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Beuers U, Trampert DC. IgG4-Related Cholangitis. Semin Liver Dis 2025. [PMID: 40342085 DOI: 10.1055/a-2588-3875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/11/2025]
Abstract
IgG4-related cholangitis (IRC) is a rare fibroinflammatory disease of the biliary tree and liver and presents the major hepatobiliary manifestation of IgG4-related systemic disease (IgG4-RD). IRC also includes the IgG4-related inflammatory pseudotumor of the liver and IgG4-related cholecystitis. IRC mimics other cholangiopathies such as primary sclerosing cholangitis or cholangiocarcinoma. IRC may be found in 30 to 60% of cases with type 1 autoimmune pancreatitis, the most frequent manifestation of IgG4-RD. The pathogenesis of IRC (and IgG4-RD) is incompletely understood. Genetic predisposition, environmental factors, oligoclonal glucocorticosteroid-sensitive expansion of IgG4+ B cells/plasmablasts in blood and affected tissue and blocking autoantibody formation against protective IgG4-specific autoantigens such as annexin A11 and laminin 511-E8 with impaired protection of biliary epithelia against toxic bile acids have been described in IRC. Specific T cell subtypes are involved in the inflammatory process. The diagnosis of IRC is made according to HISORt criteria comprising histopathology, imaging, serology, other organ manifestations, and response to therapy. Treatment of IRC aiming to prevent organ failure and improve symptoms includes remission induction with highly effective glucocorticosteroids and long-term maintenance of remission with immunomodulators such as glucocorticosteroid sparing additives or B cell depleting approaches.
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Affiliation(s)
- Ulrich Beuers
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - David C Trampert
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM, Amsterdam University Medical Center, Amsterdam, The Netherlands
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2
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Peyronel F, Della-Torre E, Maritati F, Urban ML, Bajema I, Schleinitz N, Vaglio A. IgG4-related disease and other fibro-inflammatory conditions. Nat Rev Rheumatol 2025; 21:275-290. [PMID: 40195520 DOI: 10.1038/s41584-025-01240-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/07/2025] [Indexed: 04/09/2025]
Abstract
IgG4-related disease (IgG4-RD) is a fibro-inflammatory disorder usually characterized by multi-organ involvement. Its pathogenesis is complex and involves genetic and environmental factors, while immune responses usually mediate organ damage and promote fibrosis, which is a key feature of the disease. IgG4 responses, however, are not exclusive to IgG4-RD and can be encountered in other diseases with phenotypes that partially overlap that of IgG4-RD. Although IgG4-RD has clinical and histological hallmarks, the lack of validated diagnostic criteria often makes the diagnosis challenging, requiring a multi-dimensional approach that integrates clinical, radiological and serological data. The present Review covers recent advances in the understanding of disease drivers and its clinical phenotypes, mainly focusing on the differential diagnosis with potential IgG4-RD mimickers, namely histiocytoses, lymphoproliferative disorders, systemic vasculitides and other immune-mediated conditions. The Review also provides a schematic approach to IgG4-RD treatment, including a brief overview of glucocorticoid-sparing agents and emerging therapies, from B cell-depleting monoclonal antibodies to cytokine-targeting drugs, the majority of which are currently under investigation in randomized clinical trials.
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Affiliation(s)
- Francesco Peyronel
- Nephrology and Dialysis Unit, Meyer Children's Hospital IRCCS, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Emanuel Della-Torre
- University Vita-Salute San Raffaele, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Federica Maritati
- Nephrology, Dialysis and Kidney Transplant Unit, IRCCS-Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Maria L Urban
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Ingeborg Bajema
- Department of Pathology and Medical Biology, University Medical Centre Groningen, Groningen, The Netherlands
| | - Nicolas Schleinitz
- Assistance Publique-Hôpitaux de Marseille, Aix-Marseille Université, Department of Internal Medicine Hôpital Timone, Marseille, France
| | - Augusto Vaglio
- Nephrology and Dialysis Unit, Meyer Children's Hospital IRCCS, Florence, Italy.
- Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", University of Florence, Florence, Italy.
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3
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Yang X, Zhou H, Wang W, Yan C, Ji G. Recent advances in IgG4-related autoimmune pancreatitis. Pathol Res Pract 2024; 257:155331. [PMID: 38678849 DOI: 10.1016/j.prp.2024.155331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 04/16/2024] [Accepted: 04/24/2024] [Indexed: 05/01/2024]
Abstract
The incidence of IgG4-related autoimmune pancreatitis (IgG4-AIP) is high in Asia and other countries, and unnecessary treatment is often undertaken due to both missed diagnosis and misdiagnosis in clinical practice. Although IgG4-AIP has attracted increasing attention, the details of IgG4-AIP pathogenesis and systemic immune response, including its relationship to tumor pathogenesis, are still unclear. In recent years, research on serum immunological detection, pathological features, clinical manifestations, diagnosis and treatment measures for IgG4-AIP has gradually increased. It is of great importance to summarize and discuss the latest progress regarding IgG4-AIP disease.
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Affiliation(s)
- Xisheng Yang
- Department of Gastrointestinal Surgery, Xijing Hospital, Air Force Medical University, Xi'an, China
| | - Haikun Zhou
- Department of Gastrointestinal Surgery, Xijing Hospital, Air Force Medical University, Xi'an, China
| | - Weidong Wang
- Department of Gastrointestinal Surgery, Xijing Hospital, Air Force Medical University, Xi'an, China
| | - Chunyu Yan
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
| | - Gang Ji
- Department of Gastrointestinal Surgery, Xijing Hospital, Air Force Medical University, Xi'an, China.
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Kersten R, Trampert DC, Herta T, Hubers LM, Maillette de Buy Wenniger LJ, Verheij J, van de Graaf SFJ, Beuers U. IgG4-related cholangitis - a mimicker of fibrosing and malignant cholangiopathies. J Hepatol 2023; 79:1502-1523. [PMID: 37598939 DOI: 10.1016/j.jhep.2023.08.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 07/24/2023] [Accepted: 08/14/2023] [Indexed: 08/22/2023]
Abstract
IgG4-related cholangitis (IRC) is the major hepatobiliary manifestation of IgG4-related disease (IgG4-RD), a systemic fibroinflammatory disorder. The pathogenesis of IgG4-RD and IRC is currently viewed as multifactorial, as there is evidence of a genetic predisposition while environmental factors, such as blue-collar work, are major risk factors. Various autoantigens have been described in IgG4-RD, including annexin A11 and laminin 511-E8, proteins which may exert a partially protective function in cholangiocytes by enhancing secretion and barrier function, respectively. For the other recently described autoantigens, galectin-3 and prohibitin 1, a distinct role in cholangiocytes appears less apparent. In relation to these autoantigens, oligoclonal expansions of IgG4+ plasmablasts are present in patients with IRC and disappear upon successful treatment. More recently, specific T-cell subtypes including regulatory T cells, follicular T helper 2 cells, peripheral T helper cells and cytotoxic CD8+ and CD4+ SLAMF7+ T cells have been implicated in the pathogenesis of IgG4-RD. The clinical presentation of IRC often mimics other biliary diseases such as primary sclerosing cholangitis or cholangiocarcinoma, which may lead to inappropriate medical and potentially invalidating surgical interventions. As specific biomarkers are lacking, diagnosis is made according to the HISORt criteria comprising histopathology, imaging, serology, other organ manifestations and response to therapy. Treatment of IRC aims to prevent or alleviate organ damage and to improve symptoms and consists of (i) remission induction, (ii) remission maintenance and (iii) long-term management. Glucocorticosteroids are highly effective for remission induction, after which immunomodulators can be introduced for maintenance of remission as glucocorticosteroid-sparing alternatives. Increased insight into the pathogenesis of IRC will lead to improved diagnosis and novel therapeutic strategies in the future.
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Affiliation(s)
- Remco Kersten
- Department of Gastroenterology & Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - David C Trampert
- Department of Gastroenterology & Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Toni Herta
- Department of Gastroenterology & Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM, Amsterdam University Medical Centers, Amsterdam, the Netherlands; Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Lowiek M Hubers
- Department of Gastroenterology & Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | | | - Joanne Verheij
- Department of Pathology, Amsterdam University Medical Centers, the Netherlands
| | - Stan F J van de Graaf
- Department of Gastroenterology & Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Ulrich Beuers
- Department of Gastroenterology & Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM, Amsterdam University Medical Centers, Amsterdam, the Netherlands.
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Groh M, Habert P, Ebbo M, Muller R, Gaigne L, Gaubert JY, Schleinitz N. [IgG4-related disease: A proteiform pathology with frequent chest manifestations]. Rev Mal Respir 2023; 40:768-782. [PMID: 37858433 DOI: 10.1016/j.rmr.2023.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 09/11/2023] [Indexed: 10/21/2023]
Abstract
INTRODUCTION While IgG4-related disease (IgG4-RD) was initially described in the early 2000s, its polymorphic clinical manifestations were previously reported under different names ; they have in common the presence of IgG4+ oligoclonal plasma cells and fibrosis. STATE OF THE ART Ruling out certain differential diagnoses, the diagnosis of IgG4-RD is based on a bundle of clinical, biological and histological features. Chest involvement is variable and can affect the mediastinum, bronchi, parenchyma, pleura and/or, more rarely, bones and (pericardium, aorta, coronary…) vascular structures. The most frequent radiological manifestations are peribronchovascular thickening, mediastinal lymphadenopathy, and nodular or interstitial patterns. Pleural involvement and posterior mediastinal fibrosis are less frequent, while thoracic paravertebral tissue thickening is highly specific. Systemic corticosteroids are the cornerstone of treatment. In case of relapse or as frontline therapy in case of risk factors for relapse and/or poor tolerance of corticosteroids), a steroid-sparing agent (most often rituximab) is added, and biannual maintenance infusions are associated with a lower risk of relapse. PERSPECTIVES An international consensus has recently led to the development of classification criteria that should standardize the diagnostic approach and homogenize the enrolment of patients in epidemiological as well as therapeutic studies. Other treatments are also under evaluation, including biologics targeting T2 inflammation, CD-19 (inebilizumab, obexelimab), SLAMF7 (elotuzumab) surface proteins, Bruton's tyrosine kinase, and the JAK/STAT pathway. CONCLUSIONS Substantial progress has been made over recent years in understanding IgG4-RD pathophysiology, and personalized patient care seems to be an achievable medium-term goal.
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Affiliation(s)
- M Groh
- Centre de références des syndromes hyperéosinophiliques (CEREO), service de médecine Interne, hôpital Foch, 92150 Suresnes, France; Inserm, U1286 - INFINITE-Institute for Translational Research in Inflammation, Université de Lille, CHU de Lille, 59000 Lille, France
| | - P Habert
- Service de radiologie, hôpital Nord, APHM, Aix-Marseille université, Marseille, France; LIIE (Experimental Interventional Imaging Laboratory), Aix-Marseille Université, 13000 Marseille, France
| | - M Ebbo
- Service de médecine Interne, hôpital La Timone, APHM, Aix-Marseille Université, 13005 Marseille, France
| | - R Muller
- Service de médecine Interne, hôpital La Timone, APHM, Aix-Marseille Université, 13005 Marseille, France
| | - L Gaigne
- Service de médecine Interne, hôpital La Timone, APHM, Aix-Marseille Université, 13005 Marseille, France
| | - J-Y Gaubert
- Service de radiologie, hôpital La Timone, APHM, Aix-Marseille université, 13005 Marseille, France
| | - N Schleinitz
- Service de médecine Interne, hôpital La Timone, APHM, Aix-Marseille Université, 13005 Marseille, France.
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Tsuji Y, Koga T, Nonaka F, Nobusue K, Kawashiri SY, Yamanashi H, Maeda T, Arima K, Aoyagi K, Takahashi M, Kawaguchi S, Matsuda F, Fujii H, Kawano M, Nakamura H, Kawakami A, Tamai M. Identification of risk factors for elevated serum IgG4 levels in subjects in a large-scale health checkup cohort study. Front Immunol 2023; 14:1124417. [PMID: 36969256 PMCID: PMC10031005 DOI: 10.3389/fimmu.2023.1124417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 02/27/2023] [Indexed: 03/29/2023] Open
Abstract
Introduction To allow the identification of IgG4-related disease (IgG4-RD) from a subclinical phase as it is important to understand the risk of elevated serum IgG4 levels. We planned to evaluate serum IgG4 levels in the participants of the Nagasaki Islands Study (NaIS), a large-scale health checkup cohort study. Methods This study included 3,240 individuals who participated in the NaIS between 2016 and 2018 and consented to participate in the study. Serum IgG4, IgG, and IgE levels and human leukocyte antigen (HLA) genotyping results of the NaIS subjects as well as lifestyle habits and peripheral blood test results were analyzed. The magnetic bead panel assay (MBA) and the standard nephelometry immunoassay (NIA) were used to measure serum IgG4 levels. The data were evaluated using multivariate analysis to identify lifestyle and genetic factors associated with elevated serum IgG4 levels. Results Serum IgG4 levels measured with the NIA and MBA showed a tight positive correlation between the two groups (correlation coefficient 0.942). The median age of the participants in the NaIS was 69 years [63-77]. The median serum IgG4 level was 30.2 mg/dL [IQR 12.5-59.8]. Overall, 1019 (32.1%) patients had a history of smoking. When the subjects were stratified into three groups based on the smoking intensity (pack-year), the serum IgG4 level was significantly higher among those with a higher smoking intensity. Accordingly, the multivariate analysis identified a significant relationship between smoking status and serum IgG4 elevation. Conclusion In this study, smoking was identified as a lifestyle factor correlating positively with elevated serum IgG4 levels.
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Affiliation(s)
- Yoshika Tsuji
- Department of Immunology and Rheumatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Nagasaki, Japan
| | - Tomohiro Koga
- Department of Immunology and Rheumatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Nagasaki, Japan
- Center for Bioinformatics and Molecular Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Nagasaki, Japan
| | - Fumiaki Nonaka
- Department of Island and Community Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Nagasaki, Japan
| | - Kenichi Nobusue
- Department of Island and Community Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Nagasaki, Japan
| | - Shin-ya Kawashiri
- Department of Community Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Nagasaki, Japan
| | - Hirotomo Yamanashi
- Department of General Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Nagasaki, Japan
| | - Takahiro Maeda
- Department of General Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Nagasaki, Japan
- Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Nagasaki, Japan
| | - Kazuhiko Arima
- Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Nagasaki, Japan
- Department of Public Health, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Nagasaki, Japan
| | - Kiyoshi Aoyagi
- Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Nagasaki, Japan
- Department of Public Health, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Nagasaki, Japan
| | - Meiko Takahashi
- Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
| | - Shuji Kawaguchi
- Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
| | - Fumihiko Matsuda
- Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
| | - Hiroshi Fujii
- Division of Rheumatology, Department of Internal Medicine, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Mitsuhiro Kawano
- Division of Rheumatology, Department of Internal Medicine, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Hiroyuki Nakamura
- Department of Hygiene and Public Health, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Atsushi Kawakami
- Department of Immunology and Rheumatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Nagasaki, Japan
- Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Nagasaki, Japan
| | - Mami Tamai
- Department of Immunology and Rheumatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Nagasaki, Japan
- Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Nagasaki, Japan
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7
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Capurso G, Pedica F, Palumbo D, Della-Torre E. IgG4-related autoimmune liver disease. Minerva Gastroenterol (Torino) 2023; 69:23-49. [PMID: 33267565 DOI: 10.23736/s2724-5895.20.02794-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/02/2023]
Abstract
The term IgG4-related autoimmune liver disease (AILD) refers to hepato-biliary manifestations of Immunoglobin G4-related disease (IgG4-RD) including IgG4-related sclerosing cholangitis and IgG4-related pseudotumor. The association of some forms of autoimmune hepatitis to IgG4-RD remains controversial. Although autoimmune phenomena have not been clearly observed in IgG4-AILD, perturbation of the adaptive immune system and activation of the humoral response represent established pathophysiological hallmarks and potential therapeutic targets. Clinical manifestations of IgG4-AILD are virtually indistinguishable from bile duct cancer or primary sclerosing cholangitis and are due to mass forming lesions and thickening of the biliary tract that progressively lead to biliary ducts obstruction. There are no current reliable biomarkers for IgG4-AILD and diagnosis should rely on the integration of clinical, serological, radiological, and histological findings. In analogy to most IgG4-RD manifestations, and in contrast to its major mimickers, IgG4-AILD promptly responds to glucocorticoids but frequently relapses, thus requiring long-term maintenance therapy to avoid progressive fibrosclerotic disease and liver cirrhosis. Accumulating evidence on the efficacy of B-cell depletion therapy in patients with systemic IgG4-RD is gradually changing the treatment paradigm of IgG4-AILD and biologics will be increasingly used also for gastroenterological manifestations of IgG4-RD to spare glucocorticoids and traditional immunosuppressive agents. Looking ahead, identification of reliable biomarkers and of mini-invasive strategies to obtain informative biopsies from the biliary tree represent unavoidable priorities to optimize diagnosis and management of IgG4-AILD.
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Affiliation(s)
- Gabriele Capurso
- IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy -
- Division of Pancreato-Biliary Endoscopy and Endosonography, IRCCS San Raffaele Hospital, Milan, Italy -
- Division of Pancreatic Surgery, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Hospital, Milan, Italy -
| | - Federica Pedica
- IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy
- Unit of Pathology, IRCCS San Raffaele Hospital, Milan, Italy
| | - Diego Palumbo
- IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy
- Unit of Clinical and Experimental Radiology, Experimental Imaging Center, IRCCS San Raffaele Hospital, Milan, Italy
| | - Emanuel Della-Torre
- IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy
- Division of Pancreatic Surgery, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Hospital, Milan, Italy
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Hospital, Milan, Italy
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8
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Abstract
In 1995, Yoshida et al. proposed first the concept of "autoimmune pancreatitis" (AIP). Since then, AIP has been accepted as a new pancreatic inflammatory disease and is now divided two subtypes. Type 1 AIP affected immunoglobulin G4 (IgG4) and implicates the pancreatic manifestation of IgG4-related disease, while type 2 is characterized by neutrophil infiltration and granulocytic epithelial lesions (GEL). Recent research has clarified the clinical and pathophysiological aspects of type 1 AIP, which is more than type 2 among the Japanese population. However, many details remain unclear about the pathogenesis and progression of this disease. In this review, we discuss the current knowledge and recent advances relating to type 1 AIP.
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Affiliation(s)
- Kazushige Uchida
- Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi University, Okocho-Kohasu, Nankoku, Kochi, 783-8505, Japan.
| | - Kazuichi Okazaki
- Kansai Medical University Kouri Hospital, 8-45 Kourihondori, Neyagawa, Osaka, 572-8551, Japan
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Goni E, Regel I, Mahajan UM, Amodio A, De Marchi G, Beyer G, Zuppardo RA, Di Leo M, Lanzillotta M, Bonatti F, Kauke T, Dick A, Weiss FU, Schönermarck U, Lerch MM, Frulloni L, Cavestro GM, Mayerle J. HLA-DRB1∗16 and -DQB1∗05 alleles are strongly associated with autoimmune pancreatitis in a cohort of hundred patients. Pancreatology 2022; 22:466-471. [PMID: 35379557 DOI: 10.1016/j.pan.2022.03.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 03/18/2022] [Accepted: 03/19/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND/OBJECTIVES Autoimmune diseases are often associated with human leukocyte antigen (HLA) haplotypes, indicating that changes in major histocompatibility complex (MHC)-dependent self-peptide or antigen presentation contribute to autoimmunity. In our study, we aimed to investigate HLA alleles in a large European cohort of autoimmune pancreatitis (AIP) patients. METHODS Hundred patients with AIP, diagnosed and classified according to the International Consensus Diagnostic Criteria (ICDC), were prospectively enrolled in the study. Forty-four patients with chronic pancreatitis (CP) and 254 healthy subjects served as control groups. DNA was isolated from blood samples and two-digit HLA typing was performed with sequence-specific primer (SSP-) PCR. HLA allele association strength to AIP was calculated as odds ratio. RESULTS We uncovered a strong enrichment of HLA-DQB1 homozygosity in type 1 and type 2 AIP patients. Moreover, a significantly increased incidence of the HLA-DRB1∗16 and HLA-DQB1∗05 alleles and a concomitant lack of the HLA-DRB1∗13 allele was detected in AIP type 1 and type 2 patients. In contrast, the HLA-DQB1∗02 allele was underrepresented in the 'not otherwise specified' (NOS) AIP subtype. We detected no significant difference in the HLA-DRB3, HLA-DRB4 and HLA-DRB5 allele frequency in our cohort. CONCLUSIONS Although AIP type 1 and type 2 are characterized by distinct histopathological characteristics, both subtypes are associated with the same HLA alleles, indicating that the disease might rely on similar immunogenic mechanisms. However, AIP NOS represented another subclass of AIP.
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Affiliation(s)
- Elisabetta Goni
- Department of Medicine II, University Hospital, LMU, Munich, Germany
| | - Ivonne Regel
- Department of Medicine II, University Hospital, LMU, Munich, Germany.
| | | | - Antonio Amodio
- Department of Medicine, Pancreas Center, University of Verona, Verona, Italy
| | - Giulia De Marchi
- Department of Medicine, Pancreas Center, University of Verona, Verona, Italy
| | - Georg Beyer
- Department of Medicine II, University Hospital, LMU, Munich, Germany
| | - Raffaella Alessia Zuppardo
- Gastroenterology and Gastrointestinal Endoscopy, Division of Experimental Oncology, Vita-Salute San Raffaele University, Milan, Italy
| | - Milena Di Leo
- Gastroenterology and Gastrointestinal Endoscopy, Division of Experimental Oncology, Vita-Salute San Raffaele University, Milan, Italy
| | - Marco Lanzillotta
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases, uniRAR, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Francesco Bonatti
- Department of Medicine and Surgery, Medical Genetics Unit, University of Parma, Italy
| | - Teresa Kauke
- Division of Transfusion Medicine, Cellular Therapeutics and Hemostaseology, University Clinic LMU, Munich, Germany
| | - Andrea Dick
- Division of Transfusion Medicine, Cellular Therapeutics and Hemostaseology, University Clinic LMU, Munich, Germany
| | - Frank Ulrich Weiss
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Ulf Schönermarck
- Department of Medicine IV, University Hospital, LMU, Munich, Germany
| | - Markus M Lerch
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Luca Frulloni
- Department of Medicine, Pancreas Center, University of Verona, Verona, Italy
| | - Giulia Martina Cavestro
- Gastroenterology and Gastrointestinal Endoscopy, Division of Experimental Oncology, Vita-Salute San Raffaele University, Milan, Italy
| | - Julia Mayerle
- Department of Medicine II, University Hospital, LMU, Munich, Germany
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10
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Umemura T, Fujinaga Y, Ashihara N, Ozawa M, Kuraishi Y, Watanabe T, Hamano H, Meguro A, Kawa S, Ota M. IL1R1 gene variants associate with disease susceptibility to IgG4-related periaortitis/periarteritis in IgG4-related disease. Gene X 2022; 820:146212. [PMID: 35143941 DOI: 10.1016/j.gene.2022.146212] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 11/29/2021] [Accepted: 01/13/2022] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND IgG4-related disease (IgG4-RD) is an immune-mediated disorder characterized by high serum IgG4 concentration and IgG4-bearing plasma cell infiltration in affected organs. IgG4-related periaortitis/periarteritis is a recently identified disease entity in IgG4-RD that affects the cardiovascular system. Since the genetic factors related to disease onset are unclear, we examined the genetic associations with IgG4-related periaortitis/periarteritis susceptibility. METHODS A small scale of genome-wide association analysis identified that interleukin 1 receptor type 1 (IL1R1) gene variants were correlated with the development of IgG4-related periaortitis/periarteritis in 75 patients with IgG4-RD. Accordingly, 8 single nucleotide polymorphisms (SNPs) in the IL1R1 gene were selected and genotyped in 124 patients with IgG4-RD (43 with periaortitis/periarteritis and 81 without periaortitis/periarteritis) and 344 healthy subjects. RESULTS The minor allele frequencies of 6 SNPs (rs2287049, rs3917273, rs2160227, rs951192, rs3917318, rs7582198) were significantly increased in IgG4-related periaortitis/periarteritis patients compared with those without periaortitis/periarteritis (corrected P < 0.05). In addition, the frequency of the AGAAA haplotype, comprised of 5 SNPs (rs3917273, rs2160227, rs951192, rs3917318, rs7582198), was significantly higher in patients with periaortitis/periarteritis (OR = 2.41, 95% CI:1.42-4.10). CONCLUSION Our findings indicated that IL1R1 genetic polymorphisms contributed to IgG4-related periaortitis/periarteritis and the possibility of certain genetic factors influencing the risk of specific IgG4-RD manifestations.
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Affiliation(s)
- Takeji Umemura
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan; Department of Life Innovation, Institute for Biomedical Sciences, Shinshu University, Matsumoto, Japan.
| | - Yasunari Fujinaga
- Department of Radiology, Shinshu University School of Medicine, Matsumoto, Japan.
| | - Norihiro Ashihara
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan.
| | - Makiko Ozawa
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan.
| | - Yasuhiro Kuraishi
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan.
| | - Takayuki Watanabe
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan.
| | - Hideaki Hamano
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan; Medical Informatics Division, Shinshu University Hospital, Matsumoto, Japan.
| | - Akira Meguro
- Department of Ophthalmology and Visual Science, Yokohama City University School of Medicine, Yokohama, Japan.
| | - Shigeyuki Kawa
- Department of Internal Medicine, Matsumoto Dental University, Shiojiri, Japan.
| | - Masao Ota
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan.
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11
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Drazilova S, Veseliny E, Lenartova PD, Drazilova D, Gazda J, Grgurevic I, Janicko M, Jarcuska P. IgG4-Related Sclerosing Cholangitis: Rarely Diagnosed, but not a Rare Disease. Can J Gastroenterol Hepatol 2021; 2021:1959832. [PMID: 34970512 PMCID: PMC8714375 DOI: 10.1155/2021/1959832] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 11/08/2021] [Accepted: 12/01/2021] [Indexed: 11/30/2022] Open
Abstract
IgG4-related sclerosing cholangitis, a biliary manifestation of an IgG4-related disease, belongs to the spectrum of sclerosing cholangiopathies which result in biliary stenosis. It presents with signs of cholestasis and during differential diagnosis it should be distinguished from cholangiocarcinoma or from other forms of sclerosing cholangitis (primary and secondary sclerosing cholangitis). Despite increasing information and recently established diagnostic criteria, IgG4-related sclerosing cholangitis remains underdiagnosed in routine clinical practice. The diagnosis is based on a combination of the clinical picture, laboratory parameters, histological findings, and a cholangiogram. Increased serum IgG4 levels are nonspecific but are indeed a part of the diagnostic criteria proposed by the Japan Biliary Association and the HISORt criteria for IgG4-SC. High serum IgG4 retains clinical utility depending on the magnitude of elevation. Approximately 90% of patients have concomitant autoimmune pancreatitis, while 10% present with isolated biliary involvement only. About 26% of patients have other organ involvement, such as IgG4-related dacryoadenitis/sialadenitis, IgG4-related retroperitoneal fibrosis, or IgG4-related renal lesions. A full-blown histological finding characterized by IgG4-enriched lymphoplasmacytic infiltrates, obliterative phlebitis, and storiform fibrosis is difficult to capture in practice because of its subepithelial localization. However, the histological yield is increased by immunohistochemistry, with evidence of IgG4-positive plasma cells. Based on a cholangiogram, IgG-4 related sclerosing cholangitis is classified into four subtypes according to the localization of stenoses. The first-line treatment is corticosteroids. The aim of the initial treatment is to induce clinical and laboratory remission and cholangiogram normalization. Even though 30% of patients have a recurrent course, in the literature data, there is no consensus on chronic immunosuppressive maintenance therapy. The disease has a good prognosis when diagnosed early.
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Affiliation(s)
- Sylvia Drazilova
- 2 Department of Internal Medicine, PJ Safarik University in Kosice and L. Pasteur University Hospital, Trieda SNP 1, 040 11 Kosice, Slovakia
| | - Eduard Veseliny
- 2 Department of Internal Medicine, PJ Safarik University in Kosice and L. Pasteur University Hospital, Trieda SNP 1, 040 11 Kosice, Slovakia
| | - Patricia Denisa Lenartova
- Department of Infectology and Travel Medicine, PJ Safarik University in Kosice and L. Pasteur University Hospital, Rastislavova 43, 040 01 Kosice, Slovakia
| | - Dagmar Drazilova
- 1 Faculty of Medicine, Charles University, Katerinska 1660/32, 121 08 Nove Mesto, Prague, Czech Republic
| | - Jakub Gazda
- 2 Department of Internal Medicine, PJ Safarik University in Kosice and L. Pasteur University Hospital, Trieda SNP 1, 040 11 Kosice, Slovakia
| | - Ivica Grgurevic
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University of Zagreb School of Medicine and University Hospital Dubrava, Avenija Gojka Suska 6, 10000 Zagreb, Croatia
| | - Martin Janicko
- 2 Department of Internal Medicine, PJ Safarik University in Kosice and L. Pasteur University Hospital, Trieda SNP 1, 040 11 Kosice, Slovakia
| | - Peter Jarcuska
- 2 Department of Internal Medicine, PJ Safarik University in Kosice and L. Pasteur University Hospital, Trieda SNP 1, 040 11 Kosice, Slovakia
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12
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Masood M. Autoimmune pancreatitis: What we know so far. JGH Open 2021; 6:3-10. [PMID: 35071782 PMCID: PMC8762623 DOI: 10.1002/jgh3.12688] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 11/12/2021] [Accepted: 11/20/2021] [Indexed: 12/19/2022]
Abstract
Autoimmune pancreatitis (AIP) is a rare, often‐missed disease that involves inflammation of the pancreas and strictures of the pancreatic duct. Its prevalence and incidence in the United States remain scarce. The disease has a varied presentation and often mimics pancreatic malignancy, which can make the diagnosis challenging. Most patients have an excellent response to corticosteroid therapy. Immunomodulators may be used in some cases. Rituximab is an effective, emerging treatment in steroid‐refractory cases. This study aims to review the two distinct types of AIP and provide a detailed analysis of the diagnostic approach and treatment modalities.
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Affiliation(s)
- Muaaz Masood
- Department of Internal Medicine Medical College of Georgia at Augusta University Augusta Georgia USA
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13
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Floreani A, Okazaki K, Uchida K, Gershwin ME. IgG4-related disease: Changing epidemiology and new thoughts on a multisystem disease. J Transl Autoimmun 2020; 4:100074. [PMID: 33490938 PMCID: PMC7806798 DOI: 10.1016/j.jtauto.2020.100074] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 11/19/2020] [Accepted: 12/10/2020] [Indexed: 02/07/2023] Open
Abstract
IgG4-related disease (IgG4-RD) represents an immune-mediated fibroinflammatory condition with peculiar histopathologic changes that can affect various organs. In 2012 its unified nomenclature was published, which allows to abandon other synonymous names. Up to now, only little is known about its epidemiology around the world. However, although it is generally considered a rare condition, the number of patients with IgG4-RD is increasing enormously. Likewise, the annual number of publications on this subject has increased progressively. The spectrum of clinical manifestations in IgG4-RD is highly variable, depending on the severity of the disease as well as the presence of organ(s) involvement. This review gives an overview on changing epidemiology of IgG4-RD focusing the attention on the large cohorts of patients published in the literature.
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Affiliation(s)
- Annarosa Floreani
- Scientific Consultant IRCCS Negrar, Verona, Italy
- Senior Scholar, University of Padova, Italy
| | - Kazuichi Okazaki
- Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka, Japan
| | - Kazushige Uchida
- Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka, Japan
| | - M. Eric Gershwin
- Division of Rheumatology Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, USA
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14
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Abstract
PURPOSE OF REVIEW To summarize recent advances in the understanding of the pathogenesis of IgG4-related disease. RECENT FINDINGS Limited data exist to explain genetic susceptibility to IgG4-related disease and the underlying triggers for this disease have not yet been identified. Cytotoxic CD4 T cells and activated B cells infiltrate affected organs and express proinflammatory and profibrotic molecules. Antigen presented by activated B cells likely reactivates cytotoxic CD4 T cells in disease tissues and these T cells in turn induce the targeted apoptotic death of host cells in certain organs - which presumably present the same antigenic peptide on human leukocyte antigen class II molecules of relevance that was also presented on B cells during reactivation. A subsequent exaggerated tissue remodeling process is orchestrated by cytokines, chemokines, and enzymes secreted by both activated B cells and CD4CTLs. These molecules induce an overexuberant repair process resulting in fibrosis and loss of target organ function. SUMMARY In IgG4-related disease, presumably self-reactive cytotoxic CD4 T cells infiltrate tissues, are reactivated by T cells and induce apoptotic death. Molecules secreted by activated B cells and by CD4CTLs drive an exaggerated wound healing response resulting in fibrosis and compromised tissue function.
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15
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Jaster R, Gupta Y, Rohde S, Ehlers L, Nizze H, Vorobyev A, Ludwig RJ, Ibrahim SM. Impact of diet and genes on murine autoimmune pancreatitis. J Cell Mol Med 2020; 24:8862-8870. [PMID: 32643288 PMCID: PMC7412411 DOI: 10.1111/jcmm.15540] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 05/29/2020] [Accepted: 06/05/2020] [Indexed: 12/12/2022] Open
Abstract
The impact of environmental factors, such as diet, and the genetic basis of autoimmune pancreatitis (AIP) are largely unknown. Here, we used an experimental murine AIP model to identify the contribution of diet to AIP development, as well as to fine-map AIP-associated genes in outbred mice prone to develop the disease. For this purpose, we fed mice of an autoimmune-prone intercross line (AIL) three different diets (control, calorie-reduced and western diet) for 6 months, at which point the mice were genotyped and phenotyped for AIP. Overall, 269 out of 734 mice (36.6%) developed AIP with signs of parenchymal destruction, equally affecting mice of both sexes. AIP prevalence and severity were reduced by approximately 50% in mice held under caloric restriction compared to those fed control or western diet. We identified a quantitative trait locus (QTL) on chromosome 4 to be associated with AIP, which is located within a previously reported QTL. This association does not change when considering diet or sex as an additional variable for the mapping. Using whole-genome sequences of the AIL founder strains, we resolved this QTL to a single candidate gene, namely Map3k7. Expression of Map3k7 was largely restricted to islet cells as well as lymphocytes found in the exocrine pancreas of mice with AIP. Our studies suggest a major impact of diet on AIP. Furthermore, we identify Map3k7 as a novel susceptibility gene for experimental AIP. Both findings warrant clinical translation.
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Affiliation(s)
- Robert Jaster
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock, Germany
| | - Yask Gupta
- Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck, Lübeck, Germany
| | - Sarah Rohde
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock, Germany
| | - Luise Ehlers
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock, Germany
| | - Horst Nizze
- Institute of Pathology, Rostock University Medical Center, Rostock, Germany
| | - Artem Vorobyev
- Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck, Lübeck, Germany.,Department of Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck, Lübeck, Germany
| | - Ralf J Ludwig
- Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck, Lübeck, Germany
| | - Saleh M Ibrahim
- Lübeck Institute of Experimental Dermatology and Center for Research on Inflammation of the Skin, University of Lübeck, Lübeck, Germany
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16
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Zen Y, Deshpande V. Tumefactive Inflammatory Diseases of the Pancreas. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:82-93. [PMID: 30558726 DOI: 10.1016/j.ajpath.2018.05.022] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 04/16/2018] [Accepted: 05/29/2018] [Indexed: 02/06/2023]
Abstract
Advances in the past two decades have resulted in the recognition of several tumefactive pancreatic lesions that, on histologic evaluation, show a varying combination of inflammation and fibrosis. Autoimmune pancreatitis, the prototypic tumefactive pancreatic fibroinflammatory lesion, is composed of two distinct diseases, type 1 autoimmune pancreatitis and the less common type 2 autoimmune pancreatitis. Although designated as autoimmune pancreatitis, the two diseases show little morphologic or pathogenic overlap. In type 1 disease, subsets of T lymphocytes (type 2 helper T cells, regulatory T cells, and T follicular helper 2 cells) are hypothesized to drive the inflammatory reaction. The B-cell response is characterized by an oligoclonal expansion of plasmablasts, with dominant clones that vary among patients and distinct clones that emerge at the time of relapse. Although the precise role of IgG4 in this condition remains uncertain, recent studies suggest that other IgG subclasses (eg, IgG1) may mediate the immune reactions, whereas IgG4 represents a response to dampen excessive inflammation. A recent study of type 2 autoimmune pancreatitis highlights the role of CXCL8 (alias IL-8), with duct epithelium and infiltrating T lymphocytes expressing this chemokine; the latter may contribute to the distinct form of neutrophilic inflammation in this disease. The review also highlights other forms of mass-forming chronic pancreatitis: follicular pancreatitis, groove pancreatitis, and those associated with rheumatologic diseases.
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Affiliation(s)
- Yoh Zen
- Department of Diagnostic Pathology, Kobe University, Kobe, Japan
| | - Vikram Deshpande
- The James Homer Wright Pathology Laboratories, Massachusetts General Hospital, Boston, Massachusetts.
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17
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Terao C, Ota M, Iwasaki T, Shiokawa M, Kawaguchi S, Kuriyama K, Kawaguchi T, Kodama Y, Yamaguchi I, Uchida K, Higasa K, Yamamoto M, Kubota K, Yazumi S, Hirano K, Masaki Y, Maguchi H, Origuchi T, Matsui S, Nakazawa T, Shiomi H, Kamisawa T, Hasebe O, Iwasaki E, Inui K, Tanaka Y, Ohshima KI, Akamizu T, Nakamura S, Nakamura S, Saeki T, Umehara H, Shimosegawa T, Mizuno N, Kawano M, Azumi A, Takahashi H, Mimori T, Kamatani Y, Okazaki K, Chiba T, Kawa S, Matsuda F. IgG4-related disease in the Japanese population: a genome-wide association study. THE LANCET. RHEUMATOLOGY 2019; 1:e14-e22. [PMID: 38229354 DOI: 10.1016/s2665-9913(19)30006-2] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 05/29/2019] [Accepted: 05/30/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND IgG4-related disease is a newly recognised immunopathological entity that includes autoimmune pancreatitis, IgG4-related sialadenitis, and IgG4-related kidney disease. To understand the genetic landscape of IgG4-related disease, we did a genome-wide association study. METHODS We did a genome-wide association study of Japanese individuals, initially screening 857 patients with IgG4-related disease at 50 Japanese research institutions and DNA samples from 2082 healthy control participants from the Nagahama Prospective Genome Cohort for the Comprehensive Human Bioscience. From Oct 27, 2008, to July 22, 2014, we enrolled 835 patients and used data from 1789 healthy participants. Only patients with confirmed diagnosis of IgG4-related disease according to the international diagnostic criteria were included. Genotyping was done with the Infinium HumanOmni5Exome, HumanOmni2.5Exome, or HumanOmni2.5 Illumina arrays, and genomic distributions were compared between case and control samples for 958 440 single nucleotide polymorphisms. The HLA region was extensively analysed using imputation of HLA alleles and aminoacid residues. Fine mapping of the FCGR2B region was also done. Associations between clinical manifestations of disease and the genetic variations identified in these two genes were examined. FINDINGS We identified the HLA-DRB1 (p=1·1×10-11) and FCGR2B (p=2·0×10-8) regions as susceptibility loci for IgG4-related disease. We also identified crucial aminoacid residues in the β domain of the peptide-binding groove of HLA-DRB1, in which the seventh aminoacid residue showed the strongest association signal with IgG4-related disease (p=1·7×10-14), as has been reported with other autoimmune diseases. rs1340976 in FCGR2B showed an association with increased FCGR2B expression (p=2·7×10-10) and was in weak linkage disequilibrium with rs1050501, a missense variant of FCGR2B previously associated with systemic lupus erythematosus. Furthermore, rs1340976 was associated with the number of swollen organs at diagnosis (p=0·011) and IgG4 concentration at diagnosis (p=0·035). INTERPRETATION Two susceptibility loci for IgG4-related disease were identified. Both FCGR2B and HLA loci might have important roles in IgG4-related disease development. Common molecular mechanisms might underlie IgG4-related disease and other immune-related disorders FUNDING: The Japanese Ministry of Health, Labour, and Welfare, the Japanese Agency of Medical Research and Development, and Kyoto University Grant for Top Global University Japan Project.
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Affiliation(s)
- Chikashi Terao
- Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masao Ota
- Department of Internal Medicine 2, School of Medicine, Shinshu University, Matsumoto, Japan
| | - Takeshi Iwasaki
- Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Rheumatology and Clinical Immunology, Kyoto University, Kyoto, Japan
| | - Masahiro Shiokawa
- Department of Gastroenterology and Hepatology, Kyoto University, Kyoto, Japan
| | - Shuji Kawaguchi
- Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Katsutoshi Kuriyama
- Department of Gastroenterology and Hepatology, Kyoto University, Kyoto, Japan
| | - Takahisa Kawaguchi
- Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yuzo Kodama
- Department of Gastroenterology and Hepatology, Kyoto University, Kyoto, Japan
| | - Izumi Yamaguchi
- Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kazushige Uchida
- Department of Gastroenterology and Hepatology Kansai Medical University, Hirakata, Japan
| | - Koichiro Higasa
- Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Motohisa Yamamoto
- Department of Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kensuke Kubota
- Department of Endoscopy, Yokohama City University Hospital, Yokohama, Japan
| | - Shujiro Yazumi
- Department of Gastroenterology and Hepatology, Kitano Hospital, Osaka, Japan
| | - Kenji Hirano
- Department of Gastroenterology, Tokyo Takanawa Hospital, Tokyo, Japan
| | - Yasufumi Masaki
- Department of Hematology and Immunology, Kanazawa Medical University, Uchinada, Japan
| | - Hiroyuki Maguchi
- Center for Gastroenterology, Teine-Keijinkai Hospital, Sapporo, Japan
| | - Tomoki Origuchi
- Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Shoko Matsui
- Center for Health Care and Human Sciences, University of Toyama, Toyama, Japan
| | - Takahiro Nakazawa
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Hideyuki Shiomi
- Department of Gastroenterology, Kobe University Hospital, Kobe, Japan
| | - Terumi Kamisawa
- Department of Internal Medicine, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan
| | - Osamu Hasebe
- Department of Gastroenterology, Nagano Municipal Hospital, Tomitake, Japan
| | - Eisuke Iwasaki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Kazuo Inui
- Department of Gastroenterology, Second Teaching Hospital, Fujita Health University, Toyoake, Japan
| | - Yoshiya Tanaka
- First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Koh-Ichi Ohshima
- Department of Ophthalmology, National Hospital Organization Okayama Medical Center, Okayama, Japan
| | - Takashi Akamizu
- First Department of Medicine, Wakayama Medical University, Wakayama, Japan
| | - Shigeo Nakamura
- Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Seiji Nakamura
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Takako Saeki
- Department of Internal Medicine, Nagaoka Red Cross Hospital, Nagaoka, Japan
| | - Hisanori Umehara
- Division of Rheumatology and Immunology, Nagahama City Hospital, Nagahama, Japan
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Nobumasa Mizuno
- Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Mitsuhiro Kawano
- Department of Rheumatology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | - Atsushi Azumi
- Department of Ophthalmology, Kobe Kaisei Hospital, Kobe, Japan
| | - Hiroki Takahashi
- Department of Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tsuneyo Mimori
- Department of Rheumatology and Clinical Immunology, Kyoto University, Kyoto, Japan
| | - Yoichiro Kamatani
- Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kazuichi Okazaki
- Department of Gastroenterology and Hepatology Kansai Medical University, Hirakata, Japan
| | - Tsutomu Chiba
- Department of Gastroenterology and Hepatology, Kyoto University, Kyoto, Japan
| | - Shigeyuki Kawa
- Center for Health Safety and Environmental Management, Shinshu University, Matsumoto, Japan
| | - Fumihiko Matsuda
- Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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18
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Affiliation(s)
- Yuki Ishikawa
- Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
| | - Chikashi Terao
- Center for Investigative Medical Sciences, RIKEN, Yokohama, Japan
- Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan
- Department of Applied Genetics, The School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
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19
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Li F, Ma X, Du L, Shi L, Cao Q, Li N, Pang T, Liu Y, Kijlstra A, Yang P. Identification of susceptibility SNPs in CTLA-4 and PTPN22 for scleritis in Han Chinese. Clin Exp Immunol 2019; 197:230-236. [PMID: 30921471 DOI: 10.1111/cei.13298] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/21/2019] [Indexed: 12/12/2022] Open
Abstract
The aim of this study was to determine the association between 13 single nucleotide polymorphisms (SNPs) in the cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and protein tyrosine phosphatase non-receptor type 22 (PTPN22) genes with scleritis in a Chinese Han population. We recruited 432 scleritis patients and 710 healthy controls. Four tag SNPs of CTLA4 and nine tag SNPs of PTPN22 were selected using Haploview. Genotyping was performed with the Sequenom MassArray® iPLEX GOLD Assay. Genotype and allele frequency differences were analyzed by χ2 test and Bonferroni correction. Haplotype analysis was performed to further evaluate the association of these two genes with scleritis. In this study, CTLA4/rs3087243 G allele frequency and GG genotype frequency were significantly increased in scleritis patients compared to healthy controls [corrected P-value (Pc) = 0·02, odds ratio (OR) = 1·475, 95% confidence interval (CI) = 1·175-1·851; Pc = 0·04, OR = 1·546, 95% CI = 1·190-2·008, respectively]. None of the tested SNPs in the PTPN22 gene showed an association with scleritis. Haplotype analysis revealed a lower frequency of a CTLA4 TCAA haplotype (order of SNPs: rs733618, rs5742909, rs231775, rs3087243) (Pc = 4·26 × 10-3 , OR = 0·618, 95% CI = 0·540-0·858) and a higher frequency of a PTPN22 TTATACGCG haplotype (order of SNPs: rs3789604, rs150426536, rs1746853, rs1217403, rs1217406, rs3789609, rs1217414, rs3789612, rs2488457) (Pc = 2·83 × 10-4 , OR = 1·457, 95% CI = 1·210-1·754) in scleritis patients when compared to healthy controls. In conclusion, our findings indicate that CTLA4 and PTPN22 might confer genetic susceptibility to scleritis in a Chinese Han population.
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Affiliation(s)
- F Li
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Henan Province Eye Hospital, Henan International Joint Research Laboratory for Ocular Immunology and Retinal Injury Repair, Zhengzhou, China
| | - X Ma
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Henan Province Eye Hospital, Henan International Joint Research Laboratory for Ocular Immunology and Retinal Injury Repair, Zhengzhou, China.,The Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - L Du
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, China
| | - L Shi
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Henan Province Eye Hospital, Henan International Joint Research Laboratory for Ocular Immunology and Retinal Injury Repair, Zhengzhou, China.,The Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Q Cao
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, China
| | - N Li
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Henan Province Eye Hospital, Henan International Joint Research Laboratory for Ocular Immunology and Retinal Injury Repair, Zhengzhou, China
| | - T Pang
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Henan Province Eye Hospital, Henan International Joint Research Laboratory for Ocular Immunology and Retinal Injury Repair, Zhengzhou, China.,The Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Y Liu
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Henan Province Eye Hospital, Henan International Joint Research Laboratory for Ocular Immunology and Retinal Injury Repair, Zhengzhou, China.,The Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - A Kijlstra
- University Eye Clinic Maastricht, Maastricht, the Netherlands
| | - P Yang
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Henan Province Eye Hospital, Henan International Joint Research Laboratory for Ocular Immunology and Retinal Injury Repair, Zhengzhou, China.,The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, China
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20
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Pistillo MP, Fontana V, Morabito A, Dozin B, Laurent S, Carosio R, Banelli B, Ferrero F, Spano L, Tanda E, Ferrucci PF, Martinoli C, Cocorocchio E, Guida M, Tommasi S, De Galitiis F, Pagani E, Antonini Cappellini GC, Marchetti P, Quaglino P, Fava P, Osella-Abate S, Ascierto PA, Capone M, Simeone E, Romani M, Spagnolo F, Queirolo P. Soluble CTLA-4 as a favorable predictive biomarker in metastatic melanoma patients treated with ipilimumab: an Italian melanoma intergroup study. Cancer Immunol Immunother 2019; 68:97-107. [PMID: 30311027 PMCID: PMC11028053 DOI: 10.1007/s00262-018-2258-1] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 10/04/2018] [Indexed: 12/11/2022]
Abstract
CTLA-4 blockade by means of ipilimumab (IPI) potentiates the immune response and improves overall survival (OS) in a minority of metastatic melanoma (MM) patients. We investigated the role of soluble CTLA-4 (sCTLA-4) as a possible biomarker for identifying this subset of patients. sCTLA-4 levels were analyzed at baseline in sera from 113 IPI-treated MM patients by ELISA, and the median value (200 pg/ml) was used to create two equally sized subgroups. Associations of sCTLA-4 with best overall response (BOR) to IPI and immune-related adverse events (irAEs) were evaluated through logistic regression. Kaplan-Meier and Cox regression methods were used to analyze OS. A remarkable association between sCTLA-4 levels and BOR was found. Specifically, the proportion of patients with sCTLA-4 > 200 pg/ml in irSD or irPD (immune-related stable or progressive disease) was, respectively, 80% (OR = 0.23; 95%CL = 0.03-1.88) and 89% (OR = 0.11; 95%CL = 0.02-0.71) and was lower than that observed among patients in irCR/irPR (immune-related complete/partial response). sCTLA-4 levels increased during IPI treatment, since the proportion of patients showing sCTLA > 200 pg/ml after 3 cycles was 4 times higher (OR = 4.41, 95%CL = 1.02-19.1) than that after 1 cycle. Moreover, a significantly lower death rate was estimated for patients with sCTLA-4 > 200 pg/ml (HR = 0.61, 95%CL = 0.39-0.98). Higher baseline sCTLA-4 levels were also associated with the onset of any irAE (p value = 0.029), in particular irAEs of the digestive tract (p value = 0.041). In conclusion, our results suggest that high sCTLA-4 serum levels might predict favorable clinical outcome and higher risk of irAEs in IPI-treated MM patients.
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Affiliation(s)
- Maria Pia Pistillo
- Unit of Tumor Epigenetics, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genoa, Italy.
| | - Vincenzo Fontana
- Unit of Clinical Epidemiology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Anna Morabito
- Unit of Tumor Epigenetics, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genoa, Italy
| | - Beatrice Dozin
- Unit of Clinical Epidemiology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Stefania Laurent
- Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Roberta Carosio
- Unit of Tumor Epigenetics, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genoa, Italy
| | - Barbara Banelli
- Unit of Tumor Epigenetics, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genoa, Italy
- Department of Health Sciences, University of Genoa, Genoa, Italy
| | - Francesca Ferrero
- Department of Medical Oncology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Laura Spano
- Department of Medical Oncology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Enrica Tanda
- Department of Medical Oncology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | | | - Chiara Martinoli
- Oncology of Melanoma Unit, European Institute of Oncology, Milan, Italy
- iTeos Therapeutics, Gosselies, Belgium
| | | | - Michele Guida
- Department of Medical Oncology and Molecular Genetics Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Stefania Tommasi
- Department of Medical Oncology and Molecular Genetics Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | | | - Elena Pagani
- Istituto Dermopatico dell'Immacolata IDI-IRCCS, Rome, Italy
| | | | - Paolo Marchetti
- Istituto Dermopatico dell'Immacolata IDI-IRCCS, Rome, Italy
- Sapienza University of Rome, Rome, Italy
| | - Pietro Quaglino
- Department of Medical Sciences, Dermatologic Clinic, University of Turin, Turin, Italy
| | - Paolo Fava
- Department of Medical Sciences, Dermatologic Clinic, University of Turin, Turin, Italy
| | - Simona Osella-Abate
- Department of Medical Sciences, Section of Surgical Pathology, University of Turin, Turin, Italy
| | - Paolo Antonio Ascierto
- Melanoma, Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione'G. Pascale', Naples, Italy
| | - Mariaelena Capone
- Melanoma, Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione'G. Pascale', Naples, Italy
| | - Ester Simeone
- Melanoma, Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione'G. Pascale', Naples, Italy
| | - Massimo Romani
- Unit of Tumor Epigenetics, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genoa, Italy
| | - Francesco Spagnolo
- Department of Medical Oncology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Paola Queirolo
- Department of Medical Oncology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
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21
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Fabian E, Peck-Radosavljevic M, Krones E, Mueller H, Lackner C, Spreizer C, Putz-Bankuti C, Fuerst W, Wutte N, Fickert P, Mischinger H, Krejs GJ. Clinical-Pathological Conference Series from the Medical University of Graz : Case No 161: A 42-year-old journalist with fatigue, elevated liver function tests, hyperglycemia and pruritus. Wien Klin Wochenschr 2018; 130:545-556. [PMID: 30132197 PMCID: PMC6132877 DOI: 10.1007/s00508-018-1379-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 07/30/2018] [Indexed: 10/28/2022]
Affiliation(s)
- Elisabeth Fabian
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Markus Peck-Radosavljevic
- Department of Internal Medicine and Gastroenterology, Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
| | - Elisabeth Krones
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Helmut Mueller
- Division of Transplant Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
| | - Caroline Lackner
- Department of Pathology, Medical University of Graz, Graz, Austria
| | - Christopher Spreizer
- Division of General Radiology, Department of Radiology, Medical University of Graz, Graz, Austria
| | - Csilla Putz-Bankuti
- Department of Internal Medicine, Hörgas-Enzenbach Hospital, Gratwein-Straßengel, Austria
| | - Werner Fuerst
- Department of Internal Medicine, Leoben Hosptial, Leoben, Austria
| | - Nora Wutte
- Department of Dermatology and Venerology, Medical University of Graz, Graz, Austria
| | - Peter Fickert
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria
| | - Hansjörg Mischinger
- Division of General Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
| | - Guenter J Krejs
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.
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22
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Abstract
IgG4-related disease is a heterogeneous immune-mediated fibroinflammatory condition that can affect every single organ. This disease is more prevalent in the elderly (the mean age of patients is above 60 years) and the prevalence rate is estimated to be over 4.6 per 100,000 population. Before making a diagnosis, the exclusion of malignancies, lymphoma, anti-neutrophil cytoplasmic antibody-associated vasculitis, multicentric Castleman disease, and other mimickers is crucial for appropriate treatment. Broad management guidelines have been published emphasizing the need for prompt treatment and the use of glucocorticoids as first-line drug therapy for induction of remission. However, the toxic effects of glucocorticoids are problematic because IgG4-related disease is more prevalent in patients above 60 years of age, a population with frequent comorbid conditions and polypharmacy. Immunosuppressants (cyclophosphamide, methotrexate, leflunomide, and tacrolimus) and targeted immunomodulators (rituximab, XmAb5871, and abatacept) are appealing to overcome potential toxic effects of glucocorticoids and as emerging glucocorticoid-sparing and/or maintenance treatments. In this review, we provide an overview of our understanding of the pathophysiology of the disease (T follicular helper cells, CD4+ cytotoxic T cells, plasmablasts, and alternatively activated M2 macrophages) and clinical characteristics, and highlight the potential targets for treatment intervention.
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Affiliation(s)
- Mitsuhiro Akiyama
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan
| | - Tsutomu Takeuchi
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.
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23
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Salvadori M, Tsalouchos A. Immunoglobulin G4-related kidney diseases: An updated review. World J Nephrol 2018; 7:29-40. [PMID: 29359118 PMCID: PMC5760510 DOI: 10.5527/wjn.v7.i1.29] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 12/15/2017] [Accepted: 12/28/2017] [Indexed: 02/06/2023] Open
Abstract
This review will encompass definition, pathogenesis, renal clinical manifestations and treatment of immunoglobulin G4-related diseases (IgG4-RDs). IgG4-RD is a recently recognized clinical entity that often involves multiple organs and is characterized by high levels of serum immunoglobulins G4, dense infiltration of IgG4+ cells and storiform fibrosis. Cellular immunity, particularly T-cell mediated immunity, has been implicated in the pathogenesis of IgG4-RDs. The most frequent renal manifestations of IgG4-RD are IgG4-related tubulointerstitial nephritis, membranous glomerulopathy and obstructive nephropathy secondary to urinary tract obstruction due to IgG4-related retroperitoneal fibrosis. IgG4-RD diagnosis should be based on specific histopathological findings, confirmed by tissue immunostaining, typical radiological findings and an appropriate clinical context. The first line treatment is the steroids with two warnings: Steroid resistance and relapse after discontinuation. In the case of steroid resistance, B cell depleting agents as rituximab represent the second-line treatment. In the case of relapse after discontinuation, steroid treatment may be associated with steroid sparing agents. Since the disease has been only recently identified, more prospective, long-term studies are needed to an improved understanding and a more correct and safe treatment.
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Affiliation(s)
- Maurizio Salvadori
- Renal Unit, Department of Transplantation, Careggi University Hospital, Florence 50139, Italy
| | - Aris Tsalouchos
- Division of Nephrology, Nephrology and Dialysis Unit, Saints Cosmas and Damian Hospital, Pescia 51017, Italy
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24
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Chaouali M, Carvalho A, Tezeghdenti A, Ben Azaiez M, Cunha C, Ghazouani E, Kochkar R. Cytotoxic T lymphocyte antigen-4 gene polymorphisms and susceptibility to type 1 autoimmune hepatitis in the Tunisian population. Genes Dis 2017; 5:256-262. [PMID: 30320190 PMCID: PMC6176120 DOI: 10.1016/j.gendis.2017.12.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2017] [Accepted: 12/15/2017] [Indexed: 02/06/2023] Open
Abstract
Genetic factors and gene polymorphisms leading to the onset of autoimmune response in autoimmune hepatitis (AIH) are still not full elucidated. Since the CTLA-4 molecule is a key modulator of the lymphocytes responses we hypothezied that deficiencies or mutations in the gene encoding CTLA4 protein may be involved in AIH susceptibility and trigger the autoimmune response. We investigated 3 distinct polymorphic sites (+49A > G, CT60 G > A and -318C > T) of the CTLA4 gene in 50 AIH patients and 100 healthy controls using the KASP genotyping technology. A significant positive association with AIH susceptibility was found for the GG genotype in +49 position of the CTLA4 gene which was significantly higher in AIH patients compared to controls (28% vs 9%, p = 0.003, OR = 3.93 [1.56-9.88]). The CTLA4 A/A genotype in position CT60 was more significantly frequent in controls comparing to AIH patients and could be considered as a protective genotype for the tunisian patients. CTLA4 genotyping in position -318 did not show any statistically significant difference in genotype or allele distribution. The CTLA4 gene polymorphism in position +49 is associated to AIH susceptibility in the Tunisian population. Mutation in the CTLA4 gene may lead to a modification of the CTLA4 protein structure that could have functional relevance in AIH pathogenesis and onset.
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Key Words
- AIH, Autoimmune hepatitis
- AMA-M2, Anti-mitochondrial antibody-M2
- ANA, Anti-nuclear antibodies
- Autoimmune hepatitis
- CMV, Cytomegalovirus
- CTLA4 gene polymorphisms
- CTLA4, Cytotoxic T-lymphocyte antigen 4
- Cytotoxic T-lymphocyte antigen 4
- EBV, Epstein–Barr virus
- HLA, Human leucocyte antigen
- KASP PCR, Competitive allele-specific real-time PCR
- LKM1, Anti-Liver/Kidney Microsomal Antibodies Type 1
- PBC, Primary biliary cirrhosis
- PSC, Primary sclerosing cholangitis
- SLA, Antibodies against soluble liver antigen
- SMA, Smooth-muscle antibodies
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Affiliation(s)
- Marwa Chaouali
- Department of Immunology, Military Hospital of Tunis, Montfleury 1008, Tunis, Tunisia.,El Manar University, Laboratory of Mycology, Pathologies and Biomarkers 1092, Tunis, Tunisia
| | - Agostinho Carvalho
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar 4710-057, Braga, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Aymen Tezeghdenti
- Department of Immunology, Military Hospital of Tunis, Montfleury 1008, Tunis, Tunisia
| | - Mouna Ben Azaiez
- Department of Immunology, Military Hospital of Tunis, Montfleury 1008, Tunis, Tunisia
| | - Cristina Cunha
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar 4710-057, Braga, Portugal
| | - Ezzeddine Ghazouani
- Department of Immunology, Military Hospital of Tunis, Montfleury 1008, Tunis, Tunisia
| | - Radhia Kochkar
- Department of Immunology, Military Hospital of Tunis, Montfleury 1008, Tunis, Tunisia
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25
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High-throughput RNA sequencing reveals distinct gene signatures in active IgG4-related disease. Sci Rep 2017; 7:17567. [PMID: 29242501 PMCID: PMC5730556 DOI: 10.1038/s41598-017-17602-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Accepted: 11/29/2017] [Indexed: 12/24/2022] Open
Abstract
We aimed to characterize the molecular differences and effects from prednisone treatment among IgG4-related disease with salivary gland lesions (RD-SG), without SG lesions (RD-nonSG), and IgG4-related retroperitoneal fibrosis (RF). RNA sequencing was conducted on blood from 25 RD-SG, 11 RD-nonSG, 3 RF and 10 control subjects. Among these, 8 RD-nonSG and 12 RD-SG patients were subjected to treatment with prednisone and/or glucocorticoid-sparing agents. Six RD patients had a longitudinal time point. The mRNA levels of IgG4 and IgE, genes specific for Th2 cells, eosinophils, and neutrophils were over-expressed in RD-SG and RD-nonSG. A B-cell signature was suppressed in patients group versus controls, while Th1, Th2, Treg, and eosinophil gene signatures were increased in patients without treatment. Interestingly, Tfh genes and B cell signature were decreased at flare disease state. Prednisone treatment led to increased neutrophil, but decreased Treg signatures. Serum IgG4 levels correlated with the eosinophil and neutrophil gene signatures in RD-SG patients, and with a B cell signature in only RD-nonSG patients. IgG4, IgE, and cell-specific signatures are regulated in patients, suggesting the imbalance of immune and inflammatory cells in IgG4-related disease. Prednisone treatment selectively modulates Treg, eosinophil, and neutrophil signatures.
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26
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Martínez-Valle F, Orozco-Gálvez O, Fernández-Codina A. Update in ethiopathogeny, diagnosis and treatment of the IgG4 related disease. Med Clin (Barc) 2017; 151:18-25. [PMID: 29241876 DOI: 10.1016/j.medcli.2017.10.034] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Revised: 10/17/2017] [Accepted: 10/18/2017] [Indexed: 02/06/2023]
Abstract
IgG4 related disease (IgG4-RD) is probably an autoimmune pathology of unknown etiology. Diverse interactions participate in its pathogen between the adaptive and innate immune systems, activating lymphocytes B and T which trigger the inflammatory cascade, which culminates in fibrosis of the organs and their malfunction. It can affect a multitude of organs simultaneously. The diagnosis is based on the correlation of clinical findings with anatomopathological results (lymphoplasmocitary infiltrate, storiform fibrosis, obliterative phlebitis and IgG4+plasmatic cell count) and with the presence of elevated IgG4 in serum, depending on the criteria used. Corticoids and rituximab are among the few validated treatments available. There are multiple biomarkers and treatments in development. In this review, we aim to go over the principal pathogenic and clinical characteristics of IgG4-RD, as well as its handling, in accordance with the available scientific evidence.
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Affiliation(s)
- Fernando Martínez-Valle
- Unidad de Enfermedades Autoinmunes Sistémicas, Servicio de Medicina Interna, Hospital Universitario Vall Hebron, Universitat Autònoma de Barcelona, Barcelona, España; Vall d'Hebron Institut de Recerca, Barcelona, España.
| | - Olimpia Orozco-Gálvez
- Unidad de Enfermedades Autoinmunes Sistémicas, Servicio de Medicina Interna, Hospital Universitario Vall Hebron, Universitat Autònoma de Barcelona, Barcelona, España
| | - Andreu Fernández-Codina
- Unidad de Enfermedades Autoinmunes Sistémicas, Servicio de Medicina Interna, Hospital Universitario Vall Hebron, Universitat Autònoma de Barcelona, Barcelona, España; Vall d'Hebron Institut de Recerca, Barcelona, España; Rheumatology Division, Department of Medicine, University of Western Ontario, London, Ontario, Canadá
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27
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Umemura T, Joshita S, Hamano H, Yoshizawa K, Kawa S, Tanaka E, Ota M. Association of autoimmune hepatitis with Src homology 2 adaptor protein 3 gene polymorphisms in Japanese patients. J Hum Genet 2017; 62:963-967. [DOI: 10.1038/jhg.2017.74] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 06/14/2017] [Accepted: 06/14/2017] [Indexed: 12/24/2022]
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28
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Yadlapati S, Verheyen E, Efthimiou P. IgG4-related disease: a complex under-diagnosed clinical entity. Rheumatol Int 2017; 38:169-177. [PMID: 28681251 DOI: 10.1007/s00296-017-3765-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Accepted: 06/28/2017] [Indexed: 12/11/2022]
Abstract
IgG4-related disease (IgG4-RD) encompasses a spectrum of complex fibro-inflammatory disorders which are often under diagnosed due to unfamiliarity by clinicians. A challenging multitude of clinical manifestations makes the diagnosis cumbersome. The primary clinical feature in IgG4-RD entails a tumor-like presentation coupled with tissue-destructive lesions. Histopathological findings include lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis. These findings, in combination with elevated serum immunoglobulin G4 levels, are diagnostic in the setting of single- or multi-organ involvement. A closer understanding of the role of T cells and B cells in the increased production of IgG4 has led to a notion that IgG4 can act as a pathogen, anti-inflammatory agent, or rheumatoid factor. Glucocorticoids are the primary treatment modality; however, relapse is common with prolonged therapy. Alternatively, immunomodulatory agents are being increasingly used as therapy. The aim of this article is to raise awareness of IgG4-RD and review the diagnostic algorithm, as IgG4-RD often mimics a wide array of clinical conditions. In addition, we summarize the pathogenesis and current treatment guidelines of IgG4-RD for clinicians. Awareness and accurate diagnosis are crucial in preventing progression to chronic diseases, thereby diminishing disease-related morbidity and mortality.
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Affiliation(s)
- Sujani Yadlapati
- Department of Internal Medicine, Albert Einstein Medical Center, Philadelphia, PA, USA
| | - Elijah Verheyen
- Department of Internal Medicine, St. Luke's-Roosevelt Hospital Center, New York, NY, USA
| | - Petros Efthimiou
- Division of Rheumatology, New York-Presbyterian Brooklyn Methodist Hospital, Brooklyn, NY, USA.
- Weill Cornell Medical College, New York, NY, USA.
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29
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Ghassem-Zadeh S, Gaida MM, Szanyi S, Acha-Orbea H, Frossard JL, Hinz U, Hackert T, Strobel O, Felix K. Distinct pathophysiological cytokine profiles for discrimination between autoimmune pancreatitis, chronic pancreatitis, and pancreatic ductal adenocarcinoma. J Transl Med 2017; 15:126. [PMID: 28578701 PMCID: PMC5457650 DOI: 10.1186/s12967-017-1227-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 05/27/2017] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Discriminating between autoimmune pancreatitis (AIP), chronic pancreatitis (CP), and pancreatic ductal adenocarcinoma (PDAC) can be challenging. In this retrospective study, levels of serum and tissue cytokines were analyzed as part of the clinical strategy for the preoperative differentiation between AIP and PDAC. The identification of differential cytokine profiles may help to prevent unnecessary surgical resection and allow optimal treatment of these pathologies. METHODS To compare the cytokine profiles of AIP, CP, and PDAC patients, serum and pancreatic tissue homogenates were subjected to multiplex analysis of 17 inflammatory mediators. In total, serum from 73 patients, composed of 29 AIP (14 AIP-1 and 15 AIP-2), 17 CP, and 27 PDAC, and pancreatic tissue from 36 patients, including 12 AIP (six AIP-1 and six AIP-2), 12 CP, and 12 PDAC, were analyzed. RESULTS Comparing AIP and PDAC patients' serum, significantly higher concentrations were found in AIP for interleukins IL-1β, IL-7, IL-13, and granulocyte colony-stimulating factor (G-CSF). G-CSF also allowed discrimination of AIP from CP. Furthermore, once AIP was divided into subtypes, significantly higher serum levels for IL-7 and G-CSF were measured in both subtypes of AIP and in AIP-2 for IL-1β when compared to PDAC. G-CSF and TNF-α were also significantly differentially expressed in tissue homogenates between AIP-2 and PDAC. CONCLUSIONS The cytokines IL-1β, IL-7, and G-CSF can be routinely measured in patients' serum, providing an elegant and non-invasive approach for differential diagnosis. G-CSF is a good candidate to supplement the currently known serum markers in predictive tests for AIP and represents a basis for a combined blood test to differentiate AIP and particularly AIP-2 from PDAC, enhancing the possibility of appropriate treatment.
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Affiliation(s)
- Sahar Ghassem-Zadeh
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
- Department of Biochemistry, University of Lausanne, Lausanne, Switzerland
| | - Matthias M. Gaida
- Institute of Pathology, University of Heidelberg, Heidelberg, Germany
| | - Szilard Szanyi
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - Hans Acha-Orbea
- Department of Biochemistry, University of Lausanne, Lausanne, Switzerland
| | - Jean-Louis Frossard
- Department of Medical Specialties, Gastroenterology and Hepatology Division, University Hospitals and Faculty of Medicine of Geneva, Geneva, Switzerland
| | - Ulf Hinz
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - Thilo Hackert
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - Oliver Strobel
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - Klaus Felix
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
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30
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From Pathogenesis, Clinical Manifestation, and Diagnosis to Treatment: An Overview on Autoimmune Pancreatitis. Gastroenterol Res Pract 2017; 2017:3246459. [PMID: 28197205 PMCID: PMC5288542 DOI: 10.1155/2017/3246459] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 11/01/2016] [Accepted: 12/27/2016] [Indexed: 02/06/2023] Open
Abstract
Autoimmune pancreatitis (AIP) is a special type of chronic pancreatitis which is autoimmune mediated. The international consensus diagnostic criteria (ICDC) 2011 proposed two types of AIP: type I is associated with histological pattern of lymphoplasmacytic sclerosing pancreatitis (LPSP), characterized by serum IgG4 elevation, whereas type 2 is named idiopathic duct-centric pancreatitis (IDCP), with granulocytic epithelial lesion (GEL) and immunoglobulin G4 (IgG4) negative. The pathogenic mechanism is unclear now; based on genetic factors, disease specific or related antigens, innate and adaptive immunity may be involved. The most common clinical manifestations of AIP are obstructive jaundice and upper abdominal pain. The diagnosis can be made by a combination of parenchymal and ductal imaging, serum IgG4 concentrations, pancreatic histology, extrapancreatic disease, and glucocorticoid responsiveness according to ICDC 2011. Because of the clinical and imaging similarities with pancreatic cancer, general work-up should be done carefully to exclude pancreatic malignant tumor before empirical trial of glucocorticoid treatment. Glucocorticoid is the most common drug for AIP to induce remission, while there still exists controversy on steroid maintenance and treatment for relapse. Further studies should be done to identify more specific serum biomarkers for AIP, the pathogenic mechanisms, and the treatment for relapse.
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Abstract
IgG4-related hepatobiliary diseases are part of a multiorgan fibroinflammatory condition termed IgG4-related disease, and include IgG4-related sclerosing cholangitis (IgG4-SC) and IgG4-related hepatopathy. These diseases can present with biliary strictures and/or mass lesions, making them difficult to differentiate from primary sclerosing cholangitis (PSC) or other hepatobiliary malignancies. Diagnosis is based on a combination of clinical, biochemical, radiological and histological findings. However, a gold standard diagnostic test is lacking, warranting the identification of more specific disease markers. Novel assays - such as the serum IgG4:IgG1 ratio and IgG4:IgG RNA ratio (which distinguish IgG4-SC from PSC with high serum IgG4 levels), and plasmablast expansion to recognize IgG4-SC with normal serum IgG4 levels - require further validation. Steroids and other immunosuppressive therapies can lead to clinical and radiological improvement when given in the inflammatory phase of the disease, but evidence for the efficacy of treatment regimens is limited. Progressive fibrosclerotic disease, liver cirrhosis and an increased risk of malignancy are now recognized outcomes. Insights into the genetic and immunological features of the disease have increased over the past decade, with an emphasis on HLAs, T cells, circulating memory B cells and plasmablasts, chemokine-mediated trafficking, as well as the role of the innate immune system.
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Haldar D, Cockwell P, Richter AG, Roberts KJ, Hirschfield GM. An overview of the diagnosis and management of immunoglobulin G4-related disease. CMAJ 2016; 188:953-961. [PMID: 27325130 PMCID: PMC5026513 DOI: 10.1503/cmaj.151402] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Affiliation(s)
- Debashis Haldar
- Centre for Liver Research (Haldar, Hirschfield), National Institute for Health Research Liver Biomedical Research Unit, University of Birmingham; Department of Renal Medicine (Cockwell), Institute of Translational Medicine, Queen Elizabeth Hospital Birmingham, University Hospital Birmingham, Edgbaston; Institute of Immunology and Immunotherapy (Haldar, Richter, Hirschfield), College of Medical and Dental Sciences, University of Birmingham; Department of Hepatobiliary Surgery (Roberts), Queen Elizabeth Hospital Birmingham, University Hospital Birmingham, Edgbaston, Birmingham, UK
| | - Paul Cockwell
- Centre for Liver Research (Haldar, Hirschfield), National Institute for Health Research Liver Biomedical Research Unit, University of Birmingham; Department of Renal Medicine (Cockwell), Institute of Translational Medicine, Queen Elizabeth Hospital Birmingham, University Hospital Birmingham, Edgbaston; Institute of Immunology and Immunotherapy (Haldar, Richter, Hirschfield), College of Medical and Dental Sciences, University of Birmingham; Department of Hepatobiliary Surgery (Roberts), Queen Elizabeth Hospital Birmingham, University Hospital Birmingham, Edgbaston, Birmingham, UK
| | - Alex G Richter
- Centre for Liver Research (Haldar, Hirschfield), National Institute for Health Research Liver Biomedical Research Unit, University of Birmingham; Department of Renal Medicine (Cockwell), Institute of Translational Medicine, Queen Elizabeth Hospital Birmingham, University Hospital Birmingham, Edgbaston; Institute of Immunology and Immunotherapy (Haldar, Richter, Hirschfield), College of Medical and Dental Sciences, University of Birmingham; Department of Hepatobiliary Surgery (Roberts), Queen Elizabeth Hospital Birmingham, University Hospital Birmingham, Edgbaston, Birmingham, UK
| | - Keith J Roberts
- Centre for Liver Research (Haldar, Hirschfield), National Institute for Health Research Liver Biomedical Research Unit, University of Birmingham; Department of Renal Medicine (Cockwell), Institute of Translational Medicine, Queen Elizabeth Hospital Birmingham, University Hospital Birmingham, Edgbaston; Institute of Immunology and Immunotherapy (Haldar, Richter, Hirschfield), College of Medical and Dental Sciences, University of Birmingham; Department of Hepatobiliary Surgery (Roberts), Queen Elizabeth Hospital Birmingham, University Hospital Birmingham, Edgbaston, Birmingham, UK
| | - Gideon M Hirschfield
- Centre for Liver Research (Haldar, Hirschfield), National Institute for Health Research Liver Biomedical Research Unit, University of Birmingham; Department of Renal Medicine (Cockwell), Institute of Translational Medicine, Queen Elizabeth Hospital Birmingham, University Hospital Birmingham, Edgbaston; Institute of Immunology and Immunotherapy (Haldar, Richter, Hirschfield), College of Medical and Dental Sciences, University of Birmingham; Department of Hepatobiliary Surgery (Roberts), Queen Elizabeth Hospital Birmingham, University Hospital Birmingham, Edgbaston, Birmingham, UK
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Borufka L, Volmer E, Müller S, Engelmann R, Nizze H, Ibrahim S, Jaster R. In vitro studies implicate an imbalanced activation of dendritic cells in the pathogenesis of murine autoimmune pancreatitis. Oncotarget 2016; 7:42963-42977. [PMID: 27356751 PMCID: PMC5190000 DOI: 10.18632/oncotarget.10265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Accepted: 06/09/2016] [Indexed: 11/25/2022] Open
Abstract
Objectives MRL/MpJ mice spontaneously develop an autoimmune pancreatitis (AIP) and are widely used as a model to study the genetic, molecular and immunological basis of the disease. Here, we have addressed the question whether distinctive features of their dendritic cells (DCs) may predispose MRL/MpJ mice to the chronic inflammation. Methods Pancreatic lesions were analyzed employing histological methods. Cohorts of young (healthy) MRL/MpJ mice, adult (sick) individuals, and AIP-resistant CAST/EiJ mice were used to establish cultures of bone marrow (BM)-derived conventional DCs (cDCs). The cells were subsequently characterized regarding the expression profile of CD markers and selected genes, proliferative activity as well as cytokine secretion. Results In pancreatic lesions, large numbers of cells expressing the murine DC marker CD11c were detected in close spatial proximity to CD3+ cells. A high percentage of BM-derived cDCs from adult MRL/MpJ mice expressed typical markers of DC maturation (such as CD83) already prior to a treatment with lipopolysaccharide (LPS). After LPS-stimulation, cDC cultures of both MRL/MpJ mouse cohorts contained more mature cells, proliferated at a higher rate and secreted less interleukin-10 (but also less pro-inflammatory cytokines) than cultures of CAST/EiJ mice. Compared with corresponding cultures of the control strain, LPS-free cultured cDCs from MRL/MpJ mice expressed less mRNA of the inhibitory receptor triggering receptor expressed on myeloid cells 2 (trem2). Conclusions BM-derived cDCs from AIP-prone MRL/MpJ mice display functional features that are compatible with the hypothesis of an imbalanced DC activation in the context of murine AIP.
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Affiliation(s)
- Luise Borufka
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock, Germany
| | - Erik Volmer
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock, Germany
| | - Sarah Müller
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock, Germany
| | - Robby Engelmann
- Institute of Immunology and Core Facility for Cell Sorting & Cell Analysis, Rostock University Medical Center, Rostock, Germany
| | - Horst Nizze
- Institute of Pathology, Rostock University Medical Center, Rostock, Germany
| | - Saleh Ibrahim
- Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany
| | - Robert Jaster
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Rostock, Germany
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Abstract
Autoimmune pancreatitis (AIP) is a rare, distinct and increasingly recognized form of pancreatitis which has autoimmune features. The international consensus diagnostic criteria (ICDC) for AIP recently described two subtypes; type 1[lymphoplasmacytic sclerosing pancreatitis (LPSP)] and type 2 [idiopathic duct-centric pancreatitis (IDCP) or AIP with granulocytic epithelial lesion (GEL)]. Type 1 is the more common form of the disease worldwide and current understanding suggests that it is a pancreatic manifestation of immunoglobulin G4-related disease (IgG4-RD). In contrast, type 2 AIP is a pancreas-specific disease not associated with IgG4 and mostly without the overt extra-pancreatic organ involvement seen in type 1. The pathogenesis of AIP is not completely understood and its clinical presentation is non-specific. It shares overlapping features with more sinister pathologies such as cancer of the pancreas, which continues to pose a diagnostic challenge for clinicians. The diagnostic criteria requires a variable combination of histopathological, imaging and serological features in the presence of typical extrapancreatic lesions and a predictable response to steroids.
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Zen Y, Kawakami H, Kim JH. IgG4-related sclerosing cholangitis: all we need to know. J Gastroenterol 2016; 51:295-312. [PMID: 26817943 DOI: 10.1007/s00535-016-1163-7] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2015] [Accepted: 12/24/2015] [Indexed: 02/04/2023]
Abstract
Our knowledge and experience of IgG4-related sclerosing cholangitis (ISC) have expanded in the last decade. ISC is one of the common organ manifestations of IgG4-related disease (IgG4-RD); approximately 60 % of patients with this systemic condition have ISC in the proximal and/or distal bile ducts. ISC needs to be discriminated from primary sclerosing cholangitis, cholangiocarcinoma, and other rare forms of lymphoplasmacytic cholangiopathy (e.g., follicular cholangitis and sclerosing cholangitis with granulocytic epithelial lesions). Its diagnosis requires a multidisciplinary approach, in which serology, histology, and imaging play crucial roles. Treatments with high-dose corticosteroids typically lead to the rapid and consistent induction of disease remission. Another promising therapeutic approach is B-cell depletion with rituximab. Although disease relapse is relatively common, provided that appropriate treatments are administered, ISC is considered a "benign" disease with a low risk of liver failure and biliary malignancy. Its molecular pathology is characterized by Th2-dominant immune reactions, regulatory T-cell activation, and CCL1-CCR8 interactions. Particular subsets of B cells such as plasmablasts and regulatory B cells also expand. A recent global proteomic study demonstrated that three significantly activated immunological cascades in ISC were all B-cell- or immunoglobulin-related (Fc-gamma receptor-mediated phagocytosis, B-cell receptor signaling pathway, and Fc-epsilon receptor I signaling pathway), suggesting the crucial roles of B cells in the underlying immune reactions. Despite the expansion of our knowledge of the pathophysiology of ISC, the exact role of IgG4 remains unclear. A better understanding of its immunopathology will offer some potential drug targets for this emerging biliary disease.
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Affiliation(s)
- Yoh Zen
- Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-Cho, Kobe, 650-0017, Japan.
| | - Hiroshi Kawakami
- Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan
| | - Jung Hoon Kim
- Department of Radiology and Institute of Radiation Medicine, Seoul National University College of Medicine, Seoul, Korea
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Smit WL, Culver EL, Chapman RW. New Thoughts on Immunoglobulin G4-Related Sclerosing Cholangitis. Clin Liver Dis 2016; 20:47-65. [PMID: 26593290 DOI: 10.1016/j.cld.2015.08.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Immunoglobulin G4 (IgG4)-related sclerosing cholangitis (IgG4-SC) is the biliary manifestation of the multisystem IgG4-related disease. IgG4-SC presents with biliary strictures and/or masses that can bear a striking similarity to other malignant and inflammatory diseases. Diagnosis is based on a combination of clinical, biochemical, radiological, and histologic findings with careful exclusion of malignant disease. Corticosteroids are the mainstay of treatment with good clinical, biochemical, and radiological responses. This review provides a comprehensive overview of the current knowledge of the prevalence, clinical features, radiology and histology findings, diagnosis, treatment, natural history, and pathophysiology of IgG4-SC.
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Affiliation(s)
- Wouter L Smit
- Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands; Nuffield Department of Medicine, University of Oxford, Old Road Campus, Oxford OX3 7BN, UK
| | - Emma L Culver
- Translational Gastroenterology Unit, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK; Nuffield Department of Medicine, University of Oxford, Old Road Campus, Oxford OX3 7BN, UK
| | - Roger W Chapman
- Translational Gastroenterology Unit, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK; Nuffield Department of Medicine, University of Oxford, Old Road Campus, Oxford OX3 7BN, UK.
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Abstract
Autoimmune pancreatitis (AIP) is a unique form of chronic pancreatitis characterized by high serum IgG4 concentration and a variety of complicating extra-pancreatic lesions. AIP has the features of a complex disease that is caused by multifactorial genes. However, the genetic factors underlying AIP have not been elucidated conclusively. Association studies by the candidate-gene approach and genome-wide association studies (GWAS) have revealed several susceptibility genes for AIP, including HLA DRB1*04:05-DQB1*04:01, FCRL3, CTLA4, and KCNA3, albeit in small-scale analyses. Thus, GWAS of large sample sizes and multinational collaborative meta-analyses are needed to identify the precise genetic variants that are associated with AIP onset. Systems genetics approaches that integrate DNA sequencing, expression quantitative trait locus (eQTL) mapping, proteomics, and metabolomics will also be useful in clarifying the pathogenesis of AIP.
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Affiliation(s)
- Masao Ota
- Department of Legal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
| | - Takeji Umemura
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Shigeyuki Kawa
- Center for Health, Safety, and Environmental Management, Shinshu University, Matsumoto, Japan
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Bischof J, Müller S, Borufka L, Asghari F, Möller S, Holzhüter SA, Nizze H, Ibrahim SM, Jaster R. Quantitative Trait Locus Analysis Implicates CD4⁺/CD44high Memory T Cells in the Pathogenesis of Murine Autoimmune Pancreatitis. PLoS One 2015; 10:e0136298. [PMID: 26325540 PMCID: PMC4556487 DOI: 10.1371/journal.pone.0136298] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 08/02/2015] [Indexed: 12/24/2022] Open
Abstract
The mouse strain MRL/MpJ is prone to spontaneously develop autoimmune pancreatitis (AIP). To elucidate the genetic control towards the development of the phenotype and to characterize contributions of immunocompetent cell types, MRL/MpJ mice were interbred with three additional strains (BXD2/TYJ, NZM2410/J, CAST/EIJ) for four generations in an advanced intercross line. Cellular phenotypes were determined by flow cytometric quantification of splenic leukocytes and complemented by the histopathological evaluation of pancreatic lesions. An Illumina SNP array was used for genotyping. QTL analyses were performed with the R implementation of HAPPY. Out of 41 leukocyte subpopulations (B cells, T cells and dendritic cells), only three were significantly associated with AIP: While CD4+/CD44high memory T cells and CD4+/CD69+ T helper (Th) cells correlated positively with the disease, the cytotoxic T cell phenotype CD8+/CD44low showed a negative correlation. A QTL for AIP on chromosome 2 overlapped with QTLs for CD4+/CD44high and CD8+/CD44high memory T cells, FoxP3+/CD4+ and FoxP3+/CD8+ regulatory T cells (Tregs), and CD8+/CD69+ cytotoxic T cells. On chromosome 6, overlapping QTLs for AIP and CD4+/IL17+ Th17 cells and again FoxP3+/CD8+ Tregs were observed. In conclusion, CD4+/CD44high memory T cells are the only leukocyte subtype that could be linked to AIP both by correlation studies and from observed overlapping QTL. The potential role of this cell type in the pathogenesis of AIP warrants further investigations.
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Affiliation(s)
- Julia Bischof
- Department of Dermatology, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany
| | - Sarah Müller
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, E.-Heydemann-Str. 6, 18057 Rostock, Germany
| | - Luise Borufka
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, E.-Heydemann-Str. 6, 18057 Rostock, Germany
| | - Farahnaz Asghari
- Department of Dermatology, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, E.-Heydemann-Str. 6, 18057 Rostock, Germany
| | - Steffen Möller
- Department of Dermatology, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany
| | - Stephanie-Anna Holzhüter
- Institute of Pathology, Rostock University Medical Center, Strempelstr. 14, 18057 Rostock, Germany
| | - Horst Nizze
- Institute of Pathology, Rostock University Medical Center, Strempelstr. 14, 18057 Rostock, Germany
| | - Saleh M. Ibrahim
- Department of Dermatology, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany
| | - Robert Jaster
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, E.-Heydemann-Str. 6, 18057 Rostock, Germany
- * E-mail:
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Affiliation(s)
- Kanae Kubo
- Department of Allergy and Rheumatology; The University of Tokyo Hospital; Tokyo Japan
| | - Kazuhiko Yamamoto
- Department of Allergy and Rheumatology; The University of Tokyo Hospital; Tokyo Japan
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40
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Hart PA, Zen Y, Chari ST. Recent Advances in Autoimmune Pancreatitis. Gastroenterology 2015; 149:39-51. [PMID: 25770706 DOI: 10.1053/j.gastro.2015.03.010] [Citation(s) in RCA: 150] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Revised: 02/26/2015] [Accepted: 03/03/2015] [Indexed: 12/14/2022]
Abstract
Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis that is characterized clinically by frequent presentation with obstructive jaundice, histologically by a dense lymphoplasmacytic infiltrate with fibrosis, and therapeutically by a dramatic response to corticosteroid therapy. Two distinct diseases, type 1 and type 2 AIP, share these features. However, these 2 diseases have unique pancreatic histopathologic patterns and differ significantly in their demographic profiles, clinical presentation, and natural history. Recognizing the popular and long-standing association of the term "AIP" with what is now called "type 1 AIP," we suggest using "AIP" solely for type 1 AIP and to acknowledge its own distinct disease status by using "idiopathic duct-centric chronic pancreatitis" (IDCP) for type 2 AIP. AIP is the pancreatic manifestation of immunoglobulin G4-related disease (IgG4-RD). The etiopathogenesis of AIP and IgG4-RD is largely unknown. However, the remarkable effectiveness of B-cell depletion therapy with rituximab in patients with AIP and IgG4-RD highlights the crucial role of B cells in its pathogenesis. IDCP is less commonly recognized, and little is known about its pathogenesis. IDCP has no biomarker but is associated with inflammatory bowel disease in ~25% of patients. Recently, the international consensus diagnostic criteria for AIP identified combinations of features that are diagnostic of both diseases. Both AIP and IDCP are corticosteroid responsive; however, relapses are common in AIP and rare in IDCP. Therefore, maintenance therapy with either an immunomodulator (eg, azathioprine, 6-mercaptopurine, or mycophenolate mofetil) or rituximab is often necessary for patients with AIP. Long-term survival is excellent for both patients with AIP and patients with IDCP.
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Affiliation(s)
- Phil A Hart
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Yoh Zen
- Department of Diagnostic Pathology, Kobe University, Kobe, Japan
| | - Suresh T Chari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
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Abstract
Peripheral and tissue eosinophilia can be a prominent feature of several unique rheumatologic and vascular diseases. These diseases span a wide range of clinical features, histologic findings, therapeutic approaches, and outcomes. Despite the rare nature of these entities--which makes large-scale studies challenging--knowledge has continued to grow regarding their epidemiology, pathophysiology, and management. This review compares and contrasts 5 rheumatologic and vascular conditions in which eosinophilia can be seen: eosinophilic granulomatosis with polyangiitis (Churg-Strauss), immunoglobulin G4-related disease, diffuse fasciitis with eosinophilia, eosinophilia-myalgia syndrome, and eosinophilic myositis.
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Affiliation(s)
- Hiromichi Tamaki
- Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, 9500 Euclid Avenue, A50, Cleveland, OH 44195, USA
| | - Soumya Chatterjee
- Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, 9500 Euclid Avenue, A50, Cleveland, OH 44195, USA
| | - Carol A Langford
- Department of Rheumatic and Immunologic Diseases, Center for Vasculitis Care and Research, Cleveland Clinic, 9500 Euclid Avenue, A50, Cleveland, OH 44195, USA.
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Oguchi T, Ota M, Ito T, Hamano H, Arakura N, Katsuyama Y, Meguro A, Kawa S. Investigation of susceptibility genes triggering lachrymal/salivary gland lesion complications in Japanese patients with type 1 autoimmune pancreatitis. PLoS One 2015; 10:e0127078. [PMID: 25985088 PMCID: PMC4436166 DOI: 10.1371/journal.pone.0127078] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 04/11/2015] [Indexed: 12/17/2022] Open
Abstract
Autoimmune pancreatitis (AIP) is a unique form of chronic pancreatitis characterized by high serum IgG4 concentration and a variety of complicating extra-pancreatic lesions. In particular, lachrymal/salivary gland lesions tend to manifest in a highly active AIP disease state, and several genes are speculated to be associated with the onset of this complication. We therefore searched for candidate susceptibility genes related to lachrymal/salivary gland lesions in a genome-wide association study (GWAS) with the GeneChip Human Mapping 500k Array Set (Affymetrix, CA) that was followed by fine mapping of additional single nucleotide polymorphisms (SNPs) in strongly significant genes with TaqMan assays. Venous blood samples were obtained from 50 type 1 AIP patients with lachrymal/salivary gland lesions (A group) and 53 type 1 AIP patients without (B group). The mean values of IgG and IG4 were both significantly different (P<0.05) between the groups. SNPs that showed a significant association with the A group at the genome-wide level (P<0.0001) were identified and subsequently used in fine SNP mapping of candidate genes. In total, five SNPs had a positive association with complicated AIP (most notably rs2284932 [P=0.0000021]) and five SNPs possessed a negative association (particularly rs9371942 [P=0.00000039]). Among them, KLF7, FRMD4B, LOC101928923, and MPPED2 were further examined for complication susceptibility using additional SNPs that were not included in the GWAS. Individual genotyping of KLF7 rs2284932 revealed that the frequency of the minor C allele was significantly increased (P=0.00062, Pc=0.0018, OR=2.98, 95%CI=1.58-5.65) in group A. The minor T allele of rs4473559 in FRMD4 demonstrated a significant association in the A group (P=0.00015, OR=3.38, 95%CI=1.77-7.65). In the LOC101928923 gene, the frequency of the minor C allele of rs4379306 was significantly decreased in group A in both TaqMan and GWAS analyses. Lastly, the minor C allele of MPPED2 rs514644 carried a significantly increased risk of complications. These four genes may be linked with the onset of lachrymal/salivary gland lesions in type 1 AIP patients and require further study.
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Affiliation(s)
- Takaya Oguchi
- Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Masao Ota
- Department of Legal Medicine, Shinshu University School of Medicine, Matsumoto, Japan
- * E-mail:
| | - Tetsuya Ito
- Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Hideaki Hamano
- Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Norikazu Arakura
- Endoscopic Examination Center, Shinshu University Hospital, Matsumoto, Japan
| | | | - Akira Meguro
- Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan
| | - Shigeyuki Kawa
- Center for Health, Safety, and Environmental Management, Shinshu University, Matsumoto, Japan
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Abstract
IgG4-related disease is a protean condition that mimics many malignant, infectious, and inflammatory disorders. This multi-organ immune-mediated condition links many disorders previously regarded as isolated, single-organ diseases without any known underlying systemic condition. It was recognised as a unified entity only 10 years ago. Histopathology is the key to diagnosis. The three central pathology features of IgG4-related disease are lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis. The extent of fibrosis is an important determinant of responsiveness to immunosuppressive therapies. IgG4-related disease generally responds to glucocorticoids in its inflammatory stage, but recurrent or refractory cases are common. Important mechanistic insights have been derived from studies of patients treated by B-cell depletion. Greater awareness of this disease is needed to ensure earlier diagnoses, which can prevent severe organ damage, disabling tissue fibrosis, and even death. Identification of specific antigens and T-cell clones that drive the disease will be the first steps to elucidate the pathogenesis of IgG4-related disease.
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Affiliation(s)
- Terumi Kamisawa
- Department of Internal Medicine, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan
| | - Yoh Zen
- Department of Pathology, Kobe University, Kobe, Japan
| | - Shiv Pillai
- Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - John H Stone
- Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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Cystic fibrosis transmembrane conductance regulator gene variants are associated with autoimmune pancreatitis and slow response to steroid treatment. J Cyst Fibros 2015; 14:661-7. [PMID: 25869325 DOI: 10.1016/j.jcf.2015.03.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Revised: 03/22/2015] [Accepted: 03/22/2015] [Indexed: 12/24/2022]
Abstract
BACKGROUND Autoimmune pancreatitis (AIP) is a distinct type of chronic pancreatitis. To date, the association of CFTR gene variants with AIP has not been studied. METHODS The entire coding and intronic regions of the CFTR gene were examined using next-generation sequencing in 89 AIP patients. Clinical features, including imaging, histology, serology, steroid treatment response and extra-pancreatic involvement, were compared between AIP patients with and without CFTR gene variants. RESULTS A total of 28.1% (25/89) of the AIP patients carried 26 CFTR variants, including nine with I556V, seven with 5T, four with S42F, two with I125T, and one each with R31C, R553X, S895N, and G1069R. The presence of CFTR variants and age was independent predictors of the response to steroid treatment, as shown by multivariate analysis. CONCLUSIONS CFTR variants are associated with AIP. Because AIP patients with CFTR variants show slower and reduced steroid treatment responses, different treatments should be considered in AIP patients with CFTR variants.
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Possible involvement of Toll-like receptor 7 in the development of type 1 autoimmune pancreatitis. J Gastroenterol 2015; 50:435-44. [PMID: 25005350 DOI: 10.1007/s00535-014-0977-4] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Accepted: 06/14/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND High serum immunoglobulin G4 (IgG4) levels and IgG4-positive plasma cell infiltration are characteristic of type 1 autoimmune pancreatitis (AIP). It is unclear whether innate immunity is a cause of type 1 AIP; the possible involvement of microbial infection has been suggested in its pathogenesis. To clarify the pathogenesis of type 1 AIP, we investigated Toll-like receptors (TLRs) in type 1 AIP patients. METHODS We studied nine cases of type 1 AIP with ten cases of alcoholic chronic pancreatitis (ACP) and three of the samples from non-tumorous lesion of neuroendocrine tumor (NET) as control subjects. We counted the number of TLR1-11-positive cells immunohistochemically stained with anti-TLR1-11 antibodies. To identify TLR-positive cells in pancreata from type 1 AIP patients, we used a double-immunofluorescence method and counted the numbers of identifiable CD68-, CD163-, CD123-, and CD20-positive cells. RESULTS In type 1 AIP, TLR7 (8.815 ± 1.755), TLR8 (3.852 ± 1.489), and TLR10 (3.852 ± 0.921) were highly expressed. Only the ratio of TLR7 per monocyte was significantly higher in type 1 AIP (0.053 ± 0.012) than in ACP (0.007 ± 0.004; p < 0.01) and non-tumorous lesion of NET (0.000 ± 0.000; p < 0.01). In type 1 AIP, the CD163 to TLR7 ratio (0.789 ± 0.031) was significantly higher both than that of CD123 to TLR7 ratio (0.034 ± 0.006; p < 0.001) and CD20 to TLR7 ratio (0.029 ± 0.010; p < 0.001). CONCLUSIONS TLR7 might be key pattern-recognition receptors involved in the development of type 1 AIP.
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Chang MC, Jan IS, Liang PC, Jeng YM, Yang CY, Tien YW, Wong JM, Chang YT. Human cationic trypsinogen but not serine peptidase inhibitor, Kazal type 1 variants increase the risk of type 1 autoimmune pancreatitis. J Gastroenterol Hepatol 2014; 29:2038-42. [PMID: 24909264 DOI: 10.1111/jgh.12649] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/19/2014] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIM Autoimmune pancreatitis (AIP) is a distinct disease entity. Whether the genes involved in pancreatic acinar cell injury, cationic trypsinogen gene (protease, serine, 1 [trypsin 1] [PRSS1]) and the pancreatic secretory trypsin inhibitor gene (serine peptidase inhibitor, Kazal type 1 [SPINK1]), are associated with AIP remains to be explored. METHODS Genetic analyses of PRSS1 variants (exon 2 and 3) and SPINK1 variants (exon 1, 2, and 3) including the intronic areas in 118 patients with AIP and 200 control subjects were performed by direct DNA sequencing. Clinical features including imaging, histology, serology, response to steroid, and extra-pancreatic organ involvement in AIP patients with and without variants were compared. RESULTS A total of 19 PRSS1 variants and one SPINK1 variant were identified in 20 (16.9%) out of 118 AIP patients. They included one K92N, nine R116C, seven T137M, one C139S, and one C139F of PRSS1 and one 2(IVS3 + 2) of SPINK1. No PRSS1 or SPINK1 variant was identified in the control group. Patients with PRSS1 variants had an increased risk of AIP with odds ratio 22.37 (95% confidence interval: 2.96-168.8, P = 0.003) and higher frequency of serum IgG4 above 280 mg/dL. Using immunosuppressive agent and PRSS1 variant were predictors of less disease relapse in univariate analysis. Presence of PRSS1 variants was the only negative predictor for disease relapse in multivariate analysis. CONCLUSIONS We found a significantly higher frequency of PRSS1 variants in AIP patients than in geographically and ethnically matched control subjects. PRSS1 variants are associated with less disease relapse in AIP.
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Affiliation(s)
- Ming-Chu Chang
- Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
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Abstract
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 cardinal histological features are a lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis and an abundance of IgG4+ plasma cells in affected organs. Serum IgG4 levels are elevated in approximately 70% of patients and are a useful biomarker when present. IgG4-RD is frequently misdiagnosed as malignancy. Making the correct diagnosis is important as the disease is usually steroid responsive, although relapse rates are high. Second-line immunosuppressive agents and B-cell depletion therapy have also been used in retreatment strategies. Recent data suggests that the disease is associated with both progressive organ failure and malignancy. The biological mechanisms driving IgG4-RD remain unclear but this is currently an area of intense scientific investigation. Broadly, IgG4+ B cells are thought to exhibit a regulatory phenotype, but it is not known if these are pathogenic or simply represent a bystander effect. Extending our understanding of the role of IgG4 immunoglobulins in health and disease, the assessment of B and T cell immune phenotype, and large genetic studies of IgG4-RD may enhance our understanding of disease pathogenesis. Ultimately it may be that there is not a single, simple unifying aetiology and so careful stratification of disease by clinical phenotype will be required in multi-centre prospective clinical cohorts. These cohorts will also be essential for the study of treatment outcomes with novel therapies.
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Affiliation(s)
- Wouter Smit
- Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Eleanor Barnes
- Peter Medawar Building for Pathogen Research, Translational Gastroenterology Unit, and Oxford NIHR BRC, Oxford, UK
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Kamisawa T, Chari ST, Lerch MM, Kim MH, Gress TM, Shimosegawa T. Republished: recent advances in autoimmune pancreatitis: type 1 and type 2. Postgrad Med J 2014; 90:18-25. [PMID: 24336310 DOI: 10.1136/postgradmedj-2012-304224rep] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis characterised clinically by frequent presentation with obstructive jaundice, histologically by a lymphoplasmacytic infiltrate with fibrosis, and therapeutically by a dramatic response to steroids. When so defined, AIP can be sub-classified into two subtypes, 1 and 2. Recent international consensus diagnostic criteria for AIP have been developed for diagnosis of both forms of AIP. Type 1 AIP is the pancreatic manifestation of a multiorgan disease, recently named IgG4-related disease. Little is known about the pathogenesis of either form of AIP. Despite frequent association of type 1 AIP with elevated serum IgG4 levels and infiltration with IgG4-positive plasma cells, it is unlikely that IgG4 plays a pathogenic role in AIP. Type 1 AIP responds to steroids, but there needs to be consensus on treatment regimens for induction and therapeutic end points. Relapses are common, but can be reduced by long-term use of low-dose steroids. Recent reports suggest that immunomodulators (azathioprine, 6-mercaptopurine and mycophenolate mofetil), as well biological agents (the antibody to CD20, rituximab) may have a role in maintaining remission in relapsing type 1 AIP. Future studies should clarify the best management options for treatment of relapses and maintenance of remission. Type 2 AIP is a pancreas-specific disorder not associated with IgG4. It presents in younger individuals equally with obstructive jaundice and pancreatitis. The inflammatory process responds to steroid therapy; relapses are uncommon. The clinical spectrum and long-term outcomes of medically treated type 2 AIP are still being evaluated.
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Affiliation(s)
- Terumi Kamisawa
- Department of Internal Medicine, Tokyo Metropolitan Komagome Hospital, , Tokyo, Japan
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IgG4 antibodies in autoimmune polyglandular disease and IgG4-related endocrinopathies: pathophysiology and clinical characteristics. Curr Opin Pediatr 2014; 26:493-9. [PMID: 24905103 DOI: 10.1097/mop.0000000000000107] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
PURPOSE OF REVIEW This review discusses the IgG4-related disease spectrum (IgG4-RD), the autoimmune polyglandular syndromes (APS), the association of IgG4 with APS, and possible pathobiology. RECENT FINDINGS IgG4-RD is a multiorgan autoimmune disorder characterized by fibrous inflammation, IgG4-positive plasma cell infiltration in affected tissues, and elevated serum concentrations of IgG4. IgG4-RD can affect any organ and has a heterogeneous presentation. Consensus criteria for diagnosis in specific organs have been established. The recognition and diagnosis of IgG4-RD are crucial because the disease responds favorably to immunosuppression (e.g., glucocorticoids, rituximab). The precise mechanisms leading to disease are unknown, but IgG4 antibodies may undergo a half antibody exchange, which renders them incapable of activating the complement pathway. SUMMARY Despite significant advances in disease recognition and treatment strategies, the disorder remains poorly understood. The precise role of IgG4, whether it is protective or pathogenic, is still being debated.
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Recent advances in the diagnosis and management of autoimmune pancreatitis. AJR Am J Roentgenol 2014; 202:1007-21. [PMID: 24758653 DOI: 10.2214/ajr.13.11247] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Autoimmune pancreatitis (AIP) is a rare chronic relapsing steroid-responsive fibroinflammatory disorder of the pancreas that is likely caused by immune dysregulation. It is now thought that AIP consists of two distinct clinicopathologic syndromes currently designated as types 1 and 2. CONCLUSION A current update on etiopathogenesis, pathology, and clinical and imaging findings of AIP is provided with an emphasis on diagnosis and management.
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