Why can sensitization by an HLA-DR2 mismatch lead to antibodies that react also with HLA-DR1?

HLAMatchmaker is a matching algorithm that can be used to characterize antibodies specific for structurally defined epitopes. Under the auspices of the 15(th) International Histocompatibility Workshop, we are conducting a multilaboratory collaborative project to characterize these epitopes and also to determine how often they induce specific antibodies in patients with rejected kidney transplants. This report addresses the reactivity of post-allograft nephrectomy sera tested for DRB antibodies with Luminex assays using single alleles. This analysis was performed for 19 informative kidney transplant cases contributed by 13 laboratories worldwide. There were 11 cases with a single DR2 mismatch (DR15 or DR16), and nine of them (82%) showed antibodies with both DR2 and DR1. Although these antigens might share an epitope recognized by these antibodies, this interpretation is incorrect. The HLAMatchmaker analysis offers a clearly different explanation that involves antibodies induced by DR51, which commonly associates with DR2. DR51 has an epitope defined by the 96EV eplet, which is also present on DR1 but no other DR antigen. This means that the reactivity with DR51 and DR1 reflects the presence of 96EV-specific antibodies. Conversely, we analyzed eight patients sensitized by a single DR1 mismatch that has no associated DR51. All of these patients reacted also with DR51, and this could be explained only by antibodies against the shared 96EV eplet. These findings demonstrate that 96EV represents a highly immunogenic epitope that can induce cross-sensitization between antigens encoded by the different DRB loci, and also that DR51 is important in determining DRB mismatch acceptability of potential donors. This analysis has also demonstrated that antibody responses are restricted to a few epitopes on these immunizing DR antigens. For DR2 they are 142M3 (unique for DR2), 71QAA (shared with DB5*02), and 96QV (shared with DR10). DR51 mismatches appear to have three immunogenic eplets: 96EV (shared with DR1), 108T3 (unique for DR51), and 40HFD (shared with DR9). Immunogenic eplets on DR1 are 12LKF2 (unique for DR1), 14FEH (shared with DR9 and DR10), and 25HRL (shared with DR10).