1. Human Leukocyte Antigen Class I-Restricted Activation of CD8+ T Cells Provides the Immunogenetic Basis of a Systemic Drug Hypersensitivity
- Author
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Chessman, Diana, Kostenko, Lyudmila, Lethborg, Tessa, Purcell, Anthony W., Williamson, Nicholas A., Chen, Zhenjun, Kjer-Nielsen, Lars, Mifsud, Nicole A., Tait, Brian D, Holdsworth, Rhonda, Almeida, Coral Ann, Nolan, David, Macdonald, Whitney A., Archbold, Julia K., Kellerher, Anthony D., Marriott, Debbie, Mallal, Simon, Bharadwaj, Mandvi, Rossjohn, Jamie, and McCluskey, James
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HLA histocompatibility antigens , *T cells , *CARBAMAZEPINE , *SPINE diseases - Abstract
Summary: The basis for strong immunogenetic associations between particular human leukocyte antigen (HLA) class I allotypes and inflammatory conditions like Behçet''s disease (HLA-B51) and ankylosing spondylitis (HLA-B27) remain mysterious. Recently, however, even stronger HLA associations are reported in drug hypersensitivities to the reverse-transcriptase inhibitor abacavir (HLA-B57), the gout prophylactic allopurinol (HLA-B58), and the antiepileptic carbamazepine (HLA-B∗1502), providing a defined disease trigger and suggesting a general mechanism for these associations. We show that systemic reactions to abacavir were driven by drug-specific activation of cytokine-producing, cytotoxic CD8+ T cells. Recognition of abacavir required the transporter associated with antigen presentation and tapasin, was fixation sensitive, and was uniquely restricted by HLA-B∗5701 and not closely related HLA allotypes with polymorphisms in the antigen-binding cleft. Hence, the strong association of HLA-B∗5701 with abacavir hypersensitivity reflects specificity through creation of a unique ligand as well as HLA-restricted antigen presentation, suggesting a basis for the strong HLA class I-association with certain inflammatory disorders. [Copyright &y& Elsevier]
- Published
- 2008
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