title: The structural basis of HLA-associated drug hypersensitivity syndromes.
abstract: Recent data suggest alternative mechanisms that promote human leukocyte antigen (HLA)-associated drug syndromes. Hypersensitive responses have been attributed to drug interactions with HLA molecules, peptides presented by HLA molecules and T-cell antigen receptors. Definition of an increasing number of HLA-associated drug syndromes suggests that polymorphism in the antigen-binding cleft residues influence recognition of specific drugs. Recent data demonstrate that small molecule drugs bind within the antigen-binding cleft of HLA in a manner that alters the repertoire of HLA-bound peptide ligands. This drug recognition mechanism permits presentation of self-peptides to which the host has not been tolerized. This altered repertoire mechanism is analogous to massive polyclonal T-cell responses occurring in mismatched HLA organ transplantation in which the drug in effect creates a novel HLA allele. Alteration of the self-peptide repertoire by HLA-binding small molecules may be the mechanistic basis for a diverse set of deleterious T-cell responses since the antigen-binding cleft has structural features that are compatible with binding drug-like small molecules. Small molecule drugs that bind elements of the trimolecular complex (T-cell receptor, peptide, and HLA) may cause short- and long-term adverse effects by a diverse set of mechanisms.
authors.affiliation: Department of Chemistry, University of Florida, Gainesville, USA.
authors.forename: Yuri A
authors.initials: YA
authors.lastname: Pompeu
authors.forename: Jon D
authors.initials: JD
authors.lastname: Stewart
authors.forename: Simon
authors.initials: S
authors.lastname: Mallal
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Phillips
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
authors.forename: David A
authors.initials: DA
authors.lastname: Ostrov
mesh_terms: D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D001324:Autoantigens / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D001665:Binding Sites; D004342:Drug Hypersensitivity / Q000209:etiology / Q000276:immunology*; D006680:HLA Antigens / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D013577:Syndrome; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015262:Xenobiotics / Q000009:adverse effects / Q000737:chemistry*
chemical_list: D001324:Autoantigens; D006680:HLA Antigens; D008024:Ligands; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D015262:Xenobiotics