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

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.

• Authors: Diana Chessman, Lyudmila Kostenko, Tessa Lethborg, Anthony W Purcell, Nicholas A Williamson, Zhenjun Chen, Lars Kjer-Nielsen, Nicole A Mifsud, Brian D Tait, Rhonda Holdsworth, Coral Ann Almeida, David Nolan, Whitney A Macdonald, Julia K Archbold, Anthony D Kellerher, Debbie Marriott, Simon Mallal, Mandvi Bharadwaj, Jamie Rossjohn, James McCluskey
• Journal: Immunity (Immunity) Vol. 28 Issue 6 Pg. 822-32 (Jun 2008) ISSN: 1097-4180 [Electronic] United States
• PMID: 18549801 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-HIV Agents
• Dideoxynucleosides
• HLA-B Antigens
• HLA-B*57:01 antigen
• HLA-B*57:03 antigen
• Reverse Transcriptase Inhibitors
• abacavir

Topics

• Anti-HIV Agents (adverse effects, immunology, metabolism)
• Antigen Presentation
• CD8-Positive T-Lymphocytes (immunology)
• Dideoxynucleosides (adverse effects, immunology, metabolism)
• Drug Hypersensitivity (immunology, metabolism)
• HLA-B Antigens (chemistry, immunology, metabolism)
• Humans
• Lymphocyte Activation
• Reverse Transcriptase Inhibitors (adverse effects, immunology, metabolism)