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Human leukocyte Antigen Class I-restricted activation of CD8+ T Cells provides the immunogenetic basis of a systemic drug hypersensitivity

Chessman, D., Kostenko, L., Lethborg, T., Purcell, A.W., Williamson, N.A., Chen, Z., Kjer-Nielsen, L., Mifsud, N.A., Tait, B.D., Holdsworth, R., Almeida, C.M., Nolan, D., Macdonald, W.A., Archbold, J.K., Kellerher, A.D., Marriott, D., Mallal, S., Bharadwaj, M., Rossjohn, J. and McCluskey, J. (2008) Human leukocyte Antigen Class I-restricted activation of CD8+ T Cells provides the immunogenetic basis of a systemic drug hypersensitivity. Immunity, 28 (6). pp. 822-832.

Link to Published Version: http://dx.doi.org/10.1016/j.immuni.2008.04.020
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Abstract

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.

Publication Type: Journal Article
Murdoch Affiliation: Centre for Clinical Immunology and Biomedical Statistics
Publisher: Cell Press/Elsevier
Copyright: © 2008 Elsevier Inc.
URI: http://researchrepository.murdoch.edu.au/id/eprint/15081
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