EBV infection and HLA-DR15 jointly drive multiple sclerosis by myelin peptide presentation

Jian Wang; Yuhan Qiu; Zoe Marti; Fengqi Li; Marcel Wacker; Pietro Oldrati; Lena Mühlenbruch; Linlin Jin; Hongxia Zhang; Wen Xu; Tingting Li; Bernd Roschitzki; Wolfgang Faigle; Yingjun Liu; Julie T Nguyen; Jar-How Lee; Veronika Haunerdinger; Mathias Hauri-Hohl; Frank Momburg; Jens Bauer; Hans-Georg Rammensee; Mireia Sospedra; Roberta Magliozzi; Richard Reynolds; Juliane Walz; Roland Martin

doi:10.1016/j.cell.2025.12.046

EBV infection and HLA-DR15 jointly drive multiple sclerosis by myelin peptide presentation

Cell. 2026 Jan 22;189(2):569-584.e14. doi: 10.1016/j.cell.2025.12.046. Epub 2026 Jan 13.

Authors

Jian Wang¹, Yuhan Qiu², Zoe Marti³, Fengqi Li⁴, Marcel Wacker⁵, Pietro Oldrati⁶, Lena Mühlenbruch⁷, Linlin Jin⁸, Hongxia Zhang⁴, Wen Xu⁸, Tingting Li⁹, Bernd Roschitzki¹⁰, Wolfgang Faigle¹¹, Yingjun Liu¹², Julie T Nguyen¹³, Jar-How Lee¹³, Veronika Haunerdinger¹⁴, Mathias Hauri-Hohl¹⁴, Frank Momburg¹⁵, Jens Bauer⁷, Hans-Georg Rammensee¹⁶, Mireia Sospedra¹⁷, Roberta Magliozzi¹⁸, Richard Reynolds¹⁹, Juliane Walz²⁰, Roland Martin²¹

Affiliations

¹ State Key Laboratory of Immune Response and Immunotherapy, Department of Neurology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, 230001 Hefei, China. Electronic address: ustcwj@ustc.edu.cn.
² Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland.
³ Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland; Cellerys AG, Wagistrasse 21, 8952 Schlieren, Switzerland.
⁴ State Key Laboratory of Immune Response and Immunotherapy, Department of Neurology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, 230001 Hefei, China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, 230061 Hefei, China.
⁵ Department of Peptide-Based Immunotherapy, Institute of Immunology, University and University Hospital Tübingen, 72076 Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, 72076 Tübingen, Germany.
⁶ Cellerys AG, Wagistrasse 21, 8952 Schlieren, Switzerland.
⁷ Department of Peptide-Based Immunotherapy, Institute of Immunology, University and University Hospital Tübingen, 72076 Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, 72076 Tübingen, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, 72076 Tübingen, Germany.
⁸ State Key Laboratory of Immune Response and Immunotherapy, Department of Neurology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, 230001 Hefei, China.
⁹ State Key Laboratory of Immune Response and Immunotherapy, Department of Neurology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, 230001 Hefei, China; Department of Clinical Laboratory, First Affiliated Hospital of Anhui Medical University, 230022 Hefei, China.
¹⁰ Functional Genomics Center Zurich, Swiss Federal Institute of Technology (ETHZ) and University of Zurich (UZH), Winterthurerstrasse 190, 8057 Zurich, Switzerland.
¹¹ Neuroimmunology and MS Research, Neurology Clinic, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland; Institut Curie, PSL University, Inserm U932, Immunity and Cancer, 75005 Paris, France.
¹² Faculty of Life and Health Sciences, Shenzhen University of Advanced Technology (SUAT), 518107 Shenzhen, China.
¹³ One Lambda, Inc., a part of Transplant Diagnostics Thermo Fisher Scientific, 22801 Roscoe Blvd., West Hills, CA 91304, USA.
¹⁴ Pediatric Stem Cell Transplantation, University Children's Hospital Zurich, 8032 Zurich, Switzerland.
¹⁵ Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, 69120 Heidelberg, Germany.
¹⁶ Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, 72076 Tübingen, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, 72076 Tübingen, Germany; Institute of Immunology, University of Tübingen, 72076 Tübingen, Germany.
¹⁷ Cellerys AG, Wagistrasse 21, 8952 Schlieren, Switzerland; Neuroimmunology and MS Research, Neurology Clinic, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland.
¹⁸ Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK; Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37124 Verona, Italy.
¹⁹ Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK.
²⁰ Department of Peptide-Based Immunotherapy, Institute of Immunology, University and University Hospital Tübingen, 72076 Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, 72076 Tübingen, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, 72076 Tübingen, Germany; Clinical Collaboration Unit Translational Immunology, Department of Internal Medicine, University Hospital Tübingen, 72076 Tübingen, Germany.
²¹ Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland; Cellerys AG, Wagistrasse 21, 8952 Schlieren, Switzerland; Neuroimmunology and MS Research, Neurology Clinic, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland; Therapeutic Immune Design Unit, Department of Clinical Neuroscience, Karolinska Institute, Center for Molecular Medicine, 17177 Stockholm, Sweden. Electronic address: roland.martin@uzh.ch.

PMID: 41534530
DOI: 10.1016/j.cell.2025.12.046

Abstract

Epstein-Barr virus (EBV) is involved in causing and probably also in perpetuating multiple sclerosis (MS). Among several mechanisms of how EBV may contribute are transcriptome alterations, including changes of antigen processing and preferential presentation of both viral and self-antigens. Here, we report that EBV reprograms the transcriptome and immunopeptidome presented on the MS-associated human leukocyte antigen (HLA)-DR15 molecules of infected B cells. Identical myelin basic protein (MBP) peptides were found to be presented on both EBV-infected B cells and MS brain tissue but not primary B cells and thymic tissue. Peripheral memory and cerebrospinal fluid (CSF)-derived CD4⁺ T cells of HLA-DR15⁺ MS patients responded to MBP peptides, MBP_(78-90) and/or MBP_(83-90), and T cell clones raised with these peptides recognized all MBP peptides ending at amino acid MBP₉₀ in MS brain tissue. Our study provides a new mechanistic link for how the environmental and genetic risk factors, EBV infection and HLA-DR15 haplotype, may contribute jointly to MS.

Keywords: B cells; Epstein-Barr virus; autoreactive CD4(+) T cells; brain tissue; immunopeptidome; multiple sclerosis; myelin basic protein peptide; thymic tissue.

MeSH terms

Adult
Antigen Presentation*
B-Lymphocytes / immunology
B-Lymphocytes / virology
Brain / immunology
Brain / metabolism
CD4-Positive T-Lymphocytes / immunology
Epstein-Barr Virus Infections* / complications
Epstein-Barr Virus Infections* / immunology
Female
HLA-DR Serological Subtypes*
Herpesvirus 4, Human
Humans
Male
Middle Aged
Multiple Sclerosis* / immunology
Multiple Sclerosis* / virology
Myelin Basic Protein* / immunology
Myelin Basic Protein* / metabolism

Substances

HLA-DR15 antigen
Myelin Basic Protein
HLA-DR Serological Subtypes