Broader Epstein-Barr virus-specific T cell receptor repertoire in patients with multiple sclerosis

Epstein-Barr virus (EBV) infection precedes multiple sclerosis (MS) pathology and cross-reactive antibodies might link EBV infection to CNS autoimmunity. As an altered anti-EBV T cell reaction was suggested in MS, we queried peripheral blood T cell receptor β chain (TCRβ) repertoires of 1,395 MS pat...

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Published inThe Journal of experimental medicine Vol. 219; no. 11
Main Authors Schneider-Hohendorf, Tilman, Gerdes, Lisa Ann, Pignolet, Béatrice, Gittelman, Rachel, Ostkamp, Patrick, Rubelt, Florian, Raposo, Catarina, Tackenberg, Björn, Riepenhausen, Marianne, Janoschka, Claudia, Wünsch, Christian, Bucciarelli, Florence, Flierl-Hecht, Andrea, Beltrán, Eduardo, Kümpfel, Tania, Anslinger, Katja, Gross, Catharina C, Chapman, Heidi, Kaplan, Ian, Brassat, David, Wekerle, Hartmut, Kerschensteiner, Martin, Klotz, Luisa, Lünemann, Jan D, Hohlfeld, Reinhard, Liblau, Roland, Wiendl, Heinz, Schwab, Nicholas
Format Journal Article
LanguageEnglish
Published United States Rockefeller University Press 07.11.2022
Subjects
Autoimmunity
Brief Definitive Report
CD8-Positive T-Lymphocytes
Epstein-Barr Virus Infections - complications
Herpesvirus 4, Human
Human health and pathology
Humans
Infectious Disease and Host Defense
Life Sciences
Multiple Sclerosis
Neuroinflammation
Receptors, Antigen, T-Cell, alpha-beta - genetics
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Summary:Epstein-Barr virus (EBV) infection precedes multiple sclerosis (MS) pathology and cross-reactive antibodies might link EBV infection to CNS autoimmunity. As an altered anti-EBV T cell reaction was suggested in MS, we queried peripheral blood T cell receptor β chain (TCRβ) repertoires of 1,395 MS patients, 887 controls, and 35 monozygotic, MS-discordant twin pairs for multimer-confirmed, viral antigen-specific TCRβ sequences. We detected more MHC-I-restricted EBV-specific TCRβ sequences in MS patients. Differences in genetics or upbringing could be excluded by validation in monozygotic twin pairs discordant for MS. Anti-VLA-4 treatment amplified this observation, while interferon β- or anti-CD20 treatment did not modulate EBV-specific T cell occurrence. In healthy individuals, EBV-specific CD8+ T cells were of an effector-memory phenotype in peripheral blood and cerebrospinal fluid. In MS patients, cerebrospinal fluid also contained EBV-specific central-memory CD8+ T cells, suggesting recent priming. Therefore, MS is not only preceded by EBV infection, but also associated with broader EBV-specific TCR repertoires, consistent with an ongoing anti-EBV immune reaction in MS.
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PMCID: PMC9437111
Disclosures: R. Gittelman reported personal fees from Adaptive Biotechnologies during the conduct of the study. F. Rubelt reported a patent to US10731212B2 issued and a patent to immunoPETE related pending; and is an employee of Roche Diagnostics and receives salary, stock, and options as part of his employment compensation. C. Raposo reported being an employee and shareholder of F. Hoffmann-La Roche. B. Tackenberg reported other from F. Hoffmann-LaRoche outside the submitted work; and is a full-time employee of F. Hoffmann-LaRoche. T. Kümpfel reported personal fees from Novartis Pharma, Roche Pharma, Alexion/AstraZeneca, and Biogen for advisory boards/speaker honoraria outside the submitted work. C.C. Gross reported grants from DFG SFB/TR128 A09 during the conduct of the study; grants from DFG (single grant GR3946-3/1), IZKF (grant Kl13_010_19), Horizon2020 ReSToRe, Biogen, Roche, and Novartis Pharma; personal fees from MyLan and DIU Dresden International University GmbH; and other from Biogen, Euroimmun, MyLan, and Novartis Pharma outside the submitted work. I. Kaplan reported being an employee at Adaptive Biotechnologies during the time of this work. D. Brassat reported being a current Hoffman-La Roche employee. M. Kerschensteiner reported grants from Sanofi and personal fees from Sanofi, Biogen, Merck, Teva, Novartis, and Roche outside the submitted work. L. Klotz reported personal fees from Alexion, Bayer, Biogen, Celgene, Sanofi, Horizon, Grifols, Merck Serono, Novartis, Roche, Santhera, and Teva; and grants from German Research Foundation, IZKF Münster, IMF Münster, Biogen, Immunic AG, Novartis, and Merck Serono outside the submitted work. J.D. Lünemann reported personal fees from Abbvie, Alexion, Biogen, Novartis, Sanofi, and Takeda; and grants from Argenx, Merck, and Roche outside the submitted work. R. Liblau reported grants from GlaxoSmithKline, Foundation Bristol-Myers Squibb, Agence Nationale de la Recherche, the French MS Foundation, Cancer Research Institute, French Cancer Research Foundation, ERA-Net Narcomics, Recherche Hospitalo-Universitaire-BETPSY, and Roche; personal fees from Novartis, Sanofi-Genzyme, Biogen, Merck-Serono, and Third Rock Ventures; and other from Population Bio, Inc outside the submitted work. H. Wiendl reported personal fees for Abbvie, Alexion, Argenx, Biogen, Bristol Myers Squibb/Celgene, EMD Serono, F. Hoffmann-La Roche Ltd., Fondazione Cariplo, Genzyme, Gossamer Bio, Idorsia, Immunic, Immunovant, Janssen, Lundbeck, Merck, Neurodiem, NexGen, Novartis, PSI CRO, Roche Pharma AG, Sanofi, Swiss Multiple Sclerosis Society TEVA, UCB Biopharma, WebMD Global, and Worldwide Clinical Trials outside the submitted work. He reported grants by the DFG (CRC128 A09 and 445569437) during the conduct of the study, and funding by German Federal Ministry for Education and Research (BMBF), Deutsche Myasthenie Gesellschaft e.V., Alexion, Amicus Therapeutics Inc., Argenx, Biogen, CSL Behring, Roche, Genzyme, Merck, Novartis Pharma, Roche Pharma, and UCB Biopharma outside of the submitted work. N. Schwab reported grants from DFG, Biogen, and Roche during the conduct of the study. No other disclosures were reported.
T. Schneider-Hohendorf, L.A. Gerdes, B. Pignolet, R. Liblau, H. Wiendl, and N. Schwab contributed equally to this paper.
ISSN:0022-1007
1540-9538
1540-9538
DOI:10.1084/jem.20220650