Immune self-reactivity triggered by drug-modified HLA-peptide repertoire

The paper describes the mechanism by which small-molecule drugs such as abacavir affect antigen presentation and consequently T-cell response in immunologically based drug reactions such as abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced Stevens–Johnson syndrome (SJS). HLA target in self-immune drug reactions Immunologically based drug reactions, such as abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced Steven–Johnson's syndrome (SJS), have been associated with specific human leukocyte antigen (HLA) alleles. Here the authors describe a mechanism through which these small-molecule drugs affect antigen presentation and consequently the T-cell response. By binding non-covalently to the antigen-binding cleft of HLAB*57:01, abacavir induces changes in the shape and chemistry of this site, and as a result alters the affinity of endogenous peptide to HLA. Ultimately, this leads to the systemic reaction manifesting as AHS. The generality of the mechanism is captured by showing that carbamazepine binds to the allotype HLA-B*15:02 and induces a similar response. Human leukocyte antigens (HLAs) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T cells 1 . 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 2 . 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 3 , 4 , 5 , 6 , 7 . 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 i