Institut für Laboratoriumsmedizin, Klinikum der Universität München, München, Germany.
Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
Front Immunol. 2021 Nov 1;12:757302. doi: 10.3389/fimmu.2021.757302. eCollection 2021.
Roles for viral infections and aberrant immune responses in driving localized neuroinflammation and neurodegeneration in multiple sclerosis (MS) are the focus of intense research. Epstein-Barr virus (EBV), as a persistent and frequently reactivating virus with major immunogenic influences and a near 100% epidemiological association with MS, is considered to play a leading role in MS pathogenesis, triggering localized inflammation near or within the central nervous system (CNS). This triggering may occur directly viral products (RNA and protein) and/or indirectly antigenic mimicry involving B-cells, T-cells and cytokine-activated astrocytes and microglia cells damaging the myelin sheath of neurons. The genetic MS-risk factor HLA-DR2b (DRB11501β, DRA10101α) may contribute to aberrant EBV antigen-presentation and anti-EBV reactivity but also to mimicry-induced autoimmune responses characteristic of MS. A central role is proposed for inflammatory EBER1, EBV-miRNA and LMP1 containing exosomes secreted by viable reactivating EBV+ B-cells and repetitive release of EBNA1-DNA complexes from apoptotic EBV+ B-cells, forming reactive immune complexes with EBNA1-IgG and complement. This may be accompanied by cytokine- or EBV-induced expression of human endogenous retrovirus-W/-K (HERV-W/-K) elements and possibly by activation of human herpesvirus-6A (HHV-6A) in early-stage CNS lesions, each contributing to an inflammatory cascade causing the relapsing-remitting neuro-inflammatory and/or progressive features characteristic of MS. Elimination of EBV-carrying B-cells by antibody- and EBV-specific T-cell therapy may hold the promise of reducing EBV activity in the CNS, thereby limiting CNS inflammation, MS symptoms and possibly reversing disease. Other approaches targeting HHV-6 and HERV-W and limiting inflammatory kinase-signaling to treat MS are also being tested with promising results. This article presents an overview of the evidence that EBV, HHV-6, and HERV-W may have a pathogenic role in initiating and promoting MS and possible approaches to mitigate development of the disease.
病毒感染和异常免疫反应在多发性硬化症（MS）中驱动局部神经炎症和神经退行性变的作用是研究的重点。Epstein-Barr 病毒（EBV）是一种持续且频繁激活的病毒，具有主要的免疫原性影响，并且与 MS 的流行病学关联接近 100%，被认为在 MS 发病机制中发挥主导作用，在中枢神经系统（CNS）附近或内部引发局部炎症。这种触发可能直接通过病毒产物（RNA 和蛋白质），或间接通过涉及 B 细胞、T 细胞和细胞因子激活的星形细胞和小胶质细胞的抗原模拟来发生，从而破坏神经元的髓鞘。MS 的遗传风险因素 HLA-DR2b（DRB11501β，DRA10101α）可能导致异常 EBV 抗原呈递和抗 EBV 反应，但也可能导致 MS 特征性的模拟诱导自身免疫反应。提出炎症性 EBER1、EBV-miRNA 和含有活再激活 EBV+B 细胞分泌的含 LMP1 的外泌体以及从凋亡 EBV+B 细胞重复释放 EBNA1-DNA 复合物，与 EBNA1-IgG 和补体形成反应性免疫复合物，在这一过程中发挥核心作用。这可能伴随着细胞因子或 EBV 诱导的人类内源性逆转录病毒-W/-K（HERV-W/-K）元件的表达，并且可能伴随着人类疱疹病毒-6A（HHV-6A）在早期中枢神经系统病变中的激活，每个都有助于引起复发缓解性神经炎症和/或 MS 特征性进行性特征的炎症级联反应。通过抗体和 EBV 特异性 T 细胞治疗消除携带 EBV 的 B 细胞可能有望减少 CNS 中的 EBV 活性，从而限制 CNS 炎症、MS 症状并可能逆转疾病。其他针对 HHV-6 和 HERV-W 的方法以及限制炎症激酶信号传导以治疗 MS 的方法也正在进行测试，结果有希望。本文概述了 EBV、HHV-6 和 HERV-W 可能在启动和促进 MS 中发挥致病作用的证据，以及减轻疾病发展的可能方法。
