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Immune self-reactivity triggered by drug-modified HLA-peptide repertoire (2012)

P. T. Illing ; J. P. Vivian ; N. L. Dudek ; [weitere]

Nature Publishing Group (NPG)

In: Nature. 486(7404): 554-8. doi: 10.1038/nature11147.

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Publikationsdatum: 2012-06-23

Beschreibung: 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-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 hypersensitivities that involve small-molecule drugs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Illing, Patricia T -- Vivian, Julian P -- Dudek, Nadine L -- Kostenko, Lyudmila -- Chen, Zhenjun -- Bharadwaj, Mandvi -- Miles, John J -- Kjer-Nielsen, Lars -- Gras, Stephanie -- Williamson, Nicholas A -- Burrows, Scott R -- Purcell, Anthony W -- Rossjohn, Jamie -- McCluskey, James -- England -- Nature. 2012 Jun 28;486(7404):554-8. doi: 10.1038/nature11147.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology & Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722860" target="_blank"〉PubMed〈/a〉

Schlagwort(e): Antigen Presentation/*drug effects ; Autoimmunity/*drug effects/*immunology ; Binding Sites ; Blood Donors ; CD8-Positive T-Lymphocytes/drug effects/immunology ; Carbamazepine/pharmacology ; Dideoxynucleosides/*pharmacology ; Drug Hypersensitivity ; HLA-B Antigens/chemistry/*immunology ; Humans ; Models, Molecular ; Protein Conformation ; Syndrome ; T-Lymphocytes/*drug effects/*immunology

Print ISSN: 0028-0836

Digitale ISSN: 1476-4687

Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik

Publiziert von Nature Publishing Group (NPG)

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