Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity.
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.
Department of Microbiology & Immunology, The University of Melbourne, Parkville, Victoria 3010, Australia.
Diana
D
Chessman
Lyudmila
L
Kostenko
Tessa
T
Lethborg
Anthony W
AW
Purcell
Nicholas A
NA
Williamson
Zhenjun
Z
Chen
Lars
L
Kjer-Nielsen
Nicole A
NA
Mifsud
Brian D
BD
Tait
Rhonda
R
Holdsworth
Coral Ann
CA
Almeida
David
D
Nolan
Whitney A
WA
Macdonald
Julia K
JK
Archbold
Anthony D
AD
Kellerher
Debbie
D
Marriott
Simon
S
Mallal
Mandvi
M
Bharadwaj
Jamie
J
Rossjohn
James
J
McCluskey
D019380:Anti-HIV Agents / Q000009:adverse effects / Q000276:immunology / Q000378:metabolism; D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015224:Dideoxynucleosides / Q000009:adverse effects* / Q000276:immunology / Q000378:metabolism; D004342:Drug Hypersensitivity / Q000276:immunology* / Q000378:metabolism; D015235:HLA-B Antigens / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects* / Q000276:immunology / Q000378:metabolism; D000099227:Abacavir
D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D015235:HLA-B Antigens; D018894:Reverse Transcriptase Inhibitors; D000099227:Abacavir; C484830:HLA-B*57:01 antigen; C496219:HLA-B*57:03 antigen