Nature：HLA多态性在药物基因组学中的重要性

2012年5月23日，Nature在线发表了澳大利亚墨尔本大学微生物学与免疫学部Jim McCluskey教授课题组等的一篇题为Immune self-reactivity triggered by drug-modified HLA-peptide repertoire的科研论文，研究发现了人类白细胞抗原（HLA）多态性在药物基因组学中的重要性。

人类白细胞抗原（HLAs）有很高的多态性。阿巴卡韦超敏反应综合症（AHS）和药疹病人综合症（SJS）等的药物反应与特异的HLAs等位基因有关，然而我们对其关联的潜在机制知道的还很少。

阿巴卡韦（Abacavir）与组织相容性等位基因HLA-B*57：01非共价连接，改变了抗原结合槽（antigen-binding cleft）的形状和化学特性，因此改变了内源肽结合HLA-B*57：01的能力。通过这种方式，阿巴卡韦引导选择新的内源肽，导致免疫反应的显著变化。

这些发现突出了人类白细胞抗原（HLA）多态性在药物基因组学中的重要性。

doi：10.1038/nature11147

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Immune self-reactivity triggered by drug-modified HLA-peptide repertoire

Patricia T. Illing，Julian P. Vivian，Nadine L. Dudek，Lyudmila Kostenko，Zhenjun Chen，Mandvi Bharadwaj，John J. Miles，Lars Kjer-Nielsen，  Stephanie Gras，Nicholas A. Williamson，Scott R. Burrows，Anthony W. Purcell，Jamie Rossjohn & James McCluskey

Human leukocyte antigens (HLAs) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T？cells1. HLA polymorphisms mostly map to the antigen-binding cleft， thereby diversifying the repertoire of self-derived and pathogen-derived peptide antigens selected by different HLA allotypes2. A growing number of immunologically based drug reactions， including abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced Stevens–Johnson syndrome (SJS)， are associated with specific HLA alleles. However， little is known about the underlying mechanisms of these associations， including AHS， a prototypical HLA-associated drug reaction occurring exclusively in individuals with the common histocompatibility allele HLA-B*57：01， and with a relative risk of more than 1，000 . We show that unmodified abacavir binds non-covalently to HLA-B*57：01， lying across the bottom of the antigen-binding cleft and reaching into the F-pocket， where a carboxy-terminal tryptophan typically anchors peptides bound to HLA-B*57：01. Abacavir binds with exquisite specificity to HLA-B*57：01， changing the shape and chemistry of the antigen-binding cleft， thereby altering the repertoire of endogenous peptides that can bind HLA-B*57：01. In this way， abacavir guides the selection of new endogenous peptides， inducing a marked alteration in ‘immunological self’. The resultant peptide-centric ‘altered self’ activates abacavir-specific T-cells， thereby driving polyclonal CD8 T-cell activation and a systemic reaction manifesting as AHS. We also show that carbamazepine， a widely used anti-epileptic drug associated with hypersensitivity reactions in HLA-B*15：02 individuals， binds to this allotype， producing alterations in the repertoire of presented self peptides. Our findings simultaneously highlight the importance of HLA polymorphism in the evolution of pharmacogenomics and provide a general mechanism for some of the growing number of HLA-linked