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Chen Y, Liu H, Luo Z, Zhang J, Dong M, Yin G, Xie Q. ASM is a therapeutic target in dermatomyositis by regulating the differentiation of naive CD4 + T cells into Th17 and Treg subsets. Skelet Muscle 2024; 14:16. [PMID: 39026344 PMCID: PMC11256435 DOI: 10.1186/s13395-024-00347-1] [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: 03/15/2024] [Accepted: 06/29/2024] [Indexed: 07/20/2024] Open
Abstract
BACKGROUND This study aims to investigate the involvement of acid sphingomyelinase (ASM) in the pathology of dermatomyositis (DM), making it a potential therapeutic target for DM. METHODS Patients with DM and healthy controls (HCs) were included to assess the serum level and activity of ASM, and to explore the associations between ASM and clinical indicators. Subsequently, a myositis mouse model was established using ASM gene knockout and wild-type mice to study the significant role of ASM in the pathology and to assess the treatment effect of amitriptyline, an ASM inhibitor. Additionally, we investigated the potential treatment mechanism by targeting ASM both in vivo and in vitro. RESULTS A total of 58 DM patients along with 30 HCs were included. The ASM levels were found to be significantly higher in DM patients compared to HCs, with median (quartile) values of 2.63 (1.80-4.94) ng/mL and 1.64 (1.47-1.96) ng/mL respectively. The activity of ASM in the serum of DM patients was significantly higher than that in HCs. Furthermore, the serum levels of ASM showed correlations with disease activity and muscle enzyme levels. Knockout of ASM or treatment with amitriptyline improved the severity of the disease, rebalanced the CD4 T cell subsets Th17 and Treg, and reduced the production of their secreted cytokines. Subsequent investigations revealed that targeting ASM could regulate the expression of relevant transcription factors and key regulatory proteins. CONCLUSION ASM is involved in the pathology of DM by regulating the differentiation of naive CD4 + T cells and can be a potential treatment target.
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Affiliation(s)
- Yuehong Chen
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 37 Guoxue lane, Chengdu, 610041, China
| | - Huan Liu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 37 Guoxue lane, Chengdu, 610041, China
| | - Zhongling Luo
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 37 Guoxue lane, Chengdu, 610041, China
| | - Jiaqian Zhang
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 37 Guoxue lane, Chengdu, 610041, China
| | - Min Dong
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 37 Guoxue lane, Chengdu, 610041, China
| | - Geng Yin
- Department of General Practice, West China Hospital, General Practice Medical Center, Sichuan University, 37 Guoxue lane, Chengdu, 610041, China.
| | - Qibing Xie
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 37 Guoxue lane, Chengdu, 610041, China.
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Li W, Deng C, Yang H, Tian X, Chen L, Liu Q, Gao C, Lu X, Wang G, Peng Q. Upregulation of the CD155-CD226 Axis Is Associated With Muscle Inflammation and Disease Severity in Idiopathic Inflammatory Myopathies. NEUROLOGY(R) NEUROIMMUNOLOGY & NEUROINFLAMMATION 2023; 10:e200143. [PMID: 37491355 PMCID: PMC10368451 DOI: 10.1212/nxi.0000000000200143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 06/01/2023] [Indexed: 07/27/2023]
Abstract
BACKGROUND AND OBJECTIVES The CD155-CD226/T-cell Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) pathway plays a critical role in regulating T-cell responses and is being targeted clinically. However, research on the role of this pathway in autoimmune diseases is limited. This study aimed to investigate the expression and tissue-specific roles of CD155-CD226/TIGIT pathway molecules in the inflamed muscles of patients with idiopathic inflammatory myopathies (IIMs). METHODS Immunohistochemistry, Western blot analysis, and polychromatic immunofluorescence staining were performed to examine the expression of CD155, CD226, and TIGIT in skeletal muscle biopsies from 30 patients with dermatomyositis (DM), 10 patients with amyopathic DM (ADM), 20 patients with immune-mediated necrotizing myopathy (IMNM), 5 patients with dysferlinopathy, and 4 healthy controls. Flow cytometry analysis was used to analyze the functions of T cells with different phenotypes. RESULTS Strong expression of CD155 was observed in patients with DM and IMNM, while its expression was largely negative in those with ADM and dysferlinopathy and healthy controls. The costimulatory receptor CD226 was highly expressed on muscle-infiltrating cells, while the coinhibitory receptor TIGIT was expressed at low levels. These infiltrating CD226+ cells were mainly activated effector T cells that localized adjacent to CD155-expressing myofibers, but were faintly detectable within the muscle fascicles lacking CD155. A strong positive correlation between CD155 and CD226 expression scores was also observed. Polychromatic immunofluorescence staining revealed that CD155+ muscle cells coexpressed major histocompatibility complex classes I and II, and tumor necrosis factor alpha expression was detected in CD226+ T cells at their close sites with the myofibers. Furthermore, the expression levels of CD155 and CD226 showed a positive correlation with creatine kinase, lactate dehydrogenase, and the muscle histopathology damage scores and an inverse correlation with the Manual Muscle Testing-8 scores. In addition, CD155 and CD226 expressions were significantly decreased in representative patients who achieved remission posttreatment. DISCUSSION These findings demonstrate that the CD155-CD226 axis is highly activated in inflamed muscle tissues of patients with IIM and is associated with muscle disease severity. Our data uncover the immunopathogenic role of the axis in the pathology of IIMs.
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Affiliation(s)
- Wenli Li
- From the Department of Rheumatology (W.L., H.Y., X.T., Q.L., C.G., X.L., G.W., Q.P.), Key Myositis Laboratories, China-Japan Friendship Hospital; Department of Rheumatology and Clinical Immunology (C.D.), Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; and Department of Blood Transfusion (L.C.), China-Japan Friendship Hospital, Beijing.
| | - Chuiwen Deng
- From the Department of Rheumatology (W.L., H.Y., X.T., Q.L., C.G., X.L., G.W., Q.P.), Key Myositis Laboratories, China-Japan Friendship Hospital; Department of Rheumatology and Clinical Immunology (C.D.), Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; and Department of Blood Transfusion (L.C.), China-Japan Friendship Hospital, Beijing
| | - Hanbo Yang
- From the Department of Rheumatology (W.L., H.Y., X.T., Q.L., C.G., X.L., G.W., Q.P.), Key Myositis Laboratories, China-Japan Friendship Hospital; Department of Rheumatology and Clinical Immunology (C.D.), Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; and Department of Blood Transfusion (L.C.), China-Japan Friendship Hospital, Beijing
| | - Xiaolan Tian
- From the Department of Rheumatology (W.L., H.Y., X.T., Q.L., C.G., X.L., G.W., Q.P.), Key Myositis Laboratories, China-Japan Friendship Hospital; Department of Rheumatology and Clinical Immunology (C.D.), Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; and Department of Blood Transfusion (L.C.), China-Japan Friendship Hospital, Beijing
| | - Lida Chen
- From the Department of Rheumatology (W.L., H.Y., X.T., Q.L., C.G., X.L., G.W., Q.P.), Key Myositis Laboratories, China-Japan Friendship Hospital; Department of Rheumatology and Clinical Immunology (C.D.), Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; and Department of Blood Transfusion (L.C.), China-Japan Friendship Hospital, Beijing
| | - Qingyan Liu
- From the Department of Rheumatology (W.L., H.Y., X.T., Q.L., C.G., X.L., G.W., Q.P.), Key Myositis Laboratories, China-Japan Friendship Hospital; Department of Rheumatology and Clinical Immunology (C.D.), Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; and Department of Blood Transfusion (L.C.), China-Japan Friendship Hospital, Beijing
| | - Chang Gao
- From the Department of Rheumatology (W.L., H.Y., X.T., Q.L., C.G., X.L., G.W., Q.P.), Key Myositis Laboratories, China-Japan Friendship Hospital; Department of Rheumatology and Clinical Immunology (C.D.), Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; and Department of Blood Transfusion (L.C.), China-Japan Friendship Hospital, Beijing
| | - Xin Lu
- From the Department of Rheumatology (W.L., H.Y., X.T., Q.L., C.G., X.L., G.W., Q.P.), Key Myositis Laboratories, China-Japan Friendship Hospital; Department of Rheumatology and Clinical Immunology (C.D.), Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; and Department of Blood Transfusion (L.C.), China-Japan Friendship Hospital, Beijing
| | - Guochun Wang
- From the Department of Rheumatology (W.L., H.Y., X.T., Q.L., C.G., X.L., G.W., Q.P.), Key Myositis Laboratories, China-Japan Friendship Hospital; Department of Rheumatology and Clinical Immunology (C.D.), Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; and Department of Blood Transfusion (L.C.), China-Japan Friendship Hospital, Beijing
| | - Qinglin Peng
- From the Department of Rheumatology (W.L., H.Y., X.T., Q.L., C.G., X.L., G.W., Q.P.), Key Myositis Laboratories, China-Japan Friendship Hospital; Department of Rheumatology and Clinical Immunology (C.D.), Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; and Department of Blood Transfusion (L.C.), China-Japan Friendship Hospital, Beijing.
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Patil A, Lu J, Kassir M, Babaei M, Goldust M. Adult and juvenile dermatomyositis treatment. J Cosmet Dermatol 2023; 22:395-401. [PMID: 36065712 DOI: 10.1111/jocd.15363] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 08/17/2022] [Accepted: 09/02/2022] [Indexed: 11/29/2022]
Abstract
INTRODUCTION Dermatomyositis is a rare autoimmune inflammatory condition affecting skin and muscles. The disease can be seen in both adults and children. It can be associated with malignancy. Considering involvement of skin in the disease, many patients consult dermatologists for its treatment. Hence, knowledge about its presentation, complications, prognosis, and treatment is necessary. OBJECTIVE The objective of this review article is to provide comprehensive information about treatment of dermatomyositis. METHODS In this review article, we reviewed the published literature on adult and juvenile dermatomyositis to highlight the treatment. Articles published in peer-reviewed journals including reviews, clinical trials, case series, and case reports published in electronic database (MEDLINE/PubMed) through January 2021, cross references of respective articles and trials from clinicaltrials.gov were included for qualitative analysis of the literature. RESULTS Treatment options for dermatomyositis include traditional immunosuppressive agents and immunomodulatory therapy. High-dose corticosteroids represent the first line of treatment while other immunosuppressive agents are also used, either in combination with or as an alternative to corticosteroids, after initial treatment failure. Some biological agents have been used for the treatment of dermatomyositis with variable responses. CONCLUSION Although several treatment options are available, several questions remain unanswered about the optimal treatment of dermatomyositis.
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Affiliation(s)
- Anant Patil
- Department of Pharmacology, Dr. DY Patil Medical College, Navi Mumbai, India
| | - Jun Lu
- UConn Health Department of Dermatology, Farmington, Connecticut, USA
| | | | - Mahsa Babaei
- Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohamad Goldust
- Department of Dermatology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
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Goyal NA, Coulis G, Duarte J, Farahat PK, Mannaa AH, Cauchii J, Irani T, Araujo N, Wang L, Wencel M, Li V, Zhang L, Greenberg SA, Mozaffar T, Villalta SA. Immunophenotyping of Inclusion Body Myositis Blood T and NK Cells. Neurology 2022; 98:e1374-e1383. [PMID: 35131904 PMCID: PMC8967422 DOI: 10.1212/wnl.0000000000200013] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 01/03/2022] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND AND OBJECTIVES To evaluate the therapeutic potential of targeting highly differentiated T cells in patients with inclusion body myositis (IBM) by establishing high-resolution mapping of killer cell lectin-like receptor subfamily G member 1 (KLRG1+) within the T and natural killer (NK) cell compartments. METHODS Blood was collected from 51 patients with IBM and 19 healthy age-matched donors. Peripheral blood mononuclear cells were interrogated by flow cytometry using a 12-marker antibody panel. The panel allowed the delineation of naive T cells (Tn), central memory T cells (Tcm), 4 stages of effector memory differentiation T cells (Tem 1-4), and effector memory re-expressing CD45RA T cells (TemRA), as well as total and subpopulations of NK cells based on the differential expression of CD16 and C56. RESULTS We found that a population of KLRG1+ Tem and TemRA were expanded in both the CD4+ and CD8+ T-cell subpopulations in patients with IBM. KLRG1 expression in CD8+ T cells increased with T-cell differentiation with the lowest levels of expression in Tn and highest in highly differentiated TemRA and CD56+CD8+ T cells. The frequency of KLRG1+ total NK cells and subpopulations did not differ between patients with IBM and healthy donors. IBM disease duration correlated with increased CD8+ T-cell differentiation. DISCUSSION Our findings reveal that the selective expansion of blood KLRG1+ T cells in patients with IBM is confined to the TemRA and Tem cellular compartments.
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Affiliation(s)
- Namita A Goyal
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Gérald Coulis
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Jorge Duarte
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Philip K Farahat
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Ali H Mannaa
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Jonathan Cauchii
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Tyler Irani
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Nadia Araujo
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Leo Wang
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Marie Wencel
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Vivian Li
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Lishi Zhang
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Steven A Greenberg
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - Tahseen Mozaffar
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA
| | - S Armando Villalta
- Department of Neurology (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M., S.A.V.), MDA ALS and Neuromuscular Center (N.A.G., J.C., T.I., N.A., M.W., V.L., T.M.), Department of Pathology and Laboratory Medicine (T.M.), Department of Physiology and Biophysics (G.C., J.D., P.K.F., A.H.M., S.A.V.), Institute for Immunology (G.C., J.D., P.K.F., A.H.M., T.M., S.A.V.), and Biostatistics, Epidemiology, and Research Design (BERD) Unit, Institute for Clinical Translational Sciences (L.Z.), University of California, Irvine; Department of Neurology (J.C.), University of New Mexico, Albuquerque; Department of Neurology (L.W.), University of Washington Medical Center, Seattle; Department of Neurology, Division of Neuromuscular Disease (S.A.G.), Brigham and Women's Hospital and Harvard Medical School; and Computational Health Informatics Program (S.A.G.), Boston Children's Hospital and Harvard Medical School, MA.
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5
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Kobayashi S, Nagafuchi Y, Okubo M, Sugimori Y, Hatano H, Yamada S, Nakano M, Yoshida R, Takeshima Y, Ota M, Tsuchida Y, Iwasaki Y, Setoguchi K, Kubo K, Okamura T, Yamamoto K, Shoda H, Fujio K. Dysregulation of the gene signature of effector regulatory T cells in the early phase of systemic sclerosis. Rheumatology (Oxford) 2022; 61:4163-4174. [PMID: 35040949 DOI: 10.1093/rheumatology/keac031] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 01/11/2022] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVES We evaluated flow-cytometric and transcriptome features of peripheral blood immune cells from early-phase (disease duration < 5 years) systemic sclerosis (SSc) in comparison to late-phase SSc. METHODS Fifty Japanese patients with SSc (12 early SSc cases and 38 late SSc cases) and 50 age- and sex-matched healthy controls were enrolled. A comparison of flow-cytometric subset proportions and RNA-sequencing of 24 peripheral blood immune cell subsets was performed. We evaluated differentially expressed genes (DEGs), characterized the co-expressed gene modules, and estimated the composition of subpopulations by deconvolution based on single-cell RNA-sequencing data. As a disease control, idiopathic inflammatory myositis (IIM) patients were also evaluated. RESULTS Analyzing the data from early and late SSc, Fraction II effector regulatory T cell (Fr. II eTreg) genes showed a remarkable differential gene expression, which was enriched for genes related to oxidative phosphorylation. Although the flow-cytometric proportion of Fr. II eTregs was not changed in early SSc, deconvolution indicated expansion of the activated subpopulation. Co-expressed gene modules of Fr. II eTregs demonstrated enrichment of the DEGs of early SSc and correlation with the proportion of the activated subpopulation. These results suggested that DEGs in Fr. II eTregs from patients with early SSc were closely associated with the increased proportion of the activated subpopulation. Similar dysregulation of Fr. II eTregs was also observed in data from patients with early IIM. CONCLUSIONS RNA-seq of immune cells indicated the dysregulation of Fr. II eTregs in early SSc with increased proportion of the activated subpopulation.
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Affiliation(s)
- Satomi Kobayashi
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Japan. 7-3-1 Hongo, Bunkyo-ku, 113-8655, Japan, Tokyo, Tokyo.,Department of Medicine and Rheumatology, Tokyo Metropolitan Geriatric Hospital, Japan. 35-2 Sakaechou, Itabashi-ku, 173-0015, Japan, Tokyo, Tokyo
| | - Yasuo Nagafuchi
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Japan. 7-3-1 Hongo, Bunkyo-ku, 113-8655, Japan, Tokyo, Tokyo.,Department of Functional Genomics and Immunological Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Mai Okubo
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Japan. 7-3-1 Hongo, Bunkyo-ku, 113-8655, Japan, Tokyo, Tokyo
| | - Yusuke Sugimori
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Japan. 7-3-1 Hongo, Bunkyo-ku, 113-8655, Japan, Tokyo, Tokyo
| | - Hiroaki Hatano
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Japan. 7-3-1 Hongo, Bunkyo-ku, 113-8655, Japan, Tokyo, Tokyo
| | - Saeko Yamada
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Japan. 7-3-1 Hongo, Bunkyo-ku, 113-8655, Japan, Tokyo, Tokyo
| | - Masahiro Nakano
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Japan. 7-3-1 Hongo, Bunkyo-ku, 113-8655, Japan, Tokyo, Tokyo
| | - Ryochi Yoshida
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Japan. 7-3-1 Hongo, Bunkyo-ku, 113-8655, Japan, Tokyo, Tokyo
| | - Yusuke Takeshima
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Japan. 7-3-1 Hongo, Bunkyo-ku, 113-8655, Japan, Tokyo, Tokyo
| | - Mineto Ota
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Japan. 7-3-1 Hongo, Bunkyo-ku, 113-8655, Japan, Tokyo, Tokyo.,Department of Functional Genomics and Immunological Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Yumi Tsuchida
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Japan. 7-3-1 Hongo, Bunkyo-ku, 113-8655, Japan, Tokyo, Tokyo
| | - Yukiko Iwasaki
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Japan. 7-3-1 Hongo, Bunkyo-ku, 113-8655, Japan, Tokyo, Tokyo
| | - Keigo Setoguchi
- Department of Rheumatology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Japan. 3-18-22 Honkomagome, Bunkyo-ku, 113-8677, Japan, Tokyo, Tokyo
| | - Kanae Kubo
- Department of Medicine and Rheumatology, Tokyo Metropolitan Geriatric Hospital, Japan. 35-2 Sakaechou, Itabashi-ku, 173-0015, Japan, Tokyo, Tokyo
| | - Tomohisa Okamura
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Japan. 7-3-1 Hongo, Bunkyo-ku, 113-8655, Japan, Tokyo, Tokyo.,Department of Functional Genomics and Immunological Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Kazuhiko Yamamoto
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Japan. 7-3-1 Hongo, Bunkyo-ku, 113-8655, Japan, Tokyo, Tokyo.,Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Japan. 1-7-22 Suehiro-cho, Tsurumi-ku, Kanagawa, 230-0045, Japan, Yokohama, Yokohama
| | - Hirofumi Shoda
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Japan. 7-3-1 Hongo, Bunkyo-ku, 113-8655, Japan, Tokyo, Tokyo
| | - Keishi Fujio
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Japan. 7-3-1 Hongo, Bunkyo-ku, 113-8655, Japan, Tokyo, Tokyo
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6
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Shi J, Tang M, Zhou S, Xu D, Zhao J, Wu C, Wang Q, Tian X, Li M, Zeng X. Programmed Cell Death Pathways in the Pathogenesis of Idiopathic Inflammatory Myopathies. Front Immunol 2021; 12:783616. [PMID: 34899749 PMCID: PMC8651702 DOI: 10.3389/fimmu.2021.783616] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 11/08/2021] [Indexed: 12/11/2022] Open
Abstract
Idiopathic inflammatory myopathy (IIM) is a heterogeneous group of acquired, autoimmune muscle diseases characterized by muscle inflammation and extramuscular involvements. Present literatures have revealed that dysregulated cell death in combination with impaired elimination of dead cells contribute to the release of autoantigens, damage-associated molecular patterns (DAMPs) and inflammatory cytokines, and result in immune responses and tissue damages in autoimmune diseases, including IIMs. This review summarizes the roles of various forms of programmed cell death pathways in the pathogenesis of IIMs and provides evidence for potential therapeutic targets.
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Affiliation(s)
- Jia Shi
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology & Clinical Immunology, Ministry of Education, Beijing, China.,National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, China
| | - Mingwei Tang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology & Clinical Immunology, Ministry of Education, Beijing, China.,National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, China
| | - Shuang Zhou
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology & Clinical Immunology, Ministry of Education, Beijing, China.,National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, China
| | - Dong Xu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology & Clinical Immunology, Ministry of Education, Beijing, China.,National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, China
| | - Jiuliang Zhao
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology & Clinical Immunology, Ministry of Education, Beijing, China.,National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, China
| | - Chanyuan Wu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology & Clinical Immunology, Ministry of Education, Beijing, China.,National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, China
| | - Qian Wang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology & Clinical Immunology, Ministry of Education, Beijing, China.,National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, China
| | - Xinping Tian
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology & Clinical Immunology, Ministry of Education, Beijing, China.,National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, China
| | - Mengtao Li
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology & Clinical Immunology, Ministry of Education, Beijing, China.,National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, China
| | - Xiaofeng Zeng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology & Clinical Immunology, Ministry of Education, Beijing, China.,National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, China
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7
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Boyer O, Butler-Browne G, Chinoy H, Cossu G, Galli F, Lilleker JB, Magli A, Mouly V, Perlingeiro RCR, Previtali SC, Sampaolesi M, Smeets H, Schoewel-Wolf V, Spuler S, Torrente Y, Van Tienen F. Myogenic Cell Transplantation in Genetic and Acquired Diseases of Skeletal Muscle. Front Genet 2021; 12:702547. [PMID: 34408774 PMCID: PMC8365145 DOI: 10.3389/fgene.2021.702547] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 06/16/2021] [Indexed: 01/04/2023] Open
Abstract
This article will review myogenic cell transplantation for congenital and acquired diseases of skeletal muscle. There are already a number of excellent reviews on this topic, but they are mostly focused on a specific disease, muscular dystrophies and in particular Duchenne Muscular Dystrophy. There are also recent reviews on cell transplantation for inflammatory myopathies, volumetric muscle loss (VML) (this usually with biomaterials), sarcopenia and sphincter incontinence, mainly urinary but also fecal. We believe it would be useful at this stage, to compare the same strategy as adopted in all these different diseases, in order to outline similarities and differences in cell source, pre-clinical models, administration route, and outcome measures. This in turn may help to understand which common or disease-specific problems have so far limited clinical success of cell transplantation in this area, especially when compared to other fields, such as epithelial cell transplantation. We also hope that this may be useful to people outside the field to get a comprehensive view in a single review. As for any cell transplantation procedure, the choice between autologous and heterologous cells is dictated by a number of criteria, such as cell availability, possibility of in vitro expansion to reach the number required, need for genetic correction for many but not necessarily all muscular dystrophies, and immune reaction, mainly to a heterologous, even if HLA-matched cells and, to a minor extent, to the therapeutic gene product, a possible antigen for the patient. Finally, induced pluripotent stem cell derivatives, that have entered clinical experimentation for other diseases, may in the future offer a bank of immune-privileged cells, available for all patients and after a genetic correction for muscular dystrophies and other myopathies.
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Affiliation(s)
- Olivier Boyer
- Department of Immunology & Biotherapy, Rouen University Hospital, Normandy University, Inserm U1234, Rouen, France
| | - Gillian Butler-Browne
- Sorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en Myologie, Paris, France
| | - Hector Chinoy
- Manchester Centre for Clinical Neurosciences, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, Salford, United Kingdom
- National Institute for Health Research Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, The University of Manchester, Manchester, United Kingdom
| | - Giulio Cossu
- Division of Cell Matrix Biology & Regenerative Medicine, The University of Manchester, Manchester, United Kingdom
- Muscle Research Unit, Experimental and Clinical Research Center, a Cooperation Between the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association and the Charité, Universitätsmedizin Berlin, Berlin, Germany
- InSpe and Division of Neuroscience, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milan, Italy
| | - Francesco Galli
- National Institute for Health Research Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, The University of Manchester, Manchester, United Kingdom
| | - James B. Lilleker
- Manchester Centre for Clinical Neurosciences, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, Salford, United Kingdom
- National Institute for Health Research Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, The University of Manchester, Manchester, United Kingdom
| | - Alessandro Magli
- Department of Medicine, Lillehei Heart Institute, Stem Cell Institute, University of Minnesota, Minneapolis, MN, United States
| | - Vincent Mouly
- Sorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en Myologie, Paris, France
| | - Rita C. R. Perlingeiro
- Department of Medicine, Lillehei Heart Institute, Stem Cell Institute, University of Minnesota, Minneapolis, MN, United States
| | - Stefano C. Previtali
- InSpe and Division of Neuroscience, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milan, Italy
| | - Maurilio Sampaolesi
- Translational Cardiomyology Laboratory, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
- Human Anatomy Unit, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy
| | - Hubert Smeets
- Department of Toxicogenomics, Maastricht University Medical Centre, Maastricht, Netherlands
- School for Mental Health and Neurosciences (MHeNS), Maastricht University, Maastricht, Netherlands
- School for Developmental Biology and Oncology (GROW), Maastricht University, Maastricht, Netherlands
| | - Verena Schoewel-Wolf
- Muscle Research Unit, Experimental and Clinical Research Center, a Cooperation Between the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association and the Charité, Universitätsmedizin Berlin, Berlin, Germany
| | - Simone Spuler
- Muscle Research Unit, Experimental and Clinical Research Center, a Cooperation Between the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association and the Charité, Universitätsmedizin Berlin, Berlin, Germany
| | - Yvan Torrente
- Unit of Neurology, Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Centro Dino Ferrari, Università degli Studi di Milano, Fondazione Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Florence Van Tienen
- Department of Toxicogenomics, Maastricht University Medical Centre, Maastricht, Netherlands
- School for Mental Health and Neurosciences (MHeNS), Maastricht University, Maastricht, Netherlands
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8
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Zhang SX, Wang J, Sun HH, Zhang JQ, Liu GY, Luo J, He PF, Li XF. Circulating regulatory T cells were absolutely decreased in dermatomyositis/polymyositis patients and restored by low-dose IL-2. Ann Rheum Dis 2021; 80:e130. [PMID: 31611221 DOI: 10.1136/annrheumdis-2019-216246] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Accepted: 09/04/2019] [Indexed: 12/16/2022]
Affiliation(s)
- Sheng-Xiao Zhang
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Jia Wang
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - He-Hua Sun
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Jia-Qian Zhang
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Guang-Ying Liu
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Jing Luo
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Pei-Feng He
- Department of Medical Information Management, Shanxi Medical University, Taiyuan, China
| | - Xiao-Feng Li
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
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9
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Ye Q, Chen Z. MicroRNA-409-3p regulates macrophage migration in polymyositis through targeting CXCR4. Autoimmunity 2021; 54:353-361. [PMID: 34142881 DOI: 10.1080/08916934.2021.1937610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
BACKGROUND Macrophage migration and infiltration contribute to the pathogenesis of polymyositis (PM). This study aims to investigate the effect and underlying mechanism of miR-409-3p on macrophage migration in PM. METHODS The GSE143845 database was used to predict the altered expression of microRNAs (miRNAs) in PM. The quantitative real-time PCR (qRT-PCR), western blot and Transwell assay were performed to detect migration of macrophages and expressions of related molecules. A luciferase activity assay was conducted to confirm the binding of miR-409-3p and CXCR4 3'-UTR. Next, a mouse model of experimental autoimmune myositis (EAM) was established. Haematoxylin and eosin (HE) staining, immunohistochemistry (IHC), and enzyme-linked immunosorbent assay (ELISA) were used to measure associated factors. RESULTS MiR-409-3p was downregulated in PM of GSE143845 database and patients. Differently, the serum creatine kinase (s-CK), TNF-α, and IL-6 in patients with PM were increased. Furthermore, miR-409-3p mimic transfection reduced the migration of macrophages and CXCR4 levels, while miR-409-3p inhibitor exerted the opposite effects. CXCR4 was a target of miR-409-3p, and the effect of CXCR4 on promoting macrophage migration was reversed by miR-409-3p mimic. In vivo, miR-409-3p agomir injection reduced inflammatory cells, macrophages, and TNFα and IL-6 levels in muscles and serum of EAM mouse models. CONCLUSIONS In conclusion, miR-409-3p reduces the migration of macrophages through negatively regulating CXCR4 expression in PM.
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Affiliation(s)
- Qin Ye
- Department of Pulmonary Medicine, Ningbo HwaMei Hospital, Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, P. R. China
| | - Zhaoying Chen
- Department of Neurology, Ningbo HwaMei Hospital, Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, P. R. China
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10
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Miao M, Li Y, Huang B, Chen J, Jin Y, Shao M, Zhang X, Sun X, He J, Li Z. Treatment of Active Idiopathic Inflammatory Myopathies by Low-Dose Interleukin-2: A Prospective Cohort Pilot Study. Rheumatol Ther 2021; 8:835-847. [PMID: 33852146 PMCID: PMC8217480 DOI: 10.1007/s40744-021-00301-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 03/17/2021] [Indexed: 11/01/2022] Open
Abstract
INTRODUCTION Treatment of idiopathic inflammatory myopathies (IIMs) is challenging due to a lack of safe and efficacious medication. Low-dose interleukin-2 (IL-2) treatment emerges as a new option in active IIMs. This study aims to explore the clinical and immunological effects of low-dose IL-2 in patients with active IIMs. METHODS Eighteen patients with active IIMs were enrolled and received 1 × 106 IU of IL-2 subcutaneously every other day for 12 weeks on top of standard care. The primary endpoint for the trial was change in percentage of regulatory T (Treg) cells in total CD4+ T cells at week 12. The secondary endpoints included the International Myositis Assessment and Clinical Studies (IMACS) definition of improvement (DOI), the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) myositis response criteria, safety, and steroid-sparing effect at weeks 12 and 24. RESULTS With low-dose IL-2 treatment, 77.78% (14/18) patients achieved IMACS DOI and 83.33% (15/18) patients met the 2016 ACR/EULAR myositis response criteria at week 12. All individual core set measures (CSMs) including PhGA, PGA and HAQ-DI, muscle enzymes, MMT-8 and extramuscular activity were improved at week 12. The cutaneous dermatomyositis disease area and severity index activity score (CDASI-a) decreased significantly from 7 (4.5, 13) to 2 (0, 7) after IL-2 administration (P < 0.001). Proportion of Treg cells significantly increased with low-dose IL-2 treatment at week 12 (8.97% [5.77, 9.89%] vs. 15.2% [10.4, 17.3%], P = 0.009). There were no serious adverse events. CONCLUSIONS Low-dose IL-2 was effective in active IIMs and well tolerated. The amelioration of disease activity may associate with promotion of Tregs. TRIAL REGISTRATION ClinicalTrials.gov identifier, NCT04062019.
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Affiliation(s)
- Miao Miao
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, 100044, China
- Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Yuhui Li
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, 100044, China
- Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Bo Huang
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, 100044, China
- Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Jiali Chen
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, 100044, China
- Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Yuebo Jin
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, 100044, China
- Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Miao Shao
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, 100044, China
- Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Xia Zhang
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, 100044, China
- Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Xiaolin Sun
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, 100044, China.
- Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.
| | - Jing He
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, 100044, China.
- Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.
| | - Zhanguo Li
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, 100044, China.
- Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.
- Peking-Tsinghua Center for Life Sciences, Beijing, China.
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11
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Abstract
PURPOSE OF REVIEW To review the pathogenesis of inclusion body myositis (IBM). RECENT FINDINGS IBM is an autoimmune disease. Multiple arms of the immune system are activated, but a direct attack on muscle fibers by highly differentiated T cells drives muscle destruction. SUMMARY Further understanding of the pathogenesis of IBM guides rational approaches to developing therapeutic strategies.
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12
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Zhao L, Wang Q, Zhou B, Zhang L, Zhu H. The Role of Immune Cells in the Pathogenesis of Idiopathic Inflammatory Myopathies. Aging Dis 2021; 12:247-260. [PMID: 33532139 PMCID: PMC7801271 DOI: 10.14336/ad.2020.0410] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 04/10/2020] [Indexed: 12/15/2022] Open
Abstract
Idiopathic inflammatory myopathies (IIMs) are chronic autoimmune disorders involving multiple organs, such as the muscle, skin, lungs and joints. Although the detailed pathogenesis of IIMs remains unclear, immune mechanisms have long been recognised as of key importance. Immune cells contribute to many inflammatory processes via intercellular interactions and secretion of inflammatory factors, and many studies have demonstrated the participation of a variety of immune cells, such as T cells and B cells, in the development of IIMs. Here, we summarise the current knowledge regarding immune cells in IIM patients and discuss their potential roles in IIM pathogenesis.
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Affiliation(s)
- Lijuan Zhao
- Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Qi Wang
- Department of Radiology, Hunan Provincial People's Hospital and The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China.
| | - Bin Zhou
- Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Lihua Zhang
- Department of Rheumatology, Hunan Provincial People's Hospital and The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China.
| | - Honglin Zhu
- Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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13
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The Generation and Regulation of Tissue-Resident Tregs and Their Role in Autoimmune Diseases. J Immunol Res 2020. [DOI: 10.1155/2020/8815280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Regulatory T cells (Tregs), as an important subset of T cells, play an important role in maintaining body homeostasis by regulating immune responses and preventing autoimmune diseases. In-depth research finds that Tregs have strong instability and plasticity, and according to their developmental origin, Tregs can be classified into thymic-derived Tregs (tTregs), endogenous-induced Tregs (pTregs), which are produced by antigen-stimulated T cells in the periphery in vivo, and induced Tregs (iTregs), which differentiate from naïve T cells in vitro. In recent years, studies have found that Tregs are divided into lymphatic and tissue-resident Tregs according to their location. Research on the generation and function of lymphoid Tregs has been more comprehensive and thorough, but the role of tissue Tregs is still in the exploratory stage, and it has become a research hot spot. In this review, we discuss the instability and plasticity of Tregs and the latest developments of tissue-resident Tregs in the field of biology, including adipose tissue, colon, skeletal muscle, and other Tregs that have been recently discovered as well as their production, regulation, and function in specific tissues and their role in the pathogenesis of autoimmune diseases.
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14
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Wang J, Zhang SX, Hao YF, Qiu MT, Luo J, Li YY, Gao C, Li XF. The numbers of peripheral regulatory T cells are reduced in patients with psoriatic arthritis and are restored by low-dose interleukin-2. Ther Adv Chronic Dis 2020; 11:2040622320916014. [PMID: 32523664 PMCID: PMC7236566 DOI: 10.1177/2040622320916014] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 02/18/2020] [Indexed: 12/11/2022] Open
Abstract
Background: Although regulatory T cells (Tregs) play crucial roles in the maintenance of immune hemostasis, the numbers of peripheral Tregs in patients with psoriatic arthritis (PsA) remain unclear. We measured these numbers and the efficacy and safety of low-dose interleukin-2 (IL-2) therapy. Methods: We recruited 95 PsA patients, of whom 22 received subcutaneous low-dose IL-2 [0.5 million international units (MIU) per day for 5 days] combined with conventional therapies. The absolute numbers of cells in peripheral CD4+ T cell subsets were measured via modified flow cytometry. Clinical and laboratory indicators were compared before and after treatment. Results: PsA patients had lower peripheral Treg numbers than healthy controls (p < 0.01), correlating significantly and negatively with the levels of disease indicators (p < 0.05). Although low-dose IL-2 significantly increased the Th17 and Treg numbers in PsA patients compared with the baseline values, the Treg numbers rose much more rapidly than those of Th17 cells, re-balancing the Th17 and Treg proportions. Low-dose IL-2 combination therapy rapidly reduced PsA disease activities as indicated by the DAS28 instrument, thus the number of tender joints, visual analog scale pain, physician global assessment, the dermatology life quality index score, and the health assessment questionnaire score (all p < 0.05). Conclusion: PsA patients exhibited low Treg numbers. Low-dose IL-2 combination treatment increased these numbers and relieved disease activity without any apparent side effects. Additional studies are required to explore the long-term immunoregulatory utility of IL-2 treatment.
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Affiliation(s)
- Jia Wang
- Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Sheng-Xiao Zhang
- Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yu-Fei Hao
- Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Meng-Ting Qiu
- Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jing Luo
- Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yu-Yao Li
- Department of Rheumatology, Shanxi Li Xiaofeng Medical Groups, Taiyuan, Shanxi, China
| | - Chong Gao
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Xiao-Feng Li
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China
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15
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Greenberg SA. Inclusion body myositis: clinical features and pathogenesis. Nat Rev Rheumatol 2020; 15:257-272. [PMID: 30837708 DOI: 10.1038/s41584-019-0186-x] [Citation(s) in RCA: 166] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Inclusion body myositis (IBM) is often viewed as an enigmatic disease with uncertain pathogenic mechanisms and confusion around diagnosis, classification and prospects for treatment. Its clinical features (finger flexor and quadriceps weakness) and pathological features (invasion of myofibres by cytotoxic T cells) are unique among muscle diseases. Although IBM T cell autoimmunity has long been recognized, enormous attention has been focused for decades on several biomarkers of myofibre protein aggregates, which are present in <1% of myofibres in patients with IBM. This focus has given rise, together with the relative treatment refractoriness of IBM, to a competing view that IBM is not an autoimmune disease. Findings from the past decade that implicate autoimmunity in IBM include the identification of a circulating autoantibody (anti-cN1A); the absence of any statistically significant genetic risk factor other than the common autoimmune disease 8.1 MHC haplotype in whole-genome sequencing studies; the presence of a marked cytotoxic T cell signature in gene expression studies; and the identification in muscle and blood of large populations of clonal highly differentiated cytotoxic CD8+ T cells that are resistant to many immunotherapies. Mounting evidence that IBM is an autoimmune T cell-mediated disease provides hope that future therapies directed towards depleting these cells could be effective.
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Affiliation(s)
- Steven A Greenberg
- Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA. .,Children's Hospital Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA. .,Harvard Medical School, Boston, MA, USA.
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16
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Jensen KY, Jacobsen M, Schrøder HD, Aagaard P, Nielsen JL, Jørgensen AN, Boyle E, Bech RD, Rosmark S, Diederichsen LP, Frandsen U. The immune system in sporadic inclusion body myositis patients is not compromised by blood-flow restricted exercise training. Arthritis Res Ther 2019; 21:293. [PMID: 31852482 PMCID: PMC6921522 DOI: 10.1186/s13075-019-2036-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Accepted: 10/21/2019] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Sporadic inclusion body myositis (sIBM) is clinically characterised by progressive proximal and distal muscle weakness and impaired physical function while skeletal muscle tissue displays abnormal cellular infiltration of T cells, macrophages, and dendritic cells. Only limited knowledge exists about the effects of low-load blood flow restriction exercise in sIBM patients, and its effect on the immunological responses at the myocellular level remains unknown. The present study is the first to investigate the longitudinal effects of low-load blood flow restriction exercise on innate and adaptive immune markers in skeletal muscle from sIBM patients. METHODS Twenty-two biopsy-validated sIBM patients were randomised into either 12 weeks of low-load blood flow restriction exercise (BFRE) or no exercise (CON). Five patients from the control group completed 12 weeks of BFRE immediately following participation in the 12-week control period leading to an intervention group of 16 patients. Muscle biopsies were obtained from either the m. tibialis anterior or the m. vastus lateralis for evaluation of CD3-, CD8-, CD68-, CD206-, CD244- and FOXP3-positive cells by three-colour immunofluorescence microscopy and Visiopharm-based image analysis quantification. A linear mixed model was used for the statistical analysis. RESULTS Myocellular infiltration of CD3-/CD8+ expressing natural killer cells increased following BFRE (P < 0.05) with no changes in CON. No changes were observed for CD3+/CD8- or CD3+/CD8+ T cells in BFRE or CON. CD3+/CD244+ T cells decreased in CON, while no changes were observed in BFRE. Pronounced infiltration of M1 pro-inflammatory (CD68+/CD206-) and M2 anti-inflammatory (CD68+/CD206+) macrophages were observed at baseline; however, no longitudinal changes in macrophage content were observed for both groups. CONCLUSIONS Low-load blood flow restriction exercise elicited an upregulation in CD3-/CD8+ expressing natural killer cell content, which suggests that 12 weeks of BFRE training evokes an amplified immune response in sIBM muscle. However, the observation of no changes in macrophage or T cell infiltration in the BFRE-trained patients indicates that patients with sIBM may engage in this type of exercise with no risk of intensified inflammatory activity.
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Affiliation(s)
- Kasper Yde Jensen
- Department of Sports Science and Clinical Biomechanics, SDU Muscle Research Cluster (SMRC), University of Southern Denmark, Odense, Denmark.,Department of Pathology, Odense University Hospital, Odense, Denmark.,Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Mikkel Jacobsen
- Department of Sports Science and Clinical Biomechanics, SDU Muscle Research Cluster (SMRC), University of Southern Denmark, Odense, Denmark.,Department of Rheumatology, Odense University Hospital, Odense, Denmark.,Department of Pathology, Odense University Hospital, Odense, Denmark
| | - Henrik Daa Schrøder
- Department of Pathology, Odense University Hospital, Odense, Denmark.,Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Per Aagaard
- Department of Sports Science and Clinical Biomechanics, SDU Muscle Research Cluster (SMRC), University of Southern Denmark, Odense, Denmark
| | - Jakob Lindberg Nielsen
- Department of Sports Science and Clinical Biomechanics, SDU Muscle Research Cluster (SMRC), University of Southern Denmark, Odense, Denmark
| | - Anders Nørkær Jørgensen
- Department of Sports Science and Clinical Biomechanics, SDU Muscle Research Cluster (SMRC), University of Southern Denmark, Odense, Denmark.,Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Eleanor Boyle
- Department of Sport Science and Clinical Biomechanics, Research Unit of Clinical Biomechanics, University of Southern Denmark, Odense, Denmark
| | - Rune Dueholm Bech
- Department of Orthopaedics and Traumatology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Sofie Rosmark
- Department of Rheumatology, Odense University Hospital, Odense, Denmark
| | - Louise Pyndt Diederichsen
- Department of Rheumatology, Odense University Hospital, Odense, Denmark. .,Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
| | - Ulrik Frandsen
- Department of Sports Science and Clinical Biomechanics, SDU Muscle Research Cluster (SMRC), University of Southern Denmark, Odense, Denmark
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17
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Yang SH, Chang C, Lian ZX. Polymyositis and dermatomyositis - challenges in diagnosis and management. J Transl Autoimmun 2019; 2:100018. [PMID: 32743506 PMCID: PMC7388349 DOI: 10.1016/j.jtauto.2019.100018] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 10/04/2019] [Indexed: 02/06/2023] Open
Abstract
Polymyositis (PM) and dermatomyositis (DM) are different disease subtypes of idiopathic inflammatory myopathies (IIMs). The main clinical features of PM and DM include progressive symmetric, predominantly proximal muscle weakness. Laboratory findings include elevated creatine kinase (CK), autoantibodies in serum, and inflammatory infiltrates in muscle biopsy. Dermatomyositis can also involve a characteristic skin rash. Both polymyositis and dermatomyositis can present with extramuscular involvement. The causative factor is agnogenic activation of immune system, leading to immunologic attacks on muscle fibers and endomysial capillaries. The treatment of choice is immunosuppression. PM and DM can be distinguished from other IIMs and myopathies by thorough history, physical examinations and laboratory evaluation and adherence to specific and up-to-date diagnosis criteria and classification standards. Treatment is based on correct diagnosis of these conditions.
Challenges of diagnosis and management influences the clinical research and practice of Polymyositis and dermatomyositis. Diagnostic criteria have been updated and novel therapies have been developed in PM/DM. Pathogenesis investigation and diagnosis precision improvement may help to guide future treatment strategies.
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Key Words
- APC, antigen presenting cell
- AZA, Azathioprine
- CAM, cancer associated myositis
- CK, creatine kinase
- DM, dermatomyositis
- Dermatomyositis
- Diagnosis criteria
- EMG, electromyography
- HLA, human leukocyte antigen
- IIM, idiopathic inflammatory myopathies
- ILD, interstitial lung disease
- IV, intravenous
- Idiopathic inflammatory myopathy
- JDM, juvenile dermatomyositis
- MAA, myositis associated antibody
- MAC, membrane attack complex
- MHC, major histocompatibility complex
- MMF, mycophenolate mofetil
- MRI, magnetic resonance imaging
- MSA, myositis specific antibody
- MTX, methotrexate
- MUAP, motor unit action potential
- NAM, necrotizing autoimmune myopathy
- PM, polymyositis
- Polymyositis
- TNF, tumor necrosis factor
- Treatment
- Treg, regulatory T cell
- UVR, ultraviolet radiation
- sIBM, sporadic inclusion body myositis
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Affiliation(s)
- Shu-Han Yang
- Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China
| | - Christopher Chang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA, USA.,Division of Pediatric Immunology and Allergy, Joe DiMaggio Children's Hospital, Hollywood, FL, USA
| | - Zhe-Xiong Lian
- Chronic Disease Laboratory, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, 510006, China
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18
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Anoveros-Barrera A, Bhullar AS, Stretch C, Dunichand-Hoedl AR, Martins KJB, Rieger A, Bigam D, McMullen T, Bathe OF, Putman CT, Field CJ, Baracos VE, Mazurak VC. Immunohistochemical phenotyping of T cells, granulocytes, and phagocytes in the muscle of cancer patients: association with radiologically defined muscle mass and gene expression. Skelet Muscle 2019; 9:24. [PMID: 31521204 PMCID: PMC6744687 DOI: 10.1186/s13395-019-0209-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 08/16/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Inflammation is a recognized contributor to muscle wasting. Research in injury and myopathy suggests that interactions between the skeletal muscle and immune cells confer a pro-inflammatory environment that influences muscle loss through several mechanisms; however, this has not been explored in the cancer setting. This study investigated the local immune environment of the muscle by identifying the phenotype of immune cell populations in the muscle and their relationship to muscle mass in cancer patients. METHODS Intraoperative muscle biopsies were collected from cancer patients (n = 30, 91% gastrointestinal malignancies). Muscle mass was assessed histologically (muscle fiber cross-sectional area, CSA; μm2) and radiologically (lumbar skeletal muscle index, SMI; cm2/m2 by computed tomography, CT). T cells (CD4 and CD8) and granulocytes/phagocytes (CD11b, CD14, and CD15) were assessed by immunohistochemistry. Microarray analysis was conducted in the muscle of a second cancer patient cohort. RESULTS T cells (CD3+), granulocytes/phagocytes (CD11b+), and CD3-CD4+ cells were identified. Muscle fiber CSA (μm2) was positively correlated (Spearman's r = > 0.45; p = < 0.05) with the total number of T cells, CD4, and CD8 T cells and granulocytes/phagocytes. In addition, patients with the smallest SMI exhibited fewer CD8 T cells within their muscle. Consistent with this, further exploration with gene correlation analyses suggests that the presence of CD8 T cells is negatively associated (Pearson's r = ≥ 0.5; p = <0.0001) with key genes within muscle catabolic pathways for signaling (ACVR2B), ubiquitin proteasome (FOXO4, TRIM63, FBXO32, MUL1, UBC, UBB, UBE2L3), and apoptosis/autophagy (CASP8, BECN1, ATG13, SIVA1). CONCLUSION The skeletal muscle immune environment of cancer patients is comprised of immune cell populations from the adaptive and innate immunity. Correlations of T cells, granulocyte/phagocytes, and CD3-CD4+ cells with muscle mass measurements indicate a positive relationship between immune cell numbers and muscle mass status in cancer patients. Further exploration with gene correlation analyses suggests that the presence of CD8 T cells is negatively correlated with components of muscle catabolism.
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Affiliation(s)
- Ana Anoveros-Barrera
- Department of Agricultural, Food & Nutritional Science, Faculty of Agricultural, Life and Environmental Sciences, University of Alberta, 4-002 Li Ka Shing Centre, Edmonton, Alberta, T6G 2P5, Canada
| | - Amritpal S Bhullar
- Department of Agricultural, Food & Nutritional Science, Faculty of Agricultural, Life and Environmental Sciences, University of Alberta, 4-002 Li Ka Shing Centre, Edmonton, Alberta, T6G 2P5, Canada
| | - Cynthia Stretch
- Department of Oncology, University of Calgary, Calgary, Alberta, Canada
| | - Abha R Dunichand-Hoedl
- Department of Agricultural, Food & Nutritional Science, Faculty of Agricultural, Life and Environmental Sciences, University of Alberta, 4-002 Li Ka Shing Centre, Edmonton, Alberta, T6G 2P5, Canada
| | - Karen J B Martins
- Department of Agricultural, Food & Nutritional Science, Faculty of Agricultural, Life and Environmental Sciences, University of Alberta, 4-002 Li Ka Shing Centre, Edmonton, Alberta, T6G 2P5, Canada
| | - Aja Rieger
- Flow Cytometry Facility, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - David Bigam
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Todd McMullen
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Oliver F Bathe
- Department of Oncology and Department of Surgery, University of Calgary, Calgary, Alberta, Canada
| | - Charles T Putman
- Faculty of Kinesiology, Sport, and Recreation, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Catherine J Field
- Department of Agricultural, Food & Nutritional Science, Faculty of Agricultural, Life and Environmental Sciences, University of Alberta, 4-002 Li Ka Shing Centre, Edmonton, Alberta, T6G 2P5, Canada
| | - Vickie E Baracos
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Vera C Mazurak
- Department of Agricultural, Food & Nutritional Science, Faculty of Agricultural, Life and Environmental Sciences, University of Alberta, 4-002 Li Ka Shing Centre, Edmonton, Alberta, T6G 2P5, Canada.
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19
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Helmers SB, Bruton M, Loell I, Ulfgren AK, Gracie AJ, McInnes IB, Lundberg IE. Expression of interleukin-18 in muscle tissue of patients with polymyositis or dermatomyositis and effects of conventional immunosuppressive treatment. Rheumatology (Oxford) 2019; 57:2149-2157. [PMID: 30102381 DOI: 10.1093/rheumatology/key222] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2017] [Indexed: 01/25/2023] Open
Abstract
Objectives To investigate the expression of IL-18 in symptomatic and asymptomatic muscle tissues of patients with PM and DM and the effects of conventional immunosuppressive treatment on such expression. Methods Two cohorts of patients were included in this study. The first cohort consisted of 10 new-onset myositis patients. IL-18 expression was compared between symptomatic and asymptomatic muscle biopsies that were taken prior to treatment. The second cohort consisted of another 10 patients with repeated muscle biopsies before and after 8 months with conventional immunosuppressive treatment. Using immunohistochemistry, IL-18 expression in muscle tissues was compared before and after treatment. Biopsies from seven healthy individuals were included as controls. Results IL-18 expression was predominantly localized to inflammatory cells and capillaries in patients and mostly to capillaries in healthy controls. Total IL-18 expression in muscle tissues from the new-onset patients, at both symptomatic and asymptomatic sites, was significantly higher compared with healthy controls (P = 0.007 and P = 0.002) with no statistical difference in appearances between symptomatic and asymptomatic sites. The number of IL-18 positive capillaries was not different among symptomatic, asymptomatic and healthy muscles. Total IL-18 expression appeared lower in biopsies from patients receiving and improving with immunosuppressive treatment, particularly the number of IL-18 positive inflammatory cells but not the number of IL-18 positive capillaries, which was consistent with significantly decreased expression of CD68+ macrophages (P = 0.04). Conclusion IL-18 is highly expressed in muscle tissue in the context of inflammatory myopathies and based on its plausible effector functions could provide a novel therapeutic target in future.
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Affiliation(s)
- Sevim Barbasso Helmers
- Department of Medicine, Unit of Rheumatology, Karolinska Institutet, Solna, Sweden.,Unit of Rheumatology, Karolinska University Hospital, Solna, Sweden.,Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Solna, Sweden
| | - Mei Bruton
- Department of Medicine, Unit of Rheumatology, Karolinska Institutet, Solna, Sweden.,Unit of Rheumatology, Karolinska University Hospital, Solna, Sweden
| | - Ingela Loell
- Department of Medicine, Unit of Rheumatology, Karolinska Institutet, Solna, Sweden.,Unit of Rheumatology, Karolinska University Hospital, Solna, Sweden
| | - Ann-Kristin Ulfgren
- Department of Medicine, Unit of Rheumatology, Karolinska Institutet, Solna, Sweden.,Unit of Rheumatology, Karolinska University Hospital, Solna, Sweden
| | | | - Iain B McInnes
- Centre for Rheumatic Diseases, University of Glasgow, Glasgow, UK
| | - Ingrid E Lundberg
- Department of Medicine, Unit of Rheumatology, Karolinska Institutet, Solna, Sweden.,Unit of Rheumatology, Karolinska University Hospital, Solna, Sweden
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20
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Zhang J, Wen XY, Gao RP. Hepatitis B virus-related liver cirrhosis complicated with dermatomyositis: A case report. World J Clin Cases 2019; 7:1206-1212. [PMID: 31183354 PMCID: PMC6547324 DOI: 10.12998/wjcc.v7.i10.1206] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 03/25/2019] [Accepted: 04/09/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Twenty percent of patients infected with hepatitis B virus (HBV) develop extrahepatic manifestations with HBV detected in the lymph nodes, spleen, bone marrow, kidneys, and skin. HBV infection has been associated with some autoimmune disorders. Dermatomyositis (DM) is an idiopathic inflammatory myopathy, which involves a viral infection, and DM has been identified in patients infected with HBV, but there is no direct histological evidence for an association between HBV and DM.
CASE SUMMARY We describe a familial HBV-infected patient admitted with liver function abnormality, rashes, a movement disorder, and an elevated level of creatine kinase (CK). A computed tomography scan of the lung showed pulmonary fibrosis, and a liver biopsy identified nodular cirrhosis. An electromyogram revealed myogenic damage, and a muscle biopsy showed nuclear migration in local sarcolemma and infiltration of chronic inflammatory cells. Immunohistochemical staining showed negative results for HBsAg and HBcAg. Fluorescence in situ hybridization showed a negative result for HBV DNA. The patient was diagnosed with HBV-related liver cirrhosis complicated with DM and was treated with methylprednisolone, mycophenolate mofetil, and lamivudine. Eight months later, the patient was readmitted for anorexia and fatigue. The blood examination showed elevated levels of aminotransferases and HBV DNA, however, the CK level was within the normal range. The patient developed a virological breakthrough and lamivudine was replaced with tenofovir.
CONCLUSION DM in chronic HBV-infected patients does not always associate with HBV. Antiviral and immunosuppressive drugs should be taken into consideration.
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Affiliation(s)
- Juan Zhang
- Department of Hepatic-Biliary-Pancreatic Medicine, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Xiao-Yu Wen
- Department of Hepatic-Biliary-Pancreatic Medicine, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Run-Ping Gao
- Department of Hepatic-Biliary-Pancreatic Medicine, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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21
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Hoeppli RE, Pesenacker AM. Targeting Tregs in Juvenile Idiopathic Arthritis and Juvenile Dermatomyositis-Insights From Other Diseases. Front Immunol 2019; 10:46. [PMID: 30740105 PMCID: PMC6355674 DOI: 10.3389/fimmu.2019.00046] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 01/09/2019] [Indexed: 12/22/2022] Open
Abstract
Regulatory T cells (Tregs) are believed to be dysfunctional in autoimmunity. Juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis (JDM) result from a loss of normal immune regulation in specific tissues such as joints or muscle and skin, respectively. Here, we discuss recent findings in regard to Treg biology in oligo-/polyarticular JIA and JDM, as well as what we can learn about Treg-related disease mechanism, treatment and biomarkers in JIA/JDM from studies of other diseases. We explore the potential use of Treg immunoregulatory markers and gene signatures as biomarkers for disease course and/or treatment success. Further, we discuss how Tregs are affected by several treatment strategies already employed in the therapy of JIA and JDM and by alternative immunotherapies such as anti-cytokine or co-receptor targeting. Finally, we review recent successes in using Tregs as a treatment target with low-dose IL-2 or cellular immunotherapy. Thus, this mini review will highlight our current understanding and identify open questions in regard to Treg biology, and how recent findings may advance biomarkers and new therapies for JIA and JDM.
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Affiliation(s)
- Romy E Hoeppli
- Department of Surgery, British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada
| | - Anne M Pesenacker
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, United Kingdom
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22
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Habiel DM, Espindola MS, Kitson C, Azzara AV, Coelho AL, Stripp B, Hogaboam CM. Characterization of CD28 null T cells in idiopathic pulmonary fibrosis. Mucosal Immunol 2019; 12:212-222. [PMID: 30315241 PMCID: PMC6301115 DOI: 10.1038/s41385-018-0082-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 07/02/2018] [Accepted: 08/08/2018] [Indexed: 02/04/2023]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease, with unknown etiopathogenesis and suboptimal therapeutic options. Previous reports have shown that increased T-cell numbers and CD28null phenotype is predictive of prognosis in IPF, suggesting that these cells might have a role in this disease. Flow cytometric analysis of explanted lung cellular suspensions showed a significant increase in CD8+ CD28null T cells in IPF relative to normal lung explants. Transcriptomic analysis of CD3+ T cells isolated from IPF lung explants revealed a loss of CD28-transcript expression and elevation of pro-inflammatory cytokine expression in IPF relative to normal T cells. IPF lung explant-derived T cells (enriched with CD28null T cells), but not normal donor lung CD28+ T cells induced dexamethasone-resistant lung remodeling in humanized NSG mice. Finally, CD28null T cells expressed similar CTLA4 and significantly higher levels of PD-1 proteins relative to CD28+ T cells and blockade of either proteins in humanized NSG mice, using anti-CTLA4, or anti-PD1, mAb treatment-accelerated lung fibrosis. Together, these results demonstrate that IPF CD28null T cells may promote lung fibrosis but the immune checkpoint proteins, CTLA-4 and PD-1, appears to limit this effect.
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Affiliation(s)
- David M Habiel
- Department of Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
| | - Milena S Espindola
- Department of Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Chris Kitson
- Bristol-Myers Squibb, Fibrosis Discovery Biology, Pennington, NJ, 08534, USA
| | - Anthony V Azzara
- Bristol-Myers Squibb, Fibrosis Discovery Biology, Pennington, NJ, 08534, USA
| | - Ana Lucia Coelho
- Department of Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Barry Stripp
- Department of Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Cory M Hogaboam
- Department of Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
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Tang Q, Ramsköld D, Krystufkova O, Mann HF, Wick C, Dastmalchi M, Lakshmikanth T, Chen Y, Mikes J, Alexanderson H, Achour A, Brodin P, Vencovsky J, Lundberg IE, Malmström V. Effect of CTLA4-Ig (abatacept) treatment on T cells and B cells in peripheral blood of patients with polymyositis and dermatomyositis. Scand J Immunol 2018; 89:e12732. [PMID: 30451307 DOI: 10.1111/sji.12732] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 11/07/2018] [Accepted: 11/08/2018] [Indexed: 11/29/2022]
Abstract
We aimed to evaluate in vivo effects of abatacept on phenotypes of T and B cells in the circulation of myositis patients in a sub-study of the ARTEMIS trial. Twelve patients with paired frozen PBMCs before and after 6-month abatacept treatment were included in this sub-study where mass cytometry (CyTOF) was chosen as a technology to be tested for its utility in a real-life clinical immune monitoring setting. Using CyTOF, the peripheral T cell phenotypes demonstrated considerable variation over time and between individuals precluding the identification of treatment-specific changes. We therefore conclude that studies of patient cohorts displaying wide clinical heterogeneity using mass cytometry must be relatively large in order to be suited for discovery research and immune monitoring. Still, we did find some correlations with functional muscle outcome, namely positive correlations between the ratio of CD4+ T cells and CD8+ T cells (CD4/CD8) in peripheral blood samples both at baseline and after treatment with muscle endurance improvement as assessed by the functional index-2 (FI-2) test. Our data suggest that the CD4/CD8 ratio in circulation at time of active disease may be a predictor of treatment efficacy in myositis patients.
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Affiliation(s)
- Quan Tang
- Division of Rheumatology, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Daniel Ramsköld
- Division of Rheumatology, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden
| | | | - Herman F Mann
- Institute of Rheumatology Prague, Prague, Czech Republic
| | - Cecilia Wick
- Division of Rheumatology, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Maryam Dastmalchi
- Division of Rheumatology, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Tadepally Lakshmikanth
- Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Yang Chen
- Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Jaromir Mikes
- Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Helene Alexanderson
- Division of Rheumatology, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden.,Functional Area Occupational Therapy and Physical Therapy, Karolinska University Hospital, and Division of Physiotherapy, Department of NVS, Karolinska Institutet, Stockholm, Sweden
| | - Adnane Achour
- Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Petter Brodin
- Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.,Department of Neonatology, Karolinska University Hospital, Stockholm, Sweden
| | - Jiri Vencovsky
- Institute of Rheumatology Prague, Prague, Czech Republic
| | - Ingrid E Lundberg
- Division of Rheumatology, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Vivianne Malmström
- Division of Rheumatology, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden
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24
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Abstract
PURPOSE OF REVIEW To review the novel development of standardized clinical outcome measures used in adult patients with idiopathic inflammatory myopathies (IIMs). A further aim was to determine what aspects of IIM are covered by these outcome measures according to the International Classification of Functioning, Disability and Health (ICF). RECENT FINDINGS The sporadic inclusion body myositis functional assessment (sIFA) is the first diagnosis-specific patient-driven patient-reported outcome measure. The adult myositis assessment tool (AMAT) is a new outcome measure assessing physical performance. Also, new criteria to assess response to treatment have been presented for both adults and children with IIM. The ICF provides a standardized frame and structure to report outcome, including functional disability. Using this framework, it is evident that there is a lack of validated patient-reported outcome measures to assess disease aspects important to patient, and that no studies have evaluated life-style factors such as physical activity in these patients. SUMMARY The sIFA will ensure patient-relevant patient-reported assessment of activity limitations in patients with inclusion body myositis. The AMAT is a partly validated tool that needs to be used in clinical trials for further validation. The response criteria will enhance assessment of individual response to different treatments.
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25
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Tjärnlund A, Tang Q, Wick C, Dastmalchi M, Mann H, Tomasová Studýnková J, Chura R, Gullick NJ, Salerno R, Rönnelid J, Alexanderson H, Lindroos E, Aggarwal R, Gordon P, Vencovsky J, Lundberg IE. Abatacept in the treatment of adult dermatomyositis and polymyositis: a randomised, phase IIb treatment delayed-start trial. Ann Rheum Dis 2018; 77:55-62. [PMID: 28993346 DOI: 10.1136/annrheumdis-2017-211751] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Revised: 07/14/2017] [Accepted: 08/05/2017] [Indexed: 11/04/2022]
Abstract
OBJECTIVES To study the effects of abatacept on disease activity and on muscle biopsy features of adult patients with dermatomyositis (DM) or polymyositis (PM). METHODS Twenty patients with DM (n=9) or PM (n=11) with refractory disease were enrolled in a randomised treatment delayed-start trial to receive either immediate active treatment with intravenous abatacept or a 3 month delayed-start. The primary endpoint was number of responders, defined by the International Myositis Assessment and Clinical Studies Group definition of improvement (DOI), after 6 months of treatment. Secondary endpoints included number of responders in the early treatment arm compared with the delayed treatment arm at 3 months. Repeated muscle biopsies were investigated for cellular markers and cytokines. RESULTS 8/19 patients included in the analyses achieved the DOI at 6 months. At 3 months of study, five (50%) patients were responders after active treatment but only one (11%) patient in the delayed treatment arm. Eight adverse events (AEs) were regarded as related to the drug, four mild and four moderate, and three serious AEs, none related to the drug. There was a significant increase in regulatory T cells (Tregs), whereas other markers were unchanged in repeated muscle biopsies. CONCLUSIONS In this pilot study, treatment of patients with DM and PM with abatacept resulted in lower disease activity in nearly half of the patients. In patients with repeat muscle biopsies, an increased frequency of Foxp3+ Tregs suggests a positive effect of treatment in muscle tissue.
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Affiliation(s)
- Anna Tjärnlund
- Rheumatology Unit, Department of Medicine, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden
| | - Quan Tang
- Rheumatology Unit, Department of Medicine, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden
| | - Cecilia Wick
- Rheumatology Unit, Department of Medicine, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden
| | - Maryam Dastmalchi
- Rheumatology Unit, Department of Medicine, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden
| | - Herman Mann
- Department of Rheumatology, Institute of Rheumatology, Prague, Czech Republic
| | | | - Radka Chura
- Department of Rheumatology, King's College Hospital NHS Foundation Trust, London, UK
| | - Nicola J Gullick
- Department of Rheumatology, King's College Hospital NHS Foundation Trust, London, UK
| | - Rosaria Salerno
- Department of Rheumatology, King's College Hospital NHS Foundation Trust, London, UK
| | - Johan Rönnelid
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Helene Alexanderson
- Division of Physiotherapy, Department of Neurobiology, Karolinska Institutet and Physical Therapy Clinic, Karolinska University Hospital, Stockholm, Sweden
| | - Eva Lindroos
- Rheumatology Unit, Department of Medicine, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden
| | - Rohit Aggarwal
- Division of Rheumatology and Clinical Rheumatology, University of Pittsburgh School of Medicine, Pittsburgh, USA
| | - Patrick Gordon
- Department of Rheumatology, King's College Hospital NHS Foundation Trust, London, UK
| | - Jiri Vencovsky
- Department of Rheumatology, Institute of Rheumatology, Prague, Czech Republic
| | - Ingrid E Lundberg
- Rheumatology Unit, Department of Medicine, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden
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26
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Shimojima Y, Matsuda M, Ishii W, Kishida D, Sekijima Y. T-cell receptor-mediated characteristic signaling pathway of peripheral blood T cells in dermatomyositis and polymyositis. Autoimmunity 2017; 50:481-490. [PMID: 29172719 DOI: 10.1080/08916934.2017.1405942] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The characteristics of T cell expression in peripheral blood have been previously described in dermatomyositis (DM) and polymyositis (PM); however, their intracellular signaling profiles remain unknown. The purpose of this study was to investigate the T-cell receptor (TCR)-mediated intracellular signaling in peripheral blood T cells in DM and PM. Peripheral blood T cells from 86 patients with DM (n = 57) and PM (n = 29) were used for experimental investigations. T-cell subtypes and TCR-induced phosphorylated zeta-chain-associated protein kinase 70 (pZAP70) were analyzed by flow cytometry. Signal transducer and activator of transcription (STAT) and some inhibitory factors in T cells with TCR stimulation were also investigated by quantitative real-time polymerase chain reaction. T cell counts were significantly lower in DM than in PM. In addition, STAT, forkhead box transcription factor (FoxP3), and pZAP70 expression in CD4+ T cells was suppressed in DM, whereas STAT and pZAP70 expression in CD8+ T cells was induced in PM. Especially in DM, a positive correlation between CD4+ T cell counts and STAT expression was detected. In addition, low CD4+ T cell counts as well as reduced STAT expression were prominent in patients with interstitial lung disease. STAT and pZAP70 expression significantly improved after clinical remission in both DM and PM, although expression of FoxP3 remained suppressed. Besides, upregulation of suppressor of cytokine signaling-3 (SOCS3) and downregulation of interleukin 6 signal transducer (IL6ST) in CD4+ T cells were observed in both DM and PM; however, no significant improvements were detected after clinical remission. The results of the present study suggested that TCR-mediated signaling may be a key pathway to determine the different characteristics of peripheral blood T cells between DM and PM. In addition, upregulation of SOCS3 and downregulation of IL6ST and FoxP3 in CD4+ T cells may cause an imbalance in intracellular signaling, especially in DM, suggesting that further studies are required to identify how the impaired signaling contributes to the development of the disease.
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Affiliation(s)
- Yasuhiro Shimojima
- a Department of Medicine (Neurology and Rheumatology) , Shinshu University School of Medicine , Matsumoto , Japan
| | - Masayuki Matsuda
- a Department of Medicine (Neurology and Rheumatology) , Shinshu University School of Medicine , Matsumoto , Japan
| | - Wataru Ishii
- a Department of Medicine (Neurology and Rheumatology) , Shinshu University School of Medicine , Matsumoto , Japan
| | - Dai Kishida
- a Department of Medicine (Neurology and Rheumatology) , Shinshu University School of Medicine , Matsumoto , Japan
| | - Yoshiki Sekijima
- a Department of Medicine (Neurology and Rheumatology) , Shinshu University School of Medicine , Matsumoto , Japan.,b Institute for Biomedical Sciences , Shinshu University , Matsumoto , Japan
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27
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John S, Antonia SJ, Rose TA, Seifert RP, Centeno BA, Wagner AS, Creelan BC. Progressive hypoventilation due to mixed CD8 + and CD4 + lymphocytic polymyositis following tremelimumab - durvalumab treatment. J Immunother Cancer 2017; 5:54. [PMID: 28716137 PMCID: PMC5514517 DOI: 10.1186/s40425-017-0258-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 06/14/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The combination of CTLA-4 and PD-L1 inhibitors has a manageable adverse effect profile, although rare immune-related adverse events (irAE) can occur. CASE PRESENTATION We describe an autoimmune polymyositis following a partial response to combination tremelimumab and durvalumab for the treatment of recurrent lung adenocarcinoma. Radiography revealed significant reduction in all metastases; however, the patient developed progressive neuromuscular hypoventilation due to lymphocytic destruction of the diaphragmatic musculature. Serologic testing revealed a low level of de novo circulating antibodies against striated muscle fiber. Immunohistochemistry revealed type II muscle fiber atrophy with a mixed CD8+ and CD4+ lymphocyte infiltrate, indicative of inflammatory myopathy. CONCLUSIONS This case supports the hypothesis that muscle tissue is a target for lymphocytic infiltration in immune checkpoint inhibitor-associated polymyositis. Further insights into the autoimmune mechanism of PM will hopefully contribute to the prevention and treatment of this phenomenon.
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Affiliation(s)
- Sooraj John
- Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., Tampa, FL 33612 USA
| | - Scott J. Antonia
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL 33612 USA
| | - Trevor A. Rose
- Department of Diagnostic Radiology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL 33612 USA
| | - Robert P. Seifert
- Department of Pathology and Cell Biology, University of South Florida, 12901 Bruce B. Downs Blvd., MDC 11, Tampa, FL 33612 USA
| | - Barbara A. Centeno
- Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL 33612 USA
| | - Aaron S. Wagner
- Orlando Health Pathology, 1414 Kuhl Ave., MP 44, Orlando, FL 32806 USA
| | - Ben C. Creelan
- Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612 USA
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28
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Pandya JM, Venalis P, Al-Khalili L, Shahadat Hossain M, Stache V, Lundberg IE, Malmström V, Fasth AER. CD4+ and CD8+ CD28(null) T Cells Are Cytotoxic to Autologous Muscle Cells in Patients With Polymyositis. Arthritis Rheumatol 2017; 68:2016-26. [PMID: 26895511 DOI: 10.1002/art.39650] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 02/16/2016] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Inflammatory T cell infiltrates in the skeletal muscle tissue of patients with polymyositis are dominated by CD28-negative effector (CD28(null) ) T cells of both the CD4 and CD8 lineage. These cells are potentially cytotoxic, and the aim of the present study was to develop a fully autologous cell culture system in which to investigate the functional contribution of such CD28(null) T cells to myotoxicity. METHODS In vitro cocultures of autologous skeletal muscle cells and T cell subsets obtained from 5 polymyositis patients were performed. Myotoxicity of T cells was quantified by calcein release and flow cytometric analyses. T cell degranulation was blocked with concanamycin A. Specific blocking of perforin, cytokines, and HLA was performed using antibodies. RESULTS Both CD4+CD28(null) and CD8+CD28(null) T cells induced more muscle cell death than did their CD28+ counterparts. Differentiated muscle cells (myotubes) were more sensitive to T cell-mediated cell death than were their precursors (myoblasts). Both CD8+ and CD4+ CD28(null) T cells displayed perforin polarization toward muscle cells and secreted higher levels of granzyme B and interferon-γ (IFNγ) in coculture than did CD28+ T cells. The myotoxic effects of CD28(null) T cells were reduced upon the blocking of perforin, cytokines, and HLA. Addition of IFNγ or tumor necrosis factor did not induce skeletal muscle cell death in the absence of T cells; however, it did up-regulate HLA expression on muscle cells. CONCLUSION Myotoxicity of CD4+ and CD8+ CD28(null) T cells is mediated by directed perforin-dependent killing and can be further influenced by IFNγ-induced HLA expression on muscle cells. The data suggest that CD28(null) T cells are key effector cells that contribute to the muscle cell damage in polymyositis.
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Affiliation(s)
- Jayesh M Pandya
- Karolinska University Hospital Solna, Sweden, and Karolinska Institutet, Stockholm, Sweden
| | - Paulius Venalis
- Karolinska University Hospital Solna, Sweden, and Karolinska Institutet, Stockholm, Sweden
| | | | | | - Vanessa Stache
- Karolinska University Hospital Solna, Sweden, and Karolinska Institutet, Stockholm, Sweden
| | - Ingrid E Lundberg
- Karolinska University Hospital Solna, Sweden, and Karolinska Institutet, Stockholm, Sweden
| | - Vivianne Malmström
- Karolinska University Hospital Solna, Sweden, and Karolinska Institutet, Stockholm, Sweden
| | - Andreas E R Fasth
- Andreas E. R. Fasth, PhD: Karolinska lnstitutet, Schering-Plough, MSD, and Novartis, Stockholm, Sweden
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29
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Mandel DE, Malemud CJ, Askari AD. Idiopathic Inflammatory Myopathies: A Review of the Classification and Impact of Pathogenesis. Int J Mol Sci 2017; 18:ijms18051084. [PMID: 28524083 PMCID: PMC5454993 DOI: 10.3390/ijms18051084] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 05/02/2017] [Accepted: 05/09/2017] [Indexed: 12/13/2022] Open
Abstract
Idiopathic inflammatory myopathies (IIMs) are a group of autoimmune muscle diseases with significant morbidity and mortality. This review details and updates the pathogenesis and emerging importance of myositis-specific antibodies in the development of IIMs. An increase in the understanding of how these myositis-specific antibodies play a role in IIMs has led to the further categorization of IIMs from the traditional polymyositis versus dermatomyositis, to additional subcategories of IIMs such as necrotizing autoimmune myositis (NAM). The diagnosis of IIMs, including manual muscle testing, laboratory studies, and non-invasive imaging have become important in classifying IIM subtypes and for identifying disease severity. Treatment has evolved from an era where glucocorticoid therapy was the only option to a time now that includes traditional steroid-sparing agents along with immunoglobulin therapy and biologics, such as rituximab.
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Affiliation(s)
- Dana E. Mandel
- Correspondence: ; Tel.: +1-216-844-2289; Fax: +1-216-844-2288
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30
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Loell I, Raouf J, Chen YW, Shi R, Nennesmo I, Alexanderson H, Dastmalchi M, Nagaraju K, Korotkova M, Lundberg IE. Effects on muscle tissue remodeling and lipid metabolism in muscle tissue from adult patients with polymyositis or dermatomyositis treated with immunosuppressive agents. Arthritis Res Ther 2016; 18:136. [PMID: 27287443 PMCID: PMC4902919 DOI: 10.1186/s13075-016-1033-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 05/25/2016] [Indexed: 12/24/2022] Open
Abstract
Background Polymyositis (PM) and dermatomyositis (DM) are autoimmune muscle diseases, conventionally treated with high doses of glucocorticoids in combination with immunosuppressive drugs. Treatment is often dissatisfying, with persisting muscle impairment. We aimed to investigate molecular mechanisms that might contribute to the persisting muscle impairment despite immunosuppressive treatment in adult patients with PM or DM using gene expression profiling of repeated muscle biopsies. Methods Paired skeletal muscle biopsies from six newly diagnosed adult patients with DM or PM taken before and after conventional immunosuppressive treatment were examined by gene expression microarray analysis. Selected genes that displayed changes in expression were analyzed by Western blot. Muscle biopsy sections were evaluated for inflammation, T lymphocytes (CD3), macrophages (CD68), major histocompatibility complex (MHC) class I expression and fiber type composition. Results After treatment, genes related to immune response and inflammation, including inflammasome pathways and interferon, were downregulated. This was confirmed at the protein level for AIM-2 and caspase-1 in the inflammasome pathway. Changes in genes involved in muscle tissue remodeling suggested a negative effect on muscle regeneration and growth. Gene markers for fast type II fibers were upregulated and fiber composition was switched towards type II fibers in response to treatment. The expression of genes involved in lipid metabolism was altered, suggesting a potential lipotoxic effect on muscles of the immunosuppressive treatment. Conclusion The anti-inflammatory effect of immunosuppressive treatment was combined with negative effects on genes involved in muscle tissue remodeling and lipid metabolism, suggesting a negative effect on recovery of muscle performance which may contribute to persisting muscle impairment in adult patients with DM and PM.
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Affiliation(s)
- Ingela Loell
- Karolinska Institutet, Department of Medicine, Rheumatology Unit, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Joan Raouf
- Karolinska Institutet, Department of Medicine, Rheumatology Unit, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Yi-Wen Chen
- Childrens National Medical Center, Research Center for Genetic Medicine, Washington, DC, USA
| | - Rongye Shi
- Center for Human Immunology, Autoimmunity and Inflammation, National Heart/Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Inger Nennesmo
- Karolinska University Hospital Huddinge, Institution for Laboratory Medicine (LABMED), Stockholm, Sweden
| | - Helene Alexanderson
- Karolinska Institutet, Department of NVS, Division of Physical Therapy and Karolinska University Hospital Solna, Physical Therapy Clinic, Stockholm, Sweden
| | - Maryam Dastmalchi
- Karolinska Institutet, Department of Medicine, Rheumatology Unit, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Kanneboyina Nagaraju
- Childrens National Medical Center, Research Center for Genetic Medicine, Washington, DC, USA
| | - Marina Korotkova
- Karolinska Institutet, Department of Medicine, Rheumatology Unit, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Ingrid E Lundberg
- Karolinska Institutet, Department of Medicine, Rheumatology Unit, Karolinska University Hospital Solna, Stockholm, Sweden.
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