Effects of EBV on autoimmunity and responses to immune therapy

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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.