Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.
Institute of Clinical Neuroimmunology, University Hospital and Biomedical Center, Ludwig-Maximilians Universität München, Munich, Germany.
J Exp Med. 2022 Nov 7;219(11). doi: 10.1084/jem.20220650. Epub 2022 Sep 1.
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.
爱泼斯坦-巴尔病毒（EBV）感染先于多发性硬化症（MS）发病机制，并且交叉反应性抗体可能将 EBV 感染与中枢神经系统自身免疫联系起来。由于在 MS 中提出了改变的抗 EBV T 细胞反应，我们对 1395 名 MS 患者、887 名对照者和 35 对 MS 不一致的同卵双胞胎的外周血 T 细胞受体β链（TCRβ）库进行了查询，以寻找经多聚体确认的、病毒抗原特异性 TCRβ序列。我们在 MS 患者中检测到更多 MHC-I 受限的 EBV 特异性 TCRβ序列。通过对 MS 不一致的同卵双胞胎进行验证，排除了遗传或教养差异的可能性。抗 VLA-4 治疗放大了这一观察结果，而干扰素β或抗 CD20 治疗并未调节 EBV 特异性 T 细胞的发生。在健康个体中，EBV 特异性 CD8+T 细胞在外周血和脑脊液中表现为效应记忆表型。在 MS 患者中，脑脊液中还含有 EBV 特异性中央记忆 CD8+T 细胞，提示近期启动。因此，MS 不仅先于 EBV 感染，而且与更广泛的 EBV 特异性 TCR 库相关，这与 MS 中的持续抗 EBV 免疫反应一致。
