DataSheet1_epiArt: a graphical HLA eplet amino acid repertoire translation reveals the need for an epitope driven revision of allele group nomenclature.PDF

IntroductionThe immune response after transplantation depends on recipient/donor HLA allele mismatches. To enhance our understanding of the relations of HLA alleles in terms of amino-acid polymorphisms and shared epitopes, we assessed pairwise sequence difference between HLA-alleles.
MethodsWe translated amino-acid sequences of confirmed eplets into an atlas of HLA class I and II antigens, followed by visualization of the pairwise allele distances by means of antigen-specific disparity graphs in differential amino-acid space. We obtained an overview of relationships of all alleles of an antigen, corresponding similarity/dissimilarity structures, outliers, alleles with similarity to different antigen groups. Additionally, we calculated prevalence of the amino-acids for each polymorphic sequence position and visualized them in amino-acid motif plots of all alleles belonging to an antigen.
ResultsOur visualizations show strongly varying intra-group heterogeneity of HLA class I and II alleles, as well as shared inter-group and inter-locus eplets and epitopes, indicating a benefit of epitope-based transplant matching: Single allele recipient/donor mismatches potentially refer to identical eplets, or to a set of multiple mismatched eplets.
DiscussionThis data reveals inconsistencies in the HLA group nomenclature and consequently adds a new level of quality to allocation, motivating the definition of tolerable or taboo mismatches.

引言
移植术后的免疫应答取决于受者与供者的人类白细胞抗原（HLA）等位基因错配情况。为加深对人类白细胞抗原等位基因间基于氨基酸多态性与共有表位的关联的理解，本研究评估了HLA等位基因间的成对序列差异。

方法
本研究将已验证的表位单元（eplet）的氨基酸序列构建为HLA I类与II类抗原图谱，随后借助差异氨基酸空间内的抗原特异性差异图谱，实现等位基因间成对距离的可视化展示。本研究得以全面掌握某一抗原的所有等位基因间的关联关系、对应的相似/非相似结构、异常等位基因，以及与不同抗原组具有相似性的等位基因。此外，本研究计算了每个多态性序列位点的氨基酸出现频率，并针对某一抗原的所有等位基因，在氨基酸基序图中对其进行可视化呈现。

结果
本研究的可视化结果显示，HLA I类与II类等位基因的组内异质性差异显著，同时存在共享的组间与基因座间表位单元及表位，这表明基于表位的移植配型具有应用优势：受者与供者间的单等位基因错配，可能对应完全一致的表位单元，或是多组错配的表位单元集合。

讨论
本数据集揭示了HLA组命名法中存在的不一致性，由此为移植供体分配工作带来了更高的质量标准，同时推动了可耐受错配与禁忌错配的定义确立。