Otto Carolin, Hofmann Jörg, Ruprecht Klemens
St. Josefs-Krankenhaus Potsdam, Potsdam, Germany.
Institute of Virology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; Labor Berlin, Charité-Vivantes GmbH, Berlin, Germany.
Med Hypotheses. 2016 Jun;91:109-113. doi: 10.1016/j.mehy.2016.04.025. Epub 2016 Apr 16.
Patients with multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), typically have an intrathecal synthesis of immunoglobulin (Ig)G. Intrathecal IgG is produced by B lineage cells that entered the CNS, but why and when these cells invade the CNS of patients with MS is unknown. The intrathecal IgG response in patients with MS is polyspecific and part of it is directed against different common viruses (e.g. measles virus, rubella virus, varicella zoster virus). Strong and consistent evidence suggests an association of MS and Epstein-Barr virus (EBV) infection and EBV seroprevalence in patients with MS is practically 100%. However, intriguingly, despite of the universal EBV seroprevalence, the frequency of intrathecally produced IgG to EBV in patients with MS is much lower than that of intrathecally produced IgG to other common viruses. The acute phase of primary EBV infection is characterized by a strong polyclonal B cell activation. As typical for humoral immune responses against viruses, EBV specific IgG is produced only with a temporal delay after acute EBV infection. Aiming to put the above facts into a logical structure, we here propose the hypothesis that in individuals going on to develop MS antibody producing B lineage cells invade the CNS predominantly at the time of and triggered by acute primary EBV infection. Because at the time of acute EBV infection EBV IgG producing B lineage cells have not yet occurred, the hypothesis could explain the universal EBV seroprevalence and the low frequency of intrathecally produced IgG to EBV in patients with MS. Evidence supporting the hypothesis could be provided by large prospective follow-up studies of individuals with symptomatic primary EBV infection (infectious mononucleosis). Furthermore, the clarification of the molecular mechanism underlying an EBV induced invasion of B lineage cells into the CNS of individuals going on to develop MS could corroborate it, too. If true, our hypothesis would link EBV infection, the most important environmental risk factor for MS, with intrathecal IgG synthesis, the most characteristic laboratory feature of MS. Besides explaining the origin of intrathecal IgG synthesis in patients with MS, the hypothesis could thus also provide a conceptual framework for clarifying the mechanism through which EBV contributes to the development of MS.
多发性硬化症（MS）是一种中枢神经系统（CNS）的慢性炎症性疾病，其患者通常存在鞘内免疫球蛋白（Ig）G的合成。鞘内IgG由进入中枢神经系统的B淋巴细胞系产生，但这些细胞为何以及何时侵入MS患者的中枢神经系统尚不清楚。MS患者的鞘内IgG反应具有多特异性，部分针对不同的常见病毒（如麻疹病毒、风疹病毒、水痘带状疱疹病毒）。强有力且一致的证据表明MS与爱泼斯坦-巴尔病毒（EBV）感染有关，MS患者中EBV血清阳性率几乎为100%。然而，有趣的是，尽管EBV血清阳性普遍存在，但MS患者鞘内产生的针对EBV的IgG频率远低于鞘内产生的针对其他常见病毒的IgG频率。原发性EBV感染的急性期以强烈的多克隆B细胞激活为特征。作为针对病毒的体液免疫反应的典型情况，EBV特异性IgG仅在急性EBV感染后有一定延迟才产生。为了将上述事实纳入一个逻辑结构，我们在此提出一个假说，即在即将发展为MS的个体中，产生抗体的B淋巴细胞系主要在急性原发性EBV感染时并由其触发侵入中枢神经系统。因为在急性EBV感染时，产生EBV IgG的B淋巴细胞系尚未出现，该假说可以解释MS患者中EBV血清阳性的普遍性以及鞘内产生的针对EBV的IgG频率较低的现象。对有症状的原发性EBV感染（传染性单核细胞增多症）个体进行的大型前瞻性随访研究可以提供支持该假说的证据。此外，阐明EBV诱导B淋巴细胞系侵入即将发展为MS的个体中枢神经系统的分子机制也可以证实这一点。如果该假说成立，我们的假说将把MS最重要的环境危险因素EBV感染与MS最具特征性的实验室特征鞘内IgG合成联系起来。因此，除了解释MS患者鞘内IgG合成的起源外，该假说还可以为阐明EBV促成MS发展的机制提供一个概念框架。
