Background Multiple sclerosis (MS) and presymptomatic axonal injury appear to develop only after an Epstein-Barr virus (EBV) infection. This association remains to be confirmed across a broad preclinical time range, for lytic and latent EBV seroreactivity, and for potential cross-reacting antigens. Methods We performed a case–control study with 669 individual serum samples obtained before clinical MS onset, identified through cross-linkage with the Swedish MS register. We assayed antibodies against EBV nuclear antigen 1 (EBNA1), viral capsid antigen p18, glycoprotein 350 (gp350), the potential cross-reacting protein anoctamin 2 (ANO2) and the level of sNfL, a marker of axonal injury. Results EBNA1 (latency) seroreactivity increased in the pre-MS group, at 15–20 years before clinical MS onset, followed by gp350 (lytic) seroreactivity (p=0.001–0.009), ANO2 seropositivity appeared shortly after EBNA1-seropositivity in 16.7% of pre-MS cases and 10.0% of controls (p=0.001).With an average lag of almost a decade after EBV, sNfL gradually increased, mainly in the increasing subgroup of seropositive pre-MS cases (p=8.10−5 compared with non-MS controls). Seropositive pre-MS cases reached higher sNfL levels than seronegative pre-MS (p=0.038). In the EBNA1-seropositive pre-MS group, ANO2 seropositive cases had 26% higher sNfL level (p=0.0026). Conclusions Seroreactivity against latent and lytic EBV antigens, and in a subset ANO2, was detectable on average a decade before the appearance of a gradually increasing axonal injury occurring in the last decade before the onset of clinical MS. These findings strengthen the hypothesis of latent EBV involvement in the pathogenesis of MS. Data are available on reasonable request. The data that support the findings of this study are available from the corresponding author, DJ, on reasonable request.

中文翻译：

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针对裂解性、潜伏性和可能的​​交叉反应性 EBV 抗原的血清反应性平均在 MS 诱导的临床前神经轴索损伤前 10 年出现

背景 多发性硬化症 (MS) 和症状前轴突损伤似乎仅在 Epstein-Barr 病毒 (EBV) 感染后发生。对于裂解性和潜在 EBV 血清反应性以及潜在的交叉反应抗原，这种关联仍有待在广泛的临床前时间范围内得到证实。方法 我们对临床多发性硬化症发病前获得的 669 份血清样本进行了病例对照研究，并通过与瑞典多发性硬化症登记系统的交叉链接进行鉴定。我们检测了针对 EBV 核抗原 1 (EBNA1)、病毒衣壳抗原 p18、糖蛋白 350 (gp350)、潜在交叉反应蛋白 anoctamin 2 (ANO2) 的抗体以及轴突损伤标志物 sNfL 的水平。结果 在 MS 前期组中，在临床 MS 发病前 15-20 年，EBNA1（潜伏期）血清反应性增加，随后是 gp350（裂解性）血清反应性（p=0.001-0.009），ANO2 血清反应性在 EBNA1 血清阳性后不久出现，占 16.7%的 MS 前病例和 10.0% 的对照（p=0.001）。 EBV 后平均滞后近十年，sNfL 逐渐增加，主要是在 MS 前血清阳性病例的增加亚组中（p=8.10−5 与 EBV 相比）非 MS 对照）。血清阳性 MS 前病例的 sNfL 水平高于血清阴性 MS 前病例 (p=0.038)。在 EBNA1 血清阳性 MS 前组中，ANO2 血清阳性病例的 sNfL 水平高出 26% (p=0.0026)。结论 在临床多发性硬化症发病前的最后十年中，轴突损伤逐渐增加之前，平均可检测到针对潜在和裂解性 EBV 抗原以及 ANO2 子集的血清反应性。这些发现强化了 EBV 潜在参与 MS 发病机制的假设。可根据合理要求提供数据。支持本研究结果的数据可根据合理要求从通讯作者 DJ 处获得。