Antigen presentation by B cells enables epitope spreading across an MHC barrier

A progressive increase in the breadth and specificity of autoantibodies over time, termed epitope spreading, drives pathogenic targeting of an ever-widening repertoire of self-components in many autoimmune diseases. Ostensibly, this progressive inclusion of additional B cell clones into an ongoing autoreactive response can occur through linked recognition, whereby proto-autoreactive B cells recognize distinct antigenic epitopes, which carry shared T cell epitopes. In a murine model displaying epitope spreading resembling that observed in systemic lupus erythematosus, we find that the epitope spreading process is compartmentalized by MHC. Antigen presentation by B cells carrying two MHC haplotypes can bridge the MHC barrier between two compartments of B cells that do not share MHC haplotypes, by communicating with two separate pools of MHC-restricted T cells. This leads to inclusion of distinct and diverse B cell reactivities in germinal centers. Our findings demonstrate a formidable capacity of B cells to drive the autoreactive response. To better understand the immune landscape of the ‘no-bridge’ and ‘bridge’ chimeras, we leveraged the BD Rhapsody platform to perform linked single-cell Abseq, immune profiling and BCR/TCR analyses. We analyzed total splenocytes from two no-bridge chimeras, and total splenocytes enriched for GC B cells from a bridge chimera.