ImportanceIt remains unclear why only a small proportion of individuals infected with the Epstein-Barr virus (EBV) develop multiple sclerosis (MS) and what the underlying mechanisms are.ObjectiveTo assess the serologic response to all EBV peptides before the first symptoms of MS occur, determine whether the disease is associated with a distinct immune response to EBV, and evaluate whether specific EBV epitopes drive this response.Design, Setting, and ParticipantsIn this prospective, nested case-control study, individuals were selected among US military personnel with serum samples stored in the US Department of Defense Serum Repository. Individuals with MS had serum collected at a median 1 year before onset (reported to the military in 2000-2011) and were matched to controls for age, sex, race and ethnicity, blood collection, and military branch. No individuals were excluded. The data were analyzed between September 1, 2022, and August 31, 2023.ExposureAntibodies (enrichment z scores) to the human virome measured using VirScan (phage-displayed immunoprecipitation and sequencing).Main Outcome and MeasureRate ratios (RRs) for MS for antibodies to 2263 EBV peptides (the EBV peptidome) were estimated using conditional logistic regression, adjusting for total anti–EBV nuclear antigen 1 (EBNA-1) antibodies, which have consistently been associated with a higher MS risk. The role of antibodies against other viral peptides was also explored.ResultsA total of 30 individuals with MS were matched with 30 controls. Mean (SD) age at sample collection was 27.8 (6.5) years; 46 of 60 participants (76.7%) were male. The antibody response to the EBV peptidome was stronger in individuals with MS, but without a discernible pattern. The antibody responses to 66 EBV peptides, the majority mapping to EBNA antigens, were significantly higher in preonset sera from individuals with MS (RR of highest vs lowest tertile of antibody enrichment, 33.4; 95% CI, 2.5-448.4; P for trend = .008). Higher total anti-EBNA-1 antibodies were also associated with an elevated MS risk (top vs bottom tertile: RR, 27.6; 95% CI, 2.3-327.6; P for trend = .008). After adjusting for total anti-EBNA-1 antibodies, risk estimates from most EBV peptides analyses were attenuated, with 4 remaining significantly associated with MS, the strongest within EBNA-6/EBNA-3C, while the association between total anti-EBNA-1 antibodies and MS persisted.Conclusion and RelevanceThese findings suggest that antibody response to EBNA-1 may be the strongest serologic risk factor for MS. No single EBV peptide stood out as being selectively targeted in individuals with MS but not controls. Larger investigations are needed to explore possible heterogeneity of anti-EBV humoral immunity in MS.

中文翻译：

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EB 病毒肽组的血清学反应和多发性硬化症的风险

重要性目前尚不清楚为什么只有一小部分感染 Epstein-Barr 病毒 (EBV) 的个体会发展为多发性硬化症 (MS)，其潜在机制是什么。 目的在 MS 首次症状出现之前评估对所有 EBV 肽的血清学反应，确定该疾病是否与针对 EBV 的独特免疫反应相关，并评估特定 EBV 表位是否驱动这种反应。 设计、设置和参与者在这项前瞻性、巢式病例对照研究中，从储存了血清样本的美国军事人员中选择了个体存于美国国防部血清库。多发性硬化症患者在发病前平均 1 年采集血清（2000 年至 2011 年向军队报告），并在年龄、性别、种族和民族、血液采集和军种方面与对照进行匹配。没有个人被排除在外。数据分析时间为2022年9月1日至2023年8月31日。ExposureAntibodies（富集z使用 VirScan（噬菌体展示免疫沉淀和测序）测量的人类病毒组。使用条件逻辑回归估计 2263 个 EBV 肽（EBV 肽组）抗体的 MS 的主要结果和测量率比率 (RR)，调整总抗–EBV 核抗原 1 (EBNA-1) 抗体，一直与较高的 MS 风险相关。还探讨了针对其他病毒肽的抗体的作用。结果总共 30 名 MS 患者与 30 名对照者进行了匹配。样本采集时的平均 (SD) 年龄为 27.8 (6.5) 岁； 60 名参与者中有 46 名（76.7%）是男性。 MS 个体对 EBV 肽组的抗体反应更强，但没有明显的模式。 MS 患者发病前血清中对 66 种 EBV 肽（大多数映射到 EBNA 抗原）的抗体反应显着较高（抗体富集的最高与最低三分位数的 RR，33.4；95% CI，2.5-448.4；磷趋势 = .008)。较高的总抗 EBNA-1 抗体也与 MS 风险升高相关（顶部与底部三分位数：RR，27.6；95% CI，2.3-327.6；磷趋势 = .008)。调整总抗 EBNA-1 抗体后，大多数 EBV 肽分析的风险估计值均减弱，其中 4 种仍与 MS 显着相关，其中 EBNA-6/EBNA-3C 中最强，而总抗 EBNA-1 抗体与 MS 之间的相关性最强。结论和相关性这些研究结果表明，对 EBNA-1 的抗体反应可能是 MS 最强的血清学危险因素。没有任何一种 EBV 肽能够选择性地靶向多发性硬化症患者，而对照组则不然。需要进行更大规模的研究来探索 MS 中抗 EBV 体液免疫可能存在的异质性。