Alloreactivity and autoreactivity converge to support B cell epitope targeting in transplant rejection.

Antibody (Ab) responses against human leukocyte antigen (HLA) proteins mismatched between donor and recipient are leading cause of allograft loss in kidney transplantation. However, therapies targeting alloreactive B cell and Ab-secreting cell (ASC) are lacking, motivating the need to understand how to prevent and abrogate these alloresponses. Using molecular, structural, and proteomic techniques, we profiled the B cell response in a kidney transplant recipient with antibody-mediated rejection and graft loss. We found that this response spanned the rejected organ and peripheral blood, stimulated the differentiation of multiple B cell subsets, and produced a high-affinity, donor-specific, anti-HLA response. We found epitopic immunodominance that relied on highly exposed, solvent-accessible mismatched HLA residues as well as structural and biomolecular evidence of autoreactivity against the recipient's self-HLA allele. These alloreactive and autoreactive signatures converged in the recipient's circulating donor-specific Ab repertoire, suggesting that rejection requires both the recognition of non-self and breaches of tolerance to lead to alloinjury and graft loss.