The structural basis of HLA‐associated drug hypersensitivity syndromes

YA Pompeu, JD Stewart, S Mallal… - Immunological …, 2012 - Wiley Online Library
YA Pompeu, JD Stewart, S Mallal, E Phillips, B Peters, DA Ostrov
Immunological reviews, 2012Wiley Online Library
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 …
Summary
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.
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