Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity

Diana Chessman, Lyudmila Kostenko, Tessa Lethborg, Anthony Wayne Purcell, Nicholas A Williamson, Zhenjun Chen, Lars Kjer-Nielsen, Nicole Andrea Mifsud, Brian D Tait, Rhonda Holdsworth, Coral A Almeida, David Nolan, Whitney Alison Macdonald, Julia Kate Archbold, Anthony D Kellerher, Debbie Marriott, Simon Mallal, Mandvi Bharadwaj, Jamie Rossjohn, James McCluskey

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Abstract

The basis for strong immunogenetic associations between particular human leukocyte antigen (HLA) class I allotypes and inflammatory conditions like Behcet 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.
Original languageEnglish
Pages (from-to)822 - 832
Number of pages11
JournalImmunity
Volume28
Issue number6
Publication statusPublished - 2008

Cite this

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. A., Nolan, D., Macdonald, W. A., Archbold, J. K., Kellerher, A. D., Marriott, D., Mallal, S., Bharadwaj, M., Rossjohn, J., & 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), 822 - 832.