Effects of EBV on autoimmunity and responses to immune therapy

摘要 爱泼斯坦-巴尔病毒(Epstein Barr Virus，EBV)被认为是自身免疫的致病因子或疾病修饰剂 疾病包括多发性硬化症(MS)、类风湿关节炎(RA)、系统性红斑狼疮(SLE)和 其他。然而，尽管存在这些公认的关联，但这种病毒感染引发的机制 或修改自身免疫性尚未确定。一些研究人员发现组织之间存在共同的抗原 靶点和EBV，而其他研究人员已经描述了免疫谱系的变化，可能会影响 自身免疫的进展。1型糖尿病(T1D)此前并未与EBV感染相关。 然而，在最近完成的teplizumab(一种FCR非结合人源化抗CD3单抗)试验中， 我们发现，药物治疗是否会推迟高危非糖尿病亲属的T1D诊断 在研究开始时，EBV血清阳性的患者的药物疗效比EBV阳性的患者更好 SERO-。EB病毒血清阳性对替普利单抗疗效的影响 CMV+和CMV-进行比较。此外，我们发现，在保留方面有了显著的改善 在先前的替普利单抗治疗新发T1D(缓解)患者的随机试验中， EBVsero+与EBVsero-参与者的比较。对替普利单抗的免疫反应与 部分耗尽的CD8+记忆(CD45RO+)T细胞的诱导 KLRG1和TIGIT。在TN10和ABATE试验中，这些细胞的频率在EBVsero+中更高 与基线和药物治疗后的血清个体比较，提示EBV对免疫形成的影响 以及改变T细胞对抗CD3单抗的反应。在这个提案中，我们将检验假设 EB病毒调节免疫反应，增强替普利单抗对T1D的保护和进展 是被给予的。我们将分析T和B细胞在TN10参与者中的转录组，并分析差异 EBV血清阳性与阴性个体之间的关系，并分析这些数据并计数EBV反应性T 细胞。EB病毒在B细胞中是潜伏的，我们将测试病毒对B细胞的影响可能会增强 替普利珠单抗的活性。最后，进一步了解潜伏EBV的B细胞与T细胞的关系 在T1D中，我们将测试抗CD20单抗去除B细胞是否会部分降低T细胞的频率 在新发病的T1D(Tn05)中使用来自Rituximab试验的样本的耗尽表型。使用以下设置 免疫紊乱，我们希望确定受EBV影响的T/B细胞相互作用，而不是 在稳定状态下能得到赏识。我们确定的机制广泛应用于 了解几种自身免疫性疾病，并确定免疫治疗的作用机制。

Summary Epstein Barr Virus (EBV) has been incriminated as a causative or disease modifying agent in autoimmune diseases including multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and others. Yet despite these well recognized associations, the mechanisms whereby this viral infection can trigger or modify autoimmunity have not been identified. Some investigators have found shared antigens between tissue targets and EBV while other investigators have described changes to the immune repertoire that may affect progression of autoimmunity. Type 1 diabetes (T1D) has not previously been associated with EBV infection. However, in the recently completed teplizumab (a FcR non-binding humanized anti-CD3 mAb) trial, to test whether drug treatment would delay the diagnosis of T1D in non-diabetic relatives at high-risk (TN10), we found that the drug efficacy was better in those who were EBV sero+ at study entry compared to those who were EBV sero-. The effect of EBV seropositivity on the response to teplizumab and was not seen when individuals who were CMV+ and – were compared. In addition, we found that there was a significant improvement in retention of C-peptide in a previous randomized trial of teplizumab in patients with new onset T1D (AbATE) among EBVsero+ compared to EBVsero- participants. Immune response to teplizumab have been associated with induction of partially exhausted CD8+ memory (CD45RO+) T cells which are identified by co-expression of KLRG1 and TIGIT. In both the TN10 and AbATE trials the frequency of these cells was higher in the EBVsero+ vs sero- individuals at the baseline and after drug treatment suggesting an effect of EBV on shaping the immune repertoire and in altering T cellular responses to anti-CD3 mAb. In this proposal we will test the hypothesis that EBV modulates immune responses that enhance the protection from and progression of T1D when teplizumab is given. We will analyze the transcriptome of T and B cells in the TN10 participants and analyze the differences between EBV sero+ vs – individuals and analyzing these data together with enumerating the EBV reactive T cells. EBV is latent in B cells and we will test the hypothesis that the virus’ effects on B cells may enhance the activity of teplizumab. Finally, to further understand the relationship between B cells with latent EBV and T cells in T1D, we will test whether B cell depletion with anti-CD20 mAb reduces the frequency of T cells with a partially exhausted phenotype using samples from the Rituximab trial in new onset T1D (TN05). Using these settings of immune disturbances, we expect to identify T/B cell interactions that are affected by EBV that cannot be appreciated under steady state conditions. The mechanisms that we identify have broad application to understanding several autoimmune diseases and in identifying mechanisms of action of immune therapy.