Immune self-reactivity triggered by drug-modified HLA-peptide repertoire.
Human leukocyte antigens (HLAs) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T cells. HLA polymorphisms mostly map to the antigen-binding cleft, thereby diversifying the repertoire of self-derived and pathogen-derived peptide antigens selected by different HLA allotypes. A growing number of immunologically based drug reactions, including abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced Stevens-Johnson syndrome (SJS), are associated with specific HLA alleles. However, little is known about the underlying mechanisms of these associations, including AHS, a prototypical HLA-associated drug reaction occurring exclusively in individuals with the common histocompatibility allele HLA-B*57:01, and with a relative risk of more than 1,000 (refs 6, 7). We show that unmodified abacavir binds non-covalently to HLA-B*57:01, lying across the bottom of the antigen-binding cleft and reaching into the F-pocket, where a carboxy-terminal tryptophan typically anchors peptides bound to HLA-B*57:01. Abacavir binds with exquisite specificity to HLA-B*57:01, changing the shape and chemistry of the antigen-binding cleft, thereby altering the repertoire of endogenous peptides that can bind HLA-B*57:01. In this way, abacavir guides the selection of new endogenous peptides, inducing a marked alteration in 'immunological self'. The resultant peptide-centric 'altered self' activates abacavir-specific T-cells, thereby driving polyclonal CD8 T-cell activation and a systemic reaction manifesting as AHS. We also show that carbamazepine, a widely used anti-epileptic drug associated with hypersensitivity reactions in HLA-B*15:02 individuals, binds to this allotype, producing alterations in the repertoire of presented self peptides. Our findings simultaneously highlight the importance of HLA polymorphism in the evolution of pharmacogenomics and provide a general mechanism for some of the growing number of HLA-linked hypersensitivities that involve small-molecule drugs.
Department of Microbiology & Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.
Patricia T
PT
Illing
Julian P
JP
Vivian
Nadine L
NL
Dudek
Lyudmila
L
Kostenko
Zhenjun
Z
Chen
Mandvi
M
Bharadwaj
John J
JJ
Miles
Lars
L
Kjer-Nielsen
Stephanie
S
Gras
Nicholas A
NA
Williamson
Scott R
SR
Burrows
Anthony W
AW
Purcell
Jamie
J
Rossjohn
James
J
McCluskey
D017951:Antigen Presentation / Q000187:drug effects*; D015551:Autoimmunity / Q000187:drug effects* / Q000276:immunology*; D001665:Binding Sites; D001782:Blood Donors; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002220:Carbamazepine / Q000494:pharmacology; D015224:Dideoxynucleosides / Q000494:pharmacology*; D004342:Drug Hypersensitivity; D015235:HLA-B Antigens / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D013577:Syndrome; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D000099227:Abacavir
D002220:Carbamazepine; D015224:Dideoxynucleosides; D015235:HLA-B Antigens; D000099227:Abacavir; C484830:HLA-B*57:01 antigen