|
1
|
Chen S, Dan L, Xiang L, He Q, Hu D, Gao Y. The role of gut flora-driven Th cell responses in preclinical rheumatoid arthritis. J Autoimmun 2025; 154:103426. [PMID: 40300482 DOI: 10.1016/j.jaut.2025.103426] [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: 12/03/2024] [Revised: 03/24/2025] [Accepted: 04/22/2025] [Indexed: 05/01/2025]
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder with an immune pathogenesis that evolves over decades. Preclinical RA (PreRA) represents a dynamic immune phase preceding clinical RA, marked by the loss of autoimmune tolerance, the appearance of tissue-invasive effector T cells, and the production of autoantibodies (such as antibodies against citrullinated proteins and rheumatoid factors). Extensive research has demonstrated that gut microbiota influence mucosal T-cell responses, driving the progression of PreRA through multiple mechanisms, including altered intestinal permeability, gene-environment interactions, bacterial antigenic specificity, molecular mimicry, and metabolite production. Environmental risk factors such as smoking, hormonal changes, and high-sodium (Na) diets, may contribute to RA pathogenesis via the gut microbiome. The next challenge in RA research lies in developing therapeutic strategies to intervene during the asymptomatic autoimmune phase, where dietary adjustments, natural compounds, probiotics, and other approaches could effectively modulate gut flora to prevent or delay RA onset.
Collapse
Affiliation(s)
- Shuanglan Chen
- Department of Rheumatology and Immunology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Lijuan Dan
- Department of Infection, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Li Xiang
- Department of Rheumatology and Immunology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Qingman He
- Department of Rheumatology and Immunology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Dongsen Hu
- Sichuan Jinxin Xi'nan Women's and Children's Hospital Co., Ltd, Chengdu, 610023, China
| | - Yongxiang Gao
- Department of Rheumatology and Immunology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
| |
Collapse
|
|
2
|
Christodoulou M, Moysidou E, Lioulios G, Stai S, Lazarou C, Xochelli A, Fylaktou A, Stangou M. T-Follicular Helper Cells and Their Role in Autoimmune Diseases. Life (Basel) 2025; 15:666. [PMID: 40283219 PMCID: PMC12028949 DOI: 10.3390/life15040666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 04/15/2025] [Accepted: 04/16/2025] [Indexed: 04/29/2025] Open
Abstract
T-follicular helper (Tfh) cells, a specialized subset of CD4+ cells, are the immune mediators connecting cellular and humoral immunity, as they lead B-cell proliferation within germinal centers, and orchestrate their response, including activation, class switching, and production of a diverse array of high-affinity antibodies. Their interactions with B cells is regulated by a wide complex of transcriptional and cytokine-driven pathways. A major contribution of Tfh cells to autoimmune diseases is through their production of cytokines, particularly IL-21, which supports the proliferation and differentiation of autoreactive B cells. Elevated levels of circulating Tfh-like cells and IL-21 have been observed in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) correlating strongly with disease severity and autoantibody levels. The feedback loop between Tfh cells and IL-21 or other signal pathways, such as Bcl-6, ICOS, and PD-1, not only sustains Tfh cell function but also drives the continuous expansion of autoreactive B cells, leading to chronic inflammation through the production of high-affinity pathogenic autoantibodies. By understanding these interactions, Tfh pathways may serve as potential therapeutic targets, with IL-21, ICOS, and PD1 blockades emerging as promising innovative therapeutic strategies to manage autoimmune diseases. Although a variety of studies have been conducted investigating the role of Tfh cells in SLE and RA, this review aims to reveal the gap in the literature regarding the role of such subpopulations in the pathogenesis of other autoimmune diseases, such as Anca-associated vasculitis (AAV), and express the need to conduct similar studies. Tfh cell-related biomarkers can be used to assess disease activity and transform autoimmune disease treatment, leading to more personalized and effective care for patients with chronic autoimmune conditions.
Collapse
Affiliation(s)
- Michalis Christodoulou
- School of Medicine, Aristotle University of Thessaloniki, Department of Nephrology, Hippokration Hospital, Konstantinoupoleos 49, 54642 Thessaloniki, Greece; (M.C.); (E.M.); (G.L.); (S.S.); (C.L.)
| | - Eleni Moysidou
- School of Medicine, Aristotle University of Thessaloniki, Department of Nephrology, Hippokration Hospital, Konstantinoupoleos 49, 54642 Thessaloniki, Greece; (M.C.); (E.M.); (G.L.); (S.S.); (C.L.)
| | - Georgios Lioulios
- School of Medicine, Aristotle University of Thessaloniki, Department of Nephrology, Hippokration Hospital, Konstantinoupoleos 49, 54642 Thessaloniki, Greece; (M.C.); (E.M.); (G.L.); (S.S.); (C.L.)
| | - Stamatia Stai
- School of Medicine, Aristotle University of Thessaloniki, Department of Nephrology, Hippokration Hospital, Konstantinoupoleos 49, 54642 Thessaloniki, Greece; (M.C.); (E.M.); (G.L.); (S.S.); (C.L.)
| | - Christina Lazarou
- School of Medicine, Aristotle University of Thessaloniki, Department of Nephrology, Hippokration Hospital, Konstantinoupoleos 49, 54642 Thessaloniki, Greece; (M.C.); (E.M.); (G.L.); (S.S.); (C.L.)
| | - Aliki Xochelli
- Department of Immunology, National Histocompatibility Center, Hippokration General Hospital, 54642 Thessaloniki, Greece; (A.X.); (A.F.)
| | - Asimina Fylaktou
- Department of Immunology, National Histocompatibility Center, Hippokration General Hospital, 54642 Thessaloniki, Greece; (A.X.); (A.F.)
| | - Maria Stangou
- School of Medicine, Aristotle University of Thessaloniki, Department of Nephrology, Hippokration Hospital, Konstantinoupoleos 49, 54642 Thessaloniki, Greece; (M.C.); (E.M.); (G.L.); (S.S.); (C.L.)
| |
Collapse
|
|
3
|
Huo FF, Zou XY, Zhang Y, Lu YP, Zhao MW, Yu XY, Cao FG, Yang W. Aire attenuate collagen-induced arthritis by suppressing T follicular helper cells through ICOSL. Int Immunopharmacol 2025; 144:113732. [PMID: 39626537 DOI: 10.1016/j.intimp.2024.113732] [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: 09/03/2024] [Revised: 10/26/2024] [Accepted: 11/25/2024] [Indexed: 12/15/2024]
Abstract
OBJECTIVE To assess the expression levels of autoimmune regulator (Aire) and inducible costimulator molecule ligand (ICOSL), as well as T follicular helper (Tfh) cell numbers in rheumatoid arthritis (RA) patients, and to explore their relationship with RA severity. We also aimed to investigate the effect of Aire on arthritis and its underlying mechanisms. METHODS The expression levels of Aire, ICOSL, and Tfh cell numbers were measured in RA patients. The relationship between these factors and the levels of anticyclic citrullinated peptide antibodies (Anti-CCP) as well as the Disease Activity Score in 28 joints (DAS28) was analyzed. To investigate the effect of Aire on arthritis, Aire-overexpressing bone marrow-derived dendritic cells (Aire-BMDCs) and recombinant ICOSL were transferred into collagen-induced arthritis (CIA) mice, the symptoms, clinical scores, anti-collagen type II antibodies (anti-CII Abs), rheumatoid factor (RF), proportions of Tfh cells, and percentages of germinal center (GC) B cells in CIA mice were examined. RESULTS The results showed that Aire levels were significantly decreased in CD14+ PBMCs from patients with RA, and there were negative correlations between ICOSL expression levels, Tfh cell numbers, and Aire expression. Additionally, these factors were correlated with Anti-CCP levels and DAS28. Aire-BMDCs could influence Tfh differentiation, GC B cell development, as well as the levels of anti-CII Abs and RF, which further alleviate the symptoms and reduce clinical scores partly through ICOSL in CIA mice. CONCLUSIONS The findings suggest that Aire may alleviate rheumatoid arthritis by inhibiting ICOSL, which further inhibits Tfh cell differentiation and autoantibody production.
Collapse
Affiliation(s)
- Fei-Fei Huo
- Department of Intensive Care Medicine, The First Hospital of Jilin University, Department of Immunology, College of Basic Medical Sciences. Clinical Laboratory, The First Hospital of Jilin University, Changchun, China
| | - Xue-Yang Zou
- Department of Intensive Care Medicine, The First Hospital of Jilin University, Department of Immunology, College of Basic Medical Sciences. Clinical Laboratory, The First Hospital of Jilin University, Changchun, China
| | - Yi Zhang
- Department of Intensive Care Medicine, The First Hospital of Jilin University, Department of Immunology, College of Basic Medical Sciences. Clinical Laboratory, The First Hospital of Jilin University, Changchun, China
| | - Yao-Ping Lu
- Department of Intensive Care Medicine, The First Hospital of Jilin University, Department of Immunology, College of Basic Medical Sciences. Clinical Laboratory, The First Hospital of Jilin University, Changchun, China
| | - Meng-Wei Zhao
- Department of Intensive Care Medicine, The First Hospital of Jilin University, Department of Immunology, College of Basic Medical Sciences. Clinical Laboratory, The First Hospital of Jilin University, Changchun, China
| | - Xin-Yue Yu
- Department of Intensive Care Medicine, The First Hospital of Jilin University, Department of Immunology, College of Basic Medical Sciences. Clinical Laboratory, The First Hospital of Jilin University, Changchun, China
| | - Fu-Guo Cao
- Department of Intensive Care Medicine, The First Hospital of Jilin University, Department of Immunology, College of Basic Medical Sciences. Clinical Laboratory, The First Hospital of Jilin University, Changchun, China
| | - Wei Yang
- Department of Intensive Care Medicine, The First Hospital of Jilin University, Department of Immunology, College of Basic Medical Sciences. Clinical Laboratory, The First Hospital of Jilin University, Changchun, China.
| |
Collapse
|
|
4
|
Xing Y, Guo W, Wu M, Xie J, Huang D, Hu P, Zhou M, Zhang L, Zhong Y, Liu M, Chen Y, Yi Z. A Small-Molecule BCL6 Inhibitor as an Anti-Proliferative Agent for Diffuse Large B-Cell Lymphoma. Mol Cancer Ther 2025; 24:81-92. [PMID: 39387112 DOI: 10.1158/1535-7163.mct-23-0830] [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: 11/25/2023] [Revised: 05/09/2024] [Accepted: 10/01/2024] [Indexed: 10/12/2024]
Abstract
The B-cell lymphoma 6 (BCL6) transcription factor plays a key role in the establishment of germinal center (GC) formation. Diffuse large B-cell lymphoma (DLBCL) originates from the GC reaction due to dysregulation of BCL6. Disrupting BCL6 and its corepressors' interaction has become the foundation for rationally designing lymphoma therapies. However, BCL6 inhibitors with good activities in vitro and in vivo are rare, and there are no clinically approved BCL6 inhibitors. In this study, we discovered and developed a novel range of [1,2,4] triazolo[1,5-a] pyrimidine derivatives targeting BCL6/SMRT interaction. The lead compound WK692 directly bound BCL6BTB, disrupted BCL6BTB/SMRT interaction and activated the expression of BCL6 downstream genes inside cells, inhibited DLBCL growth and induced apoptosis in vitro, inhibited GC formation, decreased the proportion of follicular helper T cells, and impaired Ig affinity maturation. Further studies showed that WK692 inhibits DLBCL growth without toxic effects in vivo and synergizes with the EZH2 and PRMT5 inhibitors. Our results demonstrated that WK692 as a BCL6 inhibitor may be developed as a novel potential anticancer agent against DLBCL.
Collapse
Affiliation(s)
- Yajing Xing
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
- Chongqing Academy of Chinese Materia Medica, Chongqing, China
| | - Weikai Guo
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Min Wu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Jiuqing Xie
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Dongxia Huang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Pan Hu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Miaoran Zhou
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lin Zhang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Yadong Zhong
- Chongqing Academy of Chinese Materia Medica, Chongqing, China
| | - Mingyao Liu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Yihua Chen
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
- School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products and Yunnan College of Modern Biomedical Industry, Kunming Medical University, Kunming, China
| | - Zhengfang Yi
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
- Changning Maternity and Infant Health Hospital, East China Normal University, Shanghai, China
| |
Collapse
|
|
5
|
Niu Q, Hao J, Li Z, Zhang H. Helper T cells: A potential target for sex hormones to ameliorate rheumatoid arthritis? (Review). Mol Med Rep 2024; 30:215. [PMID: 39370806 PMCID: PMC11450432 DOI: 10.3892/mmr.2024.13339] [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: 07/17/2024] [Accepted: 09/06/2024] [Indexed: 10/08/2024] Open
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease whose etiology is not fully understood. Defective peripheral immune tolerance and subsequent mis‑differentiation and aberrant infiltration of synovium by various immune cells, especially helper T (Th) cells, play an important role in the development of RA. There are significant sex differences in RA, but the results of studies on the effects of sex hormones on RA have been difficult to standardize and hormone replacement therapy has been limited by the potential for serious side effects. Existing research has amply demonstrated that cellular immune responses are largely determined by sex and that sex hormones play a key role in Th cell responses. Based on the aforementioned background and the plasticity of Th cells, it is reasonable to hypothesize that the action of sex hormones on Th cells will hopefully become a therapeutic target for RA. The present review discussed the role of various Th cell subsets in the pathogenesis of RA and also explored the role of sex hormones on the phenotype and function of these aberrantly regulated immune cells in RA as well as other pathologic effects on RA.
Collapse
Affiliation(s)
- Quanjun Niu
- Department of Orthopedics IV, Handan Hospital of Traditional Chinese Medicine, Handan, Hebei 056001, P.R. China
| | - Junhang Hao
- Department of Orthopedics IV, Handan Hospital of Traditional Chinese Medicine, Handan, Hebei 056001, P.R. China
| | - Zhen Li
- Department of Orthopedics IV, Handan Hospital of Traditional Chinese Medicine, Handan, Hebei 056001, P.R. China
| | - Huiping Zhang
- Department of Orthopedics IV, Handan Hospital of Traditional Chinese Medicine, Handan, Hebei 056001, P.R. China
| |
Collapse
|
|
6
|
Talib M, Gyebrovszki B, Bőgér D, Csomor R, Mészáros A, Fodor A, Rojkovich B, Sármay G. Helper T Cells are Hyperactive and Contribute to the Dysregulation of Antibody Production in Patients with Rheumatoid Arthritis. Int J Mol Sci 2024; 25:10190. [PMID: 39337675 PMCID: PMC11431999 DOI: 10.3390/ijms251810190] [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: 08/24/2024] [Revised: 09/17/2024] [Accepted: 09/19/2024] [Indexed: 09/30/2024] Open
Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disease, mediated by a complex interaction between B cells and various subsets of T cells. Dysfunction of helper T (Th) and regulatory T (Treg) cells may contribute to the breakdown of self-tolerance and the progression of autoimmune disease. In this study, we investigated the activity of Th and Treg cells on the differentiation of autologous B cells in vitro using cell cultures from the peripheral blood of healthy controls (HCs) and RA patients. The expressions of programmed death 1 (PD-1) and IL-21 were monitored as activation markers for Th cells. Unstimulated Th cells from RA patients showed remarkably higher PD-1 expression than HC samples. Stimulation of Th cells from RA patients with Staphylococcus enterotoxin B (SEB) in the presence of B cells significantly induced their PD-1 and IL-21 expression at a considerably higher level in RA compared to HCs, and Treg cells did not affect IL-21 production. When monitoring B-cell differentiation, a significantly higher frequency of plasma cells was observed, even in unstimulated samples of RA patients compared to HCs. In the SEB-stimulated co-cultures of the RA samples, plasma cell frequency and IgG production were considerably higher than in HCs and were not significantly affected by Tregs. These findings demonstrate that Th cells are constitutively active in RA, and their hyperactivity upon interaction with diseased B cells may lead to uncontrolled antibody production.
Collapse
Affiliation(s)
- Mustafa Talib
- Department of Immunology, Eötvös Loránd University, 1053 Budapest, Hungary; (M.T.); (B.G.); (D.B.); (R.C.); (A.M.); (A.F.)
| | - Balázs Gyebrovszki
- Department of Immunology, Eötvös Loránd University, 1053 Budapest, Hungary; (M.T.); (B.G.); (D.B.); (R.C.); (A.M.); (A.F.)
| | - Dorottya Bőgér
- Department of Immunology, Eötvös Loránd University, 1053 Budapest, Hungary; (M.T.); (B.G.); (D.B.); (R.C.); (A.M.); (A.F.)
| | - Réka Csomor
- Department of Immunology, Eötvös Loránd University, 1053 Budapest, Hungary; (M.T.); (B.G.); (D.B.); (R.C.); (A.M.); (A.F.)
| | - Anna Mészáros
- Department of Immunology, Eötvös Loránd University, 1053 Budapest, Hungary; (M.T.); (B.G.); (D.B.); (R.C.); (A.M.); (A.F.)
| | - Anna Fodor
- Department of Immunology, Eötvös Loránd University, 1053 Budapest, Hungary; (M.T.); (B.G.); (D.B.); (R.C.); (A.M.); (A.F.)
| | - Bernadette Rojkovich
- Rheumatology-Rehabilitation Department, Buda Hospital of the Hospitaller Order of Saint John of God, 1027 Budapest, Hungary;
| | - Gabriella Sármay
- Department of Immunology, Eötvös Loránd University, 1053 Budapest, Hungary; (M.T.); (B.G.); (D.B.); (R.C.); (A.M.); (A.F.)
| |
Collapse
|
|
7
|
Mohammad Piri S, Amin Habibi M, Shool S, Khazaeli Najafabadi M, Ahmadpour S, Alemi F, Aria Nejadghaderi S, Shokri P, Abdi M, Asghari N, Amir Asef-Agah S, Tavakolpour S. Role of T follicular helper cells in autoimmune rheumatic Diseases: A systematic review on immunopathogenesis and response to treatment. Hum Immunol 2024; 85:110838. [PMID: 38970880 DOI: 10.1016/j.humimm.2024.110838] [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: 02/07/2024] [Revised: 06/09/2024] [Accepted: 06/28/2024] [Indexed: 07/08/2024]
Abstract
BACKGROUND T follicular helper (Tfh) cells are a subdivision of T helper cells involved in antigen-specific B cell immunity. Tfh cells play an essential role in the interaction of T cells/B cells in the germinal centers (GC), and dysregulation of Tfh actions can offer pathogenic autoantibody formation and lead to the development of autoimmune diseases. This study seeks to evaluate changes in Tfh frequency and its related cytokines in autoimmune disease, its association with disease phase, severity, prognosis, and the effect of immunosuppressive treatment on the Tfh population. METHOD The study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 Statement. Electronic databases, including PubMed, Scopus, Web of Science, and Embase, were systematically searched for potentially eligible studies up to January 1, 2024. RESULTS We identified 4998 articles in the initial search, from which 1686 similar titles were removed. A total of 3312 articles were initially screened, and 3051 articles were excluded by title/abstract screening. A total of 261 studies were considered for full-text assessment, and 205 articles were excluded by reason. Finally, a total of 56 studies were included in our review. CONCLUSION The population of Tfh cells is generally higher in autoimmune diseases versus Health control. Moreover, the number of Tfh cells is associated with the disease severity and can be considered for determining the prognosis of studies. Also, peripheral blood circulating Tfh (cTfh) cells are an available sample that can be used as an indicator for diagnosing diseases.
Collapse
Affiliation(s)
- Seyed Mohammad Piri
- Department of Pathology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
| | - Mohammad Amin Habibi
- Department of Neurosurgery, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
| | - Sina Shool
- Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | | | - Sajjad Ahmadpour
- Patient Safety Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
| | - Fakhroddin Alemi
- School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Seyed Aria Nejadghaderi
- Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
| | - Pourya Shokri
- Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mohtaram Abdi
- Student Research Committe, Faculty of Medicine, North Khorasan University of Medical Sciences, Bonjnurd, Iran.
| | - Negin Asghari
- Student Research Committe, Faculty of Medicine, North Khorasan University of Medical Sciences, Bonjnurd, Iran.
| | - Seyed Amir Asef-Agah
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | | |
Collapse
|
|
8
|
Jose AM, Rasool M. A glimpse on the role of IL-21 in psoriatic arthritis pathogenesis. Life Sci 2024; 350:122766. [PMID: 38834097 DOI: 10.1016/j.lfs.2024.122766] [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: 02/04/2024] [Revised: 03/27/2024] [Accepted: 05/31/2024] [Indexed: 06/06/2024]
Abstract
Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy affecting the skin, entheses, and joints. Over the past decade, experimental evidence has revealed the activation of several immune cells and signaling cascades in modulating the pathophysiology of PsA. Recently, targeted therapies have been developed to combat the severity of disease. However, with diverse etiologies, flareups, and relapses, there has been an increased prevalence and mortality associated with PsA in recent years. Therefore, it is imperative to investigate new potential mediators and combination therapies to manage PsA pathogenesis. IL-21, an immunomodulatory cytokine, has pleiotropic effects on immune cells and the protein cascades involved in PsA pathogenesis. Recently, emerging evidence of increased IL-21 levels in patients with PsA has engendered much enthusiasm for its potential as a therapeutic target. Here, we unmasked IL-21 as a significant modulator of PsA pathogenesis and reviewed the comorbidities associated with the disease, further cataloging future therapeutic modalities to ameliorate PsA progression.
Collapse
Affiliation(s)
- Ann Miriam Jose
- Immunopathology Lab, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632 014, Tamil Nadu, India
| | - Mahaboobkhan Rasool
- Immunopathology Lab, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632 014, Tamil Nadu, India.
| |
Collapse
|
|
9
|
Noor AAM, Nor AKCM, Redzwan NM. The immunological understanding on germinal center B cells in psoriasis. J Cell Physiol 2024; 239:e31266. [PMID: 38578060 DOI: 10.1002/jcp.31266] [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: 09/14/2023] [Revised: 02/16/2024] [Accepted: 03/20/2024] [Indexed: 04/06/2024]
Abstract
The development of psoriasis is mainly driven by the dysregulation of T cells within the skin, marking a primary involvement of these cells in the pathogenesis. Although B cells are integral components of the immune system, their role in the initiation and progression of psoriasis is not as pivotal as that of T cells. The paradox of B cell suggests that, while it is crucial for adaptive immunity, B cells may contribute to the exacerbation of psoriasis. Numerous ideas proposed that there are potential relationships between psoriasis and B cells especially within germinal centers (GCs). Recent research projected that B cells might be triggered by autoantigens which then induced molecular mimicry to alter B cells activity within GC and generate autoantibodies and pro-inflammatory cytokines, form ectopic GC, and dysregulate the proliferation of keratinocytes. Hence, in this review, we gathered potential evidence indicating the participation of B cells in psoriasis within the context of GC, aiming to enhance our comprehension and advance treatment strategies for psoriasis thus inviting many new researchers to investigate this issue.
Collapse
Affiliation(s)
- Aina Akmal Mohd Noor
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
| | - Abdah Karimah Che Md Nor
- Central Research Laboratory, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
| | - Norhanani Mohd Redzwan
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
| |
Collapse
|
|
10
|
Edner NM, Houghton LP, Ntavli E, Rees-Spear C, Petersone L, Wang C, Fabri A, Elfaki Y, Rueda Gonzalez A, Brown R, Kisand K, Peterson P, McCoy LE, Walker LSK. TIGIT +Tfh show poor B-helper function and negatively correlate with SARS-CoV-2 antibody titre. Front Immunol 2024; 15:1395684. [PMID: 38868776 PMCID: PMC11167088 DOI: 10.3389/fimmu.2024.1395684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 05/15/2024] [Indexed: 06/14/2024] Open
Abstract
Circulating follicular helper T cells (cTfh) can show phenotypic alterations in disease settings, including in the context of tissue-damaging autoimmune or anti-viral responses. Using severe COVID-19 as a paradigm of immune dysregulation, we have explored how cTfh phenotype relates to the titre and quality of antibody responses. Severe disease was associated with higher titres of neutralising S1 IgG and evidence of increased T cell activation. ICOS, CD38 and HLA-DR expressing cTfh correlated with serum S1 IgG titres and neutralising strength, and interestingly expression of TIGIT by cTfh showed a negative correlation. TIGIT+cTfh expressed increased IFNγ and decreased IL-17 compared to their TIGIT-cTfh counterparts, and showed reduced capacity to help B cells in vitro. Additionally, TIGIT+cTfh expressed lower levels of CD40L than TIGIT-cTfh, providing a potential explanation for their poor B-helper function. These data identify phenotypic changes in polyclonal cTfh that correlate with specific antibody responses and reveal TIGIT as a marker of cTfh with altered function.
Collapse
Affiliation(s)
- Natalie M. Edner
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, United Kingdom
| | - Luke P. Houghton
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, United Kingdom
| | - Elisavet Ntavli
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, United Kingdom
| | - Chloe Rees-Spear
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, United Kingdom
| | - Lina Petersone
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, United Kingdom
| | - Chunjing Wang
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, United Kingdom
| | - Astrid Fabri
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, United Kingdom
| | - Yassin Elfaki
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, United Kingdom
| | - Andrea Rueda Gonzalez
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, United Kingdom
| | - Rachel Brown
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, United Kingdom
- Queen Square Institute of Neurology, University College London, London, United Kingdom
| | - Kai Kisand
- Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Pärt Peterson
- Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Laura E. McCoy
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, United Kingdom
| | - Lucy S. K. Walker
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, United Kingdom
| |
Collapse
|
|
11
|
Jiang C, Chi S, Wang F, Zhao C, Yang X, Liu M, Ma B, Chen J, Su C, Duan X. The changes of intestinal flora and its relevance with memory Tfh and B cells in rheumatoid arthritis patients treated with csDMARDs and csDMARDs + bDMARDs. Immunobiology 2024; 229:152798. [PMID: 38537424 DOI: 10.1016/j.imbio.2024.152798] [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: 12/10/2023] [Revised: 02/02/2024] [Accepted: 03/20/2024] [Indexed: 06/05/2024]
Abstract
BACKGROUND A growing body of experimental and clinical evidence has implicated gut microbiota in the onset and course of rheumatoid arthritis (RA). The imbalance of intestinal flora in RA patients may lead to abnormal expression of immune cells and related cytokines. PURPOSE Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and conventional synthetic disease-modifying antirheumatic drugs combined with biological disease-modifying antirheumatic drugs (csDMARDs + bDMARDs) are widely used to treat RA, but the characteristics of gut microbiota before and after treatment and their relationship with memory Tfh/B cells and cytokines remain unclear. METHODS Stool samples were collected from 50 RA patients and 25 healthy controls (HCs) for 16SrRNA gene sequencing. We examined the proportion of lymphocyte subsets in healthy controls and RA patients. Enzyme linked immunosorbent assay (ELISA) was used to detect the levels of related cytokines in serum. The α and β diversity of intestinal flora, and the correlation between intestinal flora and clinical indicators, lymphocyte subsets, cytokines were analyzed. RESULT At the genus level, Ruminococcaceae_Ruminococcus was decreased in the csDMARDs and csDMARDs + bDMARDs treatment group, whereas Faecalibacterium was reduced in the csDMARDs treatment group, compared to untreated group. CD4+CD45RO+CCR7+CXCR5+central memory Tfh cells and CD4+CD45RO+CCR7-CXCR5+effector memory Tfh cells were significantly lower in the csDMARDs + bDMARDs treatment group than in untreated group. CD19+CD27+IgD+pre-switched memory B cells were higher in the csDMARDs and csDMARDs + bDMARDs treatment groups, whereas CD19+CD27+IgD-switched memory B cells were significantly lower than in untreated group. Ruminococcaceae_Ruminococcus was negatively correlated with CD19+CD27+IgD+ pre-switched memory B cells but positively correlated with CD4+CD45RO+CCR7-CXCR5+effector memory Tfh and CD19+CD27+IgD-switched memory B cells in patients with RA treated with DMARDs. CONCLUSION The gut microbiota, memory Tfh cells, memory B cells, and cytokines of patients with RA changed significantly under different treatment regimens and had certain correlations with the clinical indicators of RA.
Collapse
Affiliation(s)
- Chunlei Jiang
- The First School of Clinical Medicine, Ningxia Medical University, Yinchuan, China; Department of Rheumatology, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Shuhong Chi
- The First School of Clinical Medicine, Ningxia Medical University, Yinchuan, China; Department of Rheumatology, General Hospital of Ningxia Medical University, Yinchuan, China.
| | - Fengkui Wang
- Department of Nuclear Medicine, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Chenyang Zhao
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Xiaojuan Yang
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Miao Liu
- The First School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Bin Ma
- Department of Oncology Surgery, The First People's Hospital of Yinchuan, Yinchuan, China
| | | | - Chunxia Su
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
| | - Xiangguo Duan
- School of Inspection, Ningxia Medical University, China.
| |
Collapse
|
|
12
|
Akama-Garren EH, Yin X, Prestwood TR, Ma M, Utz PJ, Carroll MC. T cell help shapes B cell tolerance. Sci Immunol 2024; 9:eadj7029. [PMID: 38363829 PMCID: PMC11095409 DOI: 10.1126/sciimmunol.adj7029] [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: 07/11/2023] [Accepted: 12/29/2023] [Indexed: 02/18/2024]
Abstract
T cell help is a crucial component of the normal humoral immune response, yet whether it promotes or restrains autoreactive B cell responses remains unclear. Here, we observe that autoreactive germinal centers require T cell help for their formation and persistence. Using retrogenic chimeras transduced with candidate TCRs, we demonstrate that a follicular T cell repertoire restricted to a single autoreactive TCR, but not a foreign antigen-specific TCR, is sufficient to initiate autoreactive germinal centers. Follicular T cell specificity influences the breadth of epitope spreading by regulating wild-type B cell entry into autoreactive germinal centers. These results demonstrate that TCR-dependent T cell help can promote loss of B cell tolerance and that epitope spreading is determined by TCR specificity.
Collapse
Affiliation(s)
- Elliot H. Akama-Garren
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Harvard-MIT Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA
| | - Xihui Yin
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Tyler R. Prestwood
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Minghe Ma
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Paul J. Utz
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Michael C. Carroll
- Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| |
Collapse
|
|
13
|
Sandner L, Alteneder M, Rica R, Woller B, Sala E, Frey T, Tosevska A, Zhu C, Madern M, Khan M, Hoffmann P, Schebesta A, Taniuchi I, Bonelli M, Schmetterer K, Iannacone M, Kuka M, Ellmeier W, Sakaguchi S, Herbst R, Boucheron N. The guanine nucleotide exchange factor Rin-like controls Tfh cell differentiation via CD28 signaling. J Exp Med 2023; 220:e20221466. [PMID: 37703004 PMCID: PMC10499045 DOI: 10.1084/jem.20221466] [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: 08/25/2022] [Revised: 06/07/2023] [Accepted: 08/21/2023] [Indexed: 09/14/2023] Open
Abstract
T follicular helper (Tfh) cells are essential for the development of germinal center B cells and high-affinity antibody-producing B cells in humans and mice. Here, we identify the guanine nucleotide exchange factor (GEF) Rin-like (Rinl) as a negative regulator of Tfh generation. Loss of Rinl leads to an increase of Tfh in aging, upon in vivo immunization and acute LCMV Armstrong infection in mice, and in human CD4+ T cell in vitro cultures. Mechanistically, adoptive transfer experiments using WT and Rinl-KO naïve CD4+ T cells unraveled T cell-intrinsic GEF-dependent functions of Rinl. Further, Rinl regulates CD28 internalization and signaling, thereby shaping CD4+ T cell activation and differentiation. Thus, our results identify the GEF Rinl as a negative regulator of global Tfh differentiation in an immunological context and species-independent manner, and furthermore, connect Rinl with CD28 internalization and signaling pathways in CD4+ T cells, demonstrating for the first time the importance of endocytic processes for Tfh differentiation.
Collapse
Affiliation(s)
- Lisa Sandner
- Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Marlis Alteneder
- Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Ramona Rica
- Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Barbara Woller
- Center for Brain Research, Medical University of Vienna, Vienna, Austria
| | - Eleonora Sala
- School of Medicine, Vita-Salute San Raffaele University and Division of Immunology, Transplantation, and Infectious Diseases, Istituto di Ricovero e Cura a Carettere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy
| | - Tobias Frey
- Department of Laboratory Medicine, Klinisches Institut für Labormedizin (KILM), Anna Spiegel Research Building, Medical University of Vienna, Vienna, Austria
| | - Anela Tosevska
- Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria
| | - Ci Zhu
- Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Moritz Madern
- Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Matarr Khan
- Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Pol Hoffmann
- Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Alexandra Schebesta
- Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Ichiro Taniuchi
- Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
| | - Michael Bonelli
- Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria
| | - Klaus Schmetterer
- Department of Laboratory Medicine, Klinisches Institut für Labormedizin (KILM), Anna Spiegel Research Building, Medical University of Vienna, Vienna, Austria
| | - Matteo Iannacone
- School of Medicine, Vita-Salute San Raffaele University and Division of Immunology, Transplantation, and Infectious Diseases, Istituto di Ricovero e Cura a Carettere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy
- Experimental Imaging Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy
| | - Mirela Kuka
- School of Medicine, Vita-Salute San Raffaele University and Division of Immunology, Transplantation, and Infectious Diseases, Istituto di Ricovero e Cura a Carettere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy
| | - Wilfried Ellmeier
- Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Shinya Sakaguchi
- Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Ruth Herbst
- Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Nicole Boucheron
- Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| |
Collapse
|
|
14
|
Nandakumar KS, Fang Q, Wingbro Ågren I, Bejmo ZF. Aberrant Activation of Immune and Non-Immune Cells Contributes to Joint Inflammation and Bone Degradation in Rheumatoid Arthritis. Int J Mol Sci 2023; 24:15883. [PMID: 37958864 PMCID: PMC10648236 DOI: 10.3390/ijms242115883] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 10/25/2023] [Accepted: 10/30/2023] [Indexed: 11/15/2023] Open
Abstract
Abnormal activation of multiple immune and non-immune cells and proinflammatory factors mediate the development of joint inflammation in genetically susceptible individuals. Although specific environmental factors like smoking and infections are associated with disease pathogenesis, until now, we did not know the autoantigens and arthritogenic factors that trigger the initiation of the clinical disease. Autoantibodies recognizing specific post-translationally modified and unmodified antigens are generated and in circulation before the onset of the joint disease, and could serve as diagnostic and prognostic markers. The characteristic features of autoantibodies change regarding sub-class, affinity, glycosylation pattern, and epitope spreading before the disease onset. Some of these antibodies were proven to be pathogenic using animal and cell-culture models. However, not all of them can induce disease in animals. This review discusses the aberrant activation of major immune and non-immune cells contributing to joint inflammation. Recent studies explored the protective effects of extracellular vesicles from mesenchymal stem cells and bacteria on joints by targeting specific cells and pathways. Current therapeutics in clinics target cells and inflammatory pathways to attenuate joint inflammation and protect the cartilage and bones from degradation, but none cure the disease. Hence, more basic research is needed to investigate the triggers and mechanisms involved in initiating the disease and relapses to prevent chronic inflammation from damaging joint architecture.
Collapse
Affiliation(s)
- Kutty Selva Nandakumar
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden
- Department of Environmental and Biosciences, Halmstad University, 30118 Halmstad, Sweden; (I.W.Å.); (Z.F.B.)
| | - Qinghua Fang
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA;
| | - Isabella Wingbro Ågren
- Department of Environmental and Biosciences, Halmstad University, 30118 Halmstad, Sweden; (I.W.Å.); (Z.F.B.)
| | - Zoe Fuwen Bejmo
- Department of Environmental and Biosciences, Halmstad University, 30118 Halmstad, Sweden; (I.W.Å.); (Z.F.B.)
| |
Collapse
|
|
15
|
Wang W, Yang Y, Shi Y, Xiang T, Xie J. E3 ubiquitin ligase STUB1 affects the mTORC1 pathway through p62 and participates in regulating the differentiation of follicular helper T cells in rheumatoid arthritis. Clin Immunol 2023; 255:109736. [PMID: 37604355 DOI: 10.1016/j.clim.2023.109736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 08/04/2023] [Accepted: 08/11/2023] [Indexed: 08/23/2023]
Abstract
OBJECTIVE The abnormal expansion of Tfh cells plays a key role in chronic inflammation of RA joint. We speculated that STUB1 is an important regulatory factor in promoting the differentiation of Tfh cells in RA. CONTENT AND METHODS The proportion of Tfh cells and the level of STUB1 in Tfh cells was measured. CD4+T cells were isolated from PBMCs of RA patients, and the percentage of Tfh cells was detected after up- or down-regulating the expression of STUB1. The levels of mTORC1 pathway activator p-mTOR and p-S6K were measured by Western blot. The ubiquitination of p62 by STUB1 and its ubiquitination type as well as the activation of mTORC1 was detected in vitro, and the activation of the mTORC1 and the differentiation of Tfh cells was detected in STUB1-upregulated CD4+ T cells with overexpressed p62. RESULTS The level of STUB1 is elevated in Tfh cells of patients. Up-regulation of STUB1 can promote the differentiation of Tfh cells. STUB1 promotes the degradation of p62 via K48-linked ubiquitination and promotes the activation of mTORC1. Overexpression of p62 can reverse the promoting effect of STUB1 on the differentiation of Tfh cells and the activation of mTORC1. CONCLUSION STUB1 can promote the differentiation of Tfh cells in RA by mediating the activation of mTORC1 pathway through ubiquitination of p62.
Collapse
Affiliation(s)
- Wen Wang
- Department of Rheumatology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yachen Yang
- Department of Rheumatology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yujia Shi
- Department of Rheumatology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ting Xiang
- Department of Rheumatology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jianmin Xie
- Department of Rheumatology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
| |
Collapse
|
|
16
|
Shi Y, Chang C, Xu L, Jiang P, Wei K, Zhao J, Xu L, Jin Y, Zhang R, Wang H, Qian Y, Qin Y, Ding Q, Jiang T, Guo S, Wang R, He D. Circulating DNA methylation level of CXCR5 correlates with inflammation in patients with rheumatoid arthritis. Immun Inflamm Dis 2023; 11:e902. [PMID: 37382265 PMCID: PMC10288483 DOI: 10.1002/iid3.902] [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: 11/02/2022] [Revised: 03/14/2023] [Accepted: 05/22/2023] [Indexed: 06/30/2023] Open
Abstract
OBJECTIVES To assess the differences in circulating DNA methylation levels of CXCR5 between rheumatoid arthritis (RA) and osteoarthritis (OA) and healthy controls (HC), and the correlation of methylation changes with clinical characteristics of RA patients. METHODS Peripheral blood samples were collected from 239 RA patients, 30 patients with OA, and 29 HC. Target region methylation sequencing to the promoter region of CXCR5 was achieved using MethylTarget. The methylation level of cg04537602 and methylation haplotype were compared among the three groups, and the correlation between methylation levels and clinical characteristics of RA patients was performed by Spearman's rank correlation analysis. RESULTS The methylation level of cg04537602 was significantly higher in the peripheral blood of RA patients compared with OA patients (p = 1.3 × 10-3 ) and in the HC group (p = 5.5 × 10- 4 ). The sensitivity was enhanced when CXCR5 methylation level combined with rheumatoid factor and anti-cyclic citrullinated peptide with area under curve (AUC) of 0.982 (95% confidence interval 0.970-0.995). The methylation level of cg04537602 in RA was positively correlated with C-reactive protein (CRP) (r = .16, p = .01), and in RA patients aged 60 years and above, cg04537602 methylation levels were positively correlated with CRP (r = .31, p = 4.7 × 10- 4 ), tender joint count (r = .21, p = .02), visual analog scales score (r = .21, p = .02), Disease Activity Score in 28 joints (DAS28) using the CRP level DAS28-CRP (r = .27, p = 2.1 × 10- 3 ), and DAS28-ESR (r = .22, p = .01). We also observed significant differences of DNA methylation haplotypes in RA patients compared with OA patients and HC, which was consistent with single-loci-based CpG methylation measurement. CONCLUSION The methylation level of CXCR5 was significantly higher in RA patients than in OA and HC, and correlated with the level of inflammation in RA patients, our study establishes a link between CXCR5 DNA methylation and clinical features that may help in the diagnosis and disease management of RA patients.
Collapse
Affiliation(s)
- Yiming Shi
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Cen Chang
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Lingxia Xu
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Ping Jiang
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Kai Wei
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Jianan Zhao
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Linshuai Xu
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Yehua Jin
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Runrun Zhang
- Department of RheumatologyThe Second Affiliated Hospital of Zhejiang Chinese Medical UniversityHangzhouChina
| | - Huijuan Wang
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Yi Qian
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Yingying Qin
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Qin Ding
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Ting Jiang
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Shicheng Guo
- Computation and Informatics in Biology and MedicineUniversity of Wisconsin‐MadisonMadisonWisconsinUSA
- Department of Medical Genetics, School of Medicine and Public HealthUniversity of Wisconsin‐ MadisonMadisonWisconsinUSA
| | - Rongsheng Wang
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| | - Dongyi He
- Department of Rheumatology, Shanghai Guanghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- Guanghua Clinical Medical CollegeShanghai University of Traditional Chinese MedicineShanghaiChina
- Institute of Arthritis Research in Integrative MedicineShanghai Academy of Traditional Chinese MedicineShanghaiChina
| |
Collapse
|
|
17
|
Zhou A, Shi C, Fan Y, Zheng Y, Wang J, Liu Z, Xie H, Liu J, Jiao Q. Involvement of CD40-CD40L and ICOS-ICOSL in the development of chronic rhinosinusitis by targeting eosinophils. Front Immunol 2023; 14:1171308. [PMID: 37325657 PMCID: PMC10267736 DOI: 10.3389/fimmu.2023.1171308] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 03/20/2023] [Indexed: 06/17/2023] Open
Abstract
Background Chronic rhinosinusitis (CRS), whose prevalence and pathogenesis are age-related, is characterized by nasal tissue eosinophil infiltration. CD40-CD40 ligand (CD40L) pathway involves in the eosinophil-mediated inflammation, and inducible co-stimulator (ICOS)-ICOS ligand (ICOSL) signal can strengthen CD40-CD40L interaction. Whether CD40-CD40L and ICOS-ICOSL have a role in the development of CRS remains unknown. Objectives The aim of this study is to investigate the association of CD40-CD40L and ICOS-ICOSL expression with CRS and underlying mechanisms. Methods Immunohistology detected the expression of CD40, CD40L, ICOS, and ICOSL. Immunofluorescence was performed to evaluate the co-localizations of CD40 or ICOSL with eosinophils. Correlations between CD40-CD40L and ICOS-ICOSL as well as clinical parameters were analyzed. Flow cytometry was used to explore the activation of eosinophils by CD69 expression and the CD40 and ICOSL expression on eosinophils. Results Compared with the non-eCRS subset, ECRS (eosinophilic CRS) subset showed significantly increased CD40, ICOS, and ICOSL expression. The CD40, CD40L, ICOS, and ICOSL expressions were all positively correlated with eosinophil infiltration in nasal tissues. CD40 and ICOSL were mainly expressed on eosinophils. ICOS expression was significantly correlated with the expression of CD40-CD40L, whereas ICOSL expression was correlated with CD40 expression. ICOS-ICOSL expression positively correlated with blood eosinophils count and disease severity. rhCD40L and rhICOS significantly enhanced the activation of eosinophils from patients with ECRS. Tumor necrosis factor-α (TNF-α) and interleukin-5 (IL-5) obviously upregulated CD40 expression on eosinophils, which was significantly inhibited by the p38 mitogen-activated protein kinase (MAPK) inhibitor. Conclusions Increased CD40-CD40L and ICOS-ICOSL expressions in nasal tissues are linked to eosinophils infiltration and disease severity of CRS. CD40-CD40L and ICOS-ICOSL signals enhance eosinophils activation of ECRS. TNF-α and IL-5 regulate eosinophils function by increasing CD40 expression partly via p38 MAPK activation in patients with CRS.
Collapse
Affiliation(s)
- Aina Zhou
- Department of Ear, Nose, and Throat, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Chenxi Shi
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yuhui Fan
- Department of Ear, Nose, and Throat, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yushuang Zheng
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jue Wang
- Department of Ear, Nose, and Throat, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhichen Liu
- Department of Ear, Nose, and Throat, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Huanxia Xie
- Department of Ear, Nose, and Throat, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jisheng Liu
- Department of Ear, Nose, and Throat, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Qingqing Jiao
- Department of Dermatology, The First Affiliated Hospital of Soochow University, Suzhou, China
| |
Collapse
|
|
18
|
Pan P, Pineda MA, Wang Y, Khan A, Nyirenda MH. Aberrant pro-inflammatory responses of CD20 + T cells in experimental arthritis. Cell Immunol 2023; 387:104717. [PMID: 37075620 DOI: 10.1016/j.cellimm.2023.104717] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/28/2023] [Accepted: 04/02/2023] [Indexed: 04/08/2023]
Abstract
CD20+ T cells comprise a highly inflammatory subset implicated in autoimmunity, including rheumatoid arthritis (RA). We sought to characterize the CD20+ T cell subset in the murine collagen-induced arthritis (CIA) model of RA and investigate the phenotype and functional relevance of CD3+CD20+ T cells in the lymph nodes and arthritic joints using flow cytometry and immunohistochemistry. We demonstrate that CD3+CD4+CD20+ and CD3+CD8+CD20+ T cells are expanded in the draining lymph nodes of CIA mice, produce increased levels of pro-inflammatory cytokines and are less susceptible to regulation by regulatory T cells. Notably, CD3+CD4+CD20+ and CD3+CD8+CD20+ T cells are enriched with CXCR5+PD-1+ T follicular helper cells and CXCR5-PD-1+ peripheral T helper cells, subsets of T cells implicated in promoting B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues in RA. Our findings suggest CD20+ T cells are associated with inflammatory responses and may exacerbate pathology by promoting inflammatory B-cell responses.
Collapse
Affiliation(s)
- Piaopiao Pan
- University of Glasgow, School of Infection and Immunity, Glasgow, UK
| | - Miguel A Pineda
- Research into Inflammatory Arthritis Centre, Versus Arthritis (RACE-VA), Glasgow, Birmingham, Newcastle, and Oxford, UK; University of Glasgow, Centre for the Cellular Microenvironment, School of Molecular Biosciences, Glasgow, UK
| | - Yilin Wang
- University of Glasgow, School of Infection and Immunity, Glasgow, UK
| | - Aneesah Khan
- University of Glasgow, School of Infection and Immunity, Glasgow, UK
| | - Mukanthu H Nyirenda
- University of Glasgow, School of Infection and Immunity, Glasgow, UK; Research into Inflammatory Arthritis Centre, Versus Arthritis (RACE-VA), Glasgow, Birmingham, Newcastle, and Oxford, UK.
| |
Collapse
|
|
19
|
Ferrero PV, Onofrio LI, Acosta CDV, Zacca ER, Ponce NE, Mussano E, Onetti LB, Cadile II, Costantino AB, Werner ML, Mas LA, Alvarellos T, Montes CL, Acosta Rodríguez EV, Gruppi A. Dynamics of circulating follicular helper T cell subsets and follicular regulatory T cells in rheumatoid arthritis patients according to HLA-DRB1 locus. Front Immunol 2022; 13:1000982. [PMID: 36582249 PMCID: PMC9793086 DOI: 10.3389/fimmu.2022.1000982] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 11/28/2022] [Indexed: 12/15/2022] Open
Abstract
B cells, follicular helper T (Tfh) cells and follicular regulatory T (Tfr) cells are part of a circuit that may play a role in the development or progression of rheumatoid arthritis (RA). With the aim of providing further insight into this topic, here we evaluated the frequency of different subsets of Tfh and Tfr in untreated and long-term treated RA patients from a cohort of Argentina, and their potential association with particular human leukocyte antigen (HLA) class-II variants and disease activity. We observed that the frequency of total Tfh cells as well as of particular Tfh subsets and Tfr cells were increased in seropositive untreated RA patients. Interestingly, when analyzing paired samples, the frequency of Tfh cells was reduced in synovial fluid compared to peripheral blood, while Tfr cells levels were similar in both biological fluids. After treatment, a decrease in the CCR7loPD1hi Tfh subset and an increase in the frequency of Tfr cells was observed in blood. In comparison to healthy donors, seropositive patients with moderate and high disease activity exhibited higher frequency of Tfh cells while seropositive patients with low disease activity presented higher Tfr cell frequency. Finally, we observed that HLA-DRB1*09 presence correlated with higher frequency of Tfh and Tfr cells, while HLA-DRB1*04 was associated with increased Tfr cell frequency. Together, our results increase our knowledge about the dynamics of Tfh and Tfr cell subsets in RA, showing that this is altered after treatment.
Collapse
Affiliation(s)
- Paola V. Ferrero
- Laboratorio de Inmunología, Hospital Nacional de Clínicas, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Luisina I. Onofrio
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Cristina del Valle Acosta
- Laboratorio de Inmunología, Hospital Nacional de Clínicas, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Estefania R. Zacca
- Laboratorio de Inmunología, Hospital Nacional de Clínicas, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Nicolas E. Ponce
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Eduardo Mussano
- Servicio de Reumatología, Hospital Nacional de Clínicas, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Laura B. Onetti
- Servicio de Reumatología, Hospital Nacional de Clínicas, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Ignacio I. Cadile
- Servicio de Reumatología, Hospital Nacional de Clínicas, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Alicia B. Costantino
- Laboratorio de Inmunología, Hospital Nacional de Clínicas, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Marina L. Werner
- Servicio de Reumatología, Hospital Nacional de Clínicas, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Luciana A. Mas
- Laboratorio de Histocompatibilidad, Hospital Privado Universitario de Córdoba e Instituto Universitario de Ciencias Biomédicas, Córdoba, Argentina
| | - Teresita Alvarellos
- Laboratorio de Histocompatibilidad, Hospital Privado Universitario de Córdoba e Instituto Universitario de Ciencias Biomédicas, Córdoba, Argentina
| | - Carolina L. Montes
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Eva V. Acosta Rodríguez
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina,*Correspondence: Adriana Gruppi, ; Eva V. Acosta Rodríguez,
| | - Adriana Gruppi
- Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina,*Correspondence: Adriana Gruppi, ; Eva V. Acosta Rodríguez,
| |
Collapse
|
|
20
|
Li T, Yang CL, Du T, Zhang P, Zhou Y, Li XL, Wang CC, Liu Y, Li H, Zhang M, Duan RS. Diabetes mellitus aggravates humoral immune response in myasthenia gravis by promoting differentiation and activation of circulating Tfh cells. Clin Immunol 2022; 245:109141. [PMID: 36270469 DOI: 10.1016/j.clim.2022.109141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 09/08/2022] [Accepted: 09/10/2022] [Indexed: 11/26/2022]
|
|
21
|
Romão VC, Fonseca JE. Disease mechanisms in preclinical rheumatoid arthritis: A narrative review. Front Med (Lausanne) 2022; 9:689711. [PMID: 36059838 PMCID: PMC9437632 DOI: 10.3389/fmed.2022.689711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 08/04/2022] [Indexed: 11/20/2022] Open
Abstract
In the last decades, the concept of preclinical rheumatoid arthritis (RA) has become established. In fact, the discovery that disease mechanisms start years before the onset of clinical RA has been one of the major recent insights in the understanding of RA pathogenesis. In accordance with the complex nature of the disease, preclinical events extend over several sequential phases. In a genetically predisposed host, environmental factors will further increase susceptibility for incident RA. In the initial steps of preclinical disease, immune disturbance mechanisms take place outside the joint compartment, namely in mucosal surfaces, such as the lung, gums or gut. Herein, the persistent immunologic response to altered antigens will lead to breach of tolerance and trigger autoimmunity. In a second phase, the immune response matures and is amplified at a systemic level, with epitope spreading and widening of the autoantibody repertoire. Finally, the synovial and bone compartment are targeted by specific autoantibodies against modified antigens, initiating a local inflammatory response that will eventually culminate in clinically evident synovitis. In this review, we discuss the elaborate disease mechanisms in place during preclinical RA, providing a broad perspective in the light of current evidence.
Collapse
Affiliation(s)
- Vasco C. Romão
- Rheumatology Department, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon Academic Medical Centre and European Reference Network on Rare Connective Tissue and Musculoskeletal Diseases Network (ERN-ReCONNET), Lisbon, Portugal
- Rheumatology Research Unit, Faculdade de Medicina, Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, Lisbon, Portugal
| | - João Eurico Fonseca
- Rheumatology Research Unit, Faculdade de Medicina, Instituto de Medicina Molecular João Lobo Antunes, Universidade de Lisboa, Lisbon, Portugal
| |
Collapse
|
|
22
|
Kotschenreuther K, Yan S, Kofler DM. Migration and homeostasis of regulatory T cells in rheumatoid arthritis. Front Immunol 2022; 13:947636. [PMID: 36016949 PMCID: PMC9398455 DOI: 10.3389/fimmu.2022.947636] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 07/20/2022] [Indexed: 12/17/2022] Open
Abstract
Regulatory T (Treg) cells are garnering increased attention in research related to autoimmune diseases, including rheumatoid arthritis (RA). They play an essential role in the maintenance of immune homeostasis by restricting effector T cell activity. Reduced functions and frequencies of Treg cells contribute to the pathogenesis of RA, a common autoimmune disease which leads to systemic inflammation and erosive joint destruction. Treg cells from patients with RA are characterized by impaired functions and by an altered phenotype. They show increased plasticity towards Th17 cells and a reduced suppressive capacity. Besides the suppressive function of Treg cells, their effectiveness is determined by their ability to migrate into inflamed tissues. In the past years, new mechanisms involved in Treg cell migration have been identified. One example of such a mechanism is the phosphorylation of vasodilator-stimulated phosphoprotein (VASP). Efficient migration of Treg cells requires the presence of VASP. IL-6, a cytokine which is abundantly present in the peripheral blood and in the synovial tissue of RA patients, induces posttranslational modifications of VASP. Recently, it has been shown in mice with collagen-induced arthritis (CIA) that this IL-6 mediated posttranslational modification leads to reduced Treg cell trafficking. Another protein which facilitates Treg cell migration is G-protein-signaling modulator 2 (GPSM2). It modulates G-protein coupled receptor functioning, thereby altering the cellular activity initiated by cell surface receptors in response to extracellular signals. The almost complete lack of GPSM2 in Treg cells from RA patients contributes to their reduced ability to migrate towards inflammatory sites. In this review article, we highlight the newly identified mechanisms of Treg cell migration and review the current knowledge about impaired Treg cell homeostasis in RA.
Collapse
Affiliation(s)
- Konstantin Kotschenreuther
- Laboratory of Molecular Immunology, Division of Rheumatology and Clinical Immunology, Department I of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Shuaifeng Yan
- Laboratory of Molecular Immunology, Division of Rheumatology and Clinical Immunology, Department I of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - David M. Kofler
- Laboratory of Molecular Immunology, Division of Rheumatology and Clinical Immunology, Department I of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Cologne, Germany
- *Correspondence: David M. Kofler,
| |
Collapse
|
|
23
|
Abuqayyas L, Cheng LE, Teixeira dos Santos M, Sullivan BA, Ruiz‐Santiago N, Wang H, Zhou Y, Chindalore V, Cohen S, Kivitz AJ, Posch MG, Parnes JR. Safety and Biological Activity of Rozibafusp alfa, a Bispecific Inhibitor of Inducible Costimulator Ligand and B Cell Activating Factor, in Patients With Rheumatoid Arthritis: Results of a Phase 1b, Randomized,
Double‐Blind
,
Placebo‐Controlled
, Multiple Ascending Dose Study. ACR Open Rheumatol 2022; 4:903-911. [PMID: 35899378 PMCID: PMC9555197 DOI: 10.1002/acr2.11487] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 06/17/2022] [Accepted: 06/20/2022] [Indexed: 12/04/2022] Open
Abstract
Objective To assess the safety and biological activity of rozibafusp alfa, a first‐in‐class bispecific antibody–peptide conjugate targeting inducible costimulator ligand (ICOSL) and B cell activating factor (BAFF), in patients with rheumatoid arthritis (RA). Methods This phase 1b, double‐blind, placebo‐controlled, multiple ascending dose study included 34 patients (18–75 years; 82.4% female) with active RA (Disease Activity Score of 28 joints–C‐reactive protein [DAS28‐CRP] >2.6, on stable methotrexate) randomized 3:1 to receive rozibafusp alfa (n = 26, in four ascending dose cohorts of 70, 140, 210, and 420 mg) or a placebo (n = 8) subcutaneously once every 2 weeks for 10 weeks (six total doses), with 24 weeks of follow‐up. The primary end point was the incidence of treatment‐emergent adverse events (TEAEs). Additional assessments included serum pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and RA disease activity measures (DAS28‐CRP, Patient Global Assessment of Disease, and Physician Global Assessment of Disease). Results TEAEs occurred in 96.2% and 87.5% of patients receiving rozibafusp alfa and the placebo, respectively; most were mild or moderate in severity. Two (7.7%) patients treated with rozibafusp alfa reported serious TEAEs; none were considered treatment related. Multiple doses of rozibafusp alfa showed nonlinear PK (mean t1/2 = 4.6–9.5 days) and dose‐related, reversible PD (>90% ICOSL receptor occupancy in 210‐ and 420‐mg cohorts; reduction in naïve B cells and increase in memory B cells in all cohorts). Five (20%) patients developed anti–rozibafusp alfa antibodies, with no apparent impact on safety. RA disease activity showed greater numerical improvement from baseline with rozibafusp alfa versus the placebo in the 210‐ and 420‐mg cohorts. Conclusion Multiple ascending doses of rozibafusp alfa were well tolerated, with PK and PD reflecting dual ICOSL and BAFF blockade. Findings support further clinical evaluation of rozibafusp alfa in autoimmune disease.
Collapse
Affiliation(s)
| | | | | | | | | | - Hui Wang
- Amgen Inc. Thousand Oaks California
| | | | | | | | - Alan J. Kivitz
- Altoona Center for Clinical Research Duncansville Pennsylvania
| | | | | |
Collapse
|
|
24
|
Zeng X, Lu S, Li M, Zheng M, Liu T, Kang R, Xu L, Xu Q, Song Y, Liu C. Inflammatory Cytokine-Neutralizing Antibody Treatment Prevented Increases in Follicular Helper T Cells and Follicular Regulatory T Cells in a Mouse Model of Arthritis. J Inflamm Res 2022; 15:3997-4011. [PMID: 35860232 PMCID: PMC9292064 DOI: 10.2147/jir.s355720] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 07/10/2022] [Indexed: 11/24/2022] Open
Abstract
Background Follicular T helper (TFH) and follicular regulatory T (TFR) cells play important roles in humoral immunity. Nevertheless, their significance in rheumatoid arthritis (RA) pathogenesis has not been fully elucidated. As an important treatment strategy, the effect of inflammatory factor-neutralizing antibodies on TFH and TFR in RA remains unclear. Methods We used the collagen-induced arthritis (CIA) mouse model to illustrate the quantity and functional changes in TFH and TFR cells. The changes of plasmablast, TFH and TFR cells in the spleen and peripheral blood of CIA mice were analyzed by flow cytometry. The levels of TFH and TFR and their functional subsets in the spleen after anti-inflammatory antibody treatment were analyzed and compared. The functional changes of TFH and TFR in CIA mice before and after treatment were detected by in vitro culture experiments. Results Plasmablast levels were increased in CIA spleen and peripheral blood and both TFH and TFR cell levels were upregulated. TFH and TFR cells were decreased significantly after the anti-inflammatory antibody treatment. TIGIT+ and TIGIT+CD226− TFH cells in CIA mouse spleen were elevated and PD-1 and ICOS expression on spleen TFH and TFR cells was increased. Both the ability of TFH cells to secrete IL-21 and aid B cells and the ability of TFR cells to secrete IL-10 and inhibit TFH cells were enhanced in the CIA mice. After antibody treatment, the cell subsets and functions were recovered. Conclusion Germinal center TFH and TFR cells were increased and their functions were enhanced. With inflammatory factor-neutralizing antibody treatment, TFH and TFR subsets and their functions returned to normal. These findings provide important information on the dynamics of humoral immune-related cell subsets in RA and the effects of treatment on them.
Collapse
Affiliation(s)
- Xingyue Zeng
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, People's Republic of China
| | - Songsong Lu
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, People's Republic of China
| | - Meng Li
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, People's Republic of China
| | - Mohan Zheng
- School of Basic Medical Sciences, Peking University Health Science Centre, Beijing, People's Republic of China
| | - Tianci Liu
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, People's Republic of China
| | - Rui Kang
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, People's Republic of China
| | - Lijuan Xu
- Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Centre, Beijing, People's Republic of China
| | - Qinzhu Xu
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, People's Republic of China
| | - Ying Song
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, People's Republic of China
| | - Chen Liu
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, People's Republic of China
| |
Collapse
|
|
25
|
Hui CW, Wu WC, Leung SO. Interleukins 4 and 21 Protect Anti-IgM Induced Cell Death in Ramos B Cells: Implication for Autoimmune Diseases. Front Immunol 2022; 13:919854. [PMID: 35911775 PMCID: PMC9326153 DOI: 10.3389/fimmu.2022.919854] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 06/20/2022] [Indexed: 01/11/2023] Open
Abstract
Interleukins 4 (IL-4) and 21 (IL-21) belong to the common gamma chain cytokine family which are highly involved in the progression of autoimmune diseases. While IL-4 is well known to be involved in the suppression of apoptosis of autoreactive B cells, the role played by IL-21 remains unclear. In the current study, we activated the human Burkitt’s lymphoma Ramos B cells with anti-IgM to mimic B cell hyperactivation observed in patients of autoimmune diseases. Consistent with other reported findings, anti-IgM led to the downregulation of proteins involved in B cell survival and proliferation, as well as the activation of caspase 3 activity and DNA damage, resulting in apoptotic cell death after 48-hour treatment. Although both IL-4 and IL-21 reversed anti-IgM-induced apoptosis and cell cycle arrest, they did so via different mechanisms: while IL-4 could directly suppress anti-IgM-induced caspase 3 activation and marker indicative of DNA damage, IL-21 could induce B cell proliferation in the presence of anti-IgM. Importantly, IL-21 also suppressed activation induced cell death in human primary B cells. Pre-treatment with clinically validated JAK inhibitors completely reversed the effects of IL-4 and IL-21 to rescue anti-IgM induced cell death and DNA damage. The results indicate the underlying mechanisms of how IL-4 and IL-21 differentially promote survival of hyperactivated B cells and provide hints to treat autoimmune diseases.
Collapse
|
|
26
|
Zhao J, Wei K, Jiang P, Chang C, Xu L, Xu L, Shi Y, Guo S, He D. G-Protein-Coupled Receptors in Rheumatoid Arthritis: Recent Insights into Mechanisms and Functional Roles. Front Immunol 2022; 13:907733. [PMID: 35874704 PMCID: PMC9304905 DOI: 10.3389/fimmu.2022.907733] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 06/20/2022] [Indexed: 12/24/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to joint damage and even disability. Although there are various clinical therapies for RA, some patients still have poor or no response. Thus, the development of new drug targets remains a high priority. In this review, we discuss the role of G-protein-coupled receptors (GPCRs), including chemokine receptors, melanocortin receptors, lipid metabolism-related receptors, adenosine receptors, and other inflammation-related receptors, on mechanisms of RA, such as inflammation, lipid metabolism, angiogenesis, and bone destruction. Additionally, we summarize the latest clinical trials on GPCR targeting to provide a theoretical basis and guidance for the development of innovative GPCR-based clinical drugs for RA.
Collapse
Affiliation(s)
- Jianan Zhao
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Kai Wei
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Ping Jiang
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Cen Chang
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Lingxia Xu
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Linshuai Xu
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Yiming Shi
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Shicheng Guo
- Computation and Informatics in Biology and Medicine, University of Wisconsin-Madison, Madison, WI, United States
- Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
| | - Dongyi He
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
- Arthritis Institute of Integrated Traditional and Western Medicine, Shanghai Chinese Medicine Research Institute, Shanghai, China
| |
Collapse
|
|
27
|
Milardi G, Di Lorenzo B, Gerosa J, Barzaghi F, Di Matteo G, Omrani M, Jofra T, Merelli I, Barcella M, Filippini M, Conti A, Ferrua F, Pozzo Giuffrida F, Dionisio F, Rovere‐Querini P, Marktel S, Assanelli A, Piemontese S, Brigida I, Zoccolillo M, Cirillo E, Giardino G, Danieli MG, Specchia F, Pacillo L, Di Cesare S, Giancotta C, Romano F, Matarese A, Chetta AA, Trimarchi M, Laurenzi A, De Pellegrin M, Darin S, Montin D, Marinoni M, Dellepiane RM, Sordi V, Lougaris V, Vacca A, Melzi R, Nano R, Azzari C, Bongiovanni L, Pignata C, Cancrini C, Plebani A, Piemonti L, Petrovas C, Di Micco R, Ponzoni M, Aiuti A, Cicalese MP, Fousteri G. Follicular helper T cell signature of replicative exhaustion, apoptosis, and senescence in common variable immunodeficiency. Eur J Immunol 2022; 52:1171-1189. [PMID: 35562849 PMCID: PMC9542315 DOI: 10.1002/eji.202149480] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 02/08/2022] [Accepted: 05/09/2022] [Indexed: 11/06/2022]
Abstract
Common variable immunodeficiency (CVID) is the most frequent primary antibody deficiency whereby follicular helper T (Tfh) cells fail to establish productive responses with B cells in germinal centers. Here, we analyzed the frequency, phenotype, transcriptome, and function of circulating Tfh (cTfh) cells in CVID patients displaying autoimmunity as an additional phenotype. A group of patients showed a high frequency of cTfh1 cells and a prominent expression of PD-1 and ICOS as well as a cTfh mRNA signature consistent with highly activated, but exhausted, senescent, and apoptotic cells. Plasmatic CXCL13 levels were elevated in this group and positively correlated with cTfh1 cell frequency and PD-1 levels. Monoallelic variants in RTEL1, a telomere length- and DNA repair-related gene, were identified in four patients belonging to this group. Their blood lymphocytes showed shortened telomeres, while their cTfh were more prone to apoptosis. These data point toward a novel pathogenetic mechanism in CVID, whereby alterations in DNA repair and telomere elongation might predispose to antibody deficiency. A Th1, highly activated but exhausted and apoptotic cTfh phenotype was associated with this form of CVID.
Collapse
Affiliation(s)
- Giulia Milardi
- Division of Immunology, Transplantation, and Infectious DiseasesDiabetes Research InstituteIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Biagio Di Lorenzo
- Division of Immunology, Transplantation, and Infectious DiseasesDiabetes Research InstituteIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Jolanda Gerosa
- Division of Immunology, Transplantation, and Infectious DiseasesDiabetes Research InstituteIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Federica Barzaghi
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
- Pathogenesis and therapy of primary immunodeficiencies UnitSan Raffaele Telethon Institute for Gene TherapySr‐TIGETIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Gigliola Di Matteo
- Department of Systems Medicine, University of Rome Tor VergataVia Cracovia 50Rome00133Italy
- Immune and Infectious Diseases Division, Research Unit of Primary Immunodeficiencies, Academic Department of PediatricsBambino Gesù Children's HospitalIRCCSPiazza di Sant'Onofrio 4Rome00165Italy
| | - Maryam Omrani
- Pathogenesis and therapy of primary immunodeficiencies UnitSan Raffaele Telethon Institute for Gene TherapySr‐TIGETIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
- Department of Computer Science, Systems and Communication, University of Milano‐BicoccaPiazza dell'Ateneo Nuovo 1Milan20126Italy
| | - Tatiana Jofra
- Division of Immunology, Transplantation, and Infectious DiseasesDiabetes Research InstituteIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Ivan Merelli
- Pathogenesis and therapy of primary immunodeficiencies UnitSan Raffaele Telethon Institute for Gene TherapySr‐TIGETIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
- Department of BioinformaticsInstitute for Biomedical TechnologiesNational Research CouncilVia Fratelli Cervi 93Segrate20090Italy
| | - Matteo Barcella
- Pathogenesis and therapy of primary immunodeficiencies UnitSan Raffaele Telethon Institute for Gene TherapySr‐TIGETIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Matteo Filippini
- Division of Immunology, Transplantation, and Infectious DiseasesDiabetes Research InstituteIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Anastasia Conti
- Pathogenesis and therapy of primary immunodeficiencies UnitSan Raffaele Telethon Institute for Gene TherapySr‐TIGETIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Francesca Ferrua
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
- Pathogenesis and therapy of primary immunodeficiencies UnitSan Raffaele Telethon Institute for Gene TherapySr‐TIGETIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Francesco Pozzo Giuffrida
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
- Pathogenesis and therapy of primary immunodeficiencies UnitSan Raffaele Telethon Institute for Gene TherapySr‐TIGETIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Francesca Dionisio
- Pathogenesis and therapy of primary immunodeficiencies UnitSan Raffaele Telethon Institute for Gene TherapySr‐TIGETIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Patrizia Rovere‐Querini
- Department of ImmunologyTransplantation and Infectious DiseasesIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Sarah Marktel
- Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Andrea Assanelli
- Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Simona Piemontese
- Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Immacolata Brigida
- Pathogenesis and therapy of primary immunodeficiencies UnitSan Raffaele Telethon Institute for Gene TherapySr‐TIGETIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Matteo Zoccolillo
- Pathogenesis and therapy of primary immunodeficiencies UnitSan Raffaele Telethon Institute for Gene TherapySr‐TIGETIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Emilia Cirillo
- Department of Translational Medical SciencesSection of PediatricsFederico II University of NaplesCorso Umberto I, 40, 80138Italy
| | - Giuliana Giardino
- Department of Translational Medical SciencesSection of PediatricsFederico II University of NaplesCorso Umberto I, 40, 80138Italy
| | - Maria Giovanna Danieli
- Department of Clinical and Molecular SciencesMarche Polytechnic University of AnconaClinica MedicaVia Tronto 10/aAncona60126Italy
| | - Fernando Specchia
- Department of PediatricsS. Orsola‐Malpighi HospitalUniversity of BolognaVia Giuseppe Massarenti 9Bologna40138Italy
| | - Lucia Pacillo
- Department of Systems Medicine, University of Rome Tor VergataVia Cracovia 50Rome00133Italy
- Immune and Infectious Diseases Division, Research Unit of Primary Immunodeficiencies, Academic Department of PediatricsBambino Gesù Children's HospitalIRCCSPiazza di Sant'Onofrio 4Rome00165Italy
| | - Silvia Di Cesare
- Department of Systems Medicine, University of Rome Tor VergataVia Cracovia 50Rome00133Italy
- Immune and Infectious Diseases Division, Research Unit of Primary Immunodeficiencies, Academic Department of PediatricsBambino Gesù Children's HospitalIRCCSPiazza di Sant'Onofrio 4Rome00165Italy
| | - Carmela Giancotta
- Department of Systems Medicine, University of Rome Tor VergataVia Cracovia 50Rome00133Italy
- Immune and Infectious Diseases Division, Research Unit of Primary Immunodeficiencies, Academic Department of PediatricsBambino Gesù Children's HospitalIRCCSPiazza di Sant'Onofrio 4Rome00165Italy
| | - Francesca Romano
- Pediatric Immunology DivisionDepartment of PediatricsAnna Meyer Children's University HospitalViale Gaetano Pieraccini 24Florence50139Italy
| | - Alessandro Matarese
- Department of Respiratory MedicineSanti AntonioBiagio and Cesare Arrigo HospitalVia Venezia 16Alessandria15121Italy
| | - Alfredo Antonio Chetta
- Department of Medicine and SurgeryRespiratory Disease and Lung Function UnitUniversity of ParmaStr. dell'Università 12Parma43121Italy
| | - Matteo Trimarchi
- Otorhinolaryngology Unit, Head and Neck Department, IRCCS San Raffaele Scientific InstituteVia Olgettina 60Milan20132Italy
- Pathology UnitIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Andrea Laurenzi
- Division of Immunology, Transplantation, and Infectious DiseasesDiabetes Research InstituteIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Maurizio De Pellegrin
- Unit of Orthopaedics, IRCCS San Raffaele Scientific InstituteVia Olgettina 60Milan20132Italy
| | - Silvia Darin
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Davide Montin
- Department of Pediatrics and Public HealthRegina Margherita HospitalPiazza Polonia 94Turin10126Italy
| | - Maddalena Marinoni
- Pediatric UnitOspedale “F. Del Ponte”Via Filippo del Ponte 19Varese21100Italy
| | - Rosa Maria Dellepiane
- Department of PediatricsFondazione IRCCS Cà Granda Ospedale Maggiore PoliclinicoUniversity of MilanVia Francesco Sforza 35Milan20122Italy
| | - Valeria Sordi
- Division of Immunology, Transplantation, and Infectious DiseasesDiabetes Research InstituteIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Vassilios Lougaris
- Department of Clinical and Experimental SciencesPediatrics Clinic and Institute for Molecular Medicine A. NocivelliUniversity of BresciaPiazza del Mercato 15Brescia25121Italy
| | - Angelo Vacca
- Department of Biomedical Sciences and Human OncologyUniversity of Bari Medical SchoolPiazza Umberto I, 1Bari70121Italy
| | - Raffaella Melzi
- Division of Immunology, Transplantation, and Infectious DiseasesDiabetes Research InstituteIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Rita Nano
- Division of Immunology, Transplantation, and Infectious DiseasesDiabetes Research InstituteIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Chiara Azzari
- Pediatric Immunology DivisionDepartment of PediatricsAnna Meyer Children's University HospitalViale Gaetano Pieraccini 24Florence50139Italy
| | - Lucia Bongiovanni
- Pathology UnitIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Claudio Pignata
- Department of Translational Medical SciencesSection of PediatricsFederico II University of NaplesCorso Umberto I, 40, 80138Italy
| | - Caterina Cancrini
- Department of Systems Medicine, University of Rome Tor VergataVia Cracovia 50Rome00133Italy
- Immune and Infectious Diseases Division, Research Unit of Primary Immunodeficiencies, Academic Department of PediatricsBambino Gesù Children's HospitalIRCCSPiazza di Sant'Onofrio 4Rome00165Italy
| | - Alessandro Plebani
- Department of Clinical and Experimental SciencesPediatrics Clinic and Institute for Molecular Medicine A. NocivelliUniversity of BresciaPiazza del Mercato 15Brescia25121Italy
| | - Lorenzo Piemonti
- Division of Immunology, Transplantation, and Infectious DiseasesDiabetes Research InstituteIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
- Faculty of MedicineUniversity Vita‐Salute San RaffaeleVia Olgettina 60Milan20132Italy
| | - Constantinos Petrovas
- Tissue Analysis Core, Immunology LaboratoryVaccine Research CenterNational Institute of Allergy and Infectious DiseasesNational Institutes of Health9000 Rockville PikeBethesdaMD20892USA
| | - Raffaella Di Micco
- Pathogenesis and therapy of primary immunodeficiencies UnitSan Raffaele Telethon Institute for Gene TherapySr‐TIGETIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Maurilio Ponzoni
- Pathology UnitIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
- Faculty of MedicineUniversity Vita‐Salute San RaffaeleVia Olgettina 60Milan20132Italy
| | - Alessandro Aiuti
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
- Pathogenesis and therapy of primary immunodeficiencies UnitSan Raffaele Telethon Institute for Gene TherapySr‐TIGETIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
- Faculty of MedicineUniversity Vita‐Salute San RaffaeleVia Olgettina 60Milan20132Italy
| | - Maria Pia Cicalese
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
- Pathogenesis and therapy of primary immunodeficiencies UnitSan Raffaele Telethon Institute for Gene TherapySr‐TIGETIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| | - Georgia Fousteri
- Division of Immunology, Transplantation, and Infectious DiseasesDiabetes Research InstituteIRCCS San Raffaele HospitalVia Olgettina 60Milan20132Italy
| |
Collapse
|
|
28
|
Akama-Garren EH, Carroll MC. T Cell Help in the Autoreactive Germinal Center. Scand J Immunol 2022; 95:e13192. [PMID: 35587582 DOI: 10.1111/sji.13192] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 05/10/2022] [Accepted: 05/13/2022] [Indexed: 11/29/2022]
Abstract
The germinal center serves as a site of B cell selection and affinity maturation, critical processes for productive adaptive immunity. In autoimmune disease tolerance is broken in the germinal center reaction, leading to production of autoreactive B cells that may propagate disease. Follicular T cells are crucial regulators of this process, providing signals necessary for B cell survival in the germinal center. Here we review the emerging roles of follicular T cells in the autoreactive germinal center. Recent advances in immunological techniques have allowed study of the gene expression profiles and repertoire of follicular T cells at unprecedented resolution. These studies provide insight into the potential role follicular T cells play in preventing or facilitating germinal center loss of tolerance. Improved understanding of the mechanisms of T cell help in autoreactive germinal centers provides novel therapeutic targets for diseases of germinal center dysfunction.
Collapse
Affiliation(s)
- Elliot H Akama-Garren
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.,Harvard-MIT Health Sciences and Technology, Harvard Medical School, Boston, MA, USA
| | - Michael C Carroll
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
29
|
Alterations in B- and circulating T-follicular helper cell subsets in immune thrombotic thrombocytopenic purpura. Blood Adv 2022; 6:3792-3802. [PMID: 35507753 PMCID: PMC9631570 DOI: 10.1182/bloodadvances.2022007025] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 04/19/2022] [Indexed: 11/20/2022] Open
Abstract
Abnormal B-cell phenotype in acute iTTP with decreased transitional and post–germinal center memory cells and increased plasmablasts. Decreased total and PD1+ circulating T-follicular helper cells and changes in B-cell CD80 expression suggest altered B- and T-cell interactions. T follicular helper (Tfh) cells regulate development of antigen-specific B-cell immunity. We prospectively investigated B-cell and circulating Tfh (cTfh) cell subsets in 45 patients with immune thrombotic thrombocytopenic purpura (iTTP) at presentation and longitudinally after rituximab (RTX). B-cell phenotype was altered at acute iTTP presentation with decreased transitional cells and post–germinal center (post-GC) memory B cells and increased plasmablasts compared with healthy controls. A higher percentage of plasmablasts was associated with higher anti-ADAMTS13 IgG and lower ADAMTS13 antigen levels. In asymptomatic patients with ADAMTS13 relapse, there were increased naïve B cells and a global decrease in memory subsets, with a trend to increased plasmablasts. Total circulating Tfh (CD4+CXCR5+) and PD1+ Tfh cells were decreased at iTTP presentation. CD80 expression was decreased on IgD+ memory cells and double-negative memory cells in acute iTTP. At repopulation after B-cell depletion in de novo iTTP, post-GC and double-negative memory B cells were reduced compared with pre-RTX. RTX did not cause alteration in cTfh cell frequency. The subsequent kinetics of naïve, transitional, memory B cells and plasmablasts did not differ significantly between patients who went on to relapse vs those who remained in remission. In summary, acute iTTP is characterized by dysregulation of B- and cTfh cell homeostasis with depletion of post-GC memory cells and cTfh cells and increased plasmablasts. Changes in CD80 expression on B cells further suggest altered interactions with T cells.
Collapse
|
|
30
|
Wang Y, Guo H, Liang Z, Feng M, Wu Y, Qin Y, Zhao X, Gao C, Liu G, Luo J. Sirolimus therapy restores the PD-1+ICOS+Tfh:CD45RA-Foxp3 high activated Tfr cell balance in primary Sjögren's syndrome. Mol Immunol 2022; 147:90-100. [PMID: 35523039 DOI: 10.1016/j.molimm.2022.04.006] [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: 10/17/2021] [Revised: 04/06/2022] [Accepted: 04/17/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND Primary Sjögren's syndrome (pSS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of salivary and lacrimal glands. The current study was performed to investigate the roles of follicular helper T (Tfh) and follicular regulatory T (Tfr) subsets in patients with pSS, and to evaluate the effects of sirolimus on these cells. METHODS Levels of circulating Tfh and Tfr subsets in 58 pSS patients and 26 healthy controls (HC) were determined by flow cytometry. These T cell subsets were also analyzed in 12 patients before and after treatment with sirolimus. Clinical features and correlations with follicular T cells were analyzed systematically. The discriminative ability of the cells and ratios was evaluated based on the area under the receiver operating characteristic curves. RESULTS Patients with pSS had higher percentage and absolute number of PD-1+ICOS+Tfh cells, while lower percentage and absolute number of Tfr, activated regulatory T (aTreg) cells, and CD45RA-Foxp3high activated Tfr cells. Furthermore, increased number of PD-1+ICOS+Tfh cells was associated with B cells, while decreased numbers of Tfr and their subsets was strongly associated with aTreg cells in pSS patients. Also, the higher proportion of PD-1+ICOS+Tfh cells was positively correlated with higher level of autoantibodies, ESR, IgG, cytokines (IL-2, IL-4, IL-10, IL-17, IFN-γ, TNF-α, IL-21 and sIL-2αR), and disease activity. Unexpectedly, the elevated PD-1+ICOS+Tfh:CD45RA-Foxp3high activated Tfr ratio had the greatest ability to discriminate between pSS and HC, and sirolimus therapy restored the PD-1+ICOS+Tfh cells:CD45RA-Foxp3high activated Tfr ratio, and controlled disease activity. CONCLUSION The novel ratio of PD-1+ICOS+Tfh to CD45RA-Foxp3high activated Tfr cells can effectively discriminate the pSS patients from controls, and Tfr cell subsets may resemble Treg cell lineages. Furthermore, the PD-1+ICOS+Tfh cells can be used as a biomarker of disease activity and to verify the therapeutic effects of sirolimus in pSS.
Collapse
Affiliation(s)
- Yanlin Wang
- Division of Rheumatology, Department of Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China
| | - Hui Guo
- Division of Nephrology, Department of Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China; Division of Nephrology, Department of Medicine, Shenzhen Baoan Shiyan People's Hospital, Shenzhen, Guangdong 518005, China
| | - Zhaojun Liang
- Division of Rheumatology, Department of Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China
| | - Min Feng
- Division of Rheumatology, Department of Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China
| | - Yanyao Wu
- Division of Rheumatology, Department of Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China
| | - Yan Qin
- Division of Rheumatology, Department of Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China
| | - Xiangcong Zhao
- Division of Rheumatology, Department of Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China
| | - Chong Gao
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Guangying Liu
- Division of Rheumatology, Department of Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China
| | - Jing Luo
- Division of Rheumatology, Department of Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China.
| |
Collapse
|
|
31
|
Vecchione A, Madley R, Danzl N, Borsotti C, Marharlooei MK, Li HW, Nauman G, Ding X, Ho SH, Fousteri G, Sykes M. T1D patient-derived hematopoietic stem cells are programmed to generate Tph, Tfh, and autoimmunity-associated B cell subsets in human immune system mice. Clin Immunol 2022; 240:109048. [PMID: 35644520 PMCID: PMC9564152 DOI: 10.1016/j.clim.2022.109048] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 05/20/2022] [Accepted: 05/21/2022] [Indexed: 11/03/2022]
Abstract
Interactions between B cells and CD4+ T cells play a central role in the development of Type 1 Diabetes (T1D). Two helper cell subsets, follicular (Tfh) and peripheral (Tph) helper T cells, are increased in patients with T1D but their role in driving B cell autoimmunity is undefined. We used a personalized immune (PI) mouse model to generate human immune systems de novo from hematopoietic stem cells (HSCs) of patients with T1D or from healthy controls (HCs). Both groups developed Tfh and Tph-like cells, and those with T1D-derived immune systems demonstrated increased numbers of Tph-like and Tfh cells compared to HC-derived PI mice. T1D-derived immune systems included increased proportions of unconventional memory CD27-IgD- B cells and reduced proportions of naïve B cells compared to HC PI mice, resembling changes reported for patients with systemic lupus erythematosus. Our findings suggest that T1D HSCs are genetically programmed to produce increased proportions of T cells that promote the development of unconventional, possibly autoreactive memory B cells. PI mice provide an avenue for further understanding of the immune abnormalities that drive autoantibody pathogenesis and T1D.
Collapse
|
|
32
|
Alsén S, Cervin J, Deng Y, Szeponik L, Wenzel UA, Karlsson J, Cucak H, Livingston M, Bryder D, Lu Q, Johansson-Lindbom B, Yrlid U. Antigen-Presenting B Cells Program the Efferent Lymph T Helper Cell Response. Front Immunol 2022; 13:813203. [PMID: 35355990 PMCID: PMC8959485 DOI: 10.3389/fimmu.2022.813203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 02/03/2022] [Indexed: 11/16/2022] Open
Abstract
B cells interact with T follicular helper (Tfh) cells in germinal centers (GCs) to generate high-affinity antibodies. Much less is known about how cognate T–B-cell interactions influence Th cells that enter circulation and peripheral tissues. Therefore, we generated mice lacking MHC-II expressing B cells and, by thoracic duct cannulation, analyzed Th cells in the efferent lymph at defined intervals post-immunization. Focusing on gut-draining mesenteric lymph nodes (MLNs), we show that antigen-specific α4β7+ gut-homing effector Th cells enter the circulation prior to CXCR5+PD-1+ Tfh-like cells. B cells appear to have no or limited impact on the early generation and egress of gut-homing Th cells but are critical for the subsequent appearance of Tfh-like cells that peak in the lymph before GCs have developed. At this stage, antigen-presenting B cells also reduce the proportion of α4β7+ Th cells in the MLN and efferent lymph. Furthermore, cognate B-cell interaction drives a broad transcriptional program in Th cells, including IL-4 that is confined to the Tfh cell lineage. The IL-4-producing Tfh-like cells originate from Bcl6+ precursors in the LNs and have gut-homing capacity. Hence, B cells program the efferent lymph Th cell response within a limited window of time after antigenic challenge.
Collapse
Affiliation(s)
- Samuel Alsén
- Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.,Sahlgrenska Center for Cancer Research, Department of Surgery, University of Gothenburg, Gothenburg, Sweden
| | - Jakob Cervin
- Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Yaxiong Deng
- Immunology Section, Lund University, Lund, Sweden.,Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, China
| | - Louis Szeponik
- Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Ulf Alexander Wenzel
- Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Joakim Karlsson
- Sahlgrenska Center for Cancer Research, Department of Surgery, University of Gothenburg, Gothenburg, Sweden.,Harry Perkins Institute of Medical Research, University of Western Australia, Perth, WA, Australia
| | - Helena Cucak
- Immunology Section, Lund University, Lund, Sweden
| | - Megan Livingston
- Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - David Bryder
- Division of Molecular Hematology, Lund University, Lund, Sweden
| | - Qianjin Lu
- Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, China
| | - Bengt Johansson-Lindbom
- Immunology Section, Lund University, Lund, Sweden.,Immunological Memory Group, Department of Health Technology, Technical University of Denmark, Kgs. Lyngby, Denmark
| | - Ulf Yrlid
- Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| |
Collapse
|
|
33
|
Chen Y, Luo L, Zheng Y, Zheng Q, Zhang N, Gan D, Yirga SK, Lin Z, Shi Q, Fu L, Hu J, Chen Y. Association of Platelet Desialylation and Circulating Follicular Helper T Cells in Patients With Thrombocytopenia. Front Immunol 2022; 13:810620. [PMID: 35450072 PMCID: PMC9016750 DOI: 10.3389/fimmu.2022.810620] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Accepted: 03/01/2022] [Indexed: 12/03/2022] Open
Abstract
Thrombocytopenia is a multifactorial condition that frequently involves concomitant defects in platelet production and clearance. The physiopathology of low platelet count in thrombocytopenia remains unclear. Sialylation on platelet membrane glycoprotein and follicular helper T cells (TFHs) are thought to be the novel platelet clearance pathways. The aim of this study was to clarify the roles of platelet desialylation and circulating TFHs in patients with immune thrombocytopenia (ITP) and non-ITP thrombocytopenia. We enrolled 190 patients with ITP and 94 patients with non-ITP related thrombocytopenia including case of aplastic anemia (AA) and myelodysplastic syndromes (MDS). One hundred and ten healthy volunteers were included as controls. We found significantly increased desialylated platelets in patients with ITP or thrombocytopenia in the context of AA and MDS. Platelet desialylation was negatively correlated with platelet count. Meanwhile, the circulating TFH levels in patients with thrombocytopenia were significantly higher than those of normal controls, and were positively correlated with desialylated platelet levels. Moreover, TFHs-related chemokine CXCL13 and apoptotic platelet levels were abnormally high in ITP patients. The upregulation of pro-apoptotic proteins and the activation of the MAPK/mTOR pathway were observed in the same cohort. These findings suggested that platelet desialylation and circulating TFHs may become the potential biomarkers for evaluating the disease process associated with thrombocytopenia in patients with ITP and non-ITP.
Collapse
Affiliation(s)
- Yuwen Chen
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Liping Luo
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Yongzhi Zheng
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Qiaoyun Zheng
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Na Zhang
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Donghui Gan
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Shimuye Kalayu Yirga
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Zhenxing Lin
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Qizhen Shi
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, United States
- Blood Research Institute, Versiti, Milwaukee, WI, United States
| | - Lin Fu
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jianda Hu
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, China
- *Correspondence: Yingyu Chen, ; Jianda Hu,
| | - Yingyu Chen
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, China
- *Correspondence: Yingyu Chen, ; Jianda Hu,
| |
Collapse
|
|
34
|
Anang DC, Ramwadhdoebe TH, Hähnlein JS, van Kuijk B, Smits N, van Lienden KP, Maas M, Gerlag DM, Tak PP, de Vries N, van Baarsen LGM. Increased Frequency of CD4+ Follicular Helper T and CD8+ Follicular T Cells in Human Lymph Node Biopsies during the Earliest Stages of Rheumatoid Arthritis. Cells 2022; 11:cells11071104. [PMID: 35406668 PMCID: PMC8997933 DOI: 10.3390/cells11071104] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/16/2022] [Accepted: 03/22/2022] [Indexed: 01/27/2023] Open
Abstract
Follicular T helper cells (Tfh cells) provide key B-cell help and are essential in germinal center formation and (auto) antibody generation. To gain more insight into their role during the earliest phase of rheumatoid arthritis (RA), we analyzed their frequencies, phenotypes, and cytokine profiles in peripheral blood and lymph node biopsies of healthy controls (HCs), autoantibody-positive individuals at risk for developing RA (RA-risk individuals), and early RA patients. Subsequently, we confirmed their presence in lymph nodes and synovial tissue of RA patients using immunofluorescence microscopy. In the blood, the frequency of Tfh cells did not differ between study groups. In lymphoid and synovial tissues, Tfh cells were localized in B-cell areas, and their frequency correlated with the frequency of CD19+ B cells. Compared to lymphoid tissues of healthy controls, those of RA patients and RA-risk individuals showed more CD19+ B cells, CD4+CXCR5+ follicular helper T cells, and CD8+CXCR5+ follicular T cells. These Tfh cells produced less IL-21 upon ex vivo stimulation. These findings suggest that Tfh cells may present a novel rationale for therapeutic targeting during the preclinical stage of RA to prevent further disease progression.
Collapse
Affiliation(s)
- Dornatien Chuo Anang
- Amsterdam Rheumatology & Immunology Center (ARC), Department of Rheumatology & Clinical Immunology, 1007 MB Amsterdam, The Netherlands; (D.C.A.); (T.H.R.); (J.S.H.); (B.v.K.); (N.S.); (D.M.G.); (P.P.T.); (N.d.V.)
- Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, 1007 MB Amsterdam, The Netherlands
| | - Tamara H. Ramwadhdoebe
- Amsterdam Rheumatology & Immunology Center (ARC), Department of Rheumatology & Clinical Immunology, 1007 MB Amsterdam, The Netherlands; (D.C.A.); (T.H.R.); (J.S.H.); (B.v.K.); (N.S.); (D.M.G.); (P.P.T.); (N.d.V.)
- Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, 1007 MB Amsterdam, The Netherlands
| | - Janine S. Hähnlein
- Amsterdam Rheumatology & Immunology Center (ARC), Department of Rheumatology & Clinical Immunology, 1007 MB Amsterdam, The Netherlands; (D.C.A.); (T.H.R.); (J.S.H.); (B.v.K.); (N.S.); (D.M.G.); (P.P.T.); (N.d.V.)
- Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, 1007 MB Amsterdam, The Netherlands
| | - Bo van Kuijk
- Amsterdam Rheumatology & Immunology Center (ARC), Department of Rheumatology & Clinical Immunology, 1007 MB Amsterdam, The Netherlands; (D.C.A.); (T.H.R.); (J.S.H.); (B.v.K.); (N.S.); (D.M.G.); (P.P.T.); (N.d.V.)
- Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, 1007 MB Amsterdam, The Netherlands
| | - Noortje Smits
- Amsterdam Rheumatology & Immunology Center (ARC), Department of Rheumatology & Clinical Immunology, 1007 MB Amsterdam, The Netherlands; (D.C.A.); (T.H.R.); (J.S.H.); (B.v.K.); (N.S.); (D.M.G.); (P.P.T.); (N.d.V.)
- Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, 1007 MB Amsterdam, The Netherlands
| | - Krijn P. van Lienden
- Department of Radiology, Amsterdam UMC, University of Amsterdam, 1007 MB Amsterdam, The Netherlands; (K.P.v.L.); (M.M.)
| | - Mario Maas
- Department of Radiology, Amsterdam UMC, University of Amsterdam, 1007 MB Amsterdam, The Netherlands; (K.P.v.L.); (M.M.)
| | - Daniëlle M. Gerlag
- Amsterdam Rheumatology & Immunology Center (ARC), Department of Rheumatology & Clinical Immunology, 1007 MB Amsterdam, The Netherlands; (D.C.A.); (T.H.R.); (J.S.H.); (B.v.K.); (N.S.); (D.M.G.); (P.P.T.); (N.d.V.)
- UCB Pharma, Slough SL1 3XE, UK
| | - Paul P. Tak
- Amsterdam Rheumatology & Immunology Center (ARC), Department of Rheumatology & Clinical Immunology, 1007 MB Amsterdam, The Netherlands; (D.C.A.); (T.H.R.); (J.S.H.); (B.v.K.); (N.S.); (D.M.G.); (P.P.T.); (N.d.V.)
- Candel Therapeutics, Needham, MA 02494, USA
- Department of Internal Medicine, Cambridge University, Cambridge CB2 0QQ, UK
| | - Niek de Vries
- Amsterdam Rheumatology & Immunology Center (ARC), Department of Rheumatology & Clinical Immunology, 1007 MB Amsterdam, The Netherlands; (D.C.A.); (T.H.R.); (J.S.H.); (B.v.K.); (N.S.); (D.M.G.); (P.P.T.); (N.d.V.)
- Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, 1007 MB Amsterdam, The Netherlands
| | - Lisa G. M. van Baarsen
- Amsterdam Rheumatology & Immunology Center (ARC), Department of Rheumatology & Clinical Immunology, 1007 MB Amsterdam, The Netherlands; (D.C.A.); (T.H.R.); (J.S.H.); (B.v.K.); (N.S.); (D.M.G.); (P.P.T.); (N.d.V.)
- Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, 1007 MB Amsterdam, The Netherlands
- Correspondence: ; Tel.: +31-20-56-64969; Fax: +31-20-69-19658
| |
Collapse
|
|
35
|
Xu T, Yan T, Li F, Li B, Li P. The Role of Different Circulating T Follicular Helper Cell Markers in Rheumatoid Arthritis. J Interferon Cytokine Res 2022; 42:108-117. [PMID: 35298288 DOI: 10.1089/jir.2021.0168] [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] [Indexed: 12/14/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic incurable inflammatory autoimmune disease. T follicular helper (Tfh) cells expressing different markers play critical roles in the development of RA. However, their specific mechanisms of action and association with RA clinical parameters are not clear. We therefore performed a cohort study to investigate the effects of different Tfh cell markers on RA pathogenesis. We retrospectively reviewed clinical data from 30 patients diagnosed with RA and 30 healthy controls (HCs) who visited our hospital. Based on X-ray findings, the patients were divided into a joint bone erosion group (n = 17) and a non-erosive joint bone group (n = 13). Using flow cytometry, we determined the frequencies of five peripheral blood CD4+ Tfh cell types characterized by different markers, and examined these cell types for correlations with clinical parameters. RA patients exhibited higher frequencies of CD4+CXCR5+, CD4+CXCR5+ICOS+, CD4+CXCR5+OX40+, and CD4+CXCR5+CD40L+ Tfh cells than HCs. CD4+CXCR5+, CD4+CXCR5+CD40L+, and CD4+CXCR5+OX40+ Tfh cell frequencies positively correlated with disease activity score-28 with erythrocyte sedimentation rate (DAS28-ESR), while those of CD4+CXCR5+ and CD4+CXCR5+CD40L+ Tfh cells were related to rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies. In RA patients without joint bone erosion, CD4+CXCR5+CD40L+ Tfh cell frequencies were positively correlated with both RF and DAS28-ESR. Serum anti-CCP antibody levels and CD4+CXCR5+ICOS+ Tfh cell frequencies were also positively correlated. Circulating CD4+CXCR5+CD40L+ Tfh cells appear to play critical roles in RA pathogenesis, and restricting CD4+CXCR5+CD40L+ Tfh cells may be a therapeutic strategy for controlling RA.
Collapse
Affiliation(s)
- Tingshuang Xu
- Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, Changchun, China.,Department of Public Laboratory Platform, The First Hospital of Jilin University, Changchun, China
| | - Tianyi Yan
- Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, Changchun, China.,Department of Dermatology, Second Hospital of Jilin University, Changchun, China
| | - Fuqiu Li
- Department of Dermatology, Second Hospital of Jilin University, Changchun, China
| | - Bingtong Li
- Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Ping Li
- Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, Changchun, China
| |
Collapse
|
|
36
|
Srivastava RK, Sapra L. The Rising Era of “Immunoporosis”: Role of Immune System in the Pathophysiology of Osteoporosis. J Inflamm Res 2022; 15:1667-1698. [PMID: 35282271 PMCID: PMC8906861 DOI: 10.2147/jir.s351918] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 02/10/2022] [Indexed: 12/21/2022] Open
Abstract
Discoveries in the last few years have emphasized the existence of an enormous breadth of communication between bone and the immune system in maintaining skeletal homeostasis. Originally, the discovery of various factors was assigned to the immune system viz. interleukin (IL)-6, IL-10, IL-17, tumor necrosis factor (TNF)-α, receptor activator of nuclear factor kappa B ligand (RANKL), nuclear factor of activated T cells (NFATc1), etc., but now these factors have also been shown to have a significant impact on osteoblasts (OBs) and osteoclasts (OCs) biology. These discoveries led to an alteration in the approach for the treatment of several bone pathologies including osteoporosis. Osteoporosis is an inflammatory bone anomaly affecting more than 500 million people globally. In 2018, to highlight the importance of the immune system in the pathophysiology of osteoporosis, our group coined the term “immunoporosis”. In the present review, we exhaustively revisit the characteristics, mechanism of action, and function of both innate and adaptive immune cells with the goal of understanding the potential of immune cells in osteoporosis. We also highlight the Immunoporotic role of gut microbiota (GM) for the treatment and management of osteoporosis. Importantly, we further discuss whether an immune cell-based strategy to treat and manage osteoporosis is feasible and relevant in clinical settings.
Collapse
Affiliation(s)
- Rupesh K Srivastava
- Immunoporosis Lab, Department of Biotechnology, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India
- Correspondence: Rupesh K Srivastava, Tel +91 11-26593548, Email ;
| | - Leena Sapra
- Immunoporosis Lab, Department of Biotechnology, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India
| |
Collapse
|
|
37
|
Cheng X, Zhou L, Li Z, Shen S, Zhao Y, Liu C, Zhong X, Chang Y, Kermode AG, Qiu W. Gut Microbiome and Bile Acid Metabolism Induced the Activation of CXCR5+ CD4+ T Follicular Helper Cells to Participate in Neuromyelitis Optica Spectrum Disorder Recurrence. Front Immunol 2022; 13:827865. [PMID: 35126400 PMCID: PMC8811147 DOI: 10.3389/fimmu.2022.827865] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 01/03/2022] [Indexed: 12/29/2022] Open
Abstract
From the perspective of the role of T follicular helper (Tfh) cells in the destruction of tolerance in disease progression, more attention has been paid to their role in autoimmunity. To address the role of Tfh cells in neuromyelitis optica spectrum disorder (NMOSD) recurrence, serum C-X-C motif ligand 13 (CXCL13) levels reflect the effects of the Tfh cells on B-cell-mediated humoral immunity. We evaluated the immunobiology of the CXCR5+CD4+ Tfh cells in 46 patients with NMOSD, including 37 patients with NMOSD with an annual recurrence rate (ARR) of<1 and 9 patients with NMOSD with an ARR of ≥1. Herein, we reported several key observations. First, there was a lower frequency of circulating Tfh cells in patients with an ARR of<1 than in those with an ARR of ≥1 (P< 0.05). Second, the serum CXCL13 levels were downregulated in individuals with an ARR<1 (P< 0.05), processing the ability to promote Tfh maturation and chemotaxis. Third, the level of the primary bile acid, glycoursodeoxycholic acid (GUDCA), was higher in patients with NMOSD with an ARR of<1 than in those with NMOSD with an ARR of ≥1, which was positively correlated with CXCL13. Lastly, the frequency of the Tfh precursor cells decreased in the spleen of keyhole limpet haemocyanin-stimulated animals following GUDCA intervention. These findings significantly broaden our understanding of Tfh cells and CXCL13 in NMOSD. Our data also reveal the potential mechanism of intestinal microbiota and metabolites involved in NMOSD recurrence.
Collapse
Affiliation(s)
- Xi Cheng
- Department of Neurology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Luyao Zhou
- Department of Neurology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zhibin Li
- Department of Neurology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shishi Shen
- Department of Neurology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yipeng Zhao
- Department of Neurology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Chunxin Liu
- Department of Neurology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaonan Zhong
- Department of Neurology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yanyu Chang
- Department of Neurology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Allan G. Kermode
- Department of Neurology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Centre for Neuromuscular and Neurological Disorders, Perron Institute, The University of Western Australia, Perth, WA, Australia
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, WA, Australia
| | - Wei Qiu
- Department of Neurology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| |
Collapse
|
|
38
|
Hart AP, Laufer TM. A review of signaling and transcriptional control in T follicular helper cell differentiation. J Leukoc Biol 2022; 111:173-195. [PMID: 33866600 DOI: 10.1002/jlb.1ri0121-066r] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
T follicular helper (Tfh) cells are a critical component of adaptive immunity and assist in optimal Ab-mediated defense. Multiple effector functions of Tfh support germinal center B cell survival, Ab class switching, and plasma cell maturation. In the past 2 decades, the phenotype and functional characteristics of GC Tfh have been clarified allowing for robust studies of the Th subset including activation signals and environmental cues controlling Tfh differentiation and migration during an immune response. A unique, 2-step differentiation process of Tfh has been proposed but the mechanisms underlying transition between unstable Tfh precursors and functional mature Tfh remain elusive. Likewise, newly identified transcriptional regulators of Tfh development have not yet been incorporated into our understanding of how these cells might function in disease. Here, we review the signals and downstream transcription factors that shape Tfh differentiation including what is known about the epigenetic processes that maintain Tfh identity. It is proposed that further evaluation of the stepwise differentiation pattern of Tfh will yield greater insights into how these cells become dysregulated in autoimmunity.
Collapse
Affiliation(s)
- Andrew P Hart
- Division of Rheumatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Terri M Laufer
- Division of Rheumatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Division of Rheumatology, Department of Medicine, Corporal Michael C. Crescenz VA Medical Center, Philadelphia, PA, 19104, USA
| |
Collapse
|
|
39
|
Cyanidin restores Th17/Treg balance and inhibits T follicular helper cell differentiation via modulation of ROCK2 signaling in an experimental model of rheumatoid arthritis. Int Immunopharmacol 2021; 101:108359. [PMID: 34863656 DOI: 10.1016/j.intimp.2021.108359] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 10/10/2021] [Accepted: 11/07/2021] [Indexed: 01/02/2023]
Abstract
Disturbed Th17/Treg balance is a critical pathological event in the disease progression of rheumatoid arthritis (RA). Recently, emerging studies have demonstrated that CD4 + T helper follicular (Tfh) cells exacerbates the pathogenic manifestations of RA. Contrarily, our previous report has shown that cyanidin, a flavonoid compound, attenuates disease severity of RA. Howbeit, this study investigated the therapeutic efficacy of cyanidin in relation to Th17/Treg balance and pathogenic Tfh cells in RA. Onto results, cyanidin inhibited increased Th17 cell differentiation and reciprocally improved FoxP3 + Treg cells both in-vivo and in-vitro. Concomitantly, cyanidin abated the detrimental effects of IL-17 via restoration of IL-10 secretion in adjuvant induced arthritic (AIA) rats. Furthermore, cyanidin reduced Tfh cells proportion and IgG levels in AIA rats, thus rectifying Tfh and follicular regulatory T (Tfr) cell ratio. Mechanistically, the restoring effect of cyanidin was associated with blunted activation of ROCK2/STAT3 signaling axis and reciprocal increase in the level of STAT-5 activity. Notwithstanding, cyanidin therapeutic efficacy correlated with specific oral ROCK2 inhibitor KD025 in-vitro. Collectively, these results demonstrate a dual promising therapeutic role of cyanidin via regulating Th17/Treg ratio and Tfh cell differentiation in an experimental model of RA.
Collapse
|
|
40
|
Vecchione A, Jofra T, Gerosa J, Shankwitz K, Di Fonte R, Galvani G, Ippolito E, Cicalese MP, Schultz AR, Seay HR, Favellato M, Milardi G, Stabilini A, Ragogna F, Grogan P, Bianconi E, Laurenzi A, Caretto A, Nano R, Melzi R, Danzl N, Bosi E, Piemonti L, Aiuti A, Brusko T, Petrovas C, Battaglia M, Fousteri G. Reduced Follicular Regulatory T Cells in Spleen and Pancreatic Lymph Nodes of Patients With Type 1 Diabetes. Diabetes 2021; 70:2892-2902. [PMID: 34620616 PMCID: PMC8660982 DOI: 10.2337/db21-0091] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 09/20/2021] [Indexed: 11/13/2022]
Abstract
In the attempt to understand the origin of autoantibody (AAb) production in patients with and at risk for type 1 diabetes (T1D), multiple studies have analyzed and reported alterations in T follicular helper (Tfh) cells in presymptomatic AAb+ subjects and patients with T1D. Yet, whether the regulatory counterpart of Tfh cells, represented by T follicular regulatory (Tfr) cells, is similarly altered is still unclear. To address this question, we performed analyses in peripheral blood, spleen, and pancreatic lymph nodes (PLN) of organ donor subjects with T1D. Blood analyses were also performed in living AAb- and AAb+ subjects. While negligible differences in the frequency and phenotype of blood Tfr cells were observed among T1D, AAb-, and AAb+ adult subjects, the frequency of Tfr cells was significantly reduced in spleen and PLN of T1D as compared with nondiabetic control subjects. Furthermore, adoptive transfer of Tfr cells delayed disease development in a mouse model of T1D, a finding that could indicate that Tfr cells play an important role in peripheral tolerance and regulation of autoreactive Tfh cells. Together, our findings provide evidence of Tfr cell alterations within disease-relevant tissues in patients with T1D, suggesting a role for Tfr cells in defective humoral tolerance and disease pathogenesis.
Collapse
Affiliation(s)
- Andrea Vecchione
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY
| | - Tatiana Jofra
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Jolanda Gerosa
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Kimberly Shankwitz
- Tissue Analysis Core, Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Roberta Di Fonte
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giuseppe Galvani
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Elio Ippolito
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Maria Pia Cicalese
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Andrew R Schultz
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL
| | - Howie R Seay
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL
| | | | - Giulia Milardi
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Angela Stabilini
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Francesca Ragogna
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Pauline Grogan
- Department of Internal Medicine, IRCCS San Raffaele Hospital, Milan, Italy
- TrialNet Clinical Center, IRCCS San Raffaele Hospital, Milan, Italy
| | - Eleonora Bianconi
- Department of Internal Medicine, IRCCS San Raffaele Hospital, Milan, Italy
- TrialNet Clinical Center, IRCCS San Raffaele Hospital, Milan, Italy
| | - Andrea Laurenzi
- Department of Internal Medicine, IRCCS San Raffaele Hospital, Milan, Italy
| | - Amelia Caretto
- Department of Internal Medicine, IRCCS San Raffaele Hospital, Milan, Italy
| | - Rita Nano
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Raffaela Melzi
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Nichole Danzl
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY
| | - Emanuele Bosi
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
- Department of Internal Medicine, IRCCS San Raffaele Hospital, Milan, Italy
- TrialNet Clinical Center, IRCCS San Raffaele Hospital, Milan, Italy
| | - Lorenzo Piemonti
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
- Department of Internal Medicine, IRCCS San Raffaele Hospital, Milan, Italy
| | - Alessandro Aiuti
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Todd Brusko
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL
| | - Constantinos Petrovas
- Tissue Analysis Core, Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Manuela Battaglia
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
- TrialNet Clinical Center, IRCCS San Raffaele Hospital, Milan, Italy
| | - Georgia Fousteri
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| |
Collapse
|
|
41
|
Akama-Garren EH, van den Broek T, Simoni L, Castrillon C, van der Poel CE, Carroll MC. Follicular T cells are clonally and transcriptionally distinct in B cell-driven mouse autoimmune disease. Nat Commun 2021; 12:6687. [PMID: 34795279 PMCID: PMC8602266 DOI: 10.1038/s41467-021-27035-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 10/23/2021] [Indexed: 11/30/2022] Open
Abstract
Pathogenic autoantibodies contribute to tissue damage and clinical decline in autoimmune disease. Follicular T cells are central regulators of germinal centers, although their contribution to autoantibody-mediated disease remains unclear. Here we perform single cell RNA and T cell receptor (TCR) sequencing of follicular T cells in a mouse model of autoantibody-mediated disease, allowing for analyses of paired transcriptomes and unbiased TCRαβ repertoires at single cell resolution. A minority of clonotypes are preferentially shared amongst autoimmune follicular T cells and clonotypic expansion is associated with differential gene signatures in autoimmune disease. Antigen prediction using algorithmic and machine learning approaches indicates convergence towards shared specificities between non-autoimmune and autoimmune follicular T cells. However, differential autoimmune transcriptional signatures are preserved even amongst follicular T cells with shared predicted specificities. These results demonstrate that follicular T cells are phenotypically distinct in B cell-driven autoimmune disease, providing potential therapeutic targets to modulate autoantibody development.
Collapse
MESH Headings
- Animals
- Autoimmune Diseases/genetics
- Autoimmune Diseases/immunology
- Autoimmune Diseases/metabolism
- B-Lymphocytes/immunology
- B-Lymphocytes/metabolism
- CD4-Positive T-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/metabolism
- Cells, Cultured
- Clone Cells/immunology
- Clone Cells/metabolism
- Gene Expression Profiling/methods
- Germinal Center/cytology
- Germinal Center/immunology
- Germinal Center/metabolism
- Mice, Inbred C57BL
- Microscopy, Confocal
- RNA-Seq/methods
- Receptors, Antigen, T-Cell/genetics
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Single-Cell Analysis/methods
- T-Lymphocytes, Helper-Inducer/immunology
- T-Lymphocytes, Helper-Inducer/metabolism
- Mice
Collapse
Affiliation(s)
- Elliot H Akama-Garren
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA
- Harvard-MIT Health Sciences and Technology, Harvard Medical School, Boston, MA, 02115, USA
| | - Theo van den Broek
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Lea Simoni
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Carlos Castrillon
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Cees E van der Poel
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Michael C Carroll
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
| |
Collapse
|
|
42
|
Amaral-Silva D, Gonçalves R, Torrão RC, Torres R, Falcão S, Gonçalves MJ, Araújo MP, Martins MJ, Lopes C, Neto A, Marona J, Costa T, Castelão W, Silva AB, Silva I, Lourenço MH, Mateus M, Gonçalves NP, Manica S, Costa M, Pimentel-Santos FM, Mourão AF, Branco JC, Soares H. Direct tissue-sensing reprograms TLR4 + Tfh-like cells inflammatory profile in the joints of rheumatoid arthritis patients. Commun Biol 2021; 4:1135. [PMID: 34580414 PMCID: PMC8476501 DOI: 10.1038/s42003-021-02659-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 09/09/2021] [Indexed: 12/20/2022] Open
Abstract
CD4+ T cells mediate rheumatoid arthritis (RA) pathogenesis through both antibody-dependent and independent mechanisms. It remains unclear how synovial microenvironment impinges on CD4+ T cells pathogenic functions. Here, we identified a TLR4+ follicular helper T (Tfh) cell-like population present in the blood and expanded in synovial fluid. TLR4+ T cells possess a two-pronged pathogenic activity whereby direct TLR4+ engagement by endogenous ligands in the arthritic joint reprograms them from an IL-21 response, known to sponsor antibody production towards an IL-17 inflammatory program recognized to fuel tissue damage. Ex vivo, synovial fluid TLR4+ T cells produced IL-17, but not IL-21. Blocking TLR4 signaling with a specific inhibitor impaired IL-17 production in response to synovial fluid recognition. Mechanistically, we unveiled that T-cell HLA-DR regulates their TLR4 expression. TLR4+ T cells appear to uniquely reconcile an ability to promote systemic antibody production with a local synovial driven tissue damage program. In order to identify how the synovial microenvironment impinges on CD4+ T cells pathogenic functions in Rheumatoid Arthritis (RA), Amaral-Silva examined RA patient blood and synovial fluif and identified the presence of a TLR4+ follicular helper T (Tfh) cell-like population. They provided mechanistic insight into how TLR4+ T cells uniquely reconcile an ability to promote systemic antibody production with a local synovial driven-tissue damage program.
Collapse
Affiliation(s)
- Daniela Amaral-Silva
- Human Immunobiology and Pathogenesis Group, Lisboa, Portugal
- grid.10772.330000000121511713iNOVA4Health | CEDOC, NOVA Medical School | Faculdade de Ciências Médicas, NOVA University of Lisbon, Lisboa, Portugal
| | - Rute Gonçalves
- Human Immunobiology and Pathogenesis Group, Lisboa, Portugal
- grid.10772.330000000121511713iNOVA4Health | CEDOC, NOVA Medical School | Faculdade de Ciências Médicas, NOVA University of Lisbon, Lisboa, Portugal
| | - Rita C. Torrão
- Human Immunobiology and Pathogenesis Group, Lisboa, Portugal
- grid.10772.330000000121511713iNOVA4Health | CEDOC, NOVA Medical School | Faculdade de Ciências Médicas, NOVA University of Lisbon, Lisboa, Portugal
| | - Rita Torres
- grid.10772.330000000121511713iNOVA4Health | CEDOC, NOVA Medical School | Faculdade de Ciências Médicas, NOVA University of Lisbon, Lisboa, Portugal
- grid.414462.10000 0001 1009 677XHospital Egas Moniz, Rua da Junqueira n° 126, Lisboa, Portugal
- Rheumatological Diseases Laboratory, Lisboa, Portugal
| | - Sandra Falcão
- grid.10772.330000000121511713iNOVA4Health | CEDOC, NOVA Medical School | Faculdade de Ciências Médicas, NOVA University of Lisbon, Lisboa, Portugal
- grid.414462.10000 0001 1009 677XHospital Egas Moniz, Rua da Junqueira n° 126, Lisboa, Portugal
- Rheumatological Diseases Laboratory, Lisboa, Portugal
| | - Maria João Gonçalves
- grid.414462.10000 0001 1009 677XHospital Egas Moniz, Rua da Junqueira n° 126, Lisboa, Portugal
| | - Maria Paula Araújo
- grid.414462.10000 0001 1009 677XHospital Egas Moniz, Rua da Junqueira n° 126, Lisboa, Portugal
| | - Maria José Martins
- grid.414462.10000 0001 1009 677XHospital Egas Moniz, Rua da Junqueira n° 126, Lisboa, Portugal
| | - Carina Lopes
- grid.414462.10000 0001 1009 677XHospital Egas Moniz, Rua da Junqueira n° 126, Lisboa, Portugal
| | - Agna Neto
- grid.10772.330000000121511713iNOVA4Health | CEDOC, NOVA Medical School | Faculdade de Ciências Médicas, NOVA University of Lisbon, Lisboa, Portugal
- grid.414462.10000 0001 1009 677XHospital Egas Moniz, Rua da Junqueira n° 126, Lisboa, Portugal
- Rheumatological Diseases Laboratory, Lisboa, Portugal
| | - José Marona
- grid.414462.10000 0001 1009 677XHospital Egas Moniz, Rua da Junqueira n° 126, Lisboa, Portugal
| | - Tiago Costa
- grid.414462.10000 0001 1009 677XHospital Egas Moniz, Rua da Junqueira n° 126, Lisboa, Portugal
| | - Walter Castelão
- grid.414462.10000 0001 1009 677XHospital Egas Moniz, Rua da Junqueira n° 126, Lisboa, Portugal
| | - Ana Bento Silva
- grid.414462.10000 0001 1009 677XHospital Egas Moniz, Rua da Junqueira n° 126, Lisboa, Portugal
| | - Inês Silva
- grid.414462.10000 0001 1009 677XHospital Egas Moniz, Rua da Junqueira n° 126, Lisboa, Portugal
| | - Maria Helena Lourenço
- grid.414462.10000 0001 1009 677XHospital Egas Moniz, Rua da Junqueira n° 126, Lisboa, Portugal
| | - Margarida Mateus
- grid.414462.10000 0001 1009 677XHospital Egas Moniz, Rua da Junqueira n° 126, Lisboa, Portugal
| | - Nuno Pina Gonçalves
- grid.10772.330000000121511713iNOVA4Health | CEDOC, NOVA Medical School | Faculdade de Ciências Médicas, NOVA University of Lisbon, Lisboa, Portugal
- grid.414462.10000 0001 1009 677XHospital Egas Moniz, Rua da Junqueira n° 126, Lisboa, Portugal
- Rheumatological Diseases Laboratory, Lisboa, Portugal
| | - Santiago Manica
- grid.10772.330000000121511713iNOVA4Health | CEDOC, NOVA Medical School | Faculdade de Ciências Médicas, NOVA University of Lisbon, Lisboa, Portugal
- grid.414462.10000 0001 1009 677XHospital Egas Moniz, Rua da Junqueira n° 126, Lisboa, Portugal
- Rheumatological Diseases Laboratory, Lisboa, Portugal
| | - Manuela Costa
- grid.414462.10000 0001 1009 677XHospital Egas Moniz, Rua da Junqueira n° 126, Lisboa, Portugal
| | - Fernando M. Pimentel-Santos
- grid.10772.330000000121511713iNOVA4Health | CEDOC, NOVA Medical School | Faculdade de Ciências Médicas, NOVA University of Lisbon, Lisboa, Portugal
- grid.414462.10000 0001 1009 677XHospital Egas Moniz, Rua da Junqueira n° 126, Lisboa, Portugal
- Rheumatological Diseases Laboratory, Lisboa, Portugal
| | - Ana Filipa Mourão
- grid.10772.330000000121511713iNOVA4Health | CEDOC, NOVA Medical School | Faculdade de Ciências Médicas, NOVA University of Lisbon, Lisboa, Portugal
- grid.414462.10000 0001 1009 677XHospital Egas Moniz, Rua da Junqueira n° 126, Lisboa, Portugal
- Rheumatological Diseases Laboratory, Lisboa, Portugal
| | - Jaime C. Branco
- grid.414462.10000 0001 1009 677XHospital Egas Moniz, Rua da Junqueira n° 126, Lisboa, Portugal
- Rheumatological Diseases Laboratory, Lisboa, Portugal
- grid.10772.330000000121511713CHRC|CEDOC, NOVA Medical School | Faculdade de Ciências Médicas, NOVA University of Lisbon, Lisboa, Portugal
| | - Helena Soares
- Human Immunobiology and Pathogenesis Group, Lisboa, Portugal
- grid.10772.330000000121511713iNOVA4Health | CEDOC, NOVA Medical School | Faculdade de Ciências Médicas, NOVA University of Lisbon, Lisboa, Portugal
- The Discoveries Centre for Regenerative and Precision Medicine, Lisbon Campus, Rua do Instituto Bacteriológico 5, Lisboa, Portugal
| |
Collapse
|
|
43
|
Zhang X, Ge R, Chen H, Ahiafor M, Liu B, Chen J, Fan X. Follicular Helper CD4 + T Cells, Follicular Regulatory CD4 + T Cells, and Inducible Costimulator and Their Roles in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis. Mediators Inflamm 2021; 2021:2058964. [PMID: 34552387 PMCID: PMC8452443 DOI: 10.1155/2021/2058964] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 08/12/2021] [Accepted: 08/26/2021] [Indexed: 12/13/2022] Open
Abstract
Follicular helper CD4+ T (TFH) cells are a specialized subset of effector T cells that play a central role in orchestrating adaptive immunity. TFH cells mainly promote germinal center (GC) formation, provide help to B cells for immunoglobulin affinity maturation and class-switch recombination of B cells, and facilitate production of long-lived plasma cells and memory B cells. TFH cells express the nuclear transcriptional repressor B cell lymphoma 6 (Bcl-6), the chemokine (C-X-C motif) receptor 5 (CXCR5), the CD28 family members programmed cell death protein-1 (PD-1) and inducible costimulator (ICOS) and are also responsible for the secretion of interleukin-21 (IL-21) and IL-4. Follicular regulatory CD4+ T (TFR) cells, as a regulatory counterpart of TFH cells, participate in the regulation of GC reactions. TFR cells not only express markers of TFH cells but also express markers of regulatory T (Treg) cells containing FOXP3, glucocorticoid-induced tumor necrosis factor receptor (GITR), cytotoxic T lymphocyte antigen 4 (CTLA-4), and IL-10, hence owing to the dual characteristic of TFH cells and Treg cells. ICOS, expressed on activated CD4+ effector T cells, participates in T cell activation, differentiation, and effector process. The expression of ICOS is highest on TFH and TFR cells, indicating it as a key regulator of humoral immunity. Multiple sclerosis (MS) is a severe autoimmune disease that affects the central nervous system and results in disability, mediated by autoreactive T cells with evolving evidence of a remarkable contribution from humoral responses. This review summarizes recent advances regarding TFH cells, TFR cells, and ICOS, as well as their functional characteristics in relation to MS.
Collapse
Affiliation(s)
- Xue Zhang
- Department of Neurology, Binzhou Medical University Hospital, Binzhou, 256603 Shandong, China
| | - Ruli Ge
- Department of Neurology, Binzhou Medical University Hospital, Binzhou, 256603 Shandong, China
| | - Hongliang Chen
- Department of Neurology, Binzhou Medical University Hospital, Binzhou, 256603 Shandong, China
| | - Maxwell Ahiafor
- School of International Studies, Binzhou Medical University, Yantai, 264003 Shandong, China
| | - Bin Liu
- Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, Binzhou, 256603 Shandong, China
| | - Jinbo Chen
- Department of Neurology, Binzhou Medical University Hospital, Binzhou, 256603 Shandong, China
| | - Xueli Fan
- Department of Neurology, Binzhou Medical University Hospital, Binzhou, 256603 Shandong, China
| |
Collapse
|
|
44
|
The role of circulating T follicular helper cells in kidney transplantation. Transpl Immunol 2021; 69:101459. [PMID: 34461243 DOI: 10.1016/j.trim.2021.101459] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 08/21/2021] [Accepted: 08/25/2021] [Indexed: 12/12/2022]
Abstract
Humoral rejection plays a crucial role in the chronic deterioration of kidney allografts, but there is no effective therapeutic strategy to prevent or treat it. T follicular helper (Tfh) cells provide help to B cells, subsequently contributing to humoral rejection. Investigation of Tfh cells may be a useful strategy for assessing the risk and level of humoral rejection. However, it is difficult to investigate Tfh cells from patient-derived lymphoid tissue. Recent studies have shown that circulating Tfh (cTfh) cells, working in parallel to Tfh cells, have the capacity to promote antibody-secreting B cell differentiation and antibody secretion. Here, we review recent studies of cTfh cells in kidney transplantation and discuss the characteristics and functions of cTfh cells in kidney transplant recipients.
Collapse
|
|
45
|
Pasquini S, Contri C, Borea PA, Vincenzi F, Varani K. Adenosine and Inflammation: Here, There and Everywhere. Int J Mol Sci 2021; 22:7685. [PMID: 34299305 PMCID: PMC8304851 DOI: 10.3390/ijms22147685] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/16/2021] [Accepted: 07/16/2021] [Indexed: 02/06/2023] Open
Abstract
Adenosine is a ubiquitous endogenous modulator with the main function of maintaining cellular and tissue homeostasis in pathological and stress conditions. It exerts its effect through the interaction with four G protein-coupled receptor (GPCR) subtypes referred as A1, A2A, A2B, and A3 adenosine receptors (ARs), each of which has a unique pharmacological profile and tissue distribution. Adenosine is a potent modulator of inflammation, and for this reason the adenosinergic system represents an excellent pharmacological target for the myriad of diseases in which inflammation represents a cause, a pathogenetic mechanism, a consequence, a manifestation, or a protective factor. The omnipresence of ARs in every cell of the immune system as well as in almost all cells in the body represents both an opportunity and an obstacle to the clinical use of AR ligands. This review offers an overview of the cardinal role of adenosine in the modulation of inflammation, showing how the stimulation or blocking of its receptors or agents capable of regulating its extracellular concentration can represent promising therapeutic strategies for the treatment of chronic inflammatory pathologies, neurodegenerative diseases, and cancer.
Collapse
Affiliation(s)
- Silvia Pasquini
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (S.P.); (C.C.); (K.V.)
| | - Chiara Contri
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (S.P.); (C.C.); (K.V.)
| | | | - Fabrizio Vincenzi
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (S.P.); (C.C.); (K.V.)
| | - Katia Varani
- Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy; (S.P.); (C.C.); (K.V.)
| |
Collapse
|
|
46
|
Su R, Wang Y, Hu F, Li B, Guo Q, Zheng X, Liu Y, Gao C, Li X, Wang C. Altered Distribution of Circulating T Follicular Helper-Like Cell Subsets in Rheumatoid Arthritis Patients. Front Med (Lausanne) 2021; 8:690100. [PMID: 34350197 PMCID: PMC8326448 DOI: 10.3389/fmed.2021.690100] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 06/09/2021] [Indexed: 12/30/2022] Open
Abstract
Objective: Recent studies on follicular regulatory T (Tfr) and follicular helper T (Tfh) cells suggest that they may participate in the pathogenesis of rheumatoid arthritis (RA). Here, we examine Tfr-like and Tfh-like cells and their subsets in RA and assess the correlations between these subsets with B cells and cytokines related to the pathogenesis of RA and their clinical significance. Methods: The study population consisted of 18 healthy controls and 47 RA patients (17 new onset, 57.00 ± 11.73 years; 30 treated RA patients, 57.56 ± 1.97 years). Disease activity scores in 28 joints were calculated. The positive rates of rheumatoid factor (RF) and anticyclic citrullinated peptide antibodies (anti-CCP) were 82.9 and 89.4%, respectively. Cell subsets were analyzed using flow cytometry, and serum cytokine levels were measured using cytometric bead array. Results: Tfh-like and PD-1+ Tfh-like cells were elevated, and the distribution of Tfh-like cell subsets was altered with increased Tfh17-like and Tfh1/17-like cells in RA patients. The receiver operating characteristics curves for Tfh-like, Tfh17-like, Tfh1/17-like, and PD-1+ Tfh-like cells indicate improved RA diagnostic potential. RA patients had decreased regulatory T (Treg), Tfr-like, and memory Tfr-like (mTfr-like) cells and increased Tfh-like/Treg, Tfh-like/Tfr-like, and Tfh-like/mTfr-like cell ratios. Tfh-like cells and their subsets, including Tfh1-like, Tfh2-like, Tfh1/17-like, and PD-1+ Tfh-like cells, were positively correlated with B cells. Tfh-like/Treg, Tfh-like/Tfr-like, and Tfh-like/mTfr-like cell ratios were positively correlated with B cells in new-onset RA. Interleukin (IL)-2, IL-4, IL-17, interferon-γ, and tumor necrosis factor-α were positively correlated with Tfr-like and mTfr-like cells. IL-2 and IL-10 were positively correlated with Tfh-like and Tfh2-like cells. IL-4 was positively correlated with Tfh-like cells. Conclusions: Tfh-like and PD-1+ Tfh-like cells are increased, whereas Treg, Tfr-like, and mTfr-like cells are decreased in RA, leading to an imbalance in Tfh-like/Treg, Tfh-like/Tfr-like, and Tfh-like/mTfr-like cell ratios. Tfh-like cells and a portion of their subsets as well as Tfh-like/Treg, Tfh-like/Tfr-like, and Tfh-like/mTfr-like cell ratios are closely related to B cells. Dysfunction of cell subsets leads to abnormal levels of cytokines involved in the pathogenesis of RA. The altered distributions of Tfh-like cell subsets, especially Tfh1/17-like cells, represent potential therapeutic targets for treatment of RA.
Collapse
Affiliation(s)
- Rui Su
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Yanyan Wang
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Fangyuan Hu
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Baochen Li
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Qiaoling Guo
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Xinyu Zheng
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Yue Liu
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Chong Gao
- Pathology, Joint Program in Transfusion Medicine, Brigham and Women's Hospital/Children's Hospital Boston, Harvard Medical School, Boston, MA, United States
| | - Xiaofeng Li
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Caihong Wang
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| |
Collapse
|
|
47
|
Zhao L, Li Z, Zeng X, Xia C, Xu L, Xu Q, Song Y, Liu C. Circulating CD4 + FoxP3 - CXCR5 - CXCR3 + PD-1 hi cells are elevated in active rheumatoid arthritis and reflect the severity of the disease. Int J Rheum Dis 2021; 24:1032-1039. [PMID: 34227243 DOI: 10.1111/1756-185x.14170] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 06/04/2021] [Accepted: 06/21/2021] [Indexed: 11/30/2022]
Abstract
OBJECTIVE To examine the expression and clinical significance of circulating CD4+ FoxP3- CXCR5- CXCR3+ PD-1hi cells in rheumatoid arthritis (RA). METHODS CD4+ FoxP3- CXCR5- CXCR3+ PD-1hi cells in peripheral blood of 35 patients with active RA, 17 with RA in stable remission, and 24 healthy controls were analyzed by flow cytometry. Serum IgG and circulating plasmablast percentages were measured and correlations with CD4+ FoxP3- CXCR5- CXCR3+ PD-1hi cells were systematically analyzed. Disease Activity Scale 28 (DAS28) scores were also calculated and correlation analysis with CD4+ FoxP3- CXCR5- CXCR3+ PD-1hi cells was conducted. The levels of CD4+ FoxP3- CXCR5- CXCR3+ PD-1hi cells were compared before and after disease-modifying anti-rheumatic drug treatment. Cytokine levels in plasma and cytokine secretion in CD4 cells were measured and their correlations with CD4+ FoxP3- CXCR5- CXCR3+ PD-1hi cells were further analyzed. RESULTS The levels of CD4+ FoxP3- CXCR5- CXCR3+ PD-1hi cells in the peripheral blood of patients with active RA were significantly increased compared with healthy controls. CD4+ FoxP3- CXCR5- CXCR3+ PD-1hi cells in patients with active RA were positively correlated with serum IgG and DAS28 scores. CD4+ FoxP3- CXCR5- CXCR3+ PD-1hi cells were significantly decreased in patients after treatment. Plasma interleukin-10 concentrations and interleukin-10-positive CD4 cell percentages were significantly positively correlated with CD4+ FoxP3- CXCR5- CXCR3+ PD-1hi cell levels. CONCLUSION Circulating CD4+ FoxP3- CXCR5- CXCR3+ PD-1hi cells in patients with active RA are increased and could reflect the severity of the disease, which may play a potential role in the pathogenesis of RA.
Collapse
Affiliation(s)
- Lei Zhao
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Zhenxue Li
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Xingyue Zeng
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Changsheng Xia
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Lijuan Xu
- Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Qinzhu Xu
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Ying Song
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Chen Liu
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| |
Collapse
|
|
48
|
Sakurai S, Furuhashi K, Horiguchi R, Nihashi F, Yasui H, Karayama M, Suzuki Y, Hozumi H, Enomoto N, Fujisawa T, Nakamura Y, Inui N, Suda T. Conventional type 2 lung dendritic cells are potent inducers of follicular helper T cells in the asthmatic lung. Allergol Int 2021; 70:351-359. [PMID: 33674189 DOI: 10.1016/j.alit.2021.01.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 01/15/2021] [Accepted: 01/28/2021] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Follicular helper T (Tfh) cells represent a unique subset of helper CD4+ T cells in lymphoid follicles. Recently, Tfh cells were shown to play an important role in asthma through B cell differentiation. Conventional lung DCs are classified into two major subsets: conventional type 1 (cDC1) and type 2 (cDC2). Although the two subsets are different in driving particular T cell responses, the subset that induces Tfh cells in the asthmatic lung primarily has yet to be fully elucidated. METHODS We evaluated Tfh cells, defined by the expression of CD4 and CXCR5, in HDM-challenged mice. Next, we characterized cDC1 and cDC2 purified from antigen-primed lung and examined their Tfh cell-inducing capacity. Additionally, the ability of lung DC-induced Tfh cells to cause germinal center B (GCB) cells to produce antigen-specific IgE was assessed. RESULTS In HDM-challenged mice, Bcl-6-expressing Tfh cells were significantly increased in the mediastinal lymph nodes. Lung cDC2, but not lung cDC1, increased after HDM priming, and cDC2 secreted larger amounts of IL-6 with higher ICOS-L expression than cDC1. In the co-cultures with OVA-specific naïve CD4+ T cells, cDC2 from OVA-primed lung induced Bcl-6-expressing Tfh cells more efficiently, together with larger amounts of IL-6 and IL-21, than cDC1. Blockage of IL-6 or ICOS-L significantly reduced Tfh cell induction. Finally, cDC2-induced Tfh cells enabled GCB cells to produce OVA-specific IgE. CONCLUSIONS In asthmatic lung, cDC2 is the primary DC subset responsible for Tfh cell differentiation and plays an important role in humoral immunity in asthma by inducing Tfh cells.
Collapse
Affiliation(s)
- Shogo Sakurai
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Kazuki Furuhashi
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan; Department of Laboratory Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan.
| | - Ryo Horiguchi
- Advanced Research Facilities and Services, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Fumiya Nihashi
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Hideki Yasui
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Masato Karayama
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Yuzo Suzuki
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Hironao Hozumi
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Noriyuki Enomoto
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Tomoyuki Fujisawa
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Yutaro Nakamura
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Naoki Inui
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Takafumi Suda
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| |
Collapse
|
|
49
|
Lu J, Wu J, Xia X, Peng H, Wang S. Follicular helper T cells: potential therapeutic targets in rheumatoid arthritis. Cell Mol Life Sci 2021; 78:5095-5106. [PMID: 33880615 PMCID: PMC11073436 DOI: 10.1007/s00018-021-03839-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/26/2021] [Accepted: 04/08/2021] [Indexed: 02/08/2023]
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease with joint and systemic inflammation that is accompanied by the production of autoantibodies, such as rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) antibodies. Follicular helper T (Tfh) cells, which are a subset of CD4+ T cells, facilitate germinal center (GC) reactions by providing signals required for high-affinity antibody production and the generation of long-lived antibody-secreting plasma cells. Uncontrolled expansion of Tfh cells is observed in various systemic autoimmune diseases. Particularly, the frequencies of circulating Tfh-like (cTfh-like) cells, their subtypes and synovial-infiltrated T helper cells correlate with disease activity in RA patients. Therefore, reducing autoantibody production and restricting excessive Tfh cell responses are ideal ways to control RA pathogenesis. The present review summarizes current knowledge of the involvement of Tfh cells in RA pathogenesis and highlights the potential of these cells as therapeutic targets.
Collapse
Affiliation(s)
- Jian Lu
- Department of Laboratory Medicine, Affiliated People's Hospital, Jiangsu University, Zhenjiang, 212002, China
- Institute of Laboratory Medicine, Jiangsu Key Laboratory for Laboratory Medicine, Jiangsu University School of Medicine, Zhenjiang, China
| | - Jing Wu
- Institute of Laboratory Medicine, Jiangsu Key Laboratory for Laboratory Medicine, Jiangsu University School of Medicine, Zhenjiang, China
| | - Xueli Xia
- Institute of Laboratory Medicine, Jiangsu Key Laboratory for Laboratory Medicine, Jiangsu University School of Medicine, Zhenjiang, China
| | - Huiyong Peng
- Department of Laboratory Medicine, Affiliated People's Hospital, Jiangsu University, Zhenjiang, 212002, China.
| | - Shengjun Wang
- Department of Laboratory Medicine, Affiliated People's Hospital, Jiangsu University, Zhenjiang, 212002, China.
- Institute of Laboratory Medicine, Jiangsu Key Laboratory for Laboratory Medicine, Jiangsu University School of Medicine, Zhenjiang, China.
| |
Collapse
|
|
50
|
Bemani P, Eklund KK, Ali-Hassanzadeh M, Kabelitz D, Schmidt RE, Meri S, Kalantar K. Proportion of T follicular helper cells in peripheral blood of rheumatoid arthritis patients: a systematic review and meta-analysis. Expert Rev Clin Immunol 2021; 17:667-680. [PMID: 33853479 DOI: 10.1080/1744666x.2021.1915770] [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] [Indexed: 12/29/2022]
Abstract
Introduction:Alterations in the levels and activity of Tfh may lead to impaired immune tolerance and autoimmune diseases. The aim of this study was to investigate the proportion and types of Tfh cells in the peripheral blood (PB) of RA patients.Areas covered:Comprehensive databases were searched for studies evaluating the proportion of Tfh cells in the PB of patients with RA compared to healthy control (HCs).The proportion of Tfh cells in RA patients was significantly higher than in HCs (SMD 0.699, [0.513, 0.884], p < 0.0001). Furthermore, Tfh cells proportion in untreated-RA and early-RA patients was markedly greater than HCs, when comparisons done without considering the definition markers, and also when Tfh cells were defined by the specified definition markers. While the proportion of Tfh cells by all definitions was higher in active-RA compared to HCs, analysis of two definitions, CD4+CXCR5+ and CD4+CXCR5+ICOS+, didn't show significant differences. Furthermore, higher proportion of Tfh cells defined by all definitions and a specified definition (CD4+CXCR5+PD-1high) was observed when S+RA compared to S-RA patients.Expert opinion:The results demonstrate that circulating Tfh are highly elevated in RA patients highlights its potential use as a biomarker and a target for RA therapy.
Collapse
Affiliation(s)
- Peyman Bemani
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Kari K Eklund
- Department of Medicine, Division of Rheumatology, Helsinki University Central Hospital, Helsinki, Finland
| | - Mohammad Ali-Hassanzadeh
- Department of Immunology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
| | | | - Reinhold E Schmidt
- Klinik Für Immunologie Und Rheumatologie, Medizinische Hochschule Hannover (MHH), Hannover, Germany
| | - Seppo Meri
- Department of Bacteriology & Immunology and the Translational Immunology Research Program (TRIMM), University of Helsinki, Helsinki, Finland
| | - Kurosh Kalantar
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| |
Collapse
|