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Sowerby JM, Rao DA. T cell-B cell interactions in human autoimmune diseases. Curr Opin Immunol 2025; 93:102539. [PMID: 40020254 PMCID: PMC11927756 DOI: 10.1016/j.coi.2025.102539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 02/11/2025] [Accepted: 02/19/2025] [Indexed: 03/05/2025]
Abstract
Activation of autoreactive B cells and production of specific autoantibodies are hallmark features of many autoimmune diseases. B cell differentiation into antibody-secreting cells typically requires help from cognate T cells, which provide both cytokines and cell surface signals in an intricate intercellular interaction. A range of T cells can provide this help to B cells, including T follicular helper cells in follicles of secondary lymphoid organs, as well as T peripheral helper cells, which accumulate within inflamed target tissues in autoimmune diseases. Here, we discuss recent observations about the phenotypes of B cell-helper T cells that accumulate in inflamed tissues and in circulation of patients with autoimmune diseases, the correlations between B cell-helper T cells and B cells in these tissues, and key mediators of productive T cell-B cell interactions, with a focus on mediators that are being targeted therapeutically. Understanding the scope of B cell-helper T cells and their functions will improve our ability to quantify and track pathologic T cell-B cell interactions in human autoimmune diseases and may highlight critical mediators that can be targeted to suppress these interactions therapeutically.
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Affiliation(s)
- John M Sowerby
- Division of Rheumatology, Inflammation, Immunity, Brigham and Women's Hospital and Harvard Medical School, USA
| | - Deepak A Rao
- Division of Rheumatology, Inflammation, Immunity, Brigham and Women's Hospital and Harvard Medical School, USA.
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2
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Akiyama M, Alshehri W, Ishigaki S, Saito K, Kaneko Y. The immunological pathogenesis of IgG4-related disease categorized by clinical characteristics. Immunol Med 2025; 48:11-23. [PMID: 39306708 DOI: 10.1080/25785826.2024.2407224] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 09/03/2024] [Indexed: 02/25/2025] Open
Abstract
IgG4-related disease (IgG4-RD) is an immune disorder characterized by organ enlargement and fibrosis leading to functional impairment. Key immune cell subsets contributing to the pathogenesis of IgG4-RD include T follicular helper 2 cells (Tfh2), Tfh1, CX3CR1 + cytotoxic T cells (CX3CR1 + CTLs), Tregs and IgG4 + B cells. Tfh2 and Tregs are commonly involved in inducing IgG4 class-switching in this disease. Importantly, IgG4-RD can be classified into four clinical phenotypes based on the distribution of affected organs, with each phenotype showing different dominant immune cell subsets involved in its pathogenesis. Specifically, the clinical phenotype of retroperitoneal fibrosis/aortitis is characterized by CX3CR1 + CTLs as the dominant key immune cell subset, while Mikulicz disease with systemic involvement is dominated by Tfh2. In addition to classification based on organ distribution, IgG4-RD can also be categorized into phenotypes associated with malignancy or allergy. The malignancy phenotype is characterized by an increase in CXCR5 + CD2-double negative T cells compared to the allergy phenotype, along with a decrease in naive CD8 + T cells. Moreover, several autoantigens have been identified, and the presence of autoimmune phenotype has been revealed. Due to the pathogenicity of IgG1-type autoantibodies, Tfh1 may be important inducing IgG1 class-switching by IFNγ in autoimmune phenotype. In IgG4-RD with hypocomplementemia, activation of the complement pathway is thought to be induced by IgG1 or IgG2 antibodies, suggesting the involvement of Tfh1 in the disease pathogenesis. Therefore, elucidating the immunological features specific to each clinical characteristic is believed to lead to a deeper understanding of the pathogenesis of IgG4-RD and the discovery of novel therapeutic targets. This review provides an overview of the immunological mechanisms common to IgG4-RD as well as those specific to each clinical characteristic.
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Affiliation(s)
- Mitsuhiro Akiyama
- Department of Internal Medicine, Division of Rheumatology, Keio University School of Medicine, Tokyo, Japan
| | - Waleed Alshehri
- Department of Internal Medicine, Division of Rheumatology, Keio University School of Medicine, Tokyo, Japan
| | - Sho Ishigaki
- Department of Internal Medicine, Division of Rheumatology, Keio University School of Medicine, Tokyo, Japan
| | - Koichi Saito
- Department of Internal Medicine, Division of Rheumatology, Keio University School of Medicine, Tokyo, Japan
| | - Yuko Kaneko
- Department of Internal Medicine, Division of Rheumatology, Keio University School of Medicine, Tokyo, Japan
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Akiyama M, Alshehri W, Saito K, Takeuchi T, Kaneko Y. Pharmacological Management of IgG4-Related Disease: From Traditional to Mechanism-Based Targeted Therapies. Drugs Aging 2025; 42:111-126. [PMID: 39755996 DOI: 10.1007/s40266-024-01172-3] [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: 12/11/2024] [Indexed: 01/07/2025]
Abstract
IgG4-related disease (IgG4-RD) is an immune-mediated disorder characterized by organ enlargement and dysfunction. The formation of tertiary lymphoid tissues (TLTs) in affected organs is crucial for understanding IgG4-RD, as T follicular helper (Tfh) 2 cells within TLTs drive IgG4+B cell differentiation, contributing to mass formation. Key cytokines IL-4 and IL-10, produced by Tfh2 cells, are essential for this process. Additionally, cytotoxic T cells and M2 macrophages significantly contribute to inflammation and fibrosis in the lesions. These insights into IgG4-RD have led to the development of innovative targeted therapies. While glucocorticoids are effective in many cases, they often cause disease flares during tapering and rarely result in long-term, treatment-free remissions. Long-term glucocorticoid use poses significant challenges owing to potential side effects, particularly in older patients who may already have complications such as diabetes and atherosclerotic diseases. In contrast, targeted therapies offer a promising alternative, potentially providing more effective disease control with fewer side effects. Current research is exploring several exciting approaches, including B-cell depletion, targeted immunomodulation of B cells, Bruton's tyrosine kinase inhibition, disruption of co-stimulation pathways, targeting the SLAMF7 cytokine or its receptor blockade (BAFF, IL-4, or IL-6), and JAK-STAT signaling pathway inhibition. These emerging strategies hold the promise of improving patient outcomes and advancing the management of IgG4-RD.
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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, 160-8582, Japan.
| | - Waleed Alshehri
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Koichi Saito
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Tsutomu Takeuchi
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Yuko Kaneko
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
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Sánchez-Gutiérrez R, Vitales-Noyola M, González-Baranda L, Portales-Pérez DP, Layseca-Espinosa E, García-Hernández MH, González-Amaro R. A detailed quantitative analysis of circulating T peripheral and follicular helper lymphocytes in patients with rheumatoid arthritis and systemic lupus erythematosus. REUMATOLOGIA CLINICA 2024; 20:476-483. [PMID: 39528317 DOI: 10.1016/j.reumae.2024.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 07/02/2024] [Indexed: 11/16/2024]
Abstract
INTRODUCTION AND OBJECTIVE Peripheral and follicular helper T lymphocytes (Tph and Tfh, respectively) have an important role in B cell immune responses and the pathogenesis of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Although several studies on the number of Tph and Tfh cells in these conditions have been published, different phenotypes have been employed for their analysis. In this study, we assessed the levels and function of Tph and Tfh cells in blood samples from patients with RA and SLE by using an extended immunophenotype. MATERIALS AND METHODS In a cross-sectional pilot study, blood samples from twenty-seven patients with RA and fifteen with SLE, and twenty-six healthy controls were studied. The levels of Tph (CD4+PD-1+CXCR5-CD38+CD69+ICOS+) and Tfh (CD4+PD-1+CXCR5+CD38+CD69+ICOS+) cells were analyzed by flow cytometry. In addition, the function of Tph/Tfh cells was estimated by measuring the synthesis of IL-21 by these lymphocytes as well as the number of circulating plasmablasts (CD19+CD27+CD20-CD38hi). RESULTS Increased percentages of Tph and Tfh lymphocytes were detected in patients with RA and SLE. Furthermore, the synthesis of IL-21 tended to be higher in both conditions, and higher levels of plasmablasts were detected in these patients, compared to controls. In patients with SLE, the number of Tph cells was associated with disease activity and with the levels of circulating plasmablasts, whereas in patients with RA a significant correlation between Tph cells and evolution time was observed. DISCUSSION AND CONCLUSIONS Our data of Tph and Tfh lymphocytes, based in the analysis of an extended phenotype of these cells, provides further evidence on their involvement in the pathogenesis of RA and SLE.
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Affiliation(s)
- Raquel Sánchez-Gutiérrez
- Section of Molecular and Translational Medicine, Research Center for Health Sciences and Biomedicine (CICSaB), UASLP, San Luis Potosí, SLP, Mexico.
| | - Marlen Vitales-Noyola
- Section of Molecular and Translational Medicine, Research Center for Health Sciences and Biomedicine (CICSaB), UASLP, San Luis Potosí, SLP, Mexico
| | - Larisa González-Baranda
- Section of Molecular and Translational Medicine, Research Center for Health Sciences and Biomedicine (CICSaB), UASLP, San Luis Potosí, SLP, Mexico; Division of Internal Medicine, Hospital Central Dr. Ignacio Morones Prieto, San Luis Potosí, SLP, Mexico
| | - Diana P Portales-Pérez
- Section of Molecular and Translational Medicine, Research Center for Health Sciences and Biomedicine (CICSaB), UASLP, San Luis Potosí, SLP, Mexico
| | - Esther Layseca-Espinosa
- Section of Molecular and Translational Medicine, Research Center for Health Sciences and Biomedicine (CICSaB), UASLP, San Luis Potosí, SLP, Mexico; School of Medicine, UASLP, San Luis Potosí, SLP, Mexico
| | | | - Roberto González-Amaro
- Section of Molecular and Translational Medicine, Research Center for Health Sciences and Biomedicine (CICSaB), UASLP, San Luis Potosí, SLP, Mexico; School of Medicine, UASLP, San Luis Potosí, SLP, Mexico
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Hara A, Watanabe T, Minaga K, Yoshikawa T, Kurimoto M, Sekai I, Masuta Y, Takada R, Otsuka Y, Kamata K, Takamura S, Kudo M, Strober W. A positive cytokine/chemokine feedback loop establishes plasmacytoid DC-driven autoimmune pancreatitis in IgG4-related disease. JCI Insight 2024; 9:e167910. [PMID: 39264798 PMCID: PMC11529986 DOI: 10.1172/jci.insight.167910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 09/10/2024] [Indexed: 09/14/2024] Open
Abstract
The pathogenesis of the murine model of autoimmune pancreatitis associated with IgG4-related disease (AIP/IgG4-RD) induced by administration of polyinosinic-polycytidylic acid (poly[I:C]) is incompletely understood. While it is known that murine and human AIP/IgG4-RD is driven by plasmacytoid dendritic cells (pDCs) producing IFN-α, the origin of these cells and their relation to effector T cells is not known. Here, we show that murine AIP was initiated by TLR3-bearing conventional DCs in the uninflamed pancreas whose activation by the TLR3 ligand poly(I:C) caused IFN-α, CXCL9, and CXCL10 secretion. This, in turn, induced pancreatic recruitment of CXCR3+ T cells and these T cells, via their secretion of CCL25, facilitated migration of pDCs bearing CCR9 into the pancreas. This established a feedback loop anchored by the now dominant pDC production of IFN-α and the continued CXCR3+ T cell facilitation of pDC migration. Remarkably, the interaction between CXCR3+ T cells and pDCs also existed at the functional level since this interaction enhanced the production of CCL25 and IFN-α by CXCR3+ T cells and pDCs, respectively. Evidence presented here that a similar disease mechanism was present in human AIP/IgG4-RD creates new avenues of disease treatment.
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Affiliation(s)
- Akane Hara
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Tomohiro Watanabe
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Kosuke Minaga
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Tomoe Yoshikawa
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Masayuki Kurimoto
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Ikue Sekai
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Yasuhiro Masuta
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Ryutaro Takada
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Yasuo Otsuka
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Ken Kamata
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Shiki Takamura
- Laboratory for Immunological Memory, RIKEN IMS Center for Integrative Medical Science, Yokohama, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Warren Strober
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
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Xu J, Zhai J, Zhao J. Pathogenic roles of follicular helper T cells in IgG4-related disease and implications for potential therapy. Front Immunol 2024; 15:1413860. [PMID: 38911857 PMCID: PMC11190345 DOI: 10.3389/fimmu.2024.1413860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 05/27/2024] [Indexed: 06/25/2024] Open
Abstract
IgG4-related disease (IgG4-RD) is a recently described autoimmune disorder characterized by elevated serum IgG4 levels and tissue infiltration of IgG4+ plasma cells in multiple organ systems. Recent advancements have significantly enhanced our understanding of the pathological mechanism underlying this immune-mediated disease. T cell immunity plays a crucial role in the pathogenesis of IgG4-RD, and follicular helper T cells (Tfh) are particularly important in germinal center (GC) formation, plasmablast differentiation, and IgG4 class-switching. Apart from serum IgG4 concentrations, the expansion of circulating Tfh2 cells and plasmablasts may also serve as novel biomarkers for disease diagnosis and activity monitoring in IgG4-RD. Further exploration into the pathogenic roles of Tfh in IgG4-RD could potentially lead to identifying new therapeutic targets that offer more effective alternatives for treating this condition. In this review, we will focus on the current knowledge regarding the pathogenic roles Tfh cells play in IgG4-RD and outline potential therapeutic targets for future clinical intervention.
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Affiliation(s)
- Jingyi Xu
- Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China
| | - Jiayu Zhai
- Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China
- Center for Rare Disease, Peking University Third Hospital, Beijing, China
| | - Jinxia Zhao
- Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China
- Center for Rare Disease, Peking University Third Hospital, Beijing, China
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7
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Wallace ZS, Katz G, Hernandez-Barco YG, Baker MC. Current and future advances in practice: IgG4-related disease. Rheumatol Adv Pract 2024; 8:rkae020. [PMID: 38601138 PMCID: PMC11003820 DOI: 10.1093/rap/rkae020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 12/28/2023] [Indexed: 04/12/2024] Open
Abstract
IgG4-related disease (IgG4-RD) is an increasingly recognized cause of fibroinflammatory lesions in patients of diverse racial and ethnic backgrounds and is associated with an increased risk of death. The aetiology of IgG4-RD is incompletely understood, but evidence to date suggests that B and T cells are important players in pathogenesis, both of which are key targets of ongoing drug development programmes. The diagnosis of IgG4-RD requires clinicopathological correlation because there is no highly specific or sensitive test. Glucocorticoids are highly effective, but their use is limited by toxicity, highlighting the need for studies investigating the efficacy of glucocorticoid-sparing agents. B cell-targeted therapies, particularly rituximab, have demonstrated benefit, but no randomized clinical trials have evaluated their efficacy. If untreated or under-treated, IgG4-RD can cause irreversible organ damage, hence close monitoring and consideration for long-term immunosuppression is warranted in certain cases.
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Affiliation(s)
- Zachary S Wallace
- Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Harvard University, Boston, MA, USA
| | - Guy Katz
- Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Harvard University, Boston, MA, USA
| | - Yasmin G Hernandez-Barco
- Harvard Medical School, Harvard University, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
| | - Matthew C Baker
- Division of Immunology and Rheumatology, Stanford University, Palo Alto, CA, USA
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Takano K, Kamekura R, Okuni T, Yamamoto K. New insights into chronic rhinosinusitis associated with IgG4-related disease. Auris Nasus Larynx 2024; 51:356-360. [PMID: 37973437 DOI: 10.1016/j.anl.2023.10.006] [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: 08/24/2023] [Revised: 10/23/2023] [Accepted: 10/25/2023] [Indexed: 11/19/2023]
Abstract
IgG4-related disease (IgG4-RD) is a chronic inflammatory disorder characterized by elevated IgG4 serum levels, abundant IgG4-positive plasmacyte infiltration, and fibrosis of various organs, including the head and neck. We aimed to provide an overall review of IgG4-RD in the sinonasal region and propose a novel entity and criteria of chronic rhinosinusitis (CRS) associated with IgG4-RD as "IgG4-CRS," a distinct manifestation of IgG4-RD in the sinonasal region. Sinonasal involvement has been increasingly recognized; however, this region is not included in the classic IgG4-RD-affected organs. The clinical features of IgG4-CRS, including its prevalence and relationship with allergies and olfactory disturbances, have also been explored. Serum IgG4 levels and IgG4-positive plasma cell infiltrations, crucial diagnostic factors, have been discussed in association with IgG4-CRS pathogenesis. Fibrosis, a hallmark of IgG4-RD, is observed in sinonasal tissues; however, typical fibrosis, such as storiform fibrosis, is not usually found. Mimics or complications in eosinophilic CRS (ECRS) and antineutrophil cytoplasmic antibody-associated vasculitis (AAV) are highlighted. Treatment often involves typically effective glucocorticoids. Organ-specific diagnostic criteria for the sinonasal region have not currently been established. Hence, this review aims to foster awareness and understanding of IgG4-CRS among ENT physicians and to provide a basis for future research and diagnostic refinement.
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Affiliation(s)
- Kenichi Takano
- Department of Otolaryngology-Head and Neck Surgery, Sapporo Medical University School of Medicine, S1W17, Chuo-ku, Sapporo 060-8556, Japan.
| | - Ryuta Kamekura
- Department of Otolaryngology-Head and Neck Surgery, Sapporo Medical University School of Medicine, S1W17, Chuo-ku, Sapporo 060-8556, Japan
| | - Tsuyoshi Okuni
- Department of Otolaryngology-Head and Neck Surgery, Sapporo Medical University School of Medicine, S1W17, Chuo-ku, Sapporo 060-8556, Japan
| | - Keisuke Yamamoto
- Department of Otolaryngology-Head and Neck Surgery, Sapporo Medical University School of Medicine, S1W17, Chuo-ku, Sapporo 060-8556, Japan
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Joseph J, Prabhu V, Thomas M, Karuppusami R, Kodiatte TA, Michael R, Rymbai ML, Mathew J. Myofibroblast and pro-fibrotic cytokines in fibrosis of IgG4-related disease (IgG4-RD) patients from South Asia: preliminary data. Clin Rheumatol 2024; 43:1103-1110. [PMID: 38308685 DOI: 10.1007/s10067-023-06861-9] [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: 10/25/2023] [Revised: 12/15/2023] [Accepted: 12/26/2023] [Indexed: 02/05/2024]
Abstract
INTRODUCTION Fibrosis is a typical pathological characteristic in IgG4-RD patients and often irreversible. There exists a lack of suitable markers for detection of earlier onset of fibrosis in various organs in IgG4-RD patients. Hence, this study aims at analysing ambispectively the myofibroblasts and the pro-fibrotic cytokines, IFN gamma and IL-33 involved in IgG4-RD associated fibrosis in South Asian patients. METHOD Archived biopsy samples of definite/probable/possible cases of IgG4-RD, classified according to diagnostic criteria, taken from patients who attended the OPD and IPD of our tertiary care centre during January 2015-January 2020 were chosen for this study. The paraffin sections were examined qualitatively for fibrosis and the excessive collagen deposition by Hematoxylin & Eosin and Masson's Trichrome staining. Also, the presence of alpha-Smooth muscle actin (α-SMA) expressing myofibroblasts and the involvement of pro-fibrotic cytokines (IFN-gamma, IL-33) were assessed by Immunohistochemistry and scored semi-quantitatively (+mild, ++moderate, +++ severe). Serum IL-33 levels were analysed by indirect Elisa (R & D Systems). RESULTS Myofibroblasts were present in 10/12 biopsy samples, in moderate levels in 4 (33%) and very high levels (+++) in 3 (25%) of the patients. IFN-gamma was expressed at low levels in 6 (50%) and absent in 6 (50%). All patients showed IL-33 expression with very high levels in tissue (6, 50%), as well as in serum samples. CONCLUSION The findings of this study reinforce the role of myofibroblasts and profibrotic cytokines like IL-33 in fibrosis of Ig4-RD patients, pointing to their potential as earlier predictive markers of onset and extent of fibrosis.
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Affiliation(s)
- Josna Joseph
- Department of Clinical Immunology & Rheumatology, Christian Medical College, Vellore, Tamil Nadu, 632004, India
| | - V Prabhu
- Department of Clinical Immunology & Rheumatology, Christian Medical College, Vellore, Tamil Nadu, 632004, India
| | - Meera Thomas
- Department of Pathology, Christian Medical College, Vellore, India
| | - Reka Karuppusami
- Department of Biostatistics, Christian Medical College, Vellore, India
| | | | - Rajiv Michael
- Head and Neck Surgery Unit I, Christian Medical College, Vellore, India
| | - Manbha L Rymbai
- Department of Hepatopancreaticobiliary (HPB) Surgery, Christian Medical College, Vellore, India
| | - John Mathew
- Department of Clinical Immunology & Rheumatology, Christian Medical College, Vellore, Tamil Nadu, 632004, India.
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Kasashima S, Kawashima A, Kurose N, Ozaki S, Kasashima F, Matsumoto Y, Takemura H, Ikeda H, Harada K. Disordered Balance of T-Cell Subsets in Arterial Tertiary Lymphoid Organs in Immunoglobulin G4-Related Vascular Disease. J Am Heart Assoc 2023; 12:e030356. [PMID: 38063185 PMCID: PMC10863754 DOI: 10.1161/jaha.123.030356] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 11/10/2023] [Indexed: 12/20/2023]
Abstract
BACKGROUND Arterial/aortic tertiary lymphoid organs (ATLOs), characterized by germinal centers, control local arterial immune responses. T follicular helper cells (Tfh), resident in germinal centers, regulate immunoglobulin production and germinal center development. They consist of Tfh1, Tfh2, and Tfh17 subsets. T follicular regulatory (Tfr) cells possess suppressive functions as regulatory T cells and migrate into germinal centers. Immunoglobulin G4 (IgG4)-related diseases manifest in vascular lesions as frequently formed inflammatory aneurysms (IgG4-related abdominal aortic aneurysm [IgG4-AAAs]). IgG4-AAAs contain several ATLOs. METHODS AND RESULTS We performed whole-slide immunohistochemical image analysis in surgical specimens of IgG4-AAAs (n=21), non-IgG4-related inflammatory AAAs (n=17), atherosclerotic AAAs (n=10), and Takayasu arteritis (n=5). IgG4-AAA was characterized by numerous, large, irregular-shaped ATLOs, and higher numbers of Tfr and Tfh2 cells than Tfh1 cells were present compared with others. The morphologic abnormalities (in number, area, and form) of ATLOs in IgG4-AAAs and the increased number of Tfr cells are closely related to the activity of IgG4-related diseases. All T-cell subsets were more enriched within ATLOs than outside ATLOs. In particular, an increase in Tfr cells in IgG4-AAAs was associated with ATLO formation. Increased Tfh17 cells were found in Takayasu arteritis, and atherosclerotic AAA and non-IgG4-related inflammatory AAAs were characterized by increased Tfh1 cells. CONCLUSIONS In the classification of vascular lesions, considering the imbalance in T-cell subsets, IgG4-AAA should be positioned as adventitial vasculitis with predominant Tfr and Tfh2 cells, accompanied by the abnormal appearance of ATLOs.
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Affiliation(s)
- Satomi Kasashima
- Department of Clinical Laboratory Science, Graduate School of Health ScienceKanazawa UniversityKanazawaJapan
- Department of PathologyNational Hospital Organization, Kanazawa Medical CenterKanazawaJapan
- Department of Clinical LaboratoryNational Hospital Organization, Kanazawa Medical CenterKanazawaJapan
| | - Atsuhiro Kawashima
- Department of PathologyNational Hospital Organization, Kanazawa Medical CenterKanazawaJapan
- Department of Clinical LaboratoryNational Hospital Organization, Kanazawa Medical CenterKanazawaJapan
| | - Nozomu Kurose
- Department of PathologyNational Hospital Organization, Kanazawa Medical CenterKanazawaJapan
- Department of Clinical LaboratoryNational Hospital Organization, Kanazawa Medical CenterKanazawaJapan
| | - Satoru Ozaki
- Department of Clinical Laboratory Science, Graduate School of Health ScienceKanazawa UniversityKanazawaJapan
| | - Fuminori Kasashima
- Department of Cardiovascular SurgeryNational Hospital Organization, Kanazawa Medical CenterKanazawaJapan
| | - Yasushi Matsumoto
- Department of Cardiovascular SurgeryNational Hospital Organization, Kanazawa Medical CenterKanazawaJapan
| | - Hirofumi Takemura
- Department of Cardiovascular SurgeryKanazawa University HospitalKanazawaJapan
| | - Hiroko Ikeda
- Department of PathologyKanazawa University HospitalKanazawaJapan
| | - Ken‐ichi Harada
- Department of Human Pathology, Graduate School of MedicineKanazawa UniversityKanazawaJapan
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Akiyama M, Alshehri W, Yoshimoto K, Kaneko Y. T follicular helper cells and T peripheral helper cells in rheumatic and musculoskeletal diseases. Ann Rheum Dis 2023; 82:1371-1381. [PMID: 37414520 DOI: 10.1136/ard-2023-224225] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 06/21/2023] [Indexed: 07/08/2023]
Abstract
Recent technological progress has greatly advanced our understanding of human immunology. In particular, the discovery of human T follicular helper (Tfh) and T peripheral helper (Tph) cells has significantly advanced our understanding of human adaptive immune system. Tfh and Tph cells share similar molecular characteristics and both play critical roles in B cell differentiation and maturation. However, they differ in their functional properties, such as chemokine receptor expression and cytokine production. As a result, Tfh cells are mainly involved in B cell differentiation and maturation in germinal centres of secondary lymphoid tissues, while Tph cells are involved in B cell differentiation and tissue damage in peripheral inflammatory lesions. Importantly, the involvement of Tfh and Tph cells in the pathogenesis of rheumatic and musculoskeletal diseases has become clear. In rheumatoid arthritis and systemic lupus erythematosus, Tph cell infiltration is predominant in peripheral inflammatory lesions, whereas Tfh cell infiltration is predominant in the affected lesions of IgG4-related disease. Therefore, the contribution of Tfh and Tph cells to the development of rheumatic and musculoskeletal diseases varies depending on each disease. In this review, we provide an overview of human Tfh and Tph cells and summarise the latest findings on these novel T cell subsets in various rheumatic and musculoskeletal diseases.
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Affiliation(s)
- Mitsuhiro Akiyama
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Shinjuku-ku, Japan
| | - Waleed Alshehri
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Shinjuku-ku, Japan
| | - Keiko Yoshimoto
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Shinjuku-ku, Japan
| | - Yuko Kaneko
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Shinjuku-ku, Japan
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Martín-Nares E, Hernández-Molina G, Priego-Ranero ÁA, Chan-Campos I, Herrera-Noguera GS, López-Verdugo F, Furuzawa-Carballeda J. Peripheral Immunophenotype in IgG4-Related Disease and Its Association with Clinical Phenotypes and Disease Activity. Cells 2023; 12:670. [PMID: 36831337 PMCID: PMC9954418 DOI: 10.3390/cells12040670] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/19/2023] [Accepted: 02/13/2023] [Indexed: 02/22/2023] Open
Abstract
Diverse immune cell subsets have been described in IgG4-related disease (IgG4-RD). If there is a different immunophenotype according to clinical phenotype and activity status is not known. Levels of IL-4-, IL-13-, IL-5-, and IL-21-producing CD4+ T cells (Th2 subsets), CD4+ cytotoxic T lymphocytes (CD4+CTLs), T helper 9 cells, T follicular helper cells (Tfh; Tfh1/Tfh2/Tfh17/Tf regulatory [Tfr]), Foxp3+ regulatory T cells, Type 1 regulatory T cells (Tr1), T helper 3 regulatory cells (Th3), IL-10-producing regulatory B cells (Bregs), IL-10-expressing regulatory plasmacytoid dendritic (pDC IL-10+) cells, and M1 and M2 monocytes were determined by flow cytometry in 43 IgG4-RD patients and 12 controls. All immune subsets were higher in patients vs. controls. CD4+/IL-4+, CD4+/IL-5+, CD4+CTLs, Tfh2, Tfh17, Tfr, and M1 monocyte cell number was different among IgG4-RD clinical phenotypes. The pancreato-hepato-biliary phenotype was characterized by a higher CD4+CTLs, Tfh17, Tfh2, and Tfr and lower M1 cell number. An increased CD4+CTLs and Th3 cell number distinguished the head and neck-limited phenotype, while the retroperitoneal/aortic and Mikulicz/systemic phenotypes were characterized by increased Th2 subsets. Tfh17, Tr1, Th3, pDC, M1, and M2 monocytes were augmented in active patients. In summary, the clinical heterogeneity of IgG4-RD might be driven by the participation of different immunophenotypes and, consequently, by a different fibroinflammatory process.
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Affiliation(s)
- Eduardo Martín-Nares
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Col. Belisario Dominguez Sección XVI, Mexico City 14080, Mexico
| | - Gabriela Hernández-Molina
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Col. Belisario Dominguez Sección XVI, Mexico City 14080, Mexico
| | - Ángel A. Priego-Ranero
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Col. Belisario Dominguez Sección XVI, Mexico City 14080, Mexico
| | - Isela Chan-Campos
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Col. Belisario Dominguez Sección XVI, Mexico City 14080, Mexico
| | - Gladys S. Herrera-Noguera
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Col. Belisario Dominguez Sección XVI, Mexico City 14080, Mexico
| | - Fidel López-Verdugo
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Col. Belisario Dominguez Sección XVI, Mexico City 14080, Mexico
| | - Janette Furuzawa-Carballeda
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Col. Belisario Dominguez Sección XVI, Mexico City 14080, Mexico
- Department of Experimental Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Col. Belisario Dominguez Sección XVI, Mexico City 14080, Mexico
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13
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Murayama K, Ikegami I, Kamekura R, Sakamoto H, Yanagi M, Kamiya S, Sato T, Sato A, Shigehara K, Yamamoto M, Takahashi H, Takano KI, Ichimiya S. CD4+CD8+ T follicular helper cells regulate humoral immunity in chronic inflammatory lesions. Front Immunol 2022; 13:941385. [PMID: 36091071 PMCID: PMC9452889 DOI: 10.3389/fimmu.2022.941385] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 07/26/2022] [Indexed: 11/29/2022] Open
Abstract
T follicular helper (Tfh) cells drive humoral immunity by facilitating B cell responses at the initial and recall phases. Recent studies have indicated the possible involvement of Tfh cells in the process of chronic inflammation. However, the functional role of Tfh cells in persistent immune settings remains unclear. Here, we report that CD4+CD8+ (double-positive, DP; CD3+CD4+CD8+CXCR5hiPD-1hi) Tfh cells, a subset of germinal-center-type Tfh cells, were abundantly present in the fibroinflammatory lesions of patients with immunoglobulin G4-related disease (IgG4-RD). Transcriptome analyses showed that these DP-Tfh cells in the lesions of IgG4-RD preferentially expressed signature genes characteristic of cytotoxic CD8+ T cells, such as Eomes, CRTAM, GPR56, and granzymes, in addition to CD70. Scatter diagram analyses to examine the relationships between tissue-resident lymphocytes and various clinical parameters revealed that the levels of DP-Tfh cells were inversely correlated to the levels of serum IgG4 and local IgG4-expressing (IgG4+) memory B cells (CD19+CD27+IgD-) in patients with IgG4-RD. Cell culture experiments using autologous tonsillar lymphocytes further suggested that DP-Tfh cells possess a poor B-cell helper function and instead regulate memory B cells. Since CD4+ (single positive, SP; CD3+CD4+CD8-CXCR5hiPD-1hi) Tfh cells differentiated into DP-Tfh cells under stimulation with IL-2 and IL-7 as assessed by in vitro experiments, these data imply that SP-Tfh cells are a possible origin of DP-Tfh cells under persistent inflammation. These findings highlight the potential feedback loop mechanism of Tfh cells in immune tolerance under chronic inflammatory conditions. Further studies on DP-Tfh cells may facilitate control of unresolved humoral responses in IgG4-RD pathological inflammation.
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Affiliation(s)
- Kosuke Murayama
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
- Department of Otolaryngology and Head and Neck Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Ippei Ikegami
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Ryuta Kamekura
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
- Department of Otolaryngology and Head and Neck Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiroshi Sakamoto
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
- Department of Otolaryngology and Head and Neck Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masahiro Yanagi
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Shiori Kamiya
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Taiki Sato
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Akinori Sato
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Katsunori Shigehara
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Motohisa Yamamoto
- Department of Rheumatology and Allergy, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Hiroki Takahashi
- Department of Clinical Immunology and Rheumatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Ken-ichi Takano
- Department of Otolaryngology and Head and Neck Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Shingo Ichimiya
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
- *Correspondence: Shingo Ichimiya,
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14
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Kasashima S, Kawashima A, Kurose N, Ozaki S, Ikeda H, Harada K. The disturbance of the distribution of T helper cell subsets in the mantle area surrounding germinal centers in immunoglobulin G4-related sclerosing sialadenitis. Virchows Arch 2022; 481:767-777. [PMID: 35902401 DOI: 10.1007/s00428-022-03384-7] [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: 05/14/2022] [Revised: 06/30/2022] [Accepted: 07/18/2022] [Indexed: 11/29/2022]
Abstract
The function of germinal centers (GCs) is an important factor in the pathogenesis of immunoglobulin G4 (IgG4)-related disease, in which inflammatory and fibrotic processes are controlled by type 2 helper T (Th) cells and regulatory T cells. T follicular helper cells (Tfh), which are present in GCs, regulate GC development, and they consist of Tfh1, Tfh2, and Tfh17 subsets. This study examined the association of Th cell subsets in IgG4-RD and pathogenesis of the disease using whole-slide image analysis for immunohistochemistry. IgG4-related sclerosing sialadenitis (IgG4-SS, n = 19) was characterized by higher numbers of Tfh2 and Tfh17 cells than Tfh1 cells compared to the findings in patients with chronic sialadenitis (n = 18) or Sjögren syndrome (n = 17). The number of Tfh2 cells was significantly associated with all parameters of GC structures and the number of IgG4 + plasmacytes, whereas the number of Tfh1 cells was inversely associated with the aforementioned parameters. Concerning extrafollicular helper T (Teh) cells, among three groups, the Tfh2/Teh2 ratio was highest and the Tfh1/Teh1 ratio was lowest in the IgG4-SS group, which exhibited a characteristically regional distribution of Tfh and Teh subsets, especially higher numbers of Teh2 cells and lower numbers of Teh1 cells in the mantle areas surrounding GCs. Mantle Teh2 cells and central Tfh17 cells were significantly correlated with morphological abnormalities of GCs. Our results indicated that the peculiar regional distribution and altered balance of Tfh and Teh subsets are novel hallmarks of IgG4-SS that are associated with GC formation in IgG4-SS.
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Affiliation(s)
- Satomi Kasashima
- Department of Clinical Laboratory Science, Graduate School of Health Science, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, 920-0942, Japan. .,Department of Pathology, Kanazawa Medical Center, Kanazawa, Japan. .,Department of Clinical Laboratory, Kanazawa Medical Center, Kanazawa, Japan.
| | - Atsuhiro Kawashima
- Department of Pathology, Kanazawa Medical Center, Kanazawa, Japan.,Department of Clinical Laboratory, Kanazawa Medical Center, Kanazawa, Japan
| | - Nozomu Kurose
- Department of Pathology, Kanazawa Medical Center, Kanazawa, Japan.,Department of Clinical Laboratory, Kanazawa Medical Center, Kanazawa, Japan
| | - Satoru Ozaki
- Department of Clinical Laboratory Science, Graduate School of Health Science, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, 920-0942, Japan
| | - Hiroko Ikeda
- Department of Pathology, Kanazawa University Hospital, Kanazawa, Japan
| | - Kenichi Harada
- Department of Human Pathology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
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15
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T Cell Roles and Activity in Chronic Sclerosing Sialadenitis as IgG4-Related Disease: Current Concepts in Immunopathogenesis. Autoimmune Dis 2022; 2022:5689883. [PMID: 35769404 PMCID: PMC9236833 DOI: 10.1155/2022/5689883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 06/07/2022] [Indexed: 11/18/2022] Open
Abstract
IgG4-related disease is a multiorgan immunological fibroinflammatory disorder characterized by lymphoplasmacytic infiltration and fibrosis in multiple organs accompanied by high serum IgG4 levels. The salivary glands are the most common organs involved in this disease. Recently, chronic sclerosing sialadenitis affecting salivary glands, formerly known as Küttner's tumor, and Mikulicz's disease have been classified as a class of IgG4-related diseases. The etiopathobiology of IgG4-related disease is not fully understood. It has recently been hypothesized that the inflammatory and fibrotic process and the increased serum IgG4+ levels in IgG4-related disease are the result of an interaction between B cells and T helper cells, suggesting that T cells may play a key role in the pathogenesis of this disease. The aim of this review is to discuss the proposed roles of different T cell subsets in the pathogenesis of IgG4-related disease focusing on their roles in immunopathogenesis of IgG4-related sialadenitis.
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16
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Wu X, Peng Y, Li J, Zhang P, Liu Z, Lu H, Peng L, Zhou J, Fei Y, Zeng X, Zhao Y, Zhang W. Single-Cell Sequencing of Immune Cell Heterogeneity in IgG4-Related Disease. Front Immunol 2022; 13:904288. [PMID: 35693817 PMCID: PMC9184520 DOI: 10.3389/fimmu.2022.904288] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 04/28/2022] [Indexed: 12/26/2022] Open
Abstract
Background The IgG4-related disease (IgG4-RD) is an immune-mediated disorder with fibrotic manifestations. However, the transcriptional profiles of immune cell subsets at single-cell level are unknown. Herein, single-cell sequencing was used to assess the specific cell subpopulations and pathways in peripheral blood mononuclear cells (PBMCs) of IgG4-RD. Methods Single-cell sequencing was performed using the PBMCs from four patients with IgG4-RD and three healthy controls (HCs). Functional enrichment and cell analysis were performed through re-clustering of PBMCs to assess functional pathways and intercellular communication networks in IgG4-RD. Western blot and flow cytometry were used to verify sequencing and functional enrichment results. Results Four major cell types and 21 subtypes were identified. Further subclustering demonstrated that plasma B-cell proportions increased with increasing glycolysis/gluconeogenesis activity in IgG4-RD. Re-clustering of myeloid cells showed that EGR1 and CD36 expressions were significantly increased in CD14+ monocytes of IgG4-RD, as validated by Western blot analysis. Moreover, tumor necrosis factor (TNF) production pathways were positively regulated in CD14+ monocytes of IgG4-RD. In vitro stimulation showed that CD14+ monocytes of IgG4-RD could secrete higher levels of TNF-α . Notably, the proportions of CD8 central memory T (TCM) and TIGIT+ CD8 cytotoxic T (CTL) increased in patients with IgG4-RD compared with HCs. Further interaction analysis showed that B cell activation factor (BAFF) signaling pathways were enriched from myeloid cells subsets to B cells. Conclusion This study enhances the understanding of the cellular heterogeneity and transcriptional features involved in the pathogenesis of IgG4-RD, providing key clinical implications.
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Affiliation(s)
- Xunyao Wu
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing, China
- Clinical Biobank, Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yu Peng
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing, China
| | - Jieqiong Li
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing, China
| | - Panpan Zhang
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing, China
| | - Zheng Liu
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing, China
| | - Hui Lu
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing, China
| | - Linyi Peng
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing, China
| | - Jiaxin Zhou
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing, China
| | - Yunyun Fei
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing, China
| | - Xiaofeng Zeng
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing, China
| | - Yan Zhao
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing, China
- *Correspondence: Yan Zhao, ; Wen Zhang,
| | - Wen Zhang
- Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Beijing, China
- *Correspondence: Yan Zhao, ; Wen Zhang,
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17
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Marks KE, Rao DA. T peripheral helper cells in autoimmune diseases. Immunol Rev 2022; 307:191-202. [PMID: 35103314 PMCID: PMC9009135 DOI: 10.1111/imr.13069] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 01/19/2022] [Indexed: 12/19/2022]
Abstract
Pathologic T cell-B cell interactions underlie many autoimmune diseases. The T cells that help B cells in autoimmune diseases vary in phenotype and include T cells that lack typical features of T follicular helper cells, such as expression of CXCR5 and BCL6. A population of PD-1hi CXCR5- T peripheral helper (Tph) cells has now been recognized in multiple autoantibody-associated diseases. Tph cells display a distinctive set of features, merging the ability to provide B cell help with the capacity to migrate to inflamed peripheral tissues. Here, we review the scope of immune-related conditions in which Tph cells have been implicated and provide a perspective on their potential contributions to pathologic B cell activation in autoimmune diseases. We discuss Tph cells as a promising therapeutic strategy in autoimmunity and consider the utility of tracking Tph cells in blood as a biomarker to quantify aberrant T cell-B cell activation in patients with autoimmune diseases.
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Affiliation(s)
- Kathryne E Marks
- Division of Rheumatology, Inflammation, Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Deepak A Rao
- Division of Rheumatology, Inflammation, Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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18
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Horwich BH, Liang TZ, Dodge JL, Chopra S, Kahn JA, Saito T. Differential IgG4-Producing Plasma Cell Infiltration in Non- and Post-Transplant Plasma Cell Hepatitis. Transpl Int 2022; 35:10182. [PMID: 35368647 PMCID: PMC8971201 DOI: 10.3389/ti.2022.10182] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 02/04/2022] [Indexed: 12/12/2022]
Abstract
Autoimmune hepatitis (AIH), post-transplant recurrent AIH (rAIH), and plasma cell-rich rejection (PCR) are clinical diagnoses with the shared histopathologic hallmark of plasma cell hepatitis (PCH). As these histologically and serologically indistinguishable diagnoses are differentiated by clinical context, it remains uncertain whether they represent distinct immunologic phenomena. Improved understanding of immunoglobulin subclass 4-producing plasma cells (IgG4-PC) has brought attention to IgG4 as an immunophenotypic biomarker. To date, degree and clinical significance of IgG4-PC infiltration in PCH remain elusive. This retrospective, single-center study assessed IgG4-PC infiltration in AIH, rAIH, and PCR via standardized immunohistochemistry analysis. Identified cases from 2005 to 2020 (n = 47) included AIH (treatment-naïve AIH (tnAIH): n = 15 and AIH-flare on treatment (fAIH); n = 10), rAIH (n = 8), and PCR (n = 14) were analyzed and correlated with clinical characteristics. IgG4-Positivity (# IgG4-PC/# pan-IgG-expressing cells) distribution was heterogenous and overlapping [tnAIH: 0.060 (IQR 0.040-0.079), fAIH: 0.000 (0.000-0.033), rAIH: 0.000 (0.000-0.035), PCR: 0.228 (0.039-0.558)]. IgG4-Positivity was inversely correlated with corticosteroid use (p < 0.001). IgG4-Positivity ≥0.500 was associated with rapid AST improvement (p = 0.03). The variable IgG4-Positivity of AIH, rAIH and PCR suggests diverse and overlapping immunopathologic mechanisms and that current diagnostic schemes inadequately capture PCH immunopathology. We propose incorporation of IgG4-Positivity to refine current PCH classification and treatment strategies.
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Affiliation(s)
- Brian H. Horwich
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Tom Z. Liang
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Jennifer L. Dodge
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Shefali Chopra
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Jeffrey A. Kahn
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- USC Transplant Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Takeshi Saito
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- USC Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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19
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Recent Advances in Understanding the Role of TIGIT+ Follicular Helper T Cells in IgG4-Related Disease. IMMUNO 2021. [DOI: 10.3390/immuno1040026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
IgG4-related disease (IgG4-RD) is a fibro-inflammatory disease characterized by elevated serum IgG4 levels and massive infiltration of IgG4+plasma cells. Although storiform fibrosis, obliterative phlebitis and IgG4+plasma cell infiltration are well described pathological features in this disease, the excessive formation of tertiary lymphoid organs (TLOs), particularly in the early phase of the disease lesions, has gained much attention. TLOs of IgG4-RD are orchestrated by specific immune cell subsets including follicular helper T cells (Tfh), CD20+ B cells, and CD21+ follicular dendritic cells (FDCs). Tfh is the key player of this disease because recent studies have suggested the pathological role of this immune cell subset in formation of TLOs, helping IgG4+plasma cell differentiation, inducing storiform fibrosis by secreting interleukin-4, and activating cytotoxic T cells by secreting interleukin-21. We have recently identified a new Tfh subset which expresses T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT). TIGIT+Tfh efficiently produces interleukin-21 through OX40 signal, and the increase in peripheral TIGIT+Tfh cells reflects disease activity in IgG4-RD. TIGIT is important to mediate the retention and positioning of TIGIT+Tfh within TLOs through interaction with CD155 expressed on CD21+ FDCs. In this review, we summarize and discuss recent progress in understanding the pathogenesis of IgG4-RD, focusing on TIGIT+Tfh.
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20
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Liu J, Yin W, Westerberg LS, Lee P, Gong Q, Chen Y, Dong L, Liu C. Immune Dysregulation in IgG 4-Related Disease. Front Immunol 2021; 12:738540. [PMID: 34539675 PMCID: PMC8440903 DOI: 10.3389/fimmu.2021.738540] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 08/09/2021] [Indexed: 12/26/2022] Open
Abstract
Immunoglobin G4-related disease (IgG4-RD) is one of the newly discovered autoimmune diseases characterized by elevated serum IgG4 concentrations and multi-organ fibrosis. Despite considerable research and recent advances in the identification of underlying immunological processes, the etiology of this disease is still not clear. Adaptive immune cells, including different types of T and B cells, and cytokines secreted by these cells play a vital role in the pathogenesis of IgG4-RD. Antigen-presenting cells are stimulated by pathogens and, thus, contribute to the activation of naïve T cells and differentiation of different T cell subtypes, including helper T cells (Th1 and Th2), regulatory T cells, and T follicular helper cells. B cells are activated and transformed to plasma cells by T cell-secreted cytokines. Moreover, macrophages, and some important factors (TGF-β, etc.) promote target organ fibrosis. Understanding the role of these cells and cytokines implicated in the pathogenesis of IgG4-RD will aid in developing strategies for future disease treatment and drug development. Here, we review the most recent insights on IgG4-RD, focusing on immune dysregulation involved in the pathogenesis of this autoimmune condition.
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Affiliation(s)
- Jiachen Liu
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Yin
- Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lisa S Westerberg
- Department of Microbiology Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Pamela Lee
- Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Quan Gong
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, China
| | - Yan Chen
- The Second Department of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Lingli Dong
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chaohong Liu
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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21
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Kasashima S, Kawashima A, Kurose N, Ozaki S, Ikeda H, Harada KI. Regional disturbance of the distribution of T regulatory cells and T helper cells associated with irregular-shaped germinal centers in immunoglobulin G4-related sialadenitis. Virchows Arch 2021; 479:1221-1232. [PMID: 34415430 DOI: 10.1007/s00428-021-03187-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 08/01/2021] [Accepted: 08/11/2021] [Indexed: 12/25/2022]
Abstract
Although many germinal centers (GCs) have been reported in immunoglobulin (Ig) G4-related disease, the significance of GCs in IgG4-related disease has not received attention. Both T follicular regulatory cells (Tfr), which are regulatory T cells (Treg) in GCs, and T follicular helper cells (Tfh) produce the cytokine interleukin (IL)-10 and regulate GC development. In whole-slide image analysis in surgical specimens using immunohistochemistry, IgG4-related sclerosing sialadenitis (IgG4-SS, n = 17) was characterized by markedly numerous, large, and irregular-shaped GCs with increased IL-10 + cells and Tfr and Tfh in the total area of the salivary gland compared with controls, including patients with chronic sialadenitis (n = 17) and Sjögren syndrome (n = 15). In particular, the central area of GC in IgG4-SS showed a higher Tfr number and Tfr/Tfh ratio than controls. The number of Tfr in the central area was significantly correlated with the number of IgG4 + plasmacytes and the number, size, and irregularity of GCs. In the mantle area, which surrounds GCs, IgG4-SS showed a higher Treg number and Treg/T helper cells (Th) ratio than controls. In IgG4-SS, the Treg/Th ratio was highest in the mantle area outside GCs and the Tfr/Tfh ratio was highest in the central area inside GCs. However, in controls, the Treg/Th ratio gradually decreased from outside to inside GCs. Our findings reveal that the morphological abnormality of GCs and the characteristic localization and altered balance of Treg and Th in the different compartments of inside and outside GCs would be the novel hallmarks of IgG4-SS.
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Affiliation(s)
- Satomi Kasashima
- Department of Clinical Laboratory Science, Graduate School of Health Science, Kanazawa University, Kanazawa, Japan.
- Department of Pathology, National Hospital Organization, Kanazawa Medical Center, Kanazawa, Japan.
- Department of Clinical Laboratory, National Hospital Organization, Kanazawa Medical Center, Kanazawa, Japan.
| | - Atsuhiro Kawashima
- Department of Pathology, National Hospital Organization, Kanazawa Medical Center, Kanazawa, Japan
- Department of Clinical Laboratory, National Hospital Organization, Kanazawa Medical Center, Kanazawa, Japan
| | - Nozomu Kurose
- Department of Pathology, National Hospital Organization, Kanazawa Medical Center, Kanazawa, Japan
- Department of Clinical Laboratory, National Hospital Organization, Kanazawa Medical Center, Kanazawa, Japan
| | - Satoru Ozaki
- Department of Clinical Laboratory Science, Graduate School of Health Science, Kanazawa University, Kanazawa, Japan
| | - Hiroko Ikeda
- Department of Pathology, Kanazawa University Hospital, Kanazawa, Japan
| | - Ken-Ichi Harada
- Department of Human Pathology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
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22
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Gao Y, Dunlap G, Elahee M, Rao DA. Patterns of T-Cell Phenotypes in Rheumatic Diseases From Single-Cell Studies of Tissue. ACR Open Rheumatol 2021; 3:601-613. [PMID: 34255929 PMCID: PMC8449042 DOI: 10.1002/acr2.11296] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 05/19/2021] [Indexed: 02/06/2023] Open
Abstract
High-dimensional analyses of tissue samples from patients with rheumatic diseases are providing increasingly detailed descriptions of the immune cell populations that infiltrate tissues in different rheumatic diseases. Here we review key observations emerging from high-dimensional analyses of T cells within tissues in different rheumatic diseases, highlighting common themes across diseases as well as distinguishing features. Single-cell RNA sequencing analyses capture several dimensions of T-cell states, yet surprisingly, these analyses generally have not demonstrated distinct clusters of paradigmatic T-cell effector subsets, such as T helper (Th) 1, Th2, and Th17 cells. Rather, global transcriptomics robustly identify both proliferating T cells and regulatory T cells and have also helped to reveal new effector subsets in inflamed tissues, including T peripheral helper cells and granzyme K+ T cells. Further characterization of the T-cell populations that accumulate within target tissues should enable more precise targeting of biologic therapies and accelerate development of more specific biomarkers to track activity of relevant immune pathways in patients with rheumatic diseases.
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Affiliation(s)
- Yidan Gao
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Garrett Dunlap
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Mehreen Elahee
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Deepak A Rao
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
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23
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Michailidou D, Schwartz DM, Mustelin T, Hughes GC. Allergic Aspects of IgG4-Related Disease: Implications for Pathogenesis and Therapy. Front Immunol 2021; 12:693192. [PMID: 34305927 PMCID: PMC8292787 DOI: 10.3389/fimmu.2021.693192] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Accepted: 06/03/2021] [Indexed: 01/05/2023] Open
Abstract
IgG4-related disease (IgG4-RD) is a rare systemic fibroinflammatory disease frequently associated with allergy. The pathogenesis of IgG4-RD is poorly understood, and effective therapies are limited. However, IgG4-RD appears to involve some of the same pathogenic mechanisms observed in allergic disease, such as T helper 2 (Th2) and regulatory T cell (Treg) activation, IgG4 and IgE hypersecretion, and blood/tissue eosinophilia. In addition, IgG4-RD tissue fibrosis appears to involve activation of basophils and mast cells and their release of alarmins and cytokines. In this article, we review allergy-like features of IgG4-RD and highlight targeted therapies for allergy that have potential in treating patients with IgG4-RD.
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Affiliation(s)
- Despina Michailidou
- Division of Rheumatology, University of Washington, Seattle, WA, United States
| | - Daniella Muallem Schwartz
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Tomas Mustelin
- Division of Rheumatology, University of Washington, Seattle, WA, United States
| | - Grant C. Hughes
- Division of Rheumatology, University of Washington, Seattle, WA, United States
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24
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Zhou W, Li Y, Yan C, Zheng L, Liu F, Sun C. The prevalence of extra-salivary gland complications in immunoglobulin G4-related sialadenitis. Oral Dis 2021; 28:1468-1483. [PMID: 34048116 DOI: 10.1111/odi.13926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 05/23/2021] [Indexed: 11/28/2022]
Abstract
OBJECTIVES To estimate the prevalence of extra-glandular lesions in patients with immunoglobulin G4-related sialadenitis (IgG4-RS). METHODS Six electronic databases (PubMed, EMBASE, Science Direct, Scopus, Web of Science, and China National Knowledge Infrastructure) were systematically searched from the date of inception of each database to March 2021. The Strengthening the Reporting of Observational Studies in Epidemiology statement was used to conduct methodological quality assessment, and a random-effect meta-analysis model was applied to estimate the prevalence. Publication bias was visually assessed using a funnel plot and calculated via Begg's and Egger's tests. The Stata 15 software was used to perform data analysis. RESULTS A total of 43 articles comprising 1,864 patients with IgG4-RS were considered to be eligible for this study. The pooled prevalence of extra-salivary gland lesions in IgG4-RS was 76.53% with a confidence interval (CI) of (69.39%, 83.04%). A higher prevalence was associated with studies published before or during 2015 (84.38%, CI [74.23%, 92.58%]) than those published after 2015 (68.55%, CI [58.44%, 77.88%]). Lacrimal gland involvement (54.68%, CI [45.61%, 63.60%]) and lymph node swelling (56.96%, CI [48.16%, 65.56%]) were the most frequent lesions. CONCLUSIONS Extra-glandular lesions were common in patients with IgG4-RS. More high-quality prospective studies with less heterogeneity are required to determine the accurate prevalence.
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Affiliation(s)
- Wanhang Zhou
- Department of Oral Maxillofacial-Head and Neck Surgery, School of Stomatology, Oral Diseases Laboratory of Liaoning, China Medical University, Shenyang, China
| | - Yanfei Li
- Department of Prosthodontics, Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Cong Yan
- Department of Oral Maxillofacial-Head and Neck Surgery, School of Stomatology, Oral Diseases Laboratory of Liaoning, China Medical University, Shenyang, China
| | - Li Zheng
- Department of Oral Maxillofacial-Head and Neck Surgery, School of Stomatology, Oral Diseases Laboratory of Liaoning, China Medical University, Shenyang, China
| | - Fayu Liu
- Department of Oral Maxillofacial-Head and Neck Surgery, School of Stomatology, Oral Diseases Laboratory of Liaoning, China Medical University, Shenyang, China
| | - Changfu Sun
- Department of Oral Maxillofacial-Head and Neck Surgery, School of Stomatology, Oral Diseases Laboratory of Liaoning, China Medical University, Shenyang, China
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25
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Matsumoto H, Fujita Y, Matsuoka N, Temmoku J, Yashiro-Furuya M, Asano T, Sato S, Watanabe H, Suzuki E, Tsuji S, Fukui S, Umeda M, Iwamoto N, Kawakami A, Migita K. Serum checkpoint molecules in patients with IgG4-related disease (IgG4-RD). Arthritis Res Ther 2021; 23:148. [PMID: 34030721 PMCID: PMC8142499 DOI: 10.1186/s13075-021-02527-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 05/10/2021] [Indexed: 01/12/2023] Open
Abstract
Background Immunoglobulin G4-related disease (IgG4-RD) is characterized by increased serum IgG4 concentration and infiltration of IgG4+ plasma cells in the affected organs. The present study aimed to characterize the serum levels of coinhibitory checkpoint molecule, T cell immunoglobulin and mucin-containing-molecule-3 (TIM-3), and its ligand, galectin-9 (Gal-9), among IgG4-related disease in patients with IgG4-RD patients with various organ involvements. Methods Serum samples were collected from untreated 59 patients with IgG4-RD, 13 patients with rheumatoid arthritis, and 37 healthy controls (HCs). HCs lacked chronic medical diseases or conditions and did not take prescription medications or over-the-counter medications within 7 days. Patients with IgG4-RD (n = 57) were subdivided into those with visceral involvement (n = 38) and those without visceral involvement (n = 21). Serum levels of Gal-9 and soluble TIM-3 (sTIM-3) were determined using enzyme-linked immunosorbent assay (ELISA). The results were compared with the clinical phenotypes of IgG4-RD. Results In untreated patients with IgG4-RD, serum levels of Gal-9 and sTIM-3 were significantly higher than in RA patients as well as in healthy controls. There were significant correlations between the serum levels of Gal-9 or sTIM-3 and serum levels of IgG, BAFF, or sIL-2R. However, there was no significant correlation between the serum levels of Gal-9 or sTIM-3 and serum IgG4 concentrations. Serum levels of sTIM-3 were significantly higher in a subset of patients with visceral involvements than in those without visceral involvements. However, there was no significant difference in the serum levels of Gal-9 between IgG4-RD patients with and without visceral involvements, although both Gal-9 and sTIM-3 were elevated in untreated IgG4-RD patients, and the levels of these checkpoint molecules remained unchanged after steroid therapy. Conclusion Serum levels of Gal-9 and sTIM-3 were significantly elevated in untreated patients with IgG4-RD. Furthermore, serum levels of sTIM-3 were significantly higher in IgG4-RD patients with visceral involvements. These checkpoint molecules could be a potentially useful biomarker for IgG4-RD and for assessing the clinical phenotypes of IgG4-RD.
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Affiliation(s)
- Haruki Matsumoto
- Department of Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan
| | - Yuya Fujita
- Department of Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan.
| | - Naoki Matsuoka
- Department of Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan
| | - Jumpei Temmoku
- Department of Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan
| | - Makiko Yashiro-Furuya
- Department of Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan
| | - Tomoyuki Asano
- Department of Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan
| | - Shuzo Sato
- Department of Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan
| | - Hiroshi Watanabe
- Department of Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan
| | - Eiji Suzuki
- Department of Rheumatology, Ohta Nishinouchi General Hospital Foundation, 2-5-20 Nishinouchi, Koriyama, Fukushima, 963-8558, Japan
| | - Sosuke Tsuji
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki University, Sakamoto1-7-1, Nagasaki, 852-8501, Japan
| | - Shoichi Fukui
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki University, Sakamoto1-7-1, Nagasaki, 852-8501, Japan
| | - Masataka Umeda
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki University, Sakamoto1-7-1, Nagasaki, 852-8501, Japan
| | - Naoki Iwamoto
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki University, Sakamoto1-7-1, Nagasaki, 852-8501, Japan
| | - Atsushi Kawakami
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki University, Sakamoto1-7-1, Nagasaki, 852-8501, Japan
| | - Kiyoshi Migita
- Department of Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan
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Hara A, Watanabe T, Minaga K, Yoshikawa T, Kamata K, Kudo M. Biomarkers in autoimmune pancreatitis and immunoglobulin G4-related disease. World J Gastroenterol 2021; 27:2257-2269. [PMID: 34040320 PMCID: PMC8130041 DOI: 10.3748/wjg.v27.i19.2257] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 03/19/2021] [Accepted: 04/26/2021] [Indexed: 02/06/2023] Open
Abstract
Solitary organ autoimmune disorders, formerly known as autoimmune pancreatitis (AIP), autoimmune sialadenitis, and autoimmune sclerosing cholangitis, are now considered organ-specific manifestations of systemic immunoglobulin G4-related disease (IgG4-RD). AIP and IgG4-RD are characterized by elevated serum concentration of IgG4 antibody (Ab), accumulation of IgG4-expressing plasmacytes in the affected organs, and involvement of multiple organs. It is well established that enhanced IgG4 Ab responses are a hallmark of AIP and IgG4-RD for diagnosis and monitoring disease activity. However, a significant fraction of patients with AIP and IgG4-RD who develop chronic fibroinflammatory responses have normal serum concentrations of this IgG subtype. In addition, disease flare-up is sometimes seen even in the presence of normalized serum concentrations of IgG4 Ab after successful induction of remission by prednisolone. Therefore, it is necessary to identify new biomarkers based on the understanding of the pathophysiology of AIP and IgG4-RD. Recently, we found that activation of plasmacytoid dendritic cells producing both interferon-α (IFN-α) and interleukin-33 (IL-33) mediate murine AIP and human IgG4-RD. More importantly, we provided evidence that serum concentrations of IFN-α and IL-33 could be useful biomarkers for the diagnosis and monitoring of AIP and IgG4-RD activity after induction of remission in these autoimmune disorders. In this Frontier article, we have summarized and discussed biomarkers of AIP and IgG4-RD, including Igs, autoAbs, and cytokines to provide useful information not only for clinicians but also for researchers.
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Affiliation(s)
- Akane Hara
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan
| | - Tomohiro Watanabe
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan
| | - Kosuke Minaga
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan
| | - Tomoe Yoshikawa
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan
| | - Ken Kamata
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Japan
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27
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Akiyama M, Suzuki K, Yoshimoto K, Yasuoka H, Kaneko Y, Takeuchi T. Peripheral TIGIT+ T Follicular Helper Cells That Produce High Levels of Interleukin-21 via OX40 Represent Disease Activity in IgG4-Related Disease. Front Immunol 2021; 12:651357. [PMID: 33936071 PMCID: PMC8079782 DOI: 10.3389/fimmu.2021.651357] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 03/26/2021] [Indexed: 12/16/2022] Open
Abstract
Objectives Multiple studies suggest that interleukin (IL)-21 plays a pivotal role in the differentiation of B cells and activation of cytotoxic T cells and is involved in the pathogenesis of IgG4-related disease (IgG4-RD). T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is a new marker of T follicular helper (Tfh) cells, yet its significance remains unknown. The objective of this study was to investigate whether TIGIT expression could detect high IL-21-producing peripheral Tfh populations and their association with disease activity in IgG4-RD. Methods TIGIT expression in peripheral CD4+T cell subsets was comprehensively analyzed by multi-color flow cytometry. Single cell mapping was performed by t-SNE method, and IL-21 production was compared in TIGIT+ and TIGIT-T cells. The effect of OX40 signal on cytokine expression was analyzed by RNA-sequencing. Clinical significance of TIGIT+ and TIGIT- peripheral T cells was analyzed in active patients with IgG4-RD, both at baseline and after 12 weeks of glucocorticoid treatment. Results Unbiased single cell mapping revealed two high IL-21-producing peripheral T cell populations; TIGIT+ Tfh and TIGIT-T helper cells. OX40 signal was associated with high IL-21 production in TIGIT+ Tfh and TIGIT-T helper cells. IL-21 production in Tfh cells correlated with the proportion of TIGIT+ cells in Tfh cells, serum IgG4 level, and scores of disease activity. Furthermore, the skewing toward peripheral TIGIT+ Tfh cells, particularly TIGIT+Tfh2 subset correlated with disease activity and was corrected by glucocorticoid treatment in IgG4-RD. Conclusions OX40 is associated with high IL-21 production in peripheral TIGIT+ Tfh cells, and the increase in peripheral TIGIT+ Tfh cells reflects disease activity in IgG4-RD.
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Affiliation(s)
- Mitsuhiro Akiyama
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Katsuya Suzuki
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Keiko Yoshimoto
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Hidekata Yasuoka
- Division of Rheumatology, Department of Internal Medicine, Fujita Health University School of Medicine, Aichi, Japan
| | - Yuko Kaneko
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Tsutomu Takeuchi
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
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28
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Characteristics and prognosis of IgG4-related skin disease: A case report and systematic literature review. Autoimmun Rev 2021; 20:102805. [PMID: 33727155 DOI: 10.1016/j.autrev.2021.102805] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 12/26/2020] [Indexed: 12/13/2022]
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29
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Increased Circulating Th1 and Tfh1 Cell Numbers Are Associated with Disease Activity in Glucocorticoid-Treated Patients with IgG4-Related Disease. J Immunol Res 2020; 2020:3757015. [PMID: 33313326 PMCID: PMC7721509 DOI: 10.1155/2020/3757015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 10/24/2020] [Accepted: 11/03/2020] [Indexed: 01/13/2023] Open
Abstract
Background This study is aimed at exploring the changes and significance of circulating Th and Tfh cell subsets in glucocorticoid-treated IgG4-RD patients. Methods 39 glucocorticoid-treated IgG4-RD patients and 22 healthy controls (HC) were enrolled. Peripheral blood mononuclear cells were separated, and circulating Th and Tfh cell subsets were examined by flow cytometry according to the surface and intranuclear markers. Disease activity was accessed by the IgG4-RD responder index (RI) score. Correlation analyses were conducted between Th/Tfh subset numbers and clinical indicators. The receiver operating characteristic (ROC) curve was used to evaluate the efficacy of Th and Tfh subsets to distinguish active IgG4-RD patients from remission IgG4-RD patients. Results Circulating Th1, Th17, Tfh1, and Tfh17 cells were significantly increased in active IgG4-RD patients compared with HC. Th1 and Tfh1 numbers were positively correlated with serum IgG4 levels in patients with IgG4-RD. Meanwhile, the absolute numbers of circulating Th1 and Tfh1 cells were positively correlated with IgG4-RD RI scores. The areas under the curve (AUC) were 0.8276 for Th1 and 0.7310 for Tfh1, 0.5862 for Tfh2, and 0.6810 for Tfh17. Conclusion Increased circulating Th1 and Tfh1 subsets are related to elevated serum IgG4 levels in active IgG4-RD patients during glucocorticoid treatment, which may play an important role in the course of IgG4-RD disease, and could be potential biomarkers for monitoring disease activity of IgG4-RD.
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31
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Kamata K, Watanabe T, Minaga K, Hara A, Yoshikawa T, Okamoto A, Yamao K, Takenaka M, Park AM, Kudo M. Intestinal dysbiosis mediates experimental autoimmune pancreatitis via activation of plasmacytoid dendritic cells. Int Immunol 2020; 31:795-809. [PMID: 31287532 DOI: 10.1093/intimm/dxz050] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 06/27/2019] [Indexed: 12/13/2022] Open
Abstract
Autoimmune pancreatitis (AIP) is a pancreatic manifestation of a newly proposed disease entity, IgG4-related disease (IgG4-RD), characterized by enhanced IgG4 antibody responses and involvement of multiple organs. We have previously reported that innate immune activation contributes to the development of AIP and IgG4-RD, as these diseases are characterized by the production of IFN-α and IL-33 by plasmacytoid dendritic cells (pDCs) that mediate chronic fibroinflammatory responses. In this study, we investigated the roles played by innate immunity against intestinal microflora in experimental AIP induced in MRL/MpJ mice by repeated administrations of 100 µg of polyinosinic-polycytidylic acid [poly (I:C)]. Bowel sterilization with a broad spectrum of antibiotics inhibited pancreatic accumulation of pDCs producing IFN-α and IL-33, and thereby suppressed the development of AIP. Mice treated with 10 µg of poly (I:C) developed severe AIP equivalent to that induced by 100 µg of poly (I:C) upon co-housing with mice treated with 100 µg of poly (I:C). Fecal microbiota transplantation (FMT) from donor mice treated with 100 µg of poly (I:C) led to the development of severe AIP in the recipient mice upon injection with 10 µg of poly (I:C). Induction of severe AIP in mice with 10 µg of poly (I:C) was associated with pancreatic accumulation of pDCs producing IFN-α and IL-33 in the co-housing and FMT experiments. These data collectively suggest that innate immune responses against intestinal microflora are involved in the development of experimental AIP, and that intestinal dysbiosis increases sensitivity to experimental AIP via activation of pDCs.
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Affiliation(s)
- Ken Kamata
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Tomohiro Watanabe
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Kosuke Minaga
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Akane Hara
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Tomoe Yoshikawa
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Ayana Okamoto
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Kentaro Yamao
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Mamoru Takenaka
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Ah-Mee Park
- Department of Microbiology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
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De Sainte Marie B, Urban ML, Vély F, Seguier J, Grados A, Daniel L, Ebbo M, Schleinitz N. Pathophysiology of IgG4-related disease: A T follicular helper cells disease? Presse Med 2020; 49:104013. [PMID: 32234383 DOI: 10.1016/j.lpm.2020.104013] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 03/05/2019] [Accepted: 03/05/2019] [Indexed: 02/06/2023] Open
Abstract
IgG4-related disease is a chronic inflammatory disease characterized by clinical, biological and pathological unifying findings. Because these criteria are not always all together available in patients and because biological and pathological markers are not totally specific, the diagnosis should be retained after exclusion of mimickers. Since the individualization of IgG4-RD, several studies have allowed to better characterize immunological abnormalities associated with this particular condition. B and T cell oligoclonal activation is associated with T helper 2 cytokine production leading to IgG4 production and profibrotic cytokine release. A central role for T follicular helper 2 cells is suggested from recent findings. We summarize here recent advances in understanding of immune abnormalities in IgG4-related disease.
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Affiliation(s)
- Benjamin De Sainte Marie
- Département de médecine interne, Hôpital de la Timone, AP-HM, Aix-Marseille Université, 13005 Marseille, France
| | - Maria Laetizia Urban
- Département de médecine interne, Hôpital de la Timone, AP-HM, Aix-Marseille Université, 13005 Marseille, France
| | - Frédéric Vély
- Aix-Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, 13009 Marseille, France; Immunology, Marseille Immunopole, Hôpital de la Timone, Assistance publique-Hôpitaux de Marseille, 13009 Marseille, France
| | - Julie Seguier
- Département de médecine interne, Hôpital de la Timone, AP-HM, Aix-Marseille Université, 13005 Marseille, France
| | - Aurélie Grados
- Service de médecine interne, CH de Niort, 79000 Niort, France
| | - Laurent Daniel
- Service d'anatomopathologie, Hôpital de la Timone, AP-HM, Aix-Marseille Université, 13005 Marseille, France
| | - Mikael Ebbo
- Département de médecine interne, Hôpital de la Timone, AP-HM, Aix-Marseille Université, 13005 Marseille, France
| | - Nicolas Schleinitz
- Département de médecine interne, Hôpital de la Timone, AP-HM, Aix-Marseille Université, 13005 Marseille, France.
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Yabe H, Kamekura R, Yamamoto M, Murayama K, Kamiya S, Ikegami I, Shigehara K, Takaki H, Chiba H, Takahashi H, Takano K, Takahashi H, Ichimiya S. Cytotoxic Tph-like cells are involved in persistent tissue damage in IgG4-related disease. Mod Rheumatol 2020; 31:249-260. [PMID: 32023137 DOI: 10.1080/14397595.2020.1719576] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES The aim of this study was to determine pathological features of T peripheral helper (Tph)-like (PD-1+CXCR5-CD4+ T) cells in IgG4-related disease (IgG4-RD). METHODS Tph-like cells in the blood and submandibular glands (SMGs) from IgG4-RD patients were analyzed by flow cytometry. Correlations between level of a Tph-like cell subset and clinical parameters of IgG4-RD were investigated. The cytotoxic capacity of Tph-like cells was also examined. Expression profiles of a molecule related to a Tph-like cell subset in IgG4-RD SMGs were assessed by immunohistochemistry. RESULTS Tph-like cells from IgG4-RD patients highly expressed a fractalkine receptor, CX3CR1. Percentages of circulating CX3CR1+ Tph-like cells were significantly correlated with clinical parameters including IgG4-RD Responder Index, number of involved organs, and serum level of soluble IL-2 receptor. CX3CR1+ Tph-like cells abundantly possessed cytotoxic T lymphocyte-related molecules such as granzyme A, perforin, and G protein-coupled receptor 56. Functional assays revealed their cytotoxic potential against vascular endothelial cells and ductal epithelial cells. Immunohistochemistry showed that fractalkine was markedly expressed in vascular endothelial cells and ductal epithelial cells in IgG4-RD SMGs. CONCLUSION CX3CR1+ Tph-like cells are thought to contribute to persistent tissue injury in IgG4-RD and are a potential clinical marker and/or therapeutic target for inhibiting progression of IgG4-RD.
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Affiliation(s)
- Hayato Yabe
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Ryuta Kamekura
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan, Sapporo, Japan
| | - Motohisa Yamamoto
- Department of Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kosuke Murayama
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan, Sapporo, Japan
| | - Shiori Kamiya
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Ippei Ikegami
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Katsunori Shigehara
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiromi Takaki
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hirofumi Chiba
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiroki Takahashi
- Department of Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kenichi Takano
- Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan, Sapporo, Japan
| | - Hiroki Takahashi
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Shingo Ichimiya
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
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Maehara T, Moriyama M, Nakamura S. Review of a novel disease entity, immunoglobulin G4-related disease. J Korean Assoc Oral Maxillofac Surg 2020; 46:3-11. [PMID: 32158675 PMCID: PMC7049757 DOI: 10.5125/jkaoms.2020.46.1.3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 01/06/2020] [Indexed: 12/20/2022] Open
Abstract
Immunoglobulin G4 (IgG4)-related dacryoadenitis and sialoadenitis (IgG4-DS) are part of a multiorgan fibroinflammatory condition of unknown etiology termed IgG4-related disease (IgG4-RD), which has been recognized as a single diagnostic entity for less than 15 years. Histopathologic examination is critical for diagnosis of IgG4-RD. CD4+ T and B cells, including IgG4-expressing plasma cells, constitute the major inflammatory cell populations in IgG4-RD and are thought to cause organ damage and tissue fibrosis. Patients with IgG4-RD who have active, untreated disease exhibit significant increase of IgG4-secreting plasmablasts in the blood. Considerable insight into the immunologic mechanisms of IgG4-RD has been achieved in the last decade using novel molecular biology approaches, including next-generation and single-cell RNA sequencing. Exploring the interactions between CD4+ T cells and B lineage cells is critical for understanding the pathophysiology of IgG4-RD. Establishment of pathogenic T cell clones and identification of antigens specific to these clones constitutes the first steps in determining the pathogenesis of the disease. Herein, the clinical features and mechanistic insights regarding pathogenesis of IgG4-RD were reviewed.
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Affiliation(s)
- Takashi Maehara
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Masafumi Moriyama
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Seiji Nakamura
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
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Borges T, Silva S. IgG4-related disease: How to place it in the spectrum of immune-mediated and rheumatologic disorders? Mod Rheumatol 2020; 30:609-616. [PMID: 31852351 DOI: 10.1080/14397595.2019.1705537] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory disorder that results from massive expansion of polyclonal IgG4-switched B and/or plasma cells. It can virtually affect all organs and its diagnosis relies on clinical, serological and histopathological criteria. The role of autoimmunity and adaptive immune system in IgG4-RD is reflected in plasmablast differentiation, germinal center formation and IgG4 production induced by CD4+ cells expressing CD40 ligand. IgG4-RD has been considered to be a Th2/Treg-driven disorder, but follicular helper T cells are important in driving the IgG subclass switch. Prompt clinical responses to rituximab, human leukocyte antigen (HLA) associations and the presence of autoantibodies also point to the importance of adaptive immune system. However, innate immunity may induce storiform fibrosis through T-cell independent responses as a consequence of toll-like receptors activation by microbe-and damage-associated molecular patterns, while macrophages and basophils also appear to have a significant role in IgG4-RD pathogenesis. Allergic mechanisms may drive IgG4-RD, but only a subgroup has elevated IgE serum levels and peripheral eosinophilia. Finally, the 2012 revised Chapel Hill Consensus Conference nomenclature pointed IgG4-RD as a cause of large-vessel vasculitis. This review aims to discuss how to place IgG4-RD in the spectrum of immune-mediated and rheumatologic disorders.
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Affiliation(s)
- Tiago Borges
- Department of Internal Medicine, Trofa Saúde Hospital Privado de Gaia, Vila Nova de Gaia, Portugal
| | - Sérgio Silva
- Department of Internal Medicine, Trofa Saúde Hospital Privado de Gaia, Vila Nova de Gaia, Portugal
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Miyajima S, Shigehara K, Kamekura R, Takaki H, Yabe H, Ikegami I, Asai Y, Nishikiori H, Chiba H, Uno E, Takahashi H, Ichimiya S. Activated circulating T follicular helper cells and skewing of T follicular helper 2 cells are down-regulated by treatment including an inhaled corticosteroid in patients with allergic asthma. Allergol Int 2020; 69:66-77. [PMID: 31648923 DOI: 10.1016/j.alit.2019.08.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 08/09/2019] [Accepted: 08/21/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND CXCR5+ T follicular helper (TFH) cells primarily promote B cells to produce an antigen-specific antibody through germinal centers (GCs). TFH cells exist in circulation, and circulating(c) TFH2 cells, a subset of cTFH cells, are able to help naïve B cells produce IgE in healthy individuals. Conversely, IL-10-producing regulatory B (Breg) cells inhibit an accelerated immune response. METHODS We investigated the roles of cTFH cells and cBreg cells based on a TH2 response in patients with atopic asthma (AA). Thirty-two patients with AA and 35 healthy volunteers (HV) were enrolled. We examined cTFH cells including their subsets, their expression of ICOS and PD-1, and cBreg cells by flow cytometry and their associations with clinical biomarkers. Plasma levels of CXCL13, which is a counterpart of CXCR5, were also measured using ELISA. RESULTS In patients with AA, cTFH2 cells were increased and cTFH1 cells were decreased compared with those in HV. The expression levels of ICOS on cTFH and their subset cells were elevated and Breg cells were greatly decreased. The plasma levels of CXCL13 in patients with AA were significantly elevated and correlated well with the cTFH2/cBreg ratio. These cells were examined in 10 patients AA before and after inhaled corticosteroid (ICS) treatment. Interestingly, the percentages and numbers of TFH2 and ICOS+ cTFH cells declined after ICS treatment together with improvements in symptoms and clinical biomarkers. CONCLUSIONS The percentages and numbers of cTFH2 and ICOS+ cTFH cells might be useful as biomarkers of TH2 typed airway inflammation in patients with AA.
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HIF1α-Dependent Metabolic Signals Control the Differentiation of Follicular Helper T Cells. Cells 2019; 8:cells8111450. [PMID: 31744227 PMCID: PMC6912655 DOI: 10.3390/cells8111450] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 11/14/2019] [Accepted: 11/15/2019] [Indexed: 12/12/2022] Open
Abstract
Follicular helper T (TFH) cells are critical for germinal center (GC) formation and are responsible for effective B cell-mediated immunity; metabolic signaling is an important regulatory mechanism for the differentiation of TFH cells. However, the precise roles of hypoxia inducible factor (HIF) 1α-dependent glycolysis and oxidative phosphorylation (OXPHOS) metabolic signaling remain unclear in TFH cell differentiation. Herein, we investigated the effects of glycolysis and OXPHOS on TFH cell differentiation and GC responses using a pharmacological approach in mice under a steady immune status or an activated immune status, which can be caused by foreign antigen stimulation and viral infection. GC and TFH cell responses are related to signals from glycolytic metabolism in mice of different ages. Foreign, specific antigen-induced GC, and TFH cell responses and metabolic signals are essential upon PR8 infection. Glycolysis and succinate-mediated OXPHOS are required for the GC response and TFH cell differentiation. Furthermore, HIF1α is responsible for glycolysis- and OXPHOS-induced alterations in the GC response and TFH cell differentiation under steady or activated conditions in vivo. Blocking glycolysis and upregulating OXPHOS signaling significantly recovered TFH cell differentiation upon PR8 infection and ameliorated inflammatory damage in mice. Thus, our data provide a comprehensive experimental basis for fully understanding the precise roles of HIF1α-mediated glycolysis and OXPHOS metabolic signaling in regulating the GC response and TFH cell differentiation during stable physiological conditions or an antiviral immune response.
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Asai Y, Chiba H, Nishikiori H, Kamekura R, Yabe H, Kondo S, Miyajima S, Shigehara K, Ichimiya S, Takahashi H. Aberrant populations of circulating T follicular helper cells and regulatory B cells underlying idiopathic pulmonary fibrosis. Respir Res 2019; 20:244. [PMID: 31694639 PMCID: PMC6836348 DOI: 10.1186/s12931-019-1216-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 10/15/2019] [Indexed: 12/17/2022] Open
Abstract
Background T follicular helper (Tfh) cells have been identified as a new category of helper T cells, which express CXCR5 on their surface and induce the production of antigen-specific antibodies. Many investigations have found morbid proliferation and/or activation of Tfh cells in systemic autoimmune and allergic diseases. It is also known that Tfh cells are regulated by regulatory B (Breg) cells in the deteriorating such diseases. Recently, CXCL13, a ligand of CXCR5, has been reported to increase in the peripheral blood and lungs of patients with idiopathic pulmonary fibrosis (IPF). This study aimed to investigate the involvement of Tfh cells and Breg cells in IPF. Methods Peripheral blood samples were obtained from 18 patients with IPF. We isolated heparinized peripheral blood mononuclear cells and investigated the proportions of Breg cells, Tfh cells, PD-1+ICOS+ Tfh cells (activated form of Tfh cells), and the Tfh-cell subsets by flow cytometry. These cell profiles were compared with those of 21 healthy controls. Furthermore, we investigated the correlations between profiles of lymphocytes and lung physiology. Results The median proportions of Tfh cells per total CD4+ T cells and of PD-1+ICOS+ proportion of Tfh cells per total Tfh cells was significantly more in the IPF patients (20.4 and 5.2%, respectively) compared with healthy controls (15.4 and 2.1%, respectively; p = 0.042 and p = 0.004, respectively). The proportion of Tfh2 cells per total Tfh cells was significantly higher and the proportion of Tfh17 was smaller in the IPF patients than healthy controls. The percentage of Breg cells to total B cells was significantly decreased in the IPF patients (median, 8.5%) compared with that in the controls (median, 19.7%; p < 0.001). The proportion of Breg cells was positively correlated with the annual relative change in diffusing capacity of the lungs for carbon monoxide in the IPF patients (r = 0.583, p = 0.018). Conclusion Proliferation and activation of Tfh cells and a decrease in Breg cells were observed in the peripheral blood of patients with IPF. The profile of the Tfh-cell subset also changed. Specific humoral immunity aberration would likely underlie complicated pathophysiology of IPF.
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Affiliation(s)
- Yuichiro Asai
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Hirofumi Chiba
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.
| | - Hirotaka Nishikiori
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Ryuta Kamekura
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.,Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hayato Yabe
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.,Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Shun Kondo
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Satsuki Miyajima
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Katsunori Shigehara
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.,Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Shingo Ichimiya
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiroki Takahashi
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
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Class-switched Primary Cutaneous Marginal Zone Lymphomas Are Frequently IgG4-positive and Have Features Distinct From IgM-positive Cases. Am J Surg Pathol 2019; 43:1403-1412. [DOI: 10.1097/pas.0000000000001363] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Tang J, Cai S, Ye C, Dong L. Biomarkers in IgG4-related disease: A systematic review. Semin Arthritis Rheum 2019; 50:354-359. [PMID: 31280934 DOI: 10.1016/j.semarthrit.2019.06.018] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 06/17/2019] [Accepted: 06/24/2019] [Indexed: 12/17/2022]
Abstract
OBJECTIVE ImmunoglobulinG4-related disease (IgG4-RD) is a recently recognized disease and, as such, there is a pressing need to identify biomarkers for diagnosis, monitoring disease activity, and predicting prognosis and response to therapy. Here, we review the recent development and identification of biomarkers for IgG4-RD. METHODS Through extensive literature review and analysis, we updated the biomarkers for IgG4-RD and further put forward our own viewpoints. RESULTS In addition to traditional biomarkers, such as serum IgG4 concentration and typical histological characteristics, several novel indicators, including IgG2, serum soluble IL-2 receptor (sIL2R), and cc-chemokine ligand 18 (CCL18), indicate inflammation and fibrosis and can be used to accurately diagnose and predict treatment response. Studies to identify target autoantigens in IgG4-RD have shed light on the unmet need for biomarkers that can identify this disorder. Additionally, both serological and histopathologic immune cells involved in antigen-induced responses, innate immune cells (macrophages, mast cells, and the I-IFN/ IL-33 pathway), as well as subsequent acquired immune cells (T and B cell subsets), may also serve as new biomarkers for IgG4-RD. Since IgG4-RD often clinically manifests with multiple organs involvement, non-invasive PET-CT can improve diagnosis and antidiastole levels. CONCLUSION These novel biomarkers provide information to help diagnose IgG4-RD, monitor disease activity, as well as predict prognosis and response to therapy.
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Affiliation(s)
- Jungen Tang
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shaozhe Cai
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Cong Ye
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| | - Lingli Dong
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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Activated T-Follicular Helper 2 Cells Are Associated With Disease Activity in IgG4-Related Sclerosing Cholangitis and Pancreatitis. Clin Transl Gastroenterol 2019; 10:e00020. [PMID: 31033594 PMCID: PMC6602789 DOI: 10.14309/ctg.0000000000000020] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) and autoimmune pancreatitis (AIP) are characterized by an abundance of circulating and tissue IgG4-positive plasma cells. T-follicular helper (Tfh) cells are necessary for B-cell differentiation into plasma cells. We aimed at elucidating the presence and phenotype of Tfh cells and their relationship with disease activity in IgG4-SC/AIP.
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Çebi M, Durmuş H, Yılmaz V, Yentür SP, Aysal F, Oflazer P, Parman Y, Deymeer F, Saruhan-Direskeneli G. Relation of HLA-DRB1 to IgG4 autoantibody and cytokine production in muscle-specific tyrosine kinase myasthenia gravis (MuSK-MG). Clin Exp Immunol 2019; 197:214-221. [PMID: 30929252 DOI: 10.1111/cei.13302] [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: 03/27/2019] [Indexed: 12/12/2022] Open
Abstract
A small subset of myasthenia gravis (MG) patients develop autoantibodies against muscle-specific kinase (MuSK), which are predominantly of the immunoglobulin (Ig)G4 isotype. MuSK-MG is strongly associated with HLA-DRB1*14, HLA-DRB1*16 and HLA-DQB1*05. In this study, the possible effects of these HLA associations on MuSK IgG autoantibody or cytokine production were investigated. Samples from 80 MG patients with MuSK antibodies were studied. The disease-associated HLA types were screened in the DNA samples. The IgG1, IgG2, IgG3 and IgG4 titres of the MuSK antibodies and the levels of interleukin (IL)-4, IL-6, IL-17A and IL-10 were measured in the sera. Comparisons were made among the groups with or without HLA-DRB1*14, HLA-DRB1*16 or HLA-DQB1*05. The IgG4 titres of the MuSK antibodies were higher than those of the IgG1, IgG2 and IgG3 isotypes among the whole group of patients. DRB1*14 (+) DRB1*16 (-) patients had higher levels of IgG4 antibodies than those of DRB1*14 (-) DRB1*16 (+) patients. DRB1*14 (+) DRB1*16 (+) patients also had higher levels of IgG4 antibodies than those of DRB1*14 (-) DRB1*16 (+) and DRB1*14 (-) DRB1*16 (-) patients. Higher IL-10 and lower IL-17A levels were measured in DRB1*14 (+) DRB1*16 (-) patients than in DRB1*14 (-) DRB1*16 (-) patients. The higher IgG4 titres of MuSK autoantibodies in patients carrying HLA-DRB1*14 than those in the other patients suggest a role for HLA in the production of the antibodies. The differences in IL-10 and IL-17A support the role of DRB1 in the etiopathogenesis of this autoimmune response.
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Affiliation(s)
- M Çebi
- Department of Physiology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
| | - H Durmuş
- Department of Neurology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
| | - V Yılmaz
- Department of Physiology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
| | - S P Yentür
- Department of Physiology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
| | - F Aysal
- Department of Neurology, Bakirkoy Research and Training Hospital for Psychiatric and Neurological Diseases, Istanbul, Turkey.,Department of Neurology, Istanbul Medipol University School of Medicine, Istanbul, Turkey
| | - P Oflazer
- Department of Neurology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
| | - Y Parman
- Department of Neurology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
| | - F Deymeer
- Department of Neurology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
| | - G Saruhan-Direskeneli
- Department of Physiology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
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Ito F, Kamekura R, Yamamoto M, Takano K, Takaki H, Yabe H, Ikegami I, Shigehara K, Himi T, Takahashi H, Ichimiya S. IL-10+ T follicular regulatory cells are associated with the pathogenesis of IgG4-related disease. Immunol Lett 2019; 207:56-63. [DOI: 10.1016/j.imlet.2019.01.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 11/30/2018] [Accepted: 01/14/2019] [Indexed: 12/24/2022]
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Abstract
In 1982, we reported a case of retroperitoneal fibrosis (RPF) exhibiting various clinical manifestations. Our current understanding of immunoglobulin G4 (IgG4)-related disease led us to consider it as a possible diagnosis because all of the patient's clinical features could be explained by this disease entity. To confirm our hypothesis, were investigated the histopathological findings of resected specimens that had been stored for 35 years postoperatively. Typical pathological findings together with predominant IgG4+ plasma cell infiltration confirmed a potential diagnosis of IgG4-related RPF. Furthermore, we observed positive immunohistochemical staining for several molecules associated with T regulatory and T follicular helper cells.
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Affiliation(s)
- Satoshi Konno
- First Department of Medicine, Hokkaido University School of Medicine, Japan
| | - Yoshihiro Matsuno
- Department of Surgical Pathology, Hokkaido University Hospital, Japan
| | - Shingo Ichimiya
- Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Japan
| | - Masaharu Nishimura
- First Department of Medicine, Hokkaido University School of Medicine, Japan
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Abstract
PURPOSE OF REVIEW New insights into IgG4-related disease (IgG4-RD) have recently been obtained. A better understanding of the mechanisms underlying this disease is important for identification of therapeutic targets, which will lead to the development of specific strategies for treatment. RECENT FINDINGS Infiltration of activated T follicular helper (Tfh) cells is observed in affected tissues of IgG4-RD. Such Tfh cells have a greater capacity than tonsillar Tfh cells to help B cells produce IgG4. Circulating PD-1CXCR5 peripheral T helper (Tph)-like cells are also increased in patients with IgG4-RD. Because Tph-like cells express high levels of chemokine receptors and granzyme A, they have the capacity to infiltrate affected tissues and exert a cytotoxic function. Tph-like cells can also produce CXCL13, and CXCR5 Tfh cells and B cells are therefore preferentially recruited to form ectopic lymphoid structures in the sites. Tph cells may have a role to ignite inflammation and maintain persistent fibroinflammation in collaboration with Tfh cells in lesions of IgG4-RD. SUMMARY Recent advances in understanding the pathogenesis of IgG4-RD are remarkable. In this review, we summarize and discuss the possible pathologic role of CD4 T-cell subsets in IgG4-RD.
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Affiliation(s)
- Ryuta Kamekura
- Department of Human Immunology, Research Institute for Frontier Medicine
- Department of Otolaryngology
| | - Hiroki Takahashi
- Department of Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Shingo Ichimiya
- Department of Human Immunology, Research Institute for Frontier Medicine
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Yoshikawa T, Watanabe T, Minaga K, Kamata K, Kudo M. Cytokines produced by innate immune cells in IgG4-related disease. Mod Rheumatol 2018; 29:219-225. [PMID: 30334477 DOI: 10.1080/14397595.2018.1536364] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
IgG4-related disease (IgG4-RD) is a newly defined multi-organ disease proposed by Japanese physicians. IgG4-RD is characterized by elevated serum levels of IgG4 and massive infiltration of IgG4-expressing plasma cells in the affected organs. Recent studies have shown that abnormal adaptive immune responses mediated by T helper type 2 cells, regulatory T cells, follicular helper T cells, cytotoxic CD4+ T cells, and plasmablasts are involved in IgG4-RD immunopathogenesis. In addition to adaptive immune responses, innate immune responses play pathogenic roles in IgG4-RD. Plasmacytoid dendritic cells (pDCs), M2 macrophages, and basophils are activated to produce various kinds of cytokines in IgG4-RD. Recent studies highlight the importance of type I IFN and IL-33 produced by pDCs in IgG4-RD immunopathogenesis.
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Affiliation(s)
- Tomoe Yoshikawa
- a Department of Gastroenterology and Hepatology , Kindai University Faculty of Medicine , Osaka , Japan
| | - Tomohiro Watanabe
- a Department of Gastroenterology and Hepatology , Kindai University Faculty of Medicine , Osaka , Japan
| | - Kosuke Minaga
- a Department of Gastroenterology and Hepatology , Kindai University Faculty of Medicine , Osaka , Japan
| | - Ken Kamata
- a Department of Gastroenterology and Hepatology , Kindai University Faculty of Medicine , Osaka , Japan
| | - Masatoshi Kudo
- a Department of Gastroenterology and Hepatology , Kindai University Faculty of Medicine , Osaka , Japan
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Touzani F, Pozdzik A. New insights into immune cells cross-talk during IgG4-related disease. Clin Immunol 2018; 198:1-10. [PMID: 30419354 DOI: 10.1016/j.clim.2018.11.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 09/25/2018] [Accepted: 11/09/2018] [Indexed: 12/24/2022]
Abstract
Immunoglobulin G4-related disease (IgG4-RD) is a newly acknowledged entity, characterized by an immune-mediated fibro-inflammatory process affecting virtually all organs, with infiltration of IgG4+ bearing plasma cells. Until today the pathogenesis of IgG4-RD remains unknown. Treatment with anti-CD20 monoclonal antibodies efficiently induced remission and attenuated the secretory phenotype of myofibroblasts responsible of uncontrolled collagen deposition. This supports the pathogenic role of the adaptive immunity, particularly B cell compartment and B cell/T cell interaction. Latest studies have also highlighted the importance of innate immune system that has been underestimated before and the key role of a specific T cell subset, T follicular helper cells that are involved in IgG4-class-switching and plasmablast differentiation. In this review, we aim to review the most recent knowledge of innate immunity, T and B cells involvement in IgG4-RD, and introduce tertiary lymphoid organs (TLO) as a potential marker of relapse in this condition.
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Affiliation(s)
- Fahd Touzani
- Internal medicine department, Hospital Brugmann, Brussels, Belgium; Nephrology and dialysis clinic, Hospital Brugmann, Brussels, Belgium.
| | - Agnieszka Pozdzik
- Nephrology and dialysis clinic, Hospital Brugmann, Brussels, Belgium; Faculty of Medicine, Université Libre de Bruxelles (ULB), Brussels, Belgium
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48
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Grunebaum E, Avitzur Y. Liver-associated immune abnormalities. Autoimmun Rev 2018; 18:15-20. [PMID: 30408587 DOI: 10.1016/j.autrev.2018.06.016] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Accepted: 06/30/2018] [Indexed: 01/19/2023]
Abstract
In recent years, the cross talk between the liver and the immune system is being uncovered, in part by studying liver involvement in primary immune deficiencies (PID) and in part by investigating the alterations of the immune system following orthotopic liver transplantation (OLT). Here we review some of the reciprocal interactions between the liver and the immune system. Patients with PID, particularly those involving inherited defects in T and B cells or innate immunity are prone to infections and inflammatory responses that often involve the liver. Omenn's syndrome, familial hemophagocytic lymphohistiocytosis, AIRE, FOXP3 and CD25 deficiencies, common variable immunodeficiency, CD40 ligand deficiency, chronic granulomatous disease and autoimmune lymphoproliferative syndrome are some of the notable PID associated with typical hepatobiliary abnormalities. Knowledge gained from studying these PID together with laboratory and histological evaluations can assist in managing PID-associated liver dysfunction. The liver itself also has important effects on the immune system, as evident from the growing experience with patients surviving OLT. Up to 40% of pediatric patients who receive OLT suffer from post transplantation allergy, autoimmunity, and immune-mediated disorders (PTAA). PTAA is more common after liver and heart transplantations than kidney transplantations. Potential contributing factors for the increased frequency of PTAA after OLT include the age of the patients, the prolonged use of tacrolimus and the reduced regulatory immune function with a shift towards a TH2 immune response. Better understanding of the mechanisms leading to the development of PTAA after OLT will also improve the management of these conditions.
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Affiliation(s)
- Eyal Grunebaum
- Division of Immunology and Allergy, Department of Pediatrics, Hospital for Sick Children, Toronto, Canada; The Food Allergy and Anaphylaxis Program, Hospital for Sick Children, Toronto, Ontario, Canada; University of Toronto, Toronto, Ontario, Canada.
| | - Yaron Avitzur
- University of Toronto, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Hospital for Sick Children, Toronto, Canada
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Watanabe T, Minaga K, Kamata K, Kudo M, Strober W. Mechanistic Insights into Autoimmune Pancreatitis and IgG4-Related Disease. Trends Immunol 2018; 39:874-889. [PMID: 30401468 DOI: 10.1016/j.it.2018.09.005] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 09/12/2018] [Accepted: 09/13/2018] [Indexed: 12/15/2022]
Abstract
Autoimmune pancreatitis (AIP) is a pancreatic manifestation of a recently defined disease form known as IgG4-related disease (AIP/IgG4-RD). AIP/IgG4-RD is characterized by elevated systemic IgG4 antibody concentrations and lesional tissues infiltrated by IgG4-expressing plasmacytes. In addition, recent studies have revealed that, in common with other autoimmune diseases, such as systemic lupus erythematosus (SLE) and psoriasis, AIP/IgG4-RD is associated with increased type I IFN (IFN-I) production by plasmacytoid dendritic cells (pDCs). However, unlike SLE, AIP/IgG4-RD is characterized by elevated IFN-I-dependent IL-33 production, the latter emerging as an important contributor to inflammation and fibrotic responses characterizing this disease. On this basis, we propose that blockade of the IFN-I/IL-33 axis might constitute a successful approach to treating this unique type of autoimmunity.
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Affiliation(s)
- Tomohiro Watanabe
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan; Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Kosuke Minaga
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan
| | - Ken Kamata
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan
| | - Warren Strober
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
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50
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Zhao J, Chen Y, Zhao Q, Shi J, Yang W, Zhu Z, Yu W, Guan J, Song Y, Wu H, Jin W, Zhou Y, Liu J. Increased circulating Tfh17 and PD-1 +Tfh cells are associated with autoantibodies in Hashimoto's thyroiditis. Autoimmunity 2018; 51:352-359. [PMID: 30345813 DOI: 10.1080/08916934.2018.1516761] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Hashimoto's thyroiditis (HT) is characterized by autoantibodies targeting the thyroid. Abnormal CD4+CXCR5+T cell levels were previously shown to be associated with HT. However, Tfh cells consist of heterogeneous subpopulations, and which T follicular helper (Tfh) cell subpopulation participates in the pathogenesis of HT remains poorly understood. METHODS Thirty healthy controls (HCs) and 52 HT patients were enrolled in the study. The percentages of Tfh, ICOS+Tfh, PD1+Tfh, Tfh1, Tfh2, Tfh17, effector Tfh, resting Tfh, effector memory Tfh, central memory Tfh, and naïve Tfh cells in the peripheral blood were all determined via flow cytometry, and the associations between the percentages of these cells and thyroid function indices were also investigated. RESULTS The percentage of Tfh cells was significantly higher in HT patients than in HCs. Examination of the Tfh cell subsets revealed that the percentages of Tfh1, Tfh2, and resting Tfh cells were significantly decreased, while those of the ICOS+Tfh, PD1+Tfh, Tfh17, and effector Tfh cells were significantly increased in HT patients. No significant differences in effector memory, central memory or naïve Tfh cell percentages were noted between the HC and HT groups. Furthermore, the percentage of PD1+Tfh cells was positively correlated with anti-thyroglobulin antibody levels. Most importantly, only Tfh17 cell percentages were positively correlated with anti-thyroglobulin and anti-thyroid peroxidase antibody levels and were negatively correlated serum free T3 and free T4 levels in HT patients. CONCLUSIONS Increased circulating Tfh17 cell and PD1+Tfh percentages are associated with higher autoantibody levels in HT patients, which imply that Tfh17 or PD1+Tfh cells may play a pathogenic role in the development of HT.
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Affiliation(s)
- Jiwei Zhao
- a Department of Clinical Laboratory , Zhejiang Sian International Hospital , Jiaxing , PR China
| | - Yanxia Chen
- b Department of Rheumatology , Zhejiang Provincial People's Hospital, Hangzhou Medical College , Hangzhou , PR China
| | - Qing Zhao
- c Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine , Shanghai JiaoTong University Affiliated Sixth People's Hospital , Shanghai , PR China
| | - Jie Shi
- d Department of Clinical Laboratory , Cixi People's Hospital , Cixi , PR China
| | - Wei Yang
- e Department of Clinical Laboratory , Zhejiang Provincial People's Hospital, Hangzhou Medical College , Hangzhou , PR China
| | - Zhongliang Zhu
- e Department of Clinical Laboratory , Zhejiang Provincial People's Hospital, Hangzhou Medical College , Hangzhou , PR China
| | - Wenge Yu
- e Department of Clinical Laboratory , Zhejiang Provincial People's Hospital, Hangzhou Medical College , Hangzhou , PR China
| | - Jinju Guan
- e Department of Clinical Laboratory , Zhejiang Provincial People's Hospital, Hangzhou Medical College , Hangzhou , PR China
| | - Yingxiang Song
- f Department of Endocrinology , Zhejiang Provincial People's Hospital, Hangzhou Medical College , Hangzhou , PR China
| | - Hui Wu
- f Department of Endocrinology , Zhejiang Provincial People's Hospital, Hangzhou Medical College , Hangzhou , PR China
| | - Weidong Jin
- e Department of Clinical Laboratory , Zhejiang Provincial People's Hospital, Hangzhou Medical College , Hangzhou , PR China
| | - Yonglie Zhou
- e Department of Clinical Laboratory , Zhejiang Provincial People's Hospital, Hangzhou Medical College , Hangzhou , PR China
| | - Jinlin Liu
- e Department of Clinical Laboratory , Zhejiang Provincial People's Hospital, Hangzhou Medical College , Hangzhou , PR China.,g Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province , Hangzhou , PR China
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