Topography of the HLA-A protein enforces shared and convergent immunodominant B cell and antibody alloresponses in transplant recipients

Donor-specific antibody responses against human leukocyte antigen (HLA) proteins mismatched between transplant donors and recipients cause allograft loss, yet the structural HLA epitopes targeted by alloreactive B cells and antibodies remain largely unresolved. We profiled the HLA-A^∗01:01-specific B cell response in the transplanted kidney and blood of a recipient undergoing antibody-mediated rejection and identified immunodominant B cell and antibody responses that emerged early in the alloimmune response. These responses were focused on topographically exposed mismatched HLA residues located in the α helices along the peptide-binding groove of HLA-A^∗01:01. We demonstrated that the anti-HLA-A^∗01:01 B cell alloresponse converged and was maintained on this same immunodominant HLA subregion, which comprises only 20% of the HLA molecule, in a diverse group of HLA-A^∗01:01-mismatched transplant recipients. Thus, the B cell and antibody alloresponses appear tightly focused on a topographically defined region on the HLA-A^∗01:01 crown that is conserved across individuals expressing distinct constellations of self-HLA-A.