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Memory B Cells Activate Brain-Homing, Autoreactive CD4+ T Cells in Multiple Sclerosis.
Jelcic, Ivan; Al Nimer, Faiez; Wang, Jian; Lentsch, Verena; Planas, Raquel; Jelcic, Ilijas; Madjovski, Aleksandar; Ruhrmann, Sabrina; Faigle, Wolfgang; Frauenknecht, Katrin; Pinilla, Clemencia; Santos, Radleigh; Hammer, Christian; Ortiz, Yaneth; Opitz, Lennart; Grönlund, Hans; Rogler, Gerhard; Boyman, Onur; Reynolds, Richard; Lutterotti, Andreas; Khademi, Mohsen; Olsson, Tomas; Piehl, Fredrik; Sospedra, Mireia; Martin, Roland.
Afiliación
  • Jelcic I; Neuroimmunology and MS Research Section (NIMS), Neurology Clinic, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland.
  • Al Nimer F; Neuroimmunology and MS Research Section (NIMS), Neurology Clinic, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland; Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, 17176 Stockholm, Sweden.
  • Wang J; Neuroimmunology and MS Research Section (NIMS), Neurology Clinic, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland.
  • Lentsch V; Neuroimmunology and MS Research Section (NIMS), Neurology Clinic, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland.
  • Planas R; Neuroimmunology and MS Research Section (NIMS), Neurology Clinic, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland.
  • Jelcic I; Neuroimmunology and MS Research Section (NIMS), Neurology Clinic, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland.
  • Madjovski A; Neuroimmunology and MS Research Section (NIMS), Neurology Clinic, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland.
  • Ruhrmann S; Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, 17176 Stockholm, Sweden.
  • Faigle W; Neuroimmunology and MS Research Section (NIMS), Neurology Clinic, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland.
  • Frauenknecht K; Institute of Neuropathology, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland.
  • Pinilla C; Torrey Pines Institute for Molecular Studies (TPIMS), San Diego, CA, USA.
  • Santos R; Torrey Pines Institute for Molecular Studies (TPIMS), Port St. Lucie, FL, USA.
  • Hammer C; School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
  • Ortiz Y; Neuroimmunology and MS Research Section (NIMS), Neurology Clinic, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland.
  • Opitz L; Functional Genomics Center Zurich, Swiss Federal Institute of Technology and University of Zurich, 8057 Zurich, Switzerland.
  • Grönlund H; Therapeutic Immune Design Unit, Department of Clinical Neuroscience, Karolinska Institutet, 17176 Stockholm, Sweden.
  • Rogler G; Department of Gastroenterology and Hepatology, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland.
  • Boyman O; Department of Immunology, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland.
  • Reynolds R; Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
  • Lutterotti A; Neuroimmunology and MS Research Section (NIMS), Neurology Clinic, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland.
  • Khademi M; Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, 17176 Stockholm, Sweden.
  • Olsson T; Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, 17176 Stockholm, Sweden.
  • Piehl F; Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, 17176 Stockholm, Sweden.
  • Sospedra M; Neuroimmunology and MS Research Section (NIMS), Neurology Clinic, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland.
  • Martin R; Neuroimmunology and MS Research Section (NIMS), Neurology Clinic, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland. Electronic address: roland.martin@usz.ch.
Cell ; 175(1): 85-100.e23, 2018 09 20.
Article en En | MEDLINE | ID: mdl-30173916
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Linfocitos B / Subtipos Serológicos HLA-DR / Esclerosis Múltiple Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Cell Año: 2018 Tipo del documento: Article País de afiliación: Suiza
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Linfocitos B / Subtipos Serológicos HLA-DR / Esclerosis Múltiple Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Cell Año: 2018 Tipo del documento: Article País de afiliación: Suiza