Epstein-Barr virus reprograms autoreactive B cells as antigen-presenting cells in systemic lupus erythematosus

Abstract Introduction Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by anti-nuclear antibodies (ANA). Epstein-Barr virus (EBV) infection has been epidemiologically associated with SLE, yet its role in pathogenesis remains incompletely defined. Methods We developed an EBV-specific single-cell RNA-sequencing platform and used it to sequence EBV-infected B cells directlry isolated form the patient. Using combined EBV-seq, CITE-seq, BCR-seq, and scRNA-seq, we sequenced the EBV genes, B cell receptor (BCR) repertoires, and transcriptomes of blood B cells from patients with SLE . Results We demonstrated that, in SLE, EBV+ B cells are predominantly CD27+CD21low memory B cells that are present at increased frequencies and express ZEB2, TBX21, and antigen presenting cell transcriptional pathways. Integrative analysis of chromatin immunoprecipitation sequencing (ChIP-seq), assay for transposase-accessible chromatin (ATAC-seq), and RNA Polymerase II occupancy data revealed EBNA2 binding at the transcriptional start sites and regulatory regions of CD27, ZEB2, and TBX21 (Tbet), 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 activate T peripheral helper cells with concomitant activation of related EBV- anti-nuclear double negative 2 B cells and plasmablasts. Conclusion Our results provide a potential mechanistic basis for EBV being a driver of SLE through infecting and reprograming nuclear antigen reactive B cells to become activated antigen presenting cells with the potential to promote systemic disease-driving autoimmune responses. Funding Source Lupus Research Alliance Topic Categories Basic Autoimmunity (BA)