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

机译：药物修饰的HLA肽库触发的免疫自反应

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摘要

基于免疫的药物反应，如“阿巴卡韦超敏反应综合症”(AHS)和“卡马西平”一诱导的“Steven_Johnson综合症”(SJS)，已被与特定的“人白细胞抗原”(HLA)等位基因联系起来。本文作者介绍了一个机制，这些小分子药物通过该机制影响抗原呈现、进而影响T．细胞反应。通过以非共价方式与HLAB*57：01的“抗原结合缝”相结合，“阿巴卡韦”诱导这个点的形状和化学性质发生变化，因而改变内生肽对HLA的亲和性。最终，这将导致表现为AHS的系统性反应。研究人员发现，“卡马西平”也能与异形HLA-B*5：02结合、诱导个类似的反应，这说明该机制具有普遍性。%Human leukocyte antigens (HLAs) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T cells. 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 allotypes. 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 (refs 6,7). We show that unmodified abacavir binds non-covalently to HLA-B57:01, 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-B57:01. Abacavir binds with exquisite specificity to HLA-B57:01, 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 hyper-sensitivities that involve small-molecule drugs.
机译：基于免疫的药物反应，如“阿巴卡韦超敏反应综合症”(AHS)和“卡马西平”一诱导的“Steven_Johnson综合症”(SJS)，已被与特定的“人白细胞抗原”(HLA)等位基因联系起来。本文作者介绍了一个机制，这些小分子药物通过该机制影响抗原呈现、进而影响T．细胞反应。通过以非共价方式与HLAB*57：01的“抗原结合缝”相结合，“阿巴卡韦”诱导这个点的形状和化学性质发生变化，因而改变内生肽对HLA的亲和性。最终，这将导致表现为AHS的系统性反应。研究人员发现，“卡马西平”也能与异形HLA-B*5：02结合、诱导个类似的反应，这说明该机制具有普遍性。%Human leukocyte antigens (HLAs) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T cells. 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 allotypes. 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 (refs 6,7). We show that unmodified abacavir binds non-covalently to HLA-B57:01, 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-B57:01. Abacavir binds with exquisite specificity to HLA-B57:01, 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 hyper-sensitivities that involve small-molecule drugs.

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  • 来源
    《Nature》 |2012年第7404期|p.554-558a2|共6页
  • 作者

    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;

  • 作者单位

    Department of Microbiology & Immunology, University of Melbourne, Parkville, Victoria 3010, Australia,Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, Un iversity of Melbourne, Parkville, Victoria 3010, Australia;

    Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia;

    Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia;

    Department of Microbiology & Immunology, University of Melbourne, Parkville, Victoria 3010, Australia;

    Department of Microbiology & Immunology, University of Melbourne, Parkville, Victoria 3010, Australia;

    Department of Microbiology & Immunology, University of Melbourne, Parkville, Victoria 3010, Australia;

    Queensland Institute of Medical Research and Australian Centre for Vaccine Development, Brisbane, Queensland 4029, Australia,Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK;

    Department of Microbiology & Immunology, University of Melbourne, Parkville, Victoria 3010, Australia;

    Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia;

    Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, Un iversity of Melbourne, Parkville, Victoria 3010, Australia;

    Queensland Institute of Medical Research and Australian Centre for Vaccine Development, Brisbane, Queensland 4029, Australia;

    Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, Un iversity of Melbourne, Parkville, Victoria 3010, Australia;

    Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia,Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK;

    Department of Microbiology & Immunology, University of Melbourne, Parkville, Victoria 3010, Australia,Victorian Transplantation and Immunogenetics Service, Australian Red Cross Blood Service, 100-154 Batman Street, West Melbourne. Victoria 3003, Australia;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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