Correlations between Terasaki's HLA class I epitopes and HLAMatchmaker-defined eplets on HLA-A, -B and -C antigens

Although the determination of human leukocyte antigen (HLA) antibody specificity has traditionally been directed toward HLA antigens, there is now increasing attention to structurally defined HLA epitopes. An understanding of the HLA epitope repertoire is important to acceptable mismatching for sensitized patients and to a new epitope-based matching algorithm aimed to reduce antibody-mediated rejection. There are two strategies to determine the HLA epitope repertoire. Terasaki's group has used an empirical method to analyze the reactivity of single allele Luminex panels with mouse monoclonal antibodies (mAbs) and absorbed/eluted alloantibodies with a computer program based on shared residues in the amino acid sequences of reactive alleles. HLAMatchmaker is a theoretical algorithm that predicts HLA epitopes on the HLA molecular surface from stereochemical modeling of epitope-paratope interfaces of antigen-antibody complexes. Our epitope repertoire is based on so-called 'eplets' representing 3-A patches of at least one polymorphic residue on the molecular surface. A comparative analysis has shown that 81/103 Terasaki's HLA class I epitopes are equivalent to individual eplets (n = 50) or pairs of eplets (n = 31) separated far enough to serve as potential contact sites for two complementarity-determining regions of antibody. An additional 12 Terasaki's epitopes (TerEps) correspond to eplets with permissible residue combinations that do not seem to affect epitope specificity. We could not identify corresponding eplets for the remaining 10 TerEps, including 8 that might be considered xeno-epitopes defined by mouse mAbs. Conversely, HLAMatchmaker has 38 additional eplets in well-exposed surface positions that do not have equivalent TerEps, and for many of them, we have found specific antibodies. These findings strengthen the concept that eplets are essential basic units of HLA epitopes and that they provide a better understanding of HLA immunogenicity (i.e. ability to induce an antibody response) and antigenicity (i.e. reactivity with specific antibody).