T cell repertoire in DQ5-positive MuSK-positive myasthenia gravis patients |
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| Institution: | 1. Department of Neurology, Research Institute and Hospital of National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Republic of Korea;2. Division of Clinical Research, National Cancer Center, Research institute, Goyang, Republic of Korea;3. Department of Biochemistry and Molecular Biology, Department of Biomedical Sciences, and Cancer Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Seoul 03080, Republic of Korea;4. Department of Neurology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea;5. Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, United Kingdom;1. Dipartimento di Medicina Sperimentale e Clinica (DMSC), Laboratory of Neuroimmunology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy;2. Department of Immunology, University of Oslo, Oslo, Norway;3. Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino (NEUROFARBA), University of Florence, Italy;4. Laboratorio Generale, Careggi University Hospital, Florence, Italy;5. Wolfson Neuroscience Laboratory, Department of Brain Sciences, Imperial College London, London, United Kingdom;6. CRTI-Inserm U1064, CIC0004 and Service de Neurologie, CHU de Nantes, Hôpital Nord Laënnec, Nantes, France;7. Institute of Clinical Medicine, University of Oslo, Postboks 1105, Blindern 0317 Oslo, Norway;1. Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands;2. Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands;3. Department of Medical Statistics, Leiden University Medical Centre, Leiden, The Netherlands;4. Department of Neurology, Hospital Santa Creu I Sant Pau, Barcelona, Spain;5. Department of Neurology, University Medical Centre Groningen, Groningen, The Netherlands;6. Department of Neurology, Università Cattolica del Sacro Cuore, Rome, Italy;1. Department of Immunology, Erasmus MC, Rotterdam, The Netherlands;2. Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, The Netherlands;1. Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China;2. Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China;3. National Frontier Center of Disease Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China;4. Department of Evidence-Based Medicine, Southwest Medical University, Luzhou, China;5. BGI-Shenzhen, Shenzhen 518083, China;6. Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China;7. Health Management Center, West China Hospital of Sichuan University, Chengdu 610041, China |
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| Abstract: | Myasthenia gravis (MG) is a prototypical antibody-mediated disease characterized by muscle weakness and fatigability. Serum antibodies to the acetylcholine receptor and muscle-specific tyrosine kinase receptor (MuSK) are found in about 85% and 8% of patients respectively. We have previously shown that more than 70% of MG patients with MuSK antibodies share the HLA DQ5 allele. The aim of the present study was to analyze the T cell receptor (TCR) repertoire specific for recombinant human MuSK protein. We used the CDR3 TRBV-TRBJ spectratyping (immunoscope) to analyze the T cell response to MuSK from 13 DQ5+ MuSK-MG patients and from 7 controls (six DQ5+ MuSK negative subjects and one DQ5− DQ3+ MuSK positive patient). DQ5+ MuSK-MG patients but not controls used a restricted set of TCR VJ rearrangements in response to MuSK stimulation. One semiprivate (TRBV29-TRBJ2.5) rearrangement was found in 5/13 patients, while 4 other semiprivate (one in TRBV28-TRBJ2.1 and in TRBV3-TRBJ1.2, and two in TRBV28-TRBJ1.2) rearrangements were differently shared by 4/13 patients each and were absent in controls. When we sequenced the TRBV29-TRBJ2.5 rearrangement, we obtained 26 different sequences of the expected 130 bp length from 117 samples of the 5 positive patients: two common motifs GXGQET/TEHQET were shared in 4 patients as semiprivate motifs. Thus, the MuSK-specific T-cell response appears to be restricted in DQ5+ MuSK-MG patients, with a semiprivate repertoire including a common motif of TRBV29. This oligoclonal restriction of T cells will allow the identification of immunodominant epitopes in the antigen, providing therefore new tools for diagnosis and targeted therapy. |
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| Keywords: | MHC Immunoscope Spectratyping CDR3 Repertoire T cell receptor |
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