Ganta Krishna Kumar, McManus Margaret, Blanc Ross, Wang Qixin, Jung Wonyeong, Brody Robin, Carrington Mary, Paris Robert, Chandramouli Sumana, McNamara Ryan, Luzuriaga Katherine
bioRxiv. 2024 Dec 21:2024.12.18.629009. doi: 10.1101/2024.12.18.629009.
Epstein-Barr Virus (EBV) infects over 95% of the world's population and is the most common cause of infectious mononucleosis (IM). Epidemiologic studies have linked EBV with certain cancers or autoimmune conditions, including multiple sclerosis (MS). Recent studies suggest that molecular mimicry between EBV proteins, particularly EBV nuclear antigen 1 (EBNA-1), and self-proteins is a plausible mechanism through which EBV infection may contribute to the development of autoimmune disorders. We used a systems immunology approach to investigate the magnitude, specificity, and functional properties of EBNA-1 specific antibodies in a cohort of 97 young adults with IM from presentation through 1-year post-primary infection compared to a control cohort of EBV-seropositive individuals. Levels of EBNA-1 specific IgG1 and IgG3 binding antibodies increased over the course of infection. EBNA-1 antibodies capable of mediating antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent complement deposition (ADCD) were detected at or after 6 months. Binding and ADCP- and ADCD-leveraged antibodies primarily targeted a region of EBNA-1 known to elicit cross-reactive antibodies to several self-peptides in individuals with MS. Significantly higher binding and ADCD-active antibodies targeting EBNA-1 were observed in individuals with at least one HLA-DRB1*15:01 allele, a known genetic risk factor for MS; Importantly, high levels of antibodies capable of binding alpha crystalline beta (CRYAB) and mediating complement deposition were detected at 6 months and 1-year following IM; CRYAB antibodies were resistant to denaturing forces, indicating an affinity matured response. Blocking experiments confirmed that CRYAB antibodies were cross-reactive with EBNA-1. Altogether, these results demonstrate that high levels of functional antibodies targeting EBNA-1 are generated in early EBV infection, some of which are cross-reactive with CRYAB. Further investigation is warranted to determine how these antibody responses may contribute to the subsequent development of MS.
爱泼斯坦-巴尔病毒（EBV）感染了全球超过95%的人口，是传染性单核细胞增多症（IM）最常见的病因。流行病学研究已将EBV与某些癌症或自身免疫性疾病联系起来，包括多发性硬化症（MS）。最近的研究表明，EBV蛋白之间的分子模拟，特别是EBV核抗原1（EBNA-1）与自身蛋白之间的分子模拟，是EBV感染可能导致自身免疫性疾病发生的一种合理机制。我们采用系统免疫学方法，在一组97名患有IM的年轻成年人中，从初次感染到感染后1年，研究了EBNA-1特异性抗体的强度、特异性和功能特性，并与一组EBV血清阳性个体作为对照队列进行比较。在感染过程中，EBNA-1特异性IgG1和IgG3结合抗体水平升高。在6个月及之后检测到了能够介导抗体依赖性细胞吞噬作用（ADCP）和抗体依赖性补体沉积作用（ADCD）的EBNA-1抗体。结合以及利用ADCP和ADCD的抗体主要靶向EBNA-1的一个区域，该区域已知会在MS患者体内引发针对几种自身肽的交叉反应性抗体。在至少携带一个HLA-DRB1*15:01等位基因（一种已知的MS遗传风险因素）的个体中，观察到针对EBNA-1的结合抗体和具有ADCD活性的抗体显著更高；重要的是，在IM后的6个月和1年时检测到了能够结合α晶状体β（CRYAB）并介导补体沉积的高水平抗体；CRYAB抗体对变性力具有抗性，表明这是一种亲和力成熟的反应。阻断实验证实CRYAB抗体与EBNA-1具有交叉反应性。总之，这些结果表明，在EBV早期感染中会产生高水平的靶向EBNA-1的功能性抗体，其中一些与CRYAB具有交叉反应性。有必要进一步研究以确定这些抗体反应如何可能促成MS的后续发展。
