The structural basis of HLA-associated drug hypersensitivity syndromes.

Pompeu YA, Stewart JD, Mallal S, Phillips E, Peters B, Ostrov DA
Immunol Rev. 2012 250 (1): 158-66

PMID: 23046128 · DOI:10.1111/j.1600-065X.2012.01163.x

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.

© 2012 John Wiley & Sons A/S.

MeSH Terms (15)

Antigen-Presenting Cells Autoantigens Binding Sites Drug Hypersensitivity HLA Antigens Humans Ligands Models, Molecular Peptides Protein Binding Protein Conformation Receptors, Antigen, T-Cell Syndrome T-Lymphocytes Xenobiotics

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