The antibody response to an HLA mismatch: a model for nonself-self discrimination in relation to HLA epitope immunogenicity

Antibodies to HLA mismatches are specific for epitopes rather than antigens. HLAMatchmaker considers each HLA antigen as a string of eplets that represent key elements of epitopes. Certain antibodies are specific for single eplets, but recent studies have demonstrated that epitopes defined by eplet pairs always involve one nonself-eplet and a self-eplet shared between the immunizing antigen and the antibody producer. This suggests an autoreactive component of the alloantibody response to an HLA mismatch and this report expands this concept. During B-cell development, VH and VL gene rearrangements produce a diversity of Ig receptors that can recognize epitopes on autologous proteins. It is hypothesized that B cells carry low-affinity receptors for self-HLA antigens. Their interactions with self-HLA proteins will not lead to B-cell activation or antibody production. In contrast, exposure to HLA mismatches induces often strong alloantibody responses. The activation of self-HLA-specific B cell by a nonself-eplet may require that the remainder of the structural epitope of the immunizing antigen has considerable structural similarity with one of the antibody producers alleles. This hypothesis has been tested in molecular modelling studies with six epitopes defined by human monoclonal antibodies. In each case, one allele of the antibody producer had no or few differences with the immunizing allele in antibody-accessible positions defined by a 15 angstrom ngstrom radius of the mismatched eplet. The other alleles of the antibody producer showed significantly greater numbers of residue differences with the immunizer (5.8 +/- 2.0 versus 1.0 +/- 0.6, P < 0.0001). These data support the concept that HLA antibodies originate from B cells with self-HLA immunoglobulin receptors that recognize mismatched eplets as nonself entities on immunizing antigens. The nonselfself paradigm provides a new insight of HLA epitope immunogenicity and may explain why sensitized patients have antibodies to a restricted number of mismatched epitopes.