EBV infection and HLA-DR15 jointly drive multiple sclerosis by myelin peptide presentation
Jian Wang1, Yuhan Qiu2, Zoe Marti3
1State 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.
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.
Insights
Epstein-Barr virus (EBV) infection and HLA-DR15 may jointly cause multiple sclerosis (MS). EBV-infected B cells present myelin peptides, triggering T cell responses in MS patients.
Area of Science:
- Neuroimmunology
- Virology
- Immunogenetics
Background:
- Epstein-Barr virus (EBV) is implicated in multiple sclerosis (MS) pathogenesis.
- Mechanisms include transcriptome alterations and altered antigen presentation.
Purpose of the Study:
- To investigate how EBV infection reprograms B cells in MS.
- To identify specific myelin peptides presented by EBV-infected B cells.
Main Methods:
- Analysis of transcriptome and immunopeptidome in EBV-infected B cells.
- Detection of myelin basic protein (MBP) peptides on HLA-DR15 molecules.
- T cell responses to MBP peptides in MS patients.
Main Results:
- EBV infection alters the immunopeptidome of HLA-DR15+ B cells.
- Identical MBP peptides found in EBV-infected B cells and MS brain tissue.
- MS patient T cells recognized these MBP peptides.
Conclusions:
- EBV infection and HLA-DR15 haplotype act synergistically in MS.
- Presents a novel mechanism linking environmental (EBV) and genetic (HLA-DR15) risk factors in MS.
