The jungle of HLA nomenclature: Why we need a new perspective – epiArt makes it visible

The immune response towards allo-HLA-antigens depends, as already demonstrated, on the HLA repertoire of the recipient and the incompatible epitopes on the donor. However, transplant allocation still focusses on mismatches on the antigen level instead of epitopes, mainly the antibody verified epitopes.

To enhance our understanding of the similarity relations of HLA alleles in terms of amino acid polymorphism and shared epitopes, we mapped epitope amino acid sequences and calculated the pairwise sequence difference between HLA alleles. In particular, we translated amino acid sequences of all currently proven epitopes into a sequence atlas comprising all classical class I and II antigens. These sequences were then transferred into a differential amino acid space, followed by visualization of the pairwise allele distances by means of antigen-specific graphs. They give an overview of relationships of all alleles of the antigen, corresponding similarity/dissimilarity structures, outlier alleles, and alleles with similarity to different antigen groups. Additionally, we calculated prevalence of the different amino acids for each polymorphic sequence position and visualized them in term of stacked bar plots, representing amino acid motif plots of all alleles belonging to an antigen.

Through our visualizations, the complexity of the different allele groups and their cross reactivity becomes graphically represented: We see strongly varying intra-group heterogeneity of the HLA class I and II alleles, as well as joint inter-group and even inter-locus epitopes.

These findings indicate a benefit of epitope-based transplant matching: Single allele mismatches between donor and recipient potentially refer to identical epitopes, or to a set of multiple mismatched epitopes. This data adds a new level of quality to allocation, allowing for the definition of potentially tolerable and of taboo allele mismatches, respectively.

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