lymphadenomegaly and chronic pancreatitis. The diagnosis was confirmed by the clinical picture and kidney and lymph node histopathology, in which immunohistochemistry of the lymphoid tissue showed policlonality and increased expression of IgG4, with a IgG4/total IgG ratio > 80%. The patient was treated with prednisone at a dose of 60 mg/day, followed by mycophenolate mofetil, and showed clinical and renal function improvement at 6 months of follow-up. The high index of suspicion of IgG4-related disease with multisystem involvement and the early treatment of this condition are essential to improve the prognosis of affected patients.

Fibrosis of the thyroid gland caused by an IgG4-related sclerosing disease: three years of follow-up.

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Oriot, P; Amraoui, A; Rousseau, E; Malvaux, P; Dechambre, S; Delcourt, A

2014-12-01

Immunoglobulin G4-related sclerosing disease (IgG4-RSD) represents a recently identified inflammatory disorder in which infiltration of IgG4 plasma cells causes fibrosis in organs. While IgG4-RSD is well documented in the pancreas and other organs, it is poorly characterized in the thyroid gland. We report a case of a 48-year-old female with a fibrotic thyroid mass associated with a retroperitoneal fibrosis. Diagnosed early as Riedel disease, the high serum IgG4, immunohistopathology and decreased fibrosis with corticosteroid therapy, finally confirm for the first time, the origin of IgG4-RSD fibrosis of the thyroid.

Establishment of a serum IgG4 cut-off value for the differential diagnosis of IgG4-related disease in Chinese population.

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Li, Ping; Chen, Hua; Deng, Chuiwen; Wu, Ziyan; Lin, Wei; Zeng, Xiaofeng; Zhang, Wen; Zhang, Fengchun; Li, Yongzhe

2016-07-01

This study was performed to better know diagnosis associated with serum IgG4 concentration, and to explore the possibility for development of a serum IgG4 for IgG4-related disease (IgG4-RD) in Chinese populations. We studied retrospectively 497 IgG4 serum subclass measurements from Peking Union Medical College Hospital during the four-year period, including 242 IgG4-RD, 130 other diseases and 125 healthy individuals. Serum IgG4 concentrations were significantly higher in IgG4-RD than in other pathologies (1662.9 ± 3760.9 mg/L, p IgG4 level between other pathologies group and healthy individuals (p = 0.075). Among the 242 IgG4-RD patients analyzed, serum IgG4 concentrations were normal in 46 patients (19.0%). We found 32 patients (24.6%) with elevated serum IgG4 levels among the 130 patients who suffered from other pathologies. There were seven (5.6%) with serum IgG4 over 1350 mg/L in healthy individuals. The ROC curve analysis revealed that the optimal sensitivity and specificity were 80.0% and 88.2%, respectively, at the concentration of 1575 mg/L for Chinese patients. Our study demonstrated that serum IgG4 elevation was not specific of IgG4-RD. Further studies are needed to define the sensibility and specificity of IgG4 values for the diagnosis of IgG4-RD.

Intrathoracic Manifestations of IgG4-Related Disease

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Sian Yik Lim

2016-10-01

Full Text Available Intrathoracic involvement with IgG4-related disease (IgG4-RD is frequently overlooked in IgG4-related disease patients. In this article we review the intrathoracic findings of IgG4-RD which are variable and protean. IgG4-related disease has been reported to affect the lung parenchyma, pleura, mediastinal/hilar lymph nodes, vasculature, and pericardium within the thorax. Mediastinal and hilar lymphadenopathy is the most common intrathoracic manifestation of IgG4-RD. Four main patterns of pulmonary disease have been described, including the solid nodular type, the bronchovascular type, the alveolar interstitial type, and the round shaped ground glass type. When feasible, a biopsy should be obtained to confirm the diagnosis. Most lesions show characteristic pathologic findings of IgG4-RD: dense lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis. While this helps establish the diagnosis, the interpretation of pathology findings in the clinical context is key in making an accurate diagnosis. Mimickers of IgG4-RD should be ruled out, before making a diagnosis. The intrathoracic findings of IgG4-RD can be treated effectively with prednisone, but may require additional immunosuppressive therapies, including rituximab.

IgG4-related kidney disease – an update

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Kawano, Mitsuhiro; Saeki, Takako

2015-01-01

Purpose of review IgG4-related disease (IgG4-RD) is a recently recognized systemic inflammatory disorder that can affect most organs/tissues such as sarcoidosis. The kidney is a frequently affected organ with tubulointerstitial nephritis (TIN), the representative lesion of IgG4-RD. This review focuses on the latest knowledge of IgG4-related kidney disease (IgG4-RKD). Recent findings A wide range of renal manifestations of IgG4-RD, that is TIN, membranous glomerulonephritis (MGN) and other glomerular lesions, and pyelitis, are collectively referred to as IgG4-RKD. Clinically, decreased renal function, or characteristic imaging findings such as multiple low-density lesions on contrast-enhanced computed tomography or diffuse thickening of the renal pelvic wall, are typical presenting features. Although a rapid response to corticosteroid therapy is a very important feature of IgG4-TIN, in cases in which renal function is moderately to severely decreased before therapy, only partial recovery of renal function is obtained. Summary TIN with characteristic imaging findings is a typical manifestation of IgG4-RKD in the interstitium, while MGN is a representative manifestation of the glomerular lesions. Although IgG4 is a central feature of IgG4-RD, the recent discovery of IgG4-negative IgG4-RD raises questions about the causative role of the IgG4 molecule in this context. PMID:25594543

Diagnosis of IgG4-related sclerosing cholangitis

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Nakazawa, Takahiro; Naitoh, Itaru; Hayashi, Kazuki; Miyabe, Katsuyuki; Simizu, Shuya; Joh, Takashi

2013-01-01

IgG4-related sclerosing cholangitis (IgG4-SC) is often associated with autoimmune pancreatitis. However, the diffuse cholangiographic abnormalities observed in IgG4-SC may resemble those observed in primary sclerosing cholangitis (PSC), and the presence of segmental stenosis suggests cholangiocarcinoma (CC). IgG4-SC responds well to steroid therapy, whereas PSC is only effectively treated with liver transplantation and CC requires surgical intervention. Since IgG4-SC was first described, it has become a third distinct clinical entity of sclerosing cholangitis. The aim of this review was to introduce the diagnostic methods for IgG4-SC. IgG4-SC should be carefully diagnosed based on a combination of characteristic clinical, serological, morphological, and histopathological features after cholangiographic classification and targeting of a disease for differential diagnosis. When intrapancreatic stenosis is detected, pancreatic cancer or CC should be ruled out. If multiple intrahepatic stenoses are evident, PSC should be distinguished on the basis of cholangiographic findings and liver biopsy with IgG4 immunostaining. Associated inflammatory bowel disease is suggestive of PSC. If stenosis is demonstrated in the hepatic hilar region, CC should be discriminated by ultrasonography, intraductal ultrasonography, bile duct biopsy, and a higher cutoff serum IgG4 level of 182 mg/dL. PMID:24282356

Increases in IgE, Eosinophils, and Mast Cells Can be Used in Diagnosis and to Predict Relapse of IgG4-Related Disease.

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Culver, Emma L; Sadler, Ross; Bateman, Adrian C; Makuch, Mateusz; Cargill, Tamsin; Ferry, Berne; Aalberse, Rob; Barnes, Eleanor; Rispens, Theo

2017-09-01

IgG subclass 4-related disease (IgG4-RD) is characterized by increased serum levels of IgG4 and infiltration of biliary, pancreatic, and other tissues by IgG4-positive plasma cells. We assessed the prevalence of allergy and/or atopy, serum, and tissue IgE antibodies, and blood and tissue eosinophils in patients with IgG4-RD. We investigated the association between serum IgE and diagnosis and relapse of this disease. We performed a prospective study of 48 patients with IgG4-RD, 42 patients with an increased serum level of IgG4 with other inflammatory and autoimmune conditions (disease control subjects), and 51 healthy individuals (healthy control subjects) recruited from Oxford, United Kingdom from March 2010 through March 2014, and followed for a median of 41 months (range, 3-73 months). Serum levels of immunoglobulin were measured at diagnosis, during steroid treatment, and at disease relapse for patients with IgG4-RD; levels at diagnosis were compared with baseline levels of control subjects. Allergen-specific IgEs were measured using the IgE ImmunoCAP. Levels and distribution of IgG4 and IgE antibodies in lymphoid, biliary, and pancreatic tissues from patients with IgG4-RD and disease control subjects were measured by immunohistochemistry. We analyzed data using the Spearman rank correlation and receiver operating characteristic curves. Serum levels of IgG4 increased to 1.4 g/L or more, and IgE increased to 125 kIU/L or more, in 81% and 54% of patients with IgG4-RD, respectively, compared with 6% and 16% of healthy control subjects (P IgG4-RD versus 9% of healthy control subjects (P = .004). Of patients with IgG4-RD, 63% had a history of allergy and 40% had a history of atopy with an IgE-specific response; these values were 60% and 53% in patients with increased serum levels of IgE (P 480 kIU/L distinguished patients with IgG4-RD from disease control subjects with 86% specificity, 36% sensitivity, and a likelihood ratio of 3.2. Level of IgE at diagnosis >380 k

Prohibitin Is Involved in Patients with IgG4 Related Disease.

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Hongwu Du

Full Text Available IgG4-related disease (IgG4-RD is a chronic systemic disease involved in many organs and tissues. As only limited autoantigens have been found since the beginning of this century, the aim of this study was to reveal new candidate autoantigens of IgG4-RD.Multiple cell lines including HT-29, EA.hy926, HEK 293 and HepG2 were used to test the binding ability of circulating autoantibodies from IgG4-RD sera. The amino-acid sequence was then analyzed by matrix-assisted laser desorption/ionization time-of-flight tandem (MALDI-TOF/TOF mass spectrometry. After the cloning and expression of recombinant putative autoantigen in a bacterial expression system, the corresponding immuno assay was set up and utilized to observe the prevalence of serum autoantibodies in a large set of confirmed clinical samples.One positive autoantigen was identified as prohibitin. ELISA analysis showed that a majority of patients with IgG4-RD have antibodies against prohibitin. Anti-prohibitin antibodies were present in the sera of patients with definite autoimmune pancreatitis (25/34; 73.5%, Mikulicz's disease (8/15; 53.3%, retroperitoneal fibrosis (6/11; 54.5%, other probable IgG4-RD (26/29; 89.7% and Sjögren's syndrome (4/30; 13.3% but not in apparently healthy donors (1/70; 1.4%.An association between prohibitin and patients with some IgG4-RD was observed, although the results were quite heterogeneous among different individuals within autoimmune pancreatitis, Mikulicz's disease and retroperitoneal fibrosis.

IgG4-Associated Cholangitis Can Mimic Hilar Cholangiocarcinoma.

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Zaydfudim, Victor M; Wang, Andrew Y; de Lange, Eduard E; Zhao, Zimin; Moskaluk, Christopher A; Bauer, Todd W; Adams, Reid B

2015-07-01

IgG4-associated cholangitis can mimic hilar cholangiocarcinoma. Previously reported patients with IgG4-associated cholangitis mimicking cholangiocarcinoma had elevated serum IgG4 levels and long-segment biliary strictures. However, in the absence of other diagnostic criteria for malignancy, IgG4-associated cholangitis should remain a consideration among patients with normal serum IgG4 and a hilar mass suspicious for cholangiocarcinoma. The presence of a hilar mass and a malignant-appearing biliary stricture in two patients with normal serum IgG4 prompted further evaluation and subsequent concomitant liver and bile duct resection and reconstruction. The diagnosis of IgG4-associated cholangitis was established during the pathologic evaluation of the resected specimens. IgG4-associated cholangitis is a known imitator of hilar cholangiocarcinoma and should be considered in the differential diagnosis even among serologically IgG4-negative patients with a hilar mass prior to operative resection.

IgG4-related disease in autoimmune lymphoproliferative syndrome.

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van de Ven, Annick A J M; Seidl, Maximilian; Drendel, Vanessa; Schmitt-Graeff, Annette; Voll, Reinhard E; Rensing-Ehl, Anne; Speckmann, Carsten; Ehl, Stephan; Warnatz, Klaus; Kollert, Florian

2017-07-01

A patient with autoimmune lymphoproliferative disorder (ALPS) developed IgG4-related disease. In retrospect, he had high levels of serum IgG4 for several years prior to presenting with IgG4-related pancreatitis. These high IgG4 levels were masked by hypergammaglobulinemia, a common feature of ALPS. We next screened 18 ALPS patients; four of them displayed increased levels of IgG4. Hence, IgG4-related disease should be considered in ALPS patients, especially in those manifesting lymphocytic organ infiltration or excessive hypergammaglobulinaemia. Screening of IgG4-related disease patients for ALPS-associated mutations would provide further information on whether this disease could be a late-onset atypical presentation of ALPS. Copyright © 2017 Elsevier Inc. All rights reserved.

Surgical management of isolated mesenteric autoimmune disease: addressing the spectrum of IgG4-related disease and sclerosing mesenteritis.

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Greenbaum, Alissa; Yadak, Nour; Perez, Steven; Rajput, Ashwani

2017-06-08

IgG 4 -related disease (IgG 4 -RD) is a rare form of autoimmune sclerosing disease, characterised by elevated serum IgG 4 and tissue IgG 4 levels, specific histopathological findings, multiorgan involvement and adequate response to glucocorticoid treatment. The low incidence and the heterogeneous nature of the disease has made consensus on diagnostic criteria for IgG 4 -RD difficult. Whether sclerosing mesenteritis (SM) is considered a manifestation of IgG 4 -RD is strongly debated. We present the case of a patient with a history of rheumatoid arthritis who presented with a calcified abdominal mass. She was found to have an isolated, pedunculated mesenteric mass positive for IgG 4 and concurrently elevated serum IgG 4 levels. Clinical features did not classify her disease as either SM or IgG 4 -RD as currently described in consensus statements. Concurrent diagnoses of IgG 4 -RD, SM and other autoimmune disorders, as well as postoperative recommendations for resected isolated IgG 4 -positive masses, are discussed. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

IgG4-RELATED DISEASE. CLINICAL NOTES

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Vladimir Ivanovich Vasilyev

2013-01-01

Full Text Available IgG4-related diseases are a new nosological entity that encompasses a few previously known diseases. IgG4-related systemic disease is diagnosed if two or more affected organs are detected. This group of diseases has two similar signs: serological (elevated serum IgG4 subclass concentrations and histological (organ and tissue infiltration from plasmo-cytes secreting IgG4, and eosinophils, and the development of fibrosclerosis and phlebitis obliterans. The paper describes two cases. In one case, a multisystemic disease was observed virtually at its onset whereas in the other this lesion was diagnosed several years after the natural course of the disease.

IgG4-related Disease and the Liver.

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Chen, Jonathan H; Deshpande, Vikram

2017-06-01

Pathologists are likely to encounter IgG4-related disease in several organ systems. This article focuses on helping pathologists diagnose IgG4-related disease in the hepatobiliary system. Missing the diagnosis can result in unnecessary organ damage and/or unnecessary surgical and cancer therapy. In the liver, tumefactive lesion(s) involving the bile ducts with storiform fibrosis and an IgG4-enriched lymphoplasmacytic infiltrate are highly concerning for IgG4-related disease. The recent identification of oligoclonal populations of T cells and B cells in IgG4-related disease may lead to molecular tests, new therapeutics, and a greater mechanistic understanding of the disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Development of an IgG4-RD Responder Index

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Mollie N. Carruthers

2012-01-01

Full Text Available IgG4-related disease (IgG4-RD is a multiorgan inflammatory disease in which diverse organ manifestations are linked by common histopathological and immunohistochemical features. Prospective studies of IgG4-RD patients are required to clarify the natural history, long-term prognosis, and treatment approaches in this recently recognized condition. Patients with IgG4-RD have different organ manifestations and are followed by multiple specialties. Divergent approaches to the assessment of patients can complicate the interpretation of studies, emphasizing the critical need for validated outcome measures, particularly assessments of disease activity and response to treatment. We developed a prototype IgG4-RD Responder Index (IgG4-RD RI based on the approach used in the development of the Birmingham Vasculitis Activity Score for Wegener’s granulomatosis (BVAS/WG. The IgG4-RD RI was refined by members of the International IgG4-RD Symposium Organizing Committee in a paper case exercise. The revised instrument was applied retrospectively to fifteen IgG4-RD patients at our institution. Those scores were compared to physician’s global assessment scale for the same visits. This paper describes the philosophy and goals of the IgG4-RD RI, the steps in the development of this instrument to date, and future plans for validation of this instrument as an outcome measure.

Development of a polyclonal anti-dugong immunoglobulin G (IgG) antibody with evaluation of total plasma IgG in a living dugong (Dugong dugon) population.

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Wong, Arthur; Lanyon, Janet M; McKee, Sara J; Linedale, Richard; Woolford, Lucy; Long, Trevor; Leggatt, Graham R

2018-06-01

Species-specific antibodies (Ab) for the measurement of immunoglobulins (Ig) are valuable tools for determining the humoral immune status of threatened and endangered wildlife species such as dugongs. However, no studies have reported antibody reagents against dugong immunoglobulin. The object of this study was to develop an Ab with specificity for dugong IgG and apply this tool to survey total IgG levels in plasma samples from a live wild population of dugongs in southern Queensland, Australia. Dugong IgG was isolated from plasma by protein A/G column chromatography and a polyclonal antiserum was successfully raised against the dugong IgG through immunization of mice. The anti-dugong antiserum was reactive with dugong serum but not immunoglobulin from other species such as rats and humans. When tested against a panel of dugong plasma samples, relative IgG levels from dugongs (n = 116) showed biologically relevant relationships with pregnancy status and a principal component of Body Mass Index (BMI)/globulin/fecal glucocorticosteroid (chronic stress) levels combined, which together accounted for 9.2% of the variation in total Ig levels. Together these data suggest that dugongs show variation in total IgG and that this correlates with some physiological parameters of dugong health. Copyright © 2018 Elsevier B.V. All rights reserved.

IgG4 subclass antibodies impair antitumor immunity in melanoma

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Karagiannis, Panagiotis; Gilbert, Amy E.; Josephs, Debra H.; Ali, Niwa; Dodev, Tihomir; Saul, Louise; Correa, Isabel; Roberts, Luke; Beddowes, Emma; Koers, Alexander; Hobbs, Carl; Ferreira, Silvia; Geh, Jenny L.C.; Healy, Ciaran; Harries, Mark; Acland, Katharine M.; Blower, Philip J.; Mitchell, Tracey; Fear, David J.; Spicer, James F.; Lacy, Katie E.; Nestle, Frank O.; Karagiannis, Sophia N.

2013-01-01

Host-induced antibodies and their contributions to cancer inflammation are largely unexplored. IgG4 subclass antibodies are present in IL-10–driven Th2 immune responses in some inflammatory conditions. Since Th2-biased inflammation is a hallmark of tumor microenvironments, we investigated the presence and functional implications of IgG4 in malignant melanoma. Consistent with Th2 inflammation, CD22+ B cells and IgG4+-infiltrating cells accumulated in tumors, and IL-10, IL-4, and tumor-reactive IgG4 were expressed in situ. When compared with B cells from patient lymph nodes and blood, tumor-associated B cells were polarized to produce IgG4. Secreted B cells increased VEGF and IgG4, and tumor cells enhanced IL-10 secretion in cocultures. Unlike IgG1, an engineered tumor antigen-specific IgG4 was ineffective in triggering effector cell–mediated tumor killing in vitro. Antigen-specific and nonspecific IgG4 inhibited IgG1-mediated tumoricidal functions. IgG4 blockade was mediated through reduction of FcγRI activation. Additionally, IgG4 significantly impaired the potency of tumoricidal IgG1 in a human melanoma xenograft mouse model. Furthermore, serum IgG4 was inversely correlated with patient survival. These findings suggest that IgG4 promoted by tumor-induced Th2-biased inflammation may restrict effector cell functions against tumors, providing a previously unexplored aspect of tumor-induced immune escape and a basis for biomarker development and patient-specific therapeutic approaches. PMID:23454746

Pathological manifestations in lymphatic filariasis correlate with lack of inhibitory properties of IgG4 antibodies on IgE-activated granulocytes.

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Prodjinotho, Ulrich F; von Horn, Charlotte; Debrah, Alex Y; Batsa Debrah, Linda; Albers, Anna; Layland, Laura E; Hoerauf, Achim; Adjobimey, Tomabu

2017-07-01

Helminth parasites are known to be efficient modulators of their host's immune system. To guarantee their own survival, they induce alongside the classical Th2 a strong regulatory response with high levels of anti-inflammatory cytokines and elevated plasma levels of IgG4. This particular antibody was shown in different models to exhibit immunosuppressive properties. How IgG4 affects the etiopathology of lymphatic filariasis (LF) is however not well characterized. Here we investigate the impact of plasma and affinity-purified IgG/IgG4 fractions from endemic normals (EN) and LF infected pathology patients (CP), asymptomatic microfilaraemic (Mf+) and amicrofilaraemic (Mf-) individuals on IgE/IL3 activated granulocytes. The activation and degranulation states were investigated by monitoring the expression of CD63/HLADR and the release of granule contents (neutrophil elastase (NE), eosinophil cationic protein (ECP) and histamine) respectively by flow cytometry and ELISA. We could show that the activation of granulocytes was inhibited in the presence of plasma from EN and Mf+ individuals whereas those of Mf- and CP presented no effect. This inhibitory capacity was impaired upon depletion of IgG in Mf+ individuals but persisted in IgG-depleted plasma from EN, where it strongly correlated with the expression of IgA. In addition, IgA-depleted fractions failed to suppress granulocyte activation. Strikingly, affinity-purified IgG4 antibodies from EN, Mf+ and Mf- individuals bound granulocytes and inhibited activation and the release of ECP, NE and histamine. In contrast, IgG4 from CP could not bind granulocytes and presented no suppressive capacity. Reduction of both the affinity to, and the suppressive properties of anti-inflammatory IgG4 on granulocytes was reached only when FcγRI and II were blocked simultaneously. These data indicate that IgG4 antibodies from Mf+, Mf- and EN, in contrast to those of CP, natively exhibit FcγRI/II-dependent suppressive properties on

IgG4 antibodies in Egyptian patients with schistosomiasis

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Iskander, R.; Das, P. K.; Aalberse, R. C.

1981-01-01

Serum immunoglobulins were determined in 40 Egyptian patients with schistosomiasis. In addition to the well-established elevation in total IgE, a striking imbalance in the IgG subclass levels was found: IgG3 and IgG4 levels were markedly elevated, whereas IgG2 levels were normal. The IgG4 level did

Isolated Liver Hilar Infiltration by IgG4 Inflammation Mimicking Cholangiocarcinoma

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Laurent Bochatay

2016-10-01

Full Text Available IgG4-related disease represents a heterogeneous group of disease characterized by infiltration of various tissues by IgG4 plasmocytes. In case of liver infiltration, this condition classically mimics primary sclerosing cholangitis or multifocal cholangiocarcinoma due to inflammation that preferentially affects the intra- and extrahepatic bile duct. Diagnostic criteria have recently been reviewed in order to better define the disease and help physicians make the diagnosis. Herein, we present the case of a patient who died after liver surgery for suspected cholangiocarcinoma that finally turned out to be IgG4-associated liver disease, a condition being out of current consensual criteria. The patient presented with progressive cholestasis identified by MR cholangiography as an isolated hilar mass responsible for dilatation of the left and right intrahepatic bile duct suspicious for a Klatskin tumor. The IgG4 blood level was normal as was biliary cytology. The patient underwent right portal embolization followed by right extended hepatectomy. Pathologic examination found no tumor but intense fibrosclerotic infiltration with a marked inflammatory infiltrate characterized by IgG4-positive plasmocytes. Despite immunosuppressive treatment, cholestasis was never controlled and successive biopsies of the remaining liver showed progressive cholestasis, liver infiltrate and no bile duct regeneration. The patient finally presented an upper gastrointestinal hemorrhage leading to death 4 months after hepatectomy and appropriate immunosuppressive therapy.

IgG4-associated sclerosing cholangitis masquerading as hilar cholangiocarcinoma.

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Yadav, Kamal Sunder; Sali, Priyanka Akhilesh; Mansukhani, Verushka M; Shah, Rajiv; Jagannath, P

2016-07-01

IgG4-sclerosing cholangitis (IgG4-SC) commonly presents with type 1 autoimmune pancreatitis. Isolated IgG4-SC is rare. Differentiating IgG4-SC from cholangiocarcinoma preoperatively is challenging due to overlapping radio-clinical manifestations and difficult preoperative histology. We present three cases preoperatively diagnosed and surgically treated as hilar cholangiocarcinoma. First and second cases presented with cholangiocarcinoma with portal vein involvement and third with a malignant-appearing hilar stricture. On histopathology, IgG4-SC was diagnosed in the first two cases. Third patient had raised serum IgG4, and histopathology was inconclusive for IgG4-SC and negative for malignancy. However, she responded to steroid therapy.

Therapeutic IgG4 antibodies engage in Fab-arm exchange with endogenous human IgG4 in vivo

NARCIS (Netherlands)

Labrijn, Aran F.; Buijsse, Antonio Ortiz; van den Bremer, Ewald T. J.; Verwilligen, Annemiek Y. W.; Bleeker, Wim K.; Thorpe, Susan J.; Killestein, Joep; Polman, Chris H.; Aalberse, Rob C.; Schuurman, Janine; van de Winkel, Jan G. J.; Parren, Paul W. H. I.

Two humanized IgG4 antibodies, natalizumab and gemtuzumab, are approved for human use, and several others, like TGN1412, are or have been in clinical development. Although IgG4 antibodies can dynamically exchange half-molecules(1), Fab-arm exchange with therapeutic antibodies has not been

Therapeutic IgG4 antibodies engage in Fab-arm exchange with endogenous human IgG4 in vivo

NARCIS (Netherlands)

Labrijn, Aran F.; Buijsse, Antonio Ortiz; van den Bremer, Ewald T. J.; Verwilligen, Annemiek Y. W.; Bleeker, Wim K.; Thorpe, Susan J.; Killestein, Joep; Polman, Chris H.; Aalberse, Rob C.; Schuurman, Janine; van de Winkel, Jan G. J.; Parren, Paul W. H. I.

2009-01-01

Two humanized IgG4 antibodies, natalizumab and gemtuzumab, are approved for human use, and several others, like TGN1412, are or have been in clinical development. Although IgG4 antibodies can dynamically exchange half-molecules, Fab-arm exchange with therapeutic antibodies has not been demonstrated

Estimation of polyclonal IgG4 hybrids in normal human serum.

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Young, Elizabeth; Lock, Emma; Ward, Douglas G; Cook, Alexander; Harding, Stephen; Wallis, Gregg L F

2014-07-01

The in vivo or in vitro formation of IgG4 hybrid molecules, wherein the immunoglobulins have exchanged half molecules, has previously been reported under experimental conditions. Here we estimate the incidence of polyclonal IgG4 hybrids in normal human serum and comment on the existence of IgG4 molecules with different immunoglobulin light chains. Polyclonal IgG4 was purified from pooled or individual donor human sera and sequentially fractionated using light-chain affinity and size exclusion chromatography. Fractions were analysed by SDS-PAGE, immunoblotting, ELISA, immunodiffusion and matrix-assisted laser-desorption mass spectrometry. Polyclonal IgG4 purified from normal serum contained IgG4κ, IgG4λ and IgG4κ/λ molecules. Size exclusion chromatography showed that IgG4 was principally present in monomeric form (150 000 MW). SDS-PAGE, immunoblotting and ELISA showed the purity of the three IgG4 samples. Immunodiffusion, light-chain sandwich ELISA and mass spectrometry demonstrated that both κ and λ light chains were present on only the IgG4κ/λ molecules. The amounts of IgG4κ/λ hybrid molecules ranged from 21 to 33% from the five sera analysed. Based on the molecular weight these molecules were formed of two IgG4 heavy chains plus one κ and one λ light chain. Polyclonal IgG (IgG4-depleted) was similarly fractionated according to light-chain specificity. No evidence of hybrid IgG κ/λ antibodies was observed. These results indicate that hybrid IgG4κ/λ antibodies compose a substantial portion of IgG4 from normal human serum. © 2014 John Wiley & Sons Ltd.

Serologic aspects of IgG4 antibodies. II. IgG4 antibodies form small, nonprecipitating immune complexes due to functional monovalency

NARCIS (Netherlands)

van der Zee, J. S.; van Swieten, P.; Aalberse, R. C.

1986-01-01

Human IgG4 antibodies directed against phospholipase A, the P1 antigen from Dermatophagoïdes pteronyssinus extracts, and cat albumin were found unable to cross-link antigen. Previously, it was demonstrated that IgG4 antibodies, in contrast to IgG1 antibodies, did not cross-link Sepharose-bound

The Fab Conformations in the Solution Structure of Human Immunoglobulin G4 (IgG4) Restrict Access to Its Fc Region

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Rayner, Lucy E.; Hui, Gar Kay; Gor, Jayesh; Heenan, Richard K.; Dalby, Paul A.; Perkins, Stephen J.

2014-01-01

Human IgG4 antibody shows therapeutically useful properties compared with the IgG1, IgG2, and IgG3 subclasses. Thus IgG4 does not activate complement and shows conformational variability. These properties are attributable to its hinge region, which is the shortest of the four IgG subclasses. Using high throughput scattering methods, we studied the solution structure of wild-type IgG4(Ser222) and a hinge mutant IgG4(Pro222) in different buffers and temperatures where the proline substitution suppresses the formation of half-antibody. Analytical ultracentrifugation showed that both IgG4 forms were principally monomeric with sedimentation coefficients s20,w0 of 6.6–6.8 S. A monomer-dimer equilibrium was observed in heavy water buffer at low temperature. Scattering showed that the x-ray radius of gyration Rg was unchanged with concentration in 50–250 mm NaCl buffers, whereas the neutron Rg values showed a concentration-dependent increase as the temperature decreased in heavy water buffers. The distance distribution curves (P(r)) revealed two peaks, M1 and M2, that shifted below 2 mg/ml to indicate concentration-dependent IgG4 structures in addition to IgG4 dimer formation at high concentration in heavy water. Constrained x-ray and neutron scattering modeling revealed asymmetric solution structures for IgG4(Ser222) with extended hinge structures. The IgG4(Pro222) structure was similar. Both IgG4 structures showed that their Fab regions were positioned close enough to the Fc region to restrict C1q binding. Our new molecular models for IgG4 explain its inability to activate complement and clarify aspects of its stability and function for therapeutic applications. PMID:24876381

A Patient with Autoimmune Pancreatitis Type 1 with Previously Known Lymphadenopathy, Both in the Context of IgG4-related Disease.

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Alidjan, Fazil M; Karim, Faiz; Verdijk, Rob M; van Esser, Joost W; van Heerde, Marianne J

2015-11-05

Autoimmune pancreatitis (AIP) is an important clinical pathologic concept of IgG-4-related disease. AIP is a rare cause of chronic pancreatitis, characterized by a fibroinflammatory process by lymphoplasmacytic infiltrates, storiform fibrosis, obliterative phlebitis, and increased IgG4+ plasma cells, leading to dysfunction of the pancreas. Affected patients with AIP frequently have disease affecting other organs or sites with similar histologic changes, elevated IgG4+ plasma cell infiltrate, and good response to corticosteroid therapy. These diseases often are not limited to the pancreas and the pancreas may not be involved at all. We report a 62-year-old man with obstructive jaundice with pre-existent submandibular lymphadenopathy. Diagnosis of AIP was based on diagnostic criteria by the HISORT-criteria in combination with elevated IgG-4 serum levels. CT revealed a focal enlargement of the head of the pancreas, as well as mesenteric peripancreatic and mediastinal lymphadenopathy. He was treated with high-dose steroid in combination with azathioprine and showed good clinical response. We report a case with pre-existent submandibular lymphadenopathy and obstructive jaundice based on AIP type 1, both in the context of IgG4-related disease.

Change of Serum IgG4 in Patients with Ocular Adnexal Marginal Zone B Cell Lymphoma Associated with IgG4-Related Ophthalmic Disease After Treatment.

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Wu, Yuan-Hung; Wang, Lei-Chi; Yen, Sang-Hue; Yu, Wei-Kuang; Kao, Shu-Ching; Kau, Hui-Chuan; Tsai, Chieh-Chih; Liu, Catherine Jui-Ling

2017-09-01

To investigate the change of serum IgG4 concentrations correlated with clinical evolution in patients with ocular adnexal marginal zone B cell lymphoma associated with IgG4-related ophthalmic disease (IgG4-ROD). Three consecutive patients with histopathologically confirmed ocular adnexal marginal zone B cell lymphoma associated with IgG4-ROD were evaluated. Two patients received radiotherapy and 1 patient received steroid therapy. Treatment outcome was evaluated by clinical symptoms, radiologic examination, and change of serum IgG4 level in these patients. All patients had elevated serum IgG4 before treatment (462, 338, and 780 mg/dL respectively.) The 2 patients who received radiotherapy achieved complete remission and the serum IgG4 decreased to 345 and 92 mg/dL, respectively. The patient who underwent systemic steroid achieved partial remission and the serum IgG4 decrease to 161 mg/dL. Our study showed elevated serum IgG4 in all patients with ocular adnexal marginal zone B cell lymphoma associated with IgG4-ROD. In addition, the elevated serum IgG4 may decrease or keep stable after treatment, accompanied by improvement in clinical symptoms and reduction of lesions.

IgG4-Related Disease Presenting as Recurrent Mastoiditis With Central Nervous System Involvement

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April L. Barnado MD

2013-09-01

Full Text Available We report a case of a 43-year-old female who presented with right ear fullness and otorrhea. She was initially diagnosed with mastoiditis that was not responsive to multiple courses of antibiotics and steroids. She was then diagnosed with refractory inflammatory pseudotumor, and subsequent treatments included several mastoidectomies, further steroids, and radiation therapy. The patient went on to develop mastoiditis on the contralateral side as well as central nervous system involvement with headaches and right-sided facial paresthesias. Reexamination of the mastoid tissue revealed a significantly increased number of IgG4-positive cells, suggesting a diagnosis of IgG4-related disease. The patient improved clinically and radiographically with rituximab and was able to taper off azathioprine and prednisone. IgG4-related disease should be considered in patients with otologic symptoms and be on the differential diagnosis in patients with inflammatory pseudotumor. Staining for IgG and IgG4 is essential to ensure a prompt diagnosis and treatment.

Acute tubulointerstitial nephritis with severe renal impairment associated with multisystem IgG4-related disease.

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Beltrame, Rafael Coimbra Ferreira; Friderichs, Maurício; Fior, Bárbara Rayanne; Schaefer, Pedro Guilherme; Thomé, Gustavo Gomes; Silva, Dirceu Reis da; Barros, Elvino José Guardão; Seligman, Renato; Veronese, Francisco Veríssimo

2016-01-01

The IgG4-related disease has a wide clinical spectrum where multiple organs can be affected, and the diagnosis depends on typical histopathological findings and an elevated IgG4 expression in plasma cells in the affected tissue. We describe the clinical presentation and evolution of a patient with acute tubulointerstitial nephritis, severe kidney failure and systemic manifestations such as lymphadenomegaly and chronic pancreatitis. The diagnosis was confirmed by the clinical picture and kidney and lymph node histopathology, in which immunohistochemistry of the lymphoid tissue showed policlonality and increased expression of IgG4, with a IgG4/total IgG ratio > 80%. The patient was treated with prednisone at a dose of 60 mg/day, followed by mycophenolate mofetil, and showed clinical and renal function improvement at 6 months of follow-up. The high index of suspicion of IgG4-related disease with multisystem involvement and the early treatment of this condition are essential to improve the prognosis of affected patients. Resumo A doença relacionada à IgG4 tem um espectro clínico amplo em que múltiplos órgãos podem ser afetados, e o diagnóstico depende de achados histopatológicos típicos e elevada expressão de IgG4 em plasmócitos no tecido afetado. Descrevemos o quadro clínico e a evolução de um paciente com nefrite túbulo-intersticial aguda, insuficiência renal grave e manifestações sistêmicas como linfoadenomegalias e pancreatite crônica. O diagnóstico foi confirmado pelas características clínicas e pela histopatologia renal e de linfonodo, na qual a imunohistoquímica mostrou tecido linfoide com policlonalidade e expressão aumentada de IgG4, com uma relação IgG4/IgG total > 80%. O paciente foi tratado com prednisona na dose de 60 mg/dia, seguido de micofenolato mofetil, e apresentou melhora clínica e da função renal depois de 6 meses de tratamento. O alto índice de suspeição da doença relacionada ao IgG4 com comprometimento multissist

Utility of Serum IgG4 Levels in a Multiethnic Population.

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Qi, Ruyu; Chen, Luke Y C; Park, Sujin; Irvine, Robert; Seidman, Michael A; Kelsall, John T; Collins, David; Yin, Vivian; Slack, Graham W; Mattman, Andre; Lam, Eric; Carruthers, Mollie N

2018-01-01

IgG4-related disease (IgG4-RD) is a recently recognized condition defined by characteristic histopathologic findings in affected organs. Serum IgG4 concentration is often but not always elevated. The sensitivity and specificity of serum IgG4 vary greatly across studies and has been anecdotally associated to ethnicity. Our study was conducted to investigate the difference in serum IgG4 levels between Asian and non-Asian patients with IgG4-RD. This is a single-center retrospective study of 26 Asian and 10 non-Asian patients with histologically confirmed IgG4-RD. Serum IgG4 levels, clinical features and other laboratory findings were compared between the 2 groups, 31 Asian and 11 non-Asian patients with non-IgG4-RD rheumatic diseases were randomly identified to evaluate test characteristics of serum IgG4 measurement. Median serum IgG4 at time of diagnosis was significantly higher in Asian (median = 11.2g/L, interquartile range: 4.6-19.7) than non-Asian patients (median = 2.9g/L, interquartile range: 0.7-5.4, P = 0.0094), as well as the median serum IgG and total protein. Asian patients had more eosinophilia and polyclonal hypergammaglobulinemia than non-Asian patients (P = 0.016 and 0.001, respectively). Test sensitivity was higher in Asian (96%) than non-Asian patients (67%), whereas test specificity was higher in non-Asian patients (91% versus 71%). Asian patients with IgG4-RD have more exuberant serum IgG4, IgG and polyclonal hypergammaglobulinemia than non-Asian patients; the mechanism of this difference requires further study. These findings have significant clinical importance and must be accounted for in the diagnostic workup of patients in multiethnic settings. Copyright © 2018 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

Relative stabilities of IgG1 and IgG4 Fab domains: Influence of the light–heavy interchain disulfide bond architecture

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Heads, James T; Adams, Ralph; D'Hooghe, Lena E; Page, Matt J T; Humphreys, David P; Popplewell, Andrew G; Lawson, Alastair D; Henry, Alistair J

2012-01-01

The stability of therapeutic antibodies is a prime pharmaceutical concern. In this work we examined thermal stability differences between human IgG1 and IgG4 Fab domains containing the same variable regions using the thermofluor assay. It was found that the IgG1 Fab domain is up to 11°C more stable than the IgG4 Fab domain containing the same variable region. We investigated the cause of this difference with the aim of developing a molecule with the enhanced stability of the IgG1 Fab and the biological properties of an IgG4 Fc. We found that replacing the seven residues, which differ between IgG1 CH1 and IgG4 CH1 domains, while retaining the native IgG1 light-heavy interchain disulfide (L–H) bond, did not affect thermal stability. Introducing the IgG1 type L–H interchain disulfide bond (DSB) into the IgG4 Fab resulted in an increase in thermal stability to levels observed in the IgG1 Fab with the same variable region. Conversely, replacement of the IgG1 L–H interchain DSB with the IgG4 type L–H interchain DSB reduced the thermal stability. We utilized the increased stability of the IgG1 Fab and designed a hybrid antibody with an IgG1 CH1 linked to an IgG4 Fc via an IgG1 hinge. This construct has the expected biophysical properties of both the IgG4 Fc and IgG1 Fab domains and may therefore be a pharmaceutically relevant format. PMID:22761163

Elevated IgG4 serum levels in patients with cystic fibrosis.

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Clerc, Axelle; Reynaud, Quitterie; Durupt, Stéphane; Chapuis-Cellier, Colette; Nové-Josserand, Raphaële; Durieu, Isabelle; Lega, Jean Christophe

2017-01-01

Serum immunoglobulin (Ig) G4 elevation has been associated with several pathological conditions other than IgG4-related disease (IgG4-RD). In cystic fibrosis (CF), an elevation of specific IgG4 has been associated with colonization and infection by Pseudomonas aeruginosa. IgG4 elevation may be a marker of chronic infection or inflammatory stimulation. The aim of this study was to explore the prevalence of elevated IgG4 levels in CF and its correlation with the major clinical and microbiological features found in CF patients. In a cross-sectional study, we analyzed data from a large cohort of adult CF patients attending the CF center of Lyon University Hospital. An elevated IgG4 level was defined as being above the cut-off value of 135 mg/dL. One hundred and sixty-five CF patients were analyzed. An IgG4 elevation was detected in 43 patients (26%). Compared with the control group (≤ 135 mg/dL), high IgG4 patients exhibited a greater prevalence of Staphylococcus aureus colonization and higher IgG, IgG1, IgG2 and IgE levels. No significant differences were observed in terms of pulmonary function, colonization with Pseudomonas aeruginosa, or the annual rate of bronchial exacerbations. An elevated IgG4 serum level was frequently detected in adult CF patients and did not appear to be associated with poor lung function. We suggest that IgG4 elevation is a marker of the activation of tolerance. Its clinical significance remains to be demonstrated.

Hybrid IgG4/IgG4 Fc antibodies form upon 'Fab-arm' exchange as demonstrated by SDS-PAGE or size-exclusion chromatography

NARCIS (Netherlands)

Rispens, Theo; den Bleker, Tamara H.; Aalberse, Rob C.

2010-01-01

Human IgG4 antibodies are dynamic molecules that in vivo exchange half-molecules to become bispecific antibodies. Here we show that IgG4 antibodies and IgG4 Fc fragments similarly exchange resulting in hybrid antibodies (a single Fab + Fc) with a molecular weight of ca. 100 kDa. These antibodies can

IgG4-Seronegative Autoimmune Pancreatitis and Sclerosing Cholangitis

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Allon Kahn

2015-01-01

Full Text Available IgG4-related disease is a relatively novel clinical entity whose gastrointestinal manifestations include type 1 autoimmune pancreatitis (AIP and IgG4-associated sclerosing cholangitis. The presence of elevated serum IgG4 is suggestive but not essential for the diagnosis of type 1 AIP and is a pervasive feature of the proposed diagnostic criteria. The differential diagnosis of type 1 AIP includes malignant conditions, emphasizing the importance of a deliberate, comprehensive evaluation. Management of patients with a suggestive clinical presentation, but without serum IgG4 elevation, is difficult. Here we present three cases of IgG4-seronegative AIP and sclerosing cholangitis that responded to empiric steroid therapy and discuss approach considerations. These cases demonstrate the value of meticulous application of existing diagnostic algorithms to achieve a clinical diagnosis and avoid surgical intervention.

Invasive cervical cancer accompanied by IgG4-related disease.

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Mizuno, Rin; Yamanishi, Yukio; Uda, Satoko; Terashima, Tsuyoshi; Higashi, Tatsuya; Higuchi, Toshihiro

2016-09-01

IgG4-related disease (IgG4-RD) is a systemic disease that affects multiple organs and generates nodules or thickening. Discriminating these diseases from malignancy is important because glucocorticoid treatment is effective for patients with IgG4-RD. Coexistence of IgG4-RD with various malignant diseases has been reported, but there are few reports with regard to gynecologic malignant diseases. We encountered a case of invasive cervical cancer stage IIB accompanied by IgG4-RD. The patient was a 46-year-old woman. On pelvic magnetic resonance imaging, fluorodeoxyglucose-positron emission tomography and computed tomography, systemic multiple lymph node swelling was seen, including in the neck and the mediastinum in addition to uterine cervix. Diagnosis (and hence, appropriate treatment choice) was achieved on pathology of the submandibular gland and uterus, and analysis of serum IgG4. IgG4-RD should be suspected in patients presenting with malignancy and unusual multiple lymph node swelling. © 2016 Japan Society of Obstetrics and Gynecology.

IgG4-Related Disease Presenting as Isolated Scleritis

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Eran Berkowitz

2017-01-01

Full Text Available A rare case of IgG4-related disease (IgG4-RD manifesting as nodular scleritis is presented in a 20-year-old female. Patient complained of left eye pain and redness for one week. Ocular examination together with ancillary testing led to the diagnosis of nodular scleritis. Since the patient did not show apparent improvement after one week of systemic steroidal treatment, she underwent a biopsy of the affected area revealing histopathological characteristics of IgG4-RD. Long-term treatment with corticosteroids and a steroid-sparing agent (methotrexate led to significant improvement in signs and symptoms. This case highlights the significance of IgG4-RD in the differential diagnosis of scleritis and raises the question as to whether various organs affected by IgG4-RD may have different underlying pathophysiological mechanisms in which pathogenic T cells play a role.

Clonal expansion of CD4+ Cytotoxic T Lymphocytes in IgG4-related disease

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Mattoo, Hamid; Mahajan, Vinay S.; Maehara, Takashi; Deshpande, Vikram; Della-Torre, Emanuel; Wallace, Zachary S.; Kulikova, Maria; Drijvers, Jefte M.; Daccache, Joe; Carruthers, Mollie N.; Castellino, Flavia; Stone, James R.; Stone, John H.; Pillai, Shiv

2016-01-01

Background IgG4-related disease (IgG4-RD) is a systemic condition of unknown etiology, characterized by highly fibrotic lesions with dense lymphoplasmacytic infiltrates. CD4+ T cells constitute the major inflammatory cell population in IgG4-RD lesions. Objective We used an unbiased approach to characterize CD4+ T cell subsets in IgG4-RD subjects based on their clonal expansion and their ability to infiltrate affected tissue sites. Methods We used flow cytometry to identify CD4+ effector/memory T cells (TEM) in a cohort of 101 IgG4-related disease (IgG4-RD) patients. These expanded cells were characterized by gene expression analysis and flow cytometry. Next-generation sequencing of the T cell receptor β chain gene was performed on CD4+SLAMF7+ CTLs and CD4+GATA3+ TH2 cells in a subset of patients to identify their clonality. Tissue infiltration by specific T cells was examined using quantitative multi-color imaging. Results CD4+ effector/memory T cells with a cytolytic phenotype were expanded in IgG4-RD patients. Next-generation sequencing revealed prominent clonal expansions of these CD4+CTLs but not CD4+GATA3+ memory TH2 cells in subjects with IgG4-RD. The dominant T cells infiltrating a range of inflamed IgG4-RD tissue sites were clonally-expanded CD4+CTLs that expressed SLAMF7, granzyme A, IL-1β, and TGF-β1. Clinical remission induced by rituximab-mediated B cell depletion was associated with a reduction in disease-associated CD4+ CTLs Conclusions IgG4-RD is prominently linked to clonally-expanded, IL-1β, and TGF- β1 secreting, CD4+ CTLs in peripheral blood as well as in inflammatory tissue lesions. These active, terminally-differentiated, cytokine-secreting effector CD4+ T cells are now linked to a human disease characterized by chronic inflammation and fibrosis. PMID:26971690

Inhibition of complement activation by IgG4 antibodies

NARCIS (Netherlands)

van der Zee, J. S.; van Swieten, P.; Aalberse, R. C.

1986-01-01

Prolonged exposure to antigens may result in high IgG4 antibody titres as was shown in a previous paper (Aalberse et al., 1983b). In novice bee keepers, a shift in the IgG1/IgG4 ratio of the response against phospholipase-A (PLA; a major component of bee venom) occurred. This resulted in an

The Geoepidemiology and Clinical Aspects of IgG4-Related Disease.

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Uchida, Kazushige; Tanaka, Toshihiro; Gershwin, M Eric; Okazaki, Kazuichi

2016-08-01

Immunoglobulin G4-related disease (IgG4-RD) is a recently described systemic inflammatory disease characterized by increased serum IgG4 concentrations, lymphoplasmacytic infiltrations, storiform fibrosis, and obliterative phlebitis. However, although IgG4-RD has become increasingly recognized, the number of patients with IgG4-RD remains unclear. Data from several studies indicate that patients who have a T-helper type 2 (Th2-) dominant immune response, which leads to the hyperproduction of Th2 cytokines, then progress to IgG4-RD. Glucocorticoids are the most common treatment for IgG4-RD and generally, patients have a good response-a characteristic of IgG4-RD. However, relapses during the tapering of glucocorticoid therapy are common. Second-line therapy after glucocorticoids includes immunosuppressant agents. Although the long-term outcome still remains unclear, there is increased interest in the relationships between IgG-RD and malignancies. In this review, the authors provide a detailed overview of the geoepidemiology, pathogenesis, diagnostic features, treatment, and prognosis of IgG4-RD. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Extrapancreatic findings of IgG4-related disease

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Tan, T.J.; Ng, Y.L.; Tan, D.; Fong, W.S.; Low, A.S.C.

2014-01-01

IgG4-related disease is a systemic fibro-inflammatory condition, which includes autoimmune pancreatitis as part of the disease spectrum. Imaging has been demonstrated to play a major role in the diagnosis of autoimmune pancreatitis. Recognizing the wide spectrum of extrapancreatic manifestations of IgG4-related disease coupled with a high clinical index of suspicion will allow for an accurate and timely diagnosis to be made, thus avoiding unnecessary invasive procedures and ensuring that early effective corticosteroid therapy is commenced. This review aims to serve as a concise reference tool for both clinicians and radiologists in the diagnosis of extrapancreatic IgG4-related disease

IgG4 autoantibodies are inhibitory in the autoimmune disease bullous pemphigoid.

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Zuo, Yagang; Evangelista, Flor; Culton, Donna; Guilabert, Antonio; Lin, Lin; Li, Ning; Diaz, Luis; Liu, Zhi

2016-09-01

The IgG4 subclass of antibodies exhibits unique characteristics that suggest it may function in an immunoregulatory capacity. The inhibitory function of IgG4 has been well documented in allergic disease by the demonstration of IgG4 blocking antibodies, but similar functions have not been explored in autoimmune disease. Bullous pemphigoid (BP) is a subepidermal autoimmune blistering disease characterized by autoantibodies directed against BP180 and an inflammatory infiltrate including eosinophils and neutrophils. Animal models have revealed that the NC16A region within BP180 harbors the critical epitopes necessary for autoantibody mediated disease induction. BP180 NC16A-specific IgG belong to the IgG1, IgG3, and IgG4 subclasses. The purpose of this study was to determine effector functions of different IgG subclasses of NC16A-specific autoantibodies in BP. We find that IgG4 anti-NC16A autoantibodies inhibit the binding of IgG1 and IgG3 autoantibodies to the NC16A region. Moreover, IgG4 anti-NC16A blocks IgG1 and IgG3 induced complement fixation, neutrophil infiltration, and blister formation clinically and histologically in a dose-dependent manner following passive transfer to humanized BP180-NC16A mice. These findings highlight the inhibitory role of IgG4 in autoimmune disease and have important implications for the treatment of BP as well as other antibody mediated inflammatory and autoimmune diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

IgG4-related tumour-forming mastitis with histological appearances of granulomatous lobular mastitis: comparison with other types of tumour-forming mastitis.

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Ogura, Kanako; Matsumoto, Toshiharu; Aoki, Yuji; Kitabatake, Toshiaki; Fujisawa, Minoru; Kojima, Kuniaki

2010-07-01

Sometimes, mastitis needs to be differentiated from carcinoma because of its association with induration and with ultrasound findings (such as low-echo lesions) that resemble those in carcinoma. The aim was to define this type of mastitis and to examine 18 cases to clarify its clinicopathological features. All cases were categorized into three types: non-specific mastitis with neutrophilic infiltration (n = 7); non-specific mastitis with lymphoplasmacytic infiltration (n = 9); and granulomatous lobular mastitis (n = 2). The three types of mastitis presented similar ultrasound findings and shared certain histological features including fibrosis and diffuse or lobulocentric inflammation. Granulomatous lobular mastitis showed specific clinicopathological features including lobulocentric inflammation with giant cells, diffuse IgG4+ plasma cells, and also a high level of serum IgG4. Granulomatous lobular mastitis could be categorized into IgG4-related and non-IgG4-related granulomatous lobular mastitis. IgG4 immunohistochemistry serum IgG4 might be useful for diagnosis of IgG4-related granulomatous lobular mastitis and could help to avoid overtreatment such as wide excision.

Potential of Murine IgG1 and Human IgG4 to Inhibit the Classical Complement and Fcγ Receptor Activation Pathways

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Gina-Maria Lilienthal

2018-05-01

Full Text Available IgG antibodies (Abs mediate their effector functions through the interaction with Fcγ receptors (FcγRs and the complement factors. The main IgG-mediated complement activation pathway is induced through the binding of complement C1q to IgG Abs. This interaction is dependent on antigen-dependent hexamer formation of human IgG1 and IgG3 to increase the affinity for the six-headed C1q molecule. By contrast, human IgG4 fails to bind to C1q. Instead, it has been suggested that human IgG4 can block IgG1 and IgG3 hexamerization required for their binding to C1q and activating the complement. Here, we show that murine IgG1, which functionally resembles human IgG4 by not interacting with C1q, inhibits the binding of IgG2a, IgG2b, and IgG3 to C1q in vitro, and suppresses IgG2a-mediated complement activation in a hemolytic assay in an antigen-dependent and IgG subclass-specific manner. From this perspective, we discuss the potential of murine IgG1 and human IgG4 to block the complement activation as well as suppressive effects of sialylated IgG subclass Abs on FcγR-mediated immune cell activation. Accumulating evidence suggests that both mechanisms seem to be responsible for preventing uncontrolled IgG (autoAb-induced inflammation in mice and humans. Distinct IgG subclass distributions and functionally opposite IgG Fc glycosylation patterns might explain different outcomes of IgG-mediated immune responses and provide new therapeutic options through the induction, enrichment, or application of antigen-specific sialylated human IgG4 to prevent complement and FcγR activation as well.

Retroperitoneal disorders associated with IgG4-related autoimmune pancreatitis

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Hara, Noboru; Kawaguchi, Makoto; Takeda, Keisuke; Zen, Yoh

2014-01-01

IgG4-related autoimmune pancreatitis is frequently accompanied by relevant lesions in the genitourinary tract and retroperitoneal organs, which cause various clinical problems, ranging from non-specific back pain or bladder outlet obstruction to renal failure. The diagnosis of IgG4-related retroperitoneal fibrosis requires a multidisciplinary approach, including serological tests, histological examination, imaging analysis, and susceptibility to steroid therapy. Radiological examinations are helpful to diagnose this condition, but surgical resection is occasionally unavoidable to exclude malignancy, particularly for patients with isolated retroperitoneal involvement. Steroid therapy is the treatment of choice for this condition, the same as for other manifestations of IgG4-related disease. For patients with severe ureteral obstruction, additional ureteral stenting needs to be considered prior to steroid therapy to preserve the renal function. Some papers have suggested that IgG4-related disease can affect male reproductive organs including the prostate and testis. IgG4-related prostatitis usually causes lower urinary tract symptoms, such as dysuria and pollakisuria. Patients sometimes state that corticosteroids given for IgG4-related disease at other sites relieve their lower urinary tract symptoms, which leads us to suspect prostatic involvement in this condition. Because of the limited number of publications available, further studies are warranted to better characterize IgG4-related disease in male reproductive organs. PMID:25469023

Enhanced IgG4 production by follicular helper 2 T cells and the involvement of follicular helper 1 T cells in the pathogenesis of IgG4-related disease.

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Akiyama, Mitsuhiro; Yasuoka, Hidekata; Yamaoka, Kunihiro; Suzuki, Katsuya; Kaneko, Yuko; Kondo, Harumi; Kassai, Yoshiaki; Koga, Keiko; Miyazaki, Takahiro; Morita, Rimpei; Yoshimura, Akihiko; Takeuchi, Tsutomu

2016-07-13

The aim of this study was to elucidate the function of circulating follicular helper T (Tfh) cell subsets in helping B cells in patients with active, untreated IgG4-related disease (IgG4-RD) and determine their relationship with disease activity. Seventeen consecutive patients with active, untreated IgG4-RD, 20 with primary Sjögren syndrome (pSS), 5 with multicentric Castleman's disease (MCD), and 12 healthy controls (HC) were enrolled. Tfh cell subset function was evaluated by co-culture with naïve B cells in vitro. Activated Tfh cell subsets were defined as a CCR7(low)PD-1(high) subset among Tfh cell subsets. Disease activity was evaluated by IgG4-RD responder index (IgG4-RD RI) score. The number of Tfh2 cells was significantly higher in IgG4-RD compared to pSS, MCD, or HC, and correlated with serum IgG4 level or the number of plasmablasts. In vitro, Tfh2 cells more efficiently induced the differentiation of naïve B cells into plasmablasts compared to Tfh1 or Tfh17 cells. Of note, while IgG production in culture supernatants of Tfh2 cells was comparable between IgG4-RD and HC, IgG4 production was significantly higher with Tfh2 cells from patients with IgG4-RD than in those from HC. Accordingly, the IgG4:IgG ratio in culture supernatants was also significantly higher with Tfh2 cells from IgG4-RD compared to HC. Moreover, the number of activated Tfh2 cells was higher in IgG4-RD compared to pSS, MCD, or HC, and strongly correlated with IgG4-RD RI score in the baseline active phase. Particularly, the number of activated Tfh2 cells was associated with the number of affected organs and serum IgG4 level. Importantly, the number of activated Tfh2 cells was decreased after glucocorticoid treatment and paralleled disease improvement. Moreover, the number of activated Tfh1 cells was also increased in IgG4-RD compared to pSS, MCD, or HC, correlating with IgG4-RD RI score, but not with serum IgG4 level. Tfh2 cells, but not Tfh1 or Tfh17 cells, induce the differentiation of

Detection of IgG1 and IgG4 subtypes reactive against potato apyrase in schistosomiasis patients

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Priscila de Faria-Pinto

2010-07-01

Full Text Available In this paper, we showed for the first time that the conserved domains within Schistosoma mansoni ATP diphosphohydrolase isoforms, shared with potato apyrase, possess epitopes for the IgG1 and IgG4 subtypes, as 24 (80% of the 30 schistosomiasis patients were seropositive for this vegetable protein. The analyses for each patient cured (n = 14 after treatment (AT with praziquantel revealed variable IgG1 and IgG4 reactivity against potato apyrase. Different antigenic epitopes shared between the vegetable and parasite proteins could be involved in susceptibility or resistance to S. mansoni AT with praziquantel and these possibilities should be explored.

The apparent monovalency of human IgG4 is due to bispecificity

NARCIS (Netherlands)

Aalberse, R. C.; Schuurman, J.; van Ree, R.

1999-01-01

A hypothesis is put forward to explain the apparent monovalency of human IgG4. It is based upon the known instability of the IgG4 hinge. IgG4 is secreted as a regular bivalent antibody, but after secretion interacts with another IgG4 molecule. This interaction results in the exchange of half

Salivary Gland Pathology in IgG4-Related Disease: A Comprehensive Review

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Ilaria Puxeddu

2018-01-01

Full Text Available IgG4-related disease (IgG4-RD is a rare fibroinflammatory condition that can affect almost any organ, characterized by swollen lesions and often by eosinophilia and elevated serum IgG4 concentrations. The diagnosis of IgG4-RD is a challenging task: in fact, single or multiple organs can be affected and clinical, serological, and histological findings can be heterogeneous. In IgG4-RD, the involvement of salivary glands is observed in 27% to 53% of patients. Several organ-specific conditions, now recognized as different manifestations of IgG4-related sialadenitis (IgG4-RS, were viewed in the past as individual disease entities. The study of salivary glands may sometimes be complex, because of the number of pathological conditions that may affect them, often with overlapping clinical pictures. Integration of different imaging techniques is often required in the case of swelling of salivary glands, even though biopsy remains the gold standard for a definite diagnosis of IgG4-RS. Thus, in this review, we discuss new insights in the pathogenesis of IgG4-RD, focusing on its clinical aspects and the tools that are currently available for a correct differential diagnosis when the salivary glands are involved.

The emerging mysteries of IgG4-related disease

NARCIS (Netherlands)

Smit, Wouter; Barnes, Eleanor

2014-01-01

IgG4-related disease (IgG4-RD) is increasingly recognised in Western societies as a multi-system, inflammatory, fibrosing disease of unknown aetiology that typically, though not exclusively, presents in older men. The clinical manifestations are diverse and almost any organ may be affected. The

Bilateral IgG4-related ophthalmic disease: a strong indication for systemic imaging.

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Wu, Albert; Andrew, Nicholas H; McNab, Alan A; Selva, Dinesh

2016-10-01

To investigate whether bilateral or unilateral IgG4-related ophthalmic disease (IgG4-ROD) is associated with extra-ophthalmic IgG4-related disease (IgG4-RD). Twin-centre retrospective observational case series of biopsy-confirmed IgG4-ROD. Clinical and radiology data were reviewed for laterality of IgG4-ROD and presence of extra-ophthalmic disease. The literature was reviewed for case series of IgG4-ROD. 40 IgG4-ROD cases were identified, with median follow-up of 36 months. At diagnosis of IgG4-ROD, all cases were screened for extra-ophthalmic disease with physical examination and blood testing. Systemic imaging was performed in 20 (50%) cases due to clinical suspicion of extra-ophthalmic disease. Of the 21 unilateral IgG4-ROD cases, 3 (14%) had extra-ophthalmic involvement. Of the 19 bilateral cases, 15 (79%) had extra-ophthalmic involvement. Extra-ophthalmic involvement was strongly associated with bilateral IgG4-ROD (pIgG4-ROD is strongly associated with extra-ophthalmic IgG4-RD. We recommend that imaging of the neck, chest, abdomen and pelvis be performed for all bilateral cases. Systemic imaging should also be considered in unilateral cases as a significant proportion of these patients will also have extra-ophthalmic disease. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Engineering an improved IgG4 molecule with reduced disulfide bond heterogeneity and increased Fab domain thermal stability.

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Peters, Shirley J; Smales, C Mark; Henry, Alistair J; Stephens, Paul E; West, Shauna; Humphreys, David P

2012-07-13

The integrity of antibody structure, stability, and biophysical characterization are becoming increasingly important as antibodies receive increasing scrutiny from regulatory authorities. We altered the disulfide bond arrangement of an IgG4 molecule by mutation of the Cys at the N terminus of the heavy chain constant domain 1 (C(H)1) (Kabat position 127) to a Ser and introduction of a Cys at a variety of positions (positions 227-230) at the C terminus of C(H)1. An inter-LC-C(H)1 disulfide bond is thus formed, which mimics the disulfide bond arrangement found in an IgG1 molecule. The antibody species present in the supernatant following transient expression in Chinese hamster ovary cells were analyzed by immunoblot to investigate product homogeneity, and purified product was analyzed by a thermofluor assay to determine thermal stability. We show that the light chain can form an inter-LC-C(H)1 disulfide bond with a Cys when present at several positions on the upper hinge (positions 227-230) and that such engineered disulfide bonds can consequently increase the Fab domain thermal stability between 3 and 6.8 °C. The IgG4 disulfide mutants displaying the greatest increase in Fab thermal stability were also the most homogeneous in terms of disulfide bond arrangement and antibody species present. Importantly, mutations did not affect the affinity for antigen of the resultant molecules. In combination with the previously described S241P mutation, we present an IgG4 molecule with increased Fab thermal stability and reduced product heterogeneity that potentially offers advantages for the production of IgG4 molecules.

IgG4-related sclerosing cholangitis overlapping with autoimmune hepatitis: Report of a case.

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Li, Hongyan; Sun, Li; Brigstock, David R; Qi, Lina; Gao, Runping

2017-05-01

IgG4-related sclerosing cholangitis (IgG4-SC) is the biliary manifestation of IgG4-related disease (IgG4-RD) but the presence of IgG4-SC in the porta hepatis is difficult to differentiate from hilar cholangiocarcinoma (HCCA). IgG4-related autoimmune hepatitis (IgG4-related AIH) is extremely rare and it is not fully clear whether IgG4-related AIH is a hepatic manifestation of IgG4-RD or a subtype of AIH. We present a rare case of a 52-year-old male who was admitted with obstructive jaundice and itchy skin. He primarily presented a severe bile duct stricture in the porta hepatis and an elevated serum level of carbohydrate antigen 19-9 (CA19-9) mimicking HCCA. The patient underwent a surgical resection of the left hepatic lobular and cholecyst as well as common bile duct with a right hepatico-jejunostomy. He was finally diagnosed as IgG4-SC accompanied with IgG4-related AIH by immunohistochemistry, but he lacked conventional autoantibodies. The patient responded well to steroid therapy and remains healthy with no signs of recurrence at six-month follow-up. This is the first case report that hepatic portal IgG4-SC overlapping with IgG4-related AIH without the presence of conventional autoantibodies. Additionally, we suggest that IgG4-RD should be always considered in case of a bile duct stricture in the porta hepatis to avoid unnecessary surgical operation. Copyright © 2017 Elsevier GmbH. All rights reserved.

Clonal expansion of CD4(+) cytotoxic T lymphocytes in patients with IgG4-related disease.

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Mattoo, Hamid; Mahajan, Vinay S; Maehara, Takashi; Deshpande, Vikram; Della-Torre, Emanuel; Wallace, Zachary S; Kulikova, Maria; Drijvers, Jefte M; Daccache, Joe; Carruthers, Mollie N; Castelino, Flavia V; Stone, James R; Stone, John H; Pillai, Shiv

2016-09-01

IgG4-related disease (IgG4-RD) is a systemic condition of unknown cause characterized by highly fibrotic lesions with dense lymphoplasmacytic infiltrates. CD4(+) T cells constitute the major inflammatory cell population in IgG4-RD lesions. We used an unbiased approach to characterize CD4(+) T-cell subsets in patients with IgG4-RD based on their clonal expansion and ability to infiltrate affected tissue sites. We used flow cytometry to identify CD4(+) effector/memory T cells in a cohort of 101 patients with IgG4-RD. These expanded cells were characterized by means of gene expression analysis and flow cytometry. Next-generation sequencing of the T-cell receptor β chain gene was performed on CD4(+)SLAMF7(+) cytotoxic T lymphocytes (CTLs) and CD4(+)GATA3(+) TH2 cells in a subset of patients to identify their clonality. Tissue infiltration by specific T cells was examined by using quantitative multicolor imaging. CD4(+) effector/memory T cells with a cytolytic phenotype were expanded in patients with IgG4-RD. Next-generation sequencing revealed prominent clonal expansions of these CD4(+) CTLs but not CD4(+)GATA3(+) memory TH2 cells in patients with IgG4-RD. The dominant T cells infiltrating a range of inflamed IgG4-RD tissue sites were clonally expanded CD4(+) CTLs that expressed SLAMF7, granzyme A, IL-1β, and TGF-β1. Clinical remission induced by rituximab-mediated B-cell depletion was associated with a reduction in numbers of disease-associated CD4(+) CTLs. IgG4-RD is prominently linked to clonally expanded IL-1β- and TGF-β1-secreting CD4(+) CTLs in both peripheral blood and inflammatory tissue lesions. These active, terminally differentiated, cytokine-secreting effector CD4(+) T cells are now linked to a human disease characterized by chronic inflammation and fibrosis. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Clinical Features of Patients with Basedow's Disease and High Serum IgG4 Levels.

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Torimoto, Keiichi; Okada, Yosuke; Kurozumi, Akira; Narisawa, Manabu; Arao, Tadashi; Tanaka, Yoshiya

2017-01-01

Objective IgG4-related disease is a recently characterized condition presenting with high blood IgG4 levels, swelling of organs, and hypertrophic lesions. This disease is associated with thyroid disease, Hashimoto's disease, and Riedel's thyroiditis. However, there is little information on the association between IgG4-related disease and Basedow's disease. We herein defined the clinical features of patients with Basedow's disease and high IgG4 levels. Methods We compared two groups of patients with Basedow's disease (n=72) who had either normal IgG4 levels (IgG4 levels (≥135 mg/dL; n=5 [6.9%], mean IgG4: 206±116 mg/dL, IgG4/IgG ratio: 10.6%±3.3%). Patients Seventy-two newly diagnosed, untreated patients with Basedow's disease. Results Compared to the normal IgG4 group, patients in the high IgG4 group were predominantly male and showed a significantly higher thyroid low-echo score (1.8±0.4 vs. 1.2±0.5) and eosinophil count (363±354/mm 2 vs. 136±122/mm 2 ). Five patients had high IgG4 levels: one had a pancreatic lesion, and four had thyroid lesions. Conclusion Patients with Basedow's disease and high IgG4 levels may represent a new subtype of Basedow's disease. Further studies with larger sample sizes are needed.

A case of IgG4-related lung disease complicated by asymptomatic chronic Epstein-Barr virus infection.

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Kotetsu, Yasuaki; Ikegame, Satoshi; Takebe-Akazawa, Keiko; Koga, Takaomi; Okabayashi, Kan; Takata, Shohei

2017-11-01

IgG4-related disease is characterized by IgG4-positive plasmacyte infiltration into various organs, but its etiology is not unknown. To elucidate the etiology of IgG4-related disease. We experienced an interesting case of IgG4-related lung disease complicated by chronic EB virus infection. A 70-year-old male visited our hospital due to failure of pneumonia treatment. Chest computed tomography (CT) showed consolidation in the right middle field and slight mediastinal lymphadenopathy in the subcarinal region. Lung consolidation improved with antibiotics; subcarinal lymphadenopathy progressed after 4 months. Malignant lymphoma was suspected given elevated sIL2-R levels (1862 U/mL). Patchy ground glass opacities appeared in the bilateral lung field just before surgical biopsy. He was diagnosed with IgG4-related lung disease after inspection of a pathological specimen obtained from the right upper lung and right hilar lymph node. EB virus-infected cells were also detected in the lymph node. Blood examination revealed EB virus viremia, but the patient did not present with symptoms or organ involvement. This led to a diagnosis of asymptomatic chronic EB virus infection. Recent studies have suggested an association between EB virus infection and IgG4-related diseases in the pathological exploration of surgically resected lymph nodes. Our case is the first case of IgG4-related lung disease in which EB virus infection was both pathologically and clinically proved. The present case is of particular interest in view of this newly reported association, and may serve as a fundamental report for future studies connecting EB virus infection with IgG4-related diseases. © 2016 John Wiley & Sons Ltd.

Spectrum of Disorders Associated with Elevated Serum IgG4 Levels Encountered in Clinical Practice

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Jay H. Ryu

2012-01-01

Full Text Available IgG4-related disease (IgG4-RD is a recently described systemic fibroinflammatory disease associated with elevated circulating levels of IgG4 and manifests a wide spectrum of clinical presentations. Although serum IgG4 level has been described to be the most sensitive and specific laboratory test for the diagnosis of IgG4-RD, it is recognized that an elevated serum IgG4 level can be encountered in other diseases. In this study, we sought to identify the frequency of IgG4-RD and other disease associations in patients with elevated serum IgG4 levels seen in clinical practice. Among 3,300 patients who underwent IgG subclass testing over a 2-year period from January 2009 to December 2010, 158 (4.8% had an elevated serum IgG4 level (>140 mg/dL. IgG4 subclass testing was performed for evaluation of suspected IgG4-RD or immunodeficiency. Twenty-nine patients (18.4% had definite or possible IgG4-RD. Among those patients without IgG4-RD, a broad spectrum of biliary tract, pancreatic, liver, and lung diseases, as well as systemic vasculitis, was diagnosed. We conclude that patients with elevated serum IgG4 levels encountered in clinical practice manifest a wide array of disorders, and only a small minority of them has IgG4-RD.

Seroprevalence of Epstein-Barr virus among HIV positive patients moreover and its association with CD4 positive lymphocyte count.

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Alireza Abdollahi

2014-12-01

Full Text Available Opportunistic infections are the leading cause of hospitalization and morbidity in human immunodeficiency virus (HIV positive patients and are the most common cause of death between them. We aimed to measure IgG antibody against EBV viral capsid antigen (EBV-VCA IgG to determine the seroprevalence of this infection in HIV-positive population. A case-control study between September 2011 and October 2012 was conducted in a teaching hospital enrolling 114 HIV-positive patients as case group and 114 healthy individuals as control with similar age and sex. Enzyme-linked immunosurbant assay (ELISA technique was used for determination of EBV-VAC IgG in obtained samples. Of 114 serum samples obtained from HIV-positive patients, 103 (90.4% samples were found positive for EBV-VCA IgG antibody. There was no significant difference in seroprevalence of EBV VCA IgG antibody between patients received antiretroviral therapy and naive patients (91.5% vs. 87.5%, P>0.05. There was no statistically significant difference in EBV-VCA IgG seroprevalence between three groups of CD4+ in HIV positive group. In conclusion current study showed that seroprevalence of EBV in HIV-positive patients is higher than HIV-negative healthy participants; however, administration of HAART and CD4+ lymphocyte count did not reveal a significant effect in seroprevalence of EBV. Due to the significance of this virus in mortality and morbidity and causing certain malignancies in patients with AIDS, these patients are strongly recommended to be tested for this virus.

Perivascular fibrosis and IgG4-related disease: a case report

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S. Monti

2014-11-01

Full Text Available Immunoglobulin G4-related disease (IgG4-RD is a newly recognized fibroinflammatory condition which can potentially involve any organ. Some characteristic histopathologic features with lymphoplasmacytic infiltrate, an increased number of IgG4+ cells, storiform fibrosis and obliterative phlebitis are the mainstay for diagnosis. Serum IgG4 levels often increase. We report the case of a patient with perivascular fibrotic lesions involving the aortic arch and the splenic hilum, with a surgical biopsy-proven diagnosis of IgG4-related disease. The patient is now undergoing a low-dose corticosteroid maintenance therapy without evidence of new localizations of the disease. This case highlights the need for increasing awareness and recognition of this new, emerging clinical condition.

Increase in serum concentrations of IgG2 and IgG4 by selenium supplementation in children with Down's syndrome.

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Annerén, G; Magnusson, C G; Nordvall, S L

1990-01-01

In a previous study on children with Down's syndrome a reduced rate of infections was reported by their parents after the children had received six months' treatment with selenium supplements. In the present study the concentrations of the four IgG subclasses were measured in 29 of these children in samples of serum obtained before and immediately after the period of supplementation and one year after it had finished. Selenium had a significant augmentative effect on the serum concentrations of IgG2 and IgG4, but not of IgG1 and IgG3. This effect was not related to age, as among children over the age of 6 years the serum concentrations of IgG2 and IgG4 had decreased significantly one year after the treatment had been stopped. This study suggests that selenium has an immunoregulatory effect, which might be of importance in both basic research and clinical practice. PMID:2148668

What is IgG4? A review of the biology of a unique immunoglobulin subtype.

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Nirula, Ajay; Glaser, Scott M; Kalled, Susan L; Taylor, Frederick R; Taylora, Frederick R

2011-01-01

Recent descriptions of the group of clinical disorders collectively defined as IgG4-related systemic disease (IgG4-RSD) have prompted this review of the unique biology of the IgG4 antibody. This article will discuss IgG4 structure and function, the unique phenomenon of half-antibody exchange, and the implications of IgG4 biology for its proposed role in immunologic diseases. IgG4 antibodies have unique structural and functional properties and undergo 'half-antibody exchange' in vivo, resulting in recombined antibodies composed of two different binding specificities. The production of IgG4 antibodies appears to be driven in part by T helper 2 (Th2) cytokines that mediate allergic responses and IgE production. Although serum IgG4 levels in healthy individuals vary significantly, data from multiple sclerosis (MS) patients suggest tight regulation of individual IgG4 levels over time. IgG4-RSD represents a diverse group of clinical disorders unified by elevated IgG4 levels and specific histopathologic findings. A key unanswered question is whether IgG4, a relatively weak activator of effector cells, is pathogenic in these disorders. IgG4 is a unique antibody biologically and structurally. Increased understanding of its precise role in the clinical syndromes that comprise IgG4-RSD may ultimately elucidate the underlying pathogenesis.

Positive IgG Western Blot for Borrelia burgdorferi in Colombia

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Palacios Ricardo

1999-01-01

Full Text Available In order to evaluate the presence of specific IgG antibodies to Borrelia burgdorferi in patients with clinical manifestations associated with Lyme borreliosis in Cali, Colombia, 20 serum samples from patients with dermatologic signs, one cerebrospinal fluid (CSF sample from a patient with chronic neurologic and arthritic manifestations, and twelve serum samples from individuals without clinical signs associated with Lyme borreliosis were analyzed by IgG Western blot. The results were interpreted following the recommendations of the Centers for Diseases Control and Prevention (CDC for IgG Western blots. Four samples fulfilled the CDC criteria: two serum specimens from patients with morphea (localized scleroderma, the CSF from the patient with neurologic and arthritic manifestations, and one of the controls. Interpretation of positive serology for Lyme disease in non-endemic countries must be cautious. However these results suggest that the putative "Lyme-like" disease may correlate with positivity on Western blots, thus raising the possibility that a spirochete genospecies distinct from B. burgdorferi sensu stricto, or a Borrelia species other than B. burgdorferi sensu lato is the causative agent. Future work will focus on a survey of the local tick and rodent population for evidence of spirochete species that could be incriminated as the etiologic agent.

IgG4-related disease of the biliary tract and pancreas: clinical and experimental advances.

Science.gov (United States)

Hubers, Lowiek M; Beuers, Ulrich

2017-07-01

IgG4-related disease (IgG4-RD) is an immune-mediated disease of unknown cause. It predominantly affects the biliary tract [IgG4-associated cholangitis (IAC)] and pancreas [autoimmune pancreatitis (AIP)] of mostly elderly men. Accurate diagnostic tests are lacking. Patients benefit from predniso(lo)ne treatment. However, disease relapse is often seen. This review will address pathophysiological aspects and advances in diagnostic and therapeutic strategies. The role of IgG1 and IgG4 in the pathophysiology of IgG4-RD was studied in mice which showed more intense organ damage of pancreas and salivary glands when IgG1 rather than IgG4 of patients with IgG4-RD was injected. Coadministration of IgG1+IgG4 led to dampening of IgG1-mediated injury supporting the view that IgG4 exerts immune-dampening effects. IgG4+ B-cell receptor clones identified by next-generation sequencing and the IgG4/IgG RNA ratio in human blood assessed by quantitative PCR were able to accurately distinguish IAC/AIP from primary sclerosing cholangitis or pancreatobiliary malignancies. Long-term treatment with low-dose prednisolone was safe and reduced the number of flare-ups in patients with AIP. Early diagnosis by a novel accurate and easy-to-use qPCR test may prevent life-threatening complications, unnecessary interventions and fatal course because of misdiagnosis. Prednisolone treatment remains the standard of care in patients with IgG4-RD.

Exposure to occupational antigens might predispose to IgG4-related disease

NARCIS (Netherlands)

de Buy Wenniger, Lucas J. Maillette; Culver, Emma L.; Beuers, Ulrich

2014-01-01

Evidence is mounting that the immune system of patients with IgG4-related disease (IgG4-RD) shows indications of chronic antigenic stimulation. Hypothesizing a possible role for occupational antigenic exposure, we observed in two independent cohorts of patients with IgG4-RD that the majority had had

IgG4-related disease: a systemic condition with characteristic microscopic features

DEFF Research Database (Denmark)

Detlefsen, Sönke

2013-01-01

that a significant proportion of the AIP patients had a variety of extrapancreatic fibroinflammatory lesions, and that AIP therefore was the pancreatic manifestation of a systemic disease. Among these extrapancreatic manifestations, the extrahepatic bile ducts, salivary glands, thyroid, lymph nodes......During the first decade of the 21st century, IgG4-related disease (IgG4-RD), a fibroinflammatory condition occurring at multiple sites of the body, has been newly recognized. As indicated by its name, elevation of IgG4 in the serum and tissue is a common denominator of IgG4-RD. Since...... diseases on their own, others have been included under the umbrella of "multifocal fibrosclerosis". Biopsies or resection specimens from affected organs in IgG4-RD reveal several common microscopic features irrespective of the site of the lesion. Cellular and storiform fibrosis, lymphoplasmacytic...

IgG4 anti-phospholipase A2 receptor might activate lectin and alternative complement pathway meanwhile in idiopathic membranous nephropathy: an inspiration from a cross-sectional study.

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Yang, Yang; Wang, Chao; Jin, Liping; He, Fagui; Li, Changchun; Gao, Qingman; Chen, Guanglei; He, Zhijun; Song, Minghui; Zhou, Zhuliang; Shan, Fujun; Qi, Ka; Ma, Lu

2016-08-01

The deposition of IgG4 of antibodies against phospholipase A2 receptor (anti-PLA2R) is predominating in the kidneys of patients with idiopathic membranous nephropathy, while its predictive value has not been determined. It was a retrospective study, and 438 patients were included. Serum samples of two time points [before intervention (baseline) and after 1.5-year treatment (endpoint)] were detected for total and IgG4 anti-PLA2R. IgG4 IgG4 subclass and the achievement of CR; (3) bi-negativity of IgG4 has a high accuracy of predicting CR compared with total antibodies; (4) in patients of bi-positivity, those achieving CR showed lower MASP-1/2, MBL, C3a, C5a, FB, Ba and Bb than patients failing to achieve CR; (5) the titers of endpoint and decrease in Ba and Bb were associated with improvement of 24 h-UP in those of bi-positivity; and (6) the decrease in Ba was a significant factor for achieving CR in those of bi-positivity. Continuous IgG4 negativity was a useful tool to predict the achievement of CR; however, in patients of continuous IgG4 positivity, those with lower activation of lectin and alternative pathways would still more probably achieve CR.

Natural IgG autoantibodies are abundant and ubiquitous in human sera, and their number is influenced by age, gender, and disease.

Directory of Open Access Journals (Sweden)

Eric P Nagele

Full Text Available The presence of self-reactive IgG autoantibodies in human sera is largely thought to represent a breakdown in central tolerance and is typically regarded as a harbinger of autoimmune pathology. In the present study, immune-response profiling of human serum from 166 individuals via human protein microarrays demonstrates that IgG autoantibodies are abundant in all human serum, usually numbering in the thousands. These IgG autoantibodies bind to human antigens from organs and tissues all over the body and their serum diversity is strongly influenced by age, gender, and the presence of specific diseases. We also found that serum IgG autoantibody profiles are unique to an individual and remarkably stable over time. Similar profiles exist in rat and swine, suggesting conservation of this immunological feature among mammals. The number, diversity, and apparent evolutionary conservation of autoantibody profiles suggest that IgG autoantibodies have some important, as yet unrecognized, physiological function. We propose that IgG autoantibodies have evolved as an adaptive mechanism for debris-clearance, a function consistent with their apparent utility as diagnostic indicators of disease as already established for Alzheimer's and Parkinson's diseases.

Cloning of pCDNA3-IgG4 and pQE-2-IgG4 human hinge region ...

African Journals Online (AJOL)

GREGORY

2011-12-16

Dec 16, 2011 ... diseases and in allergy-related immunoassays, thus, anti-hIgG4 antibody is of interest in the development of ... pQE-2-. IgG4 will be used for protein expression in M15 prokaryotic .... Solution conformation of wild-type and ...

Antineutrophil cytoplasmic antibody-associated vasculitides and IgG4-related disease: A new overlap syndrome.

Science.gov (United States)

Danlos, François-Xavier; Rossi, Giovanni Maria; Blockmans, Daniel; Emmi, Giacomo; Kronbichler, Andreas; Durupt, Stéphane; Maynard, Claire; Luca, Luminita; Garrouste, Cyril; Lioger, Bertrand; Mourot-Cottet, Rachel; Dhote, Robin; Arlet, Jean-Benoit; Hanslik, Thomas; Rouvier, Philippe; Ebbo, Mikael; Puéchal, Xavier; Nochy, Dominique; Carlotti, Agnès; Mouthon, Luc; Guillevin, Loïc; Vaglio, Augusto; Terrier, Benjamin

2017-10-01

Atypical manifestations have been described in patients with ANCA-associated vasculitides (AAV), such as pachymeningitis, orbital mass or chronic periaortitis. Because these manifestations have been associated to the spectrum of IgG4-related disease (IgG4-RD), we hypothesized that both diseases could overlap. We conducted a European retrospective multicenter observational study including patients fulfilling ACR and Chapel Hill criteria for AAV and IgG4-RD Comprehensive Diagnostic Criteria. Eighteen patients were included (median age 55.5years, 13 men). AAV and IgG4-RD were diagnosed concomitantly in 13/18 (72%) patients; AAV preceded IgG4-RD in 3/18 (17%) while IgG4-RD preceded AAV in 2/18 (11%). AAV diagnoses included granulomatosis with polyangiitis in 14 (78%), microscopic polyangiitis in 3 (17%), and eosinophilic granulomatosis with polyangiitis in one case. IgG4-RD diagnosis included definite IgG4-RD in 5 (28%) cases, probable IgG4-RD in 5 (28%) and possible IgG4-RD in 8 (44%). IgG4-RD manifestations were chronic periaortitis in 9/18 (50%) patients, orbital mass and tubulointerstitial nephritis in 4 (22%) cases, prevertebral fibrosis in 3 (17%), pachymeningitis and autoimmune pancreatitis in 2 (11%) cases. Patients required median number of 2 (range 0-4) lines of immunosuppressants in combination with glucocorticoids. During the follow-up (median 49,8months, range 17,25-108months), AAV manifestations relapsed in 10/18 (56%) cases and IgG4-RD lesions in 5/18 (28%). When used, mainly for relapses, rituximab showed response in all cases. AAV and IgG4-RD may overlap. Clinicians should consider that atypical manifestations during AAV could be related to IgG4-RD rather than to refractory granulomatous or vasculitic lesions. Copyright © 2017 Elsevier B.V. All rights reserved.

[IgG4-related kidney disease: what the nephrologist needs to know].

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Galeano, Dario; Zanoli, Luca; Scarfia, Viviana Rosalia; L'Imperio, Vincenzo; Malatino, Lorenzo; Fatuzzo, Pasquale; Granata, Antonio

2016-01-01

IgG4 related disease is a systemic fibro-inflammatory disorder characterized by multiple organ and multiple tissue lesions. The real pathogenesis is currentlyactually unknown. For these reasons many authors compare IgG4 related disease to sarcoidosis. Lesions are often localized in the pancreas, salivary and lacrimal glands, biliary ducts, retroperitoneum and in many other organs. The diagnosisis difficult because of mild symptoms and the possibility of mimicking other severe diseases. Therefore, histopathology together with clinical and radiological typical findings are mandatory tools for diagnosis. Steroidtherapy usually enables disappearance of tumor like lesions and complete recovery. Kidney has an extensive organ involvement in the contextof IgG4-related disease. Historically, tubule - interstitial nephritis(TIN) is considered the main renal feature of renal lesions, however recent studies extend the spectrum of renal lesions also to glomerular tuft. These findings allow to introduce in the nosography the term of IgG4related kidney disease (IgG4 RKD). This review focuses on renal involvement in IgG4related disease, in order to help nephrologists to improve their clinical, diagnostic and therapeutic approach to this emerging pleiotropic clinical pattern.

IgG4-related multiorgan disease: report of the first autopsy case.

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Ochoa, Minerva Lazos; López, Belem Gabiño; Cabello, Raúl Romero; Feregrino, Raúl Romero

2013-05-02

IgG4-related disease (IgG4RD) is a chronic recurring fibro-inflammatory pathology that is considered to be of autoimmune origin. Histopathology is considered to be the gold standard method for diagnosis. IgG4RD affects multiple organs. IgG4RD was first identified in the pancreas and was called autoimmune pancreatitis (AIP). During the following years, the disease spectrum was expanded and it was realised that the extrapancreatic lesions can precede, coexist or appear after the diagnosis of AIP. At present, several illnesses such as Mikulicz disease, Küttner tumour, multifocal fibrosclerosis, etc, are considered to be part of the IgG4RD spectrum. The symptoms of the disease tend to appear over months and years and diagnosis is achieved on average 13.5 months (4-60 months) after the onset. The purpose of this report was to provide information about a case that was sadly fatal but that permitted a complete histopathological study of the damaged tissues.

Pulmonary manifestation of immunoglobulin G4-related disease in a 7-year-old immunodeficient boy with Epstein-Barr virus infection: a case report.

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Szczawinska-Poplonyk, Aleksandra; Wojsyk-Banaszak, Irena; Jonczyk-Potoczna, Katarzyna; Breborowicz, Anna

2016-06-08

Immunoglobulin G4-related disease (IgG4-RD) is a multiorgan fibroinflammatory condition with lymphoplasmacytic infiltrates containing abundant IgG4-positive plasma cells. The immunopathogenesis of the disease and the potential role of triggering autoantigens or infectious factors have not been clearly defined. Immunoglobulin G4-related lung disease is a new and emerging condition in pediatric patients and to date, there have been only two reports regarding pulmonary manifestation of IgG4-RD in children recently published. This is the first report of IgG4-related lung disease in an immunodeficient child with Epstein-Barr virus infection. We report on the case of a 7-year old atopic boy who was hospitalized with an initial clinical and radiological diagnosis of pneumonia, positive Epstein-Barr virus (EBV)-DNA in the blood and defective adaptive immunity. The lung CT showed a consolidated mass lesion adjacent to the posterior wall of the chest and the diaphragm. The child underwent surgical resection of the tumor, and the histologic examination of the lung specimens revealed lymphoplasmacytic infiltrates with fibrosis and vasculitis correlating with IgG4-related lung disease. Subsequent monitoring of the patient with lung CT, pulmonary function tests and IgG4 levels did not show signs of active disease. The diagnosis of IgG4-related lung disease in children is challenging because of its rarity, nonspecific symptomatology and heterogeneous morphological manifestations. Further studies are required in children with pulmonary presentation of IgG4-RD to better understand pathogenesis of this condition, possible immunological or infectious triggering factors, and finally, to determine pediatric patient-targeted therapeutic interventions.

IgG4-related disease and lymphocyte-variant hypereosinophilic syndrome: A comparative case series.

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Carruthers, Mollie N; Park, Sujin; Slack, Graham W; Dalal, Bakul I; Skinnider, Brian F; Schaeffer, David F; Dutz, Jan P; Law, Joanna K; Donnellan, Fergal; Marquez, Vladimir; Seidman, Michael; Wong, Patrick C; Mattman, Andre; Chen, Luke Y C

2017-04-01

To compare the clinical and laboratory features of IgG4-related disease (IgG4-RD) and lymphocyte-variant hypereosinophilic syndrome (L-HES), two rare diseases that often present with lymphadenopathy, gastrointestinal symptoms, eosinophilia, and elevated immunoglobulins/IgE. Comparative case series of 31 patients with IgG4-RD and 13 patients with L-HES. Peripheral blood eosinophilia was present in eight of 31 patients with IgG4-RD compared to 13 of 13 patients with L-HES (median eosinophils 0.4 vs 7.0 giga/L, P=.001) and 12 of 20 patients with IgG4-RD had increased serum IgE compared to eight of 13 patients with L-HES, P=.930. Twenty-seven of 30 patients with IgG4-RD had elevated serum IgG4 compared to five of 12 patients with L-HES (median IgG4 9.6 g/L vs 0.80 g/L, P=.002). Flow cytometry demonstrated an aberrant T-cell phenotype in 7 of 23 patients with IgG4-RD and 13 of 13 patients with L-HES (PIgG4-RD vs 10 of 13 patients with L-HES (P=.143). Patients in both groups received corticosteroids as first-line therapy. For refractory disease in IgG4-RD, rituximab was the most common steroid-sparing agent, whereas in L-HES, it was pegylated interferon-α-2a. The overlapping features of these two diseases with divergent treatment options demonstrate the importance of familiarity with both entities to optimize diagnosis and treatment. © 2016 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.

Consensus statement on the pathology of IgG4-related disease

NARCIS (Netherlands)

Deshpande, Vikram; Zen, Yoh; Chan, John Kc; Yi, Eunhee E.; Sato, Yasuharu; Yoshino, Tadashi; Klöppel, Günter; Heathcote, J. Godfrey; Khosroshahi, Arezou; Ferry, Judith A.; Aalberse, Rob C.; Bloch, Donald B.; Brugge, William R.; Bateman, Adrian C.; Carruthers, Mollie N.; Chari, Suresh T.; Cheuk, Wah; Cornell, Lynn D.; Fernandez-del Castillo, Carlos; Forcione, David G.; Hamilos, Daniel L.; Kamisawa, Terumi; Kasashima, Satomi; Kawa, Shigeyuki; Kawano, Mitsuhiro; Lauwers, Gregory Y.; Masaki, Yasufumi; Nakanuma, Yasuni; Notohara, Kenji; Okazaki, Kazuichi; Ryu, Ji Kon; Saeki, Takako; Sahani, Dushyant V.; Smyrk, Thomas C.; Stone, James R.; Takahira, Masayuki; Webster, George J.; Yamamoto, Motohisa; Zamboni, Giuseppe; Umehara, Hisanori; Stone, John H.

2012-01-01

IgG4-related disease is a newly recognized fibro-inflammatory condition characterized by several features: a tendency to form tumefactive lesions in multiple sites; a characteristic histopathological appearance; and-often but not always-elevated serum IgG4 concentrations. An international symposium

Distribution and components of interstitial inflammation and fibrosis in IgG4-related kidney disease: analysis of autopsy specimens.

Science.gov (United States)

Hara, Satoshi; Kawano, Mitsuhiro; Mizushima, Ichiro; Harada, Kenichi; Takata, Takuma; Saeki, Takako; Ubara, Yoshifumi; Sato, Yasuharu; Nagata, Michio

2016-09-01

IgG4-related kidney disease (IgG4-RKD) occasionally progresses to chronic renal failure and is pathologically characterized by IgG4-positive lymphoplasmacyte-rich tubulointerstitial nephritis with storiform fibrosis (bird's-eye pattern fibrosis). Although radiology reveals a heterogeneous distribution of affected areas in this disease, their true distribution within the whole kidney is still unknown because of difficulty in estimating this from needle biopsy samples. Using 5 autopsy specimens, the present study histologically characterized the distribution and components of interstitial inflammation and fibrosis in IgG4-RKD. Interstitial lymphoplasmacytic infiltration or fibrosis was observed in a variety of anatomical locations such as intracapsular, subcapsular, cortical, perivascular, and perineural regions heterogeneously in a patchy distribution. They tended to be more markedly accumulated around medium- and small-sized vessels. Storiform fibrosis was limited to the cortex. Immunostaining revealed nonfibrillar collagens (collagen IV and VI) and fibronectin predominance in the cortical lesion, including storiform fibrosis. In contrast, fibril-forming collagens (collagen I and III), collagen VI, and fibronectin were the main components in the perivascular lesion. In addition, α-smooth muscle actin-positive myofibroblasts were prominently accumulated in the early lesion and decreased with progression, suggesting that myofibroblasts produce extracellular matrices forming a peculiar fibrosis. In conclusion, perivascular inflammation or fibrosis of medium- and small-sized vessels is a newly identified pathologic feature of IgG4-RKD. Because storiform fibrosis contains mainly nonfibrillar collagens, "interstitial fibrosclerosis" would be a suitable term to reflect this. The relation between the location and components of fibrosis determined in whole kidney samples provides new clues to the pathophysiology underlying IgG4-RKD. Copyright © 2016 The Authors. Published

Retroperitoneal disorders associated with IgG4-related autoimmune pancreatitis

OpenAIRE

Hara, Noboru; Kawaguchi, Makoto; Takeda, Keisuke; Zen, Yoh

2014-01-01

IgG4-related autoimmune pancreatitis is frequently accompanied by relevant lesions in the genitourinary tract and retroperitoneal organs, which cause various clinical problems, ranging from non-specific back pain or bladder outlet obstruction to renal failure. The diagnosis of IgG4-related retroperitoneal fibrosis requires a multidisciplinary approach, including serological tests, histological examination, imaging analysis, and susceptibility to steroid therapy. Radiological examinations are ...

Kinetics of IgG antibody to cytomegalovirus (CMV) after birth and seroprevalence of anti-CMV IgG in Chinese children.

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Chen, Jie; Hu, Lingqing; Wu, Meiling; Zhong, Tianying; Zhou, Yi-Hua; Hu, Yali

2012-12-10

Prevalence of cytomegalovirus (CMV) infection is 90-100% in developing countries; however, the kinetics of anti-CMV IgG in infants remains elusive. Sera from 112 mother-newborn pairs and longitudinal samples from 41 infants up to 2-year old were tested for anti-CMV IgG and IgM. Additionally, samples from 837 healthy children were included. Of 112 mothers, 108 (96.4%) were anti-CMV IgG positive; their 108 newborns were also seropositive. In a 2-year follow-up among 40 infants of positive mothers, anti-CMV IgG level in 8 individuals decreased with time and became undetectable by age of 3.5-8 months, and that in 32 others decreased at 1- and 3.5-month old, and then increased. Based on the positive IgM, rising IgG levels, and low anti-CMV IgG avidity index, 76.7% of the primary infections were demonstrated to occur during 1-3.5 months of age. The overall seroprevalence of anti-CMV in 837 children was 82.4%, which was generally constant from 2 to 8 years old (χ2 = 3.150, p = 0.790). The maternally acquired anti-CMV IgG in infants disappears before 8-month old. Primary CMV infection in Chinese children mostly occurs during 1-3.5 months of age. Whether the relatively lower seroprevalence of anti-CMV in Chinese children found in this survey may reflect the positive rate in child-bearing age women in the future remains to be further studied.

Quantitative measurement of 18F-FDG PET/CT uptake reflects the expansion of circulating plasmablasts in IgG4-related disease.

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Berti, Alvise; Della-Torre, Emanuel; Gallivanone, Francesca; Canevari, Carla; Milani, Raffaella; Lanzillotta, Marco; Campochiaro, Corrado; Ramirez, Giuseppe Alvise; Bozzalla Cassione, Emanuele; Bozzolo, Enrica; Pedica, Federica; Castiglioni, Isabella; Arcidiacono, Paolo Giorgio; Balzano, Gianpaolo; Falconi, Massimo; Gianolli, Luigi; Dagna, Lorenzo

2017-12-01

[18F]Fluorodeoxyglucose (18F-FDG) PET/CT is increasingly used to assess organ involvement and response to treatment in IgG4-related disease (IgG4-RD), but clear correlations between 18F-FDG uptake and disease activity have not been established yet. We aimed to correlate the intensity and distribution of 18F-FDG uptake with validated clinical, serological and immunological parameters of IgG4-RD activity. Twenty patients with active IgG4-RD underwent a baseline 18F-FDG PET/CT. Ten patients repeated 18F-FDG PET/CT after immunosuppressive treatments. 18F-FDG tissue uptake was measured using the standardized uptake value corrected for the partial volume effect (PVC-SUV) and the total lesion glycolysis (TLG) with (TLGtot+ln) and without (TLGtot-ln) lymph nodes. Disease activity was assessed by means of clinical parameters [IgG4-RD Responder Index (RI)], serological (ESR and CRP) and immunological (serum IgG4 and circulating plasmablasts) biomarkers. The enhanced liver fibrosis score was exploited as a biomarker for fibroblast activation. Thirteen (65%) patients had two or more organs affected by IgG4-RD. All patients had active IgG4-RD as defined by a median IgG4-RD RI value of 9 (range 6-15; normal IgG4 and plasmablasts were elevated in 85% of patients. Circulating plasmablasts positively correlated with PVC-SUV (P = 0.027), inversely correlated with TLGtot-ln (P = 0.023) and did not correlate with TLGtot+ln (P > 0.05). No statistically significant correlation was found between PVC-SUV or TLG and IgG4-RD RI, ESR, CRP, serum IgG4 or enhanced liver fibrosis score (P > 0.05). Clinical response to immunosuppressive therapies was associated with a consensual reduction of circulating plasmablasts, PVC-SUV, TLGtot+ln and TLGtot-ln values (P IgG4-RD lesions reflects immunological perturbations of the B cell compartment rather than fibroblast activation and extracellular matrix deposition. Conventional biomarkers of disease activity, namely IgG4-RD RI, ESR, CRP and serum IgG4

The blocking activity of birch pollen-specific immunotherapy-induced IgG4 is not qualitatively superior to that of other IgG subclasses

DEFF Research Database (Denmark)

Ejrnaes, Anne M; Bødtger, Uffe; Larsen, Jørgen N

2004-01-01

IgE were detected using 125I-labelled rBet v 1.2801, a recombinant variant of the major allergen of Betula verrucosa pollen. Results show that IgG4-depletion resulted in equivalent reductions in binding and blocking activities. In contrast, a significant but less than two-fold higher relative...... for the clinical efficacy of SIT. In this study, fractionated serum samples from 14 SIT-treated birch pollen allergic individuals enabled determination of the inhibitory capacity of IgG4 alone versus non-IgG4 IgG. Allergen-binding activities of IgG and the IgG-mediated inhibition of allergen binding to autologous...

Serum Concentrations of IgG4 in the Spanish Adult Population: Relationship with Age, Gender, and Atopy

Science.gov (United States)

Carballo, Iago; Alvela, Lucía; Pérez, Luis-Fernando; Gude, Francisco; Vidal, Carmen; Alonso, Manuela; Sopeña, Bernardo; Gonzalez-Quintela, Arturo

2016-01-01

Background and Aim Serum IgG4 concentrations are commonly measured in clinical practice. The aim of this study was to investigate serum IgG4 concentrations in adults and their potential relationship with demographic, lifestyle, metabolic, and allergy-related factors. Methods Serum IgG4 concentrations were measured with a commercial assay in 413 individuals (median age 55 years, 45% males) who were randomly selected from a general adult population. Results Median IgG4 concentration was 26.8 mg/dL. Five out of the 413 individuals (1.2%) exhibited IgG4 concentrations >135 mg/dL, and 17 out of 411 (4.1%) exhibited an IgG4/total IgG ratio >8%. Serum IgG4 concentrations were significantly higher in males than in females and decreased with age. After adjusting for age and sex, serum IgG4 concentrations were not significantly influenced by alcohol consumption, smoking or common metabolic abnormalities (obesity and the related metabolic syndrome). Serum IgG4 concentrations were not significantly correlated with serum concentrations of proinflammatory cytokines and inflammation markers. Serum IgG4 concentrations were significantly correlated with IgE concentrations. Serum IgG4 concentrations tended to be higher in atopics (individuals with IgE-mediated sensitization to aeroallergens) than in non-atopics, particularly among atopics without respiratory symptoms. Serum IgG4 concentrations were not significantly correlated with total eosinophil blood count. Cases of IgG4-related disease were neither present at baseline nor detected after a median of 11 years of follow-up. Conclusions Studies aimed at defining reference IgG4 values should consider partitioning by age and sex. Further studies are needed to confirm the potential influence of atopy status on serum IgG4 concentrations. PMID:26910567

IgG4 autoantibodies against muscle-specific kinase undergo Fab-arm exchange in myasthenia gravis patients.

Science.gov (United States)

Koneczny, Inga; Stevens, Jo A A; De Rosa, Anna; Huda, Saif; Huijbers, Maartje G; Saxena, Abhishek; Maestri, Michelangelo; Lazaridis, Konstantinos; Zisimopoulou, Paraskevi; Tzartos, Socrates; Verschuuren, Jan; van der Maarel, Silvère M; van Damme, Philip; De Baets, Marc H; Molenaar, Peter C; Vincent, Angela; Ricciardi, Roberta; Martinez-Martinez, Pilar; Losen, Mario

2017-02-01

Autoimmunity mediated by IgG4 subclass autoantibodies is an expanding field of research. Due to their structural characteristics a key feature of IgG4 antibodies is the ability to exchange Fab-arms with other, unrelated, IgG4 molecules, making the IgG4 molecule potentially monovalent for the specific antigen. However, whether those disease-associated antigen-specific IgG4 are mono- or divalent for their antigens is unknown. Myasthenia gravis (MG) with antibodies to muscle specific kinase (MuSK-MG) is a well-recognized disease in which the predominant pathogenic IgG4 antibody binds to extracellular epitopes on MuSK at the neuromuscular junction; this inhibits a pathway that clusters the acetylcholine (neurotransmitter) receptors and leads to failure of neuromuscular transmission. In vitro Fab-arm exchange-inducing conditions were applied to MuSK antibodies in sera, purified IgG4 and IgG1-3 sub-fractions. Solid-phase cross-linking assays were established to determine the extent of pre-existing and inducible Fab-arm exchange. Functional effects of the resulting populations of IgG4 antibodies were determined by measuring inhibition of agrin-induced AChR clustering in C2C12 cells. To confirm the results, κ/κ, λ/λ and hybrid κ/λ IgG4s were isolated and tested for MuSK antibodies. At least fifty percent of patients had IgG4, but not IgG1-3, MuSK antibodies that could undergo Fab-arm exchange in vitro under reducing conditions. Also MuSK antibodies were found in vivo that were divalent (monospecific for MuSK). Fab-arm exchange with normal human IgG4 did not prevent the inhibitory effect of serum derived MuSK antibodies on AChR clustering in C2C12 mouse myotubes. The results suggest that a considerable proportion of MuSK IgG4 could already be Fab-arm exchanged in vivo. This was confirmed by isolating endogenous IgG4 MuSK antibodies containing both κ and λ light chains, i.e. hybrid IgG4 molecules. These new findings demonstrate that Fab-arm exchanged antibodies

Sphingosine-1-phosphate (S1P) enhances glomerular endothelial cells activation mediated by anti-myeloperoxidase antibody-positive IgG.

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Sun, Xiao-Jing; Chen, Min; Zhao, Ming-Hui

2018-03-01

Cumulating evidences suggested an important role of sphingosine-1-phosphate (S1P) and its receptors in regulating endothelial barrier integrity. Our previous study revealed that the circulating S1P levels and renal expression of S1PRs correlated with disease activity and renal damage in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This study investigated the role of S1P and its receptors in myeloperoxidase (MPO)-ANCA-positive IgG-mediated glomerular endothelial cell (GEnC) activation. The effect of S1P on morphological alteration of GEnCs in the presence of MPO-ANCA-positive IgG was observed. Permeability assay was performed to determine endothelial monolayer activation in quantity. Both membrane-bound and soluble ICAM-1 and VCAM-1 levels were measured. Furthermore, antagonists and/or agonists of various S1PRs were employed to determine the role of different S1PRs. S1P enhanced MPO-ANCA-positive IgG-induced disruption of tight junction and disorganization of cytoskeleton in GEnCs. S1P induced further increase in monolayer permeability of GEnC monolayers in the presence of MPO-ANCA-positive IgG. S1P enhanced MPO-ANCA-positive IgG-induced membrane-bound and soluble ICAM-1/VCAM-1 up-regulation of GEnCs. Soluble ICAM-1 levels in the supernatants of GEnCs stimulated by S1P and MPO-ANCA-positive IgG increased upon pre-incubation of S1PR1 antagonist, while pre-incubation of GEnCs with the S1PR1 agonist down-regulated sICAM-1 level. Blocking S1PR2-4 reduced sICAM-1 levels in the supernatants of GEnCs stimulated by S1P and MPO-ANCA-positive IgG. Pre-incubation with S1PR5 agonist could increase sICAM-1 level in the supernatants of GEnC stimulated by S1P and MPO-ANCA-positive IgG. S1P can enhance MPO-ANCA-positive IgG-mediated GEnC activation through S1PR2-5. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Kinetics of IgG antibody to cytomegalovirus (CMV after birth and seroprevalence of anti-CMV IgG in Chinese children

Directory of Open Access Journals (Sweden)

Chen Jie

2012-12-01

Full Text Available Abstract Background Prevalence of cytomegalovirus (CMV infection is 90–100% in developing countries; however, the kinetics of anti-CMV IgG in infants remains elusive. Methods Sera from 112 mother-newborn pairs and longitudinal samples from 41 infants up to 2-year old were tested for anti-CMV IgG and IgM. Additionally, samples from 837 healthy children were included. Results Of 112 mothers, 108 (96.4% were anti-CMV IgG positive; their 108 newborns were also seropositive. In a 2-year follow-up among 40 infants of positive mothers, anti-CMV IgG level in 8 individuals decreased with time and became undetectable by age of 3.5–8 months, and that in 32 others decreased at 1- and 3.5-month old, and then increased. Based on the positive IgM, rising IgG levels, and low anti-CMV IgG avidity index, 76.7% of the primary infections were demonstrated to occur during 1–3.5 months of age. The overall seroprevalence of anti-CMV in 837 children was 82.4%, which was generally constant from 2 to 8 years old (χ2 = 3.150, p = 0.790. Conclusions The maternally acquired anti-CMV IgG in infants disappears before 8-month old. Primary CMV infection in Chinese children mostly occurs during 1–3.5 months of age. Whether the relatively lower seroprevalence of anti-CMV in Chinese children found in this survey may reflect the positive rate in child-bearing age women in the future remains to be further studied.

Human placenta: relative content of antibodies of different classes and subclasses (IgG1-IgG4) containing lambda- and kappa-light chains and chimeric lambda-kappa-immunoglobulins.

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Lekchnov, Evgenii A; Sedykh, Sergey E; Dmitrenok, Pavel S; Buneva, Valentina N; Nevinsky, Georgy A

2015-06-01

The specific organ placenta is much more than a filter: it is an organ that protects, feeds and regulates the growth of the embryo. Affinity chromatography, ELISA, SDS-PAGE and matrix-assisted laser desorption ionization mass spectrometry were used. Using 10 intact human placentas deprived of blood, a quantitative analysis of average relative content [% of total immunoglobulins (Igs)] was carried out for the first time: (92.7), IgA (2.4), IgM (2.5), kappa-antibodies (51.4), lambda-antibodies (48.6), IgG1 (47.0), IgG2 (39.5), IgG3 (8.8) and IgG4 (4.3). It was shown for the first time that placenta contains sIgA (2.5%). In the classic paradigm, Igs represent products of clonal B-cell populations, each producing antibodies recognizing a single antigen. There is a common belief that IgGs in mammalian biological fluids are monovalent molecules having stable structures and two identical antigen-binding sites. However, similarly to human milk Igs, placenta antibodies undergo extensive half-molecule exchange and the IgG pool consists of 43.5 ± 15.0% kappa-kappa-IgGs and 41.6 ± 17.0% lambda-lambda-IgGs, while 15.0 ± 4.0% of the IgGs contained both kappa- and lambda-light chains. Kappa-kappa-IgGs and lambda-lambda-IgGs contained, respectively (%): IgG1 (47.7 and 34.4), IgG2 (36.3 and 44.5), IgG3 (7.4 and 11.8) and IgG4 (7.5 and 9.1), while chimeric kappa-lambda-IgGs consisted of (%): 43.5 IgG1, 41.0 IgG2, 5.6 IgG3 and 7.9 IgG4. Our data are indicative of the possibility of half-molecule exchange between placenta IgGs of various subclasses, raised against different antigens, which explains a very well-known polyspecificity and cross-reactivity of different human IgGs. © The Japanese Society for Immunology. 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The S228P mutation prevents in vivo and in vitro IgG4 Fab-arm exchange as demonstrated using a combination of novel quantitative immunoassays and physiological matrix preparation.

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Silva, John-Paul; Vetterlein, Olivia; Jose, Joby; Peters, Shirley; Kirby, Hishani

2015-02-27

Human immunoglobulin G isotype 4 (IgG4) antibodies (Abs) are potential candidates for immunotherapy when reduced effector functions are desirable. IgG4 Abs are dynamic molecules able to undergo a process known as Fab arm exchange (FAE). This results in functionally monovalent, bispecific antibodies (bsAbs) with unknown specificity and hence, potentially, reduced therapeutic efficacy. IgG4 FAE is suggested to be an important biological mechanism that provides the basis for the anti-inflammatory activity attributed to IgG4 Abs. To date, the mechanism of FAE is not entirely understood and studies measuring FAE in ex vivo matrices have been hampered by the presence and abundance of endogenous IgG4 wild-type (WT) Abs. Using representative humanized WT IgG4 monoclonal Abs, namely, anti-IL-6 and anti-TNF, and a core-hinge stabilized serine 228 to proline (S228P) anti-IL-6 IgG4 mutant, it is demonstrated for the first time how anti-IgG4 affinity chromatography can be used to prepare physiologically relevant matrices for assessing and quantifying FAE. A novel method for quantifying FAE using a single MSD immunoassay is also reported and confirms previous findings that, dependent on the redox conditions, the S228P mutation can prevent IgG4 FAE to undetectable levels both in vitro and in vivo. Together, the findings and novel methodologies will allow researchers to monitor and quantify FAE of their own IgG4 molecules in physiologically relevant matrices. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

IgG4-related membranous glomerulonephritis and generalized lymphadenopathy without pancreatitis: a case report.

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Huart, Justine; Grosch, Stéphanie; Bovy, Christophe; Moutschen, Michel; Krzesinski, Jean-Marie

2017-04-26

IgG4-related disease is a recently described pathologic entity. This is the case of a patient with nephrotic syndrome and lymphadenopathy due to IgG4-related disease. Such a kidney involvement is quite peculiar and has only been described a few times recently. Renal biopsy showed a glomerular involvement with membranous glomerulonephritis in association with a tubulo-interstitial nephropathy. Moreover, the patient was not suffering from pancreatitis. The patient is a middle-aged man of Moroccan origin. He has developed recurrent episodes of diffuse lymphadenopathies, renal failure and nephrotic syndrome. Renal biopsies showed membranous glomerulonephritis. The diagnostic approach of this atypical presentation is discussed in this case report as well as diagnostic criteria, therapeutic strategies, biomarkers and pathophysiology of IgG4-related disease. IgG4-related membranous glomerulonephritis is a well-established cause of membranous glomerulonephritis. It must be sought after in every patient with a previous diagnosis of IgG4-related disease and in every patient with this histological finding on renal biopsy. Corticoids are still the first-line treatment of IgG4-related disease. New therapeutic strategies are needed to avoid glucocorticoids long term side-effects. Interestingly, the patient was prescribed cyclophosphamide in addition to glucocorticoids for an immune thrombocytopenia. This treatment had a very good impact on his IgG4-related disease.

IgG4 related renal disease: A wolf in sheep′s clothing

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