Epstein-Barr virus reprograms autoreactive B cells as antigen-presenting cells in systemic lupus erythematosus
Shady Younis, Salvinaz Islam Moutusy, Sajede Rasouli, Shaghayegh Jahanbani, Mahesh Pandit, Xiaohao Wu, Suman Acharya, Orr Sharpe, Tilini U. Wijeratne, Marlayna L. Harris, Emily Yang, Yashaar Chaichian, Shima Parsafar, Matthew Baker, John B. Harley, Eric Meffre, Lawrence Steinman, Ann Marshak‐Rothstein, Judith A. James, Olivia M. Martinez, Paul J. Utz, Dana E. Orange, Tobias V. Lanz, William H. Robinson
Abstract
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by antinuclear antibodies (ANAs). Epstein-Barr virus (EBV) infection has been epidemiologically associated with SLE, yet its role in pathogenesis remains incompletely defined. Here, we developed an EBV-specific single-cell RNA-sequencing platform and used it to demonstrate that EBV infection reprograms autoreactive antinuclear antigen B cells to drive autoimmunity in SLE. We demonstrated that, in SLE, EBV + B cells are predominantly CD27 + CD21 low memory B cells that are present at increased frequencies and express ZEB2 , TBX21 (T-bet), and antigen-presenting cell transcriptional pathways. Integrative analysis of chromatin immunoprecipitation sequencing (ChIP-seq), assay for transposase-accessible chromatin sequencing (ATAC-seq), and RNA polymerase II occupancy data revealed EBV nuclear antigen 2 (EBNA2) binding at the transcriptional start sites and regulatory regions of CD27 , ZEB2 , and TBX21 , as well as the antigen-presenting cell genes demonstrated to be up-regulated in SLE EBV + B cells. We expressed recombinant antibodies from SLE EBV + B cells and demonstrated that they bind prototypical SLE nuclear autoantigens, whereas those from healthy individuals do not. We further found that SLE EBV + B cells can serve as antigen-presenting cells to drive activation of T peripheral helper cells with concomitant activation of related EBV − antinuclear double-negative 2 B cells and plasmablasts. Our results provide a mechanistic basis for EBV being a driver of SLE through infecting and reprogramming nuclear antigen-reactive B cells to become activated antigen-presenting cells with the potential to promote systemic disease–driving autoimmune responses.