- Erratum in:
- Immunity. 2008 Jul;29(1):165.
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 AW,
Williamson NA,
Chen Z,
Kjer-Nielsen L,
Mifsud NA,
Tait BD,
Holdsworth R,
Almeida CA,
Nolan D,
Macdonald WA,
Archbold JK,
Kellerher AD,
Marriott D,
Mallal S,
Bharadwaj M,
Rossjohn J,
McCluskey J.
Department of Microbiology & Immunology, The University of Melbourne, Parkville, Victoria 3010, Australia.
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.
PMID: 18549801 [PubMed - indexed for MEDLINE]