Memory B Cells Activate Brain-Homing, Autoreactive CD4+ T Cells in Multiple Sclerosis
| Autor: | Mireia Sospedra, Mohsen Khademi, Yanneth Ortiz, Katrin Frauenknecht, Lennart Opitz, Sabrina Ruhrmann, Radleigh G. Santos, Tomas Olsson, Verena Lentsch, Richard Reynolds, Andreas Lutterotti, Christian Hammer, Aleksandar Madjovski, Ilijas Jelcic, Wolfgang Faigle, Onur Boyman, Faiez Al Nimer, Gerhard Rogler, Raquel Planas, Clemencia Pinilla, Roland Martin, Hans Grönlund, Frederik Piehl, Ivan Jelcic, Jian Wang |
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| Přispěvatelé: | University of Zurich, Martin, Roland |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
CD4-Positive T-Lymphocytes HOMEOSTASIS AUTOIMMUNITY Cell medicine.disease_cause multiple sclerosis Autoantigens Epitope Autoimmunity SELF-ANTIGENS Guanine Nucleotide Exchange Factors B cells T cells pathogenesis HLA-DR15 autoproliferation brain T cell receptor RASGRP2 11 Medical and Health Sciences GENE-EXPRESSION HLA-DR Serological Subtypes B-Lymphocytes INDUCTION 3. Good health medicine.anatomical_structure 10219 Clinic for Gastroenterology and Hepatology Antibody Life Sciences & Biomedicine TCR Biochemistry & Molecular Biology T cell Receptors Antigen T-Cell 10208 Institute of Neuropathology 610 Medicine & health Genetics and Molecular Biology Biology General Biochemistry Genetics and Molecular Biology Article MECHANISMS Autoimmune Diseases 03 medical and health sciences 1300 General Biochemistry Genetics and Molecular Biology medicine Humans Science & Technology LESIONS Multiple sclerosis T-cell receptor Cell Biology 06 Biological Sciences Th1 Cells medicine.disease 10040 Clinic for Neurology 030104 developmental biology Immunology ANTIBODIES General Biochemistry biology.protein 10033 Clinic for Immunology REPERTOIRES Homing (hematopoietic) Developmental Biology |
| Zdroj: | Cell Cell, 175 (1) |
| Popis: | Summary Multiple sclerosis is an autoimmune disease that is caused by the interplay of genetic, particularly the HLA-DR15 haplotype, and environmental risk factors. How these etiologic factors contribute to generating an autoreactive CD4+ T cell repertoire is not clear. Here, we demonstrate that self-reactivity, defined as “autoproliferation” of peripheral Th1 cells, is elevated in patients carrying the HLA-DR15 haplotype. Autoproliferation is mediated by memory B cells in a HLA-DR-dependent manner. Depletion of B cells in vitro and therapeutically in vivo by anti-CD20 effectively reduces T cell autoproliferation. T cell receptor deep sequencing showed that in vitro autoproliferating T cells are enriched for brain-homing T cells. Using an unbiased epitope discovery approach, we identified RASGRP2 as target autoantigen that is expressed in the brain and B cells. These findings will be instrumental to address important questions regarding pathogenic B-T cell interactions in multiple sclerosis and possibly also to develop novel therapies. Graphical Abstract Highlights • Autoproliferation of CD4+ T cells and B cells is involved in multiple sclerosis • The main genetic factor of MS, HLA-DR15, plays a central role in autoproliferation • Memory B cells drive autoproliferation of Th1 brain-homing CD4+ T cells • Autoproliferating T cells recognize antigens expressed in B cells and brain lesions Memory B cells drive proliferation of self-reactive brain-homing CD4+ T cells, which recognize autoantigens expressed in B cells and in brain lesions with target potential in multiple sclerosis. |
| Databáze: | OpenAIRE |
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