Abstract
Among patients treated with the anticonvulsive and psychotropic drug carbamazepine (CBZ), approximately 10% develop severe and life-threatening adverse drug reactions. These immunological conditions are resolved upon withdrawal of the medicament, suggesting that the drug does not manifest in the body in long term. The HLA allele B∗15:02 has been described to be a genomic biomarker for CBZ-mediated immune reactions. It is not well understood if the immune reactions are triggered by the original drug or by its metabolite carbamazepine-10,11-epoxide (EPX) and how the interaction between the drug and the distinct HLA molecule occurs. Genetically engineered human B-lymphoblastoid cells expressing soluble HLA-B∗15:02 molecules were treated with the drug or its metabolite. Functional pHLA complexes were purified; peptides were eluted and sequenced. Applying mass spectrometric analysis, CBZ and EPX were monitored by analyzing the heavy chain and peptide fractions separately for the presence of the drug. This method enabled the detection of the drug in a biological situation post-pHLA assembly. Both drugs were bound to the HLA-B∗15:02 heavy chain; however, solely EPX altered the peptide-binding motif of B∗15:02-restricted peptides. This observation could be explained through structural insight; EPX binds to the peptide-binding region and alters the biochemical features of the F pocket and thus the peptide motif. Understanding the nature of immunogenic interactions between CBZ and EPX with the HLA immune complex will guide towards effective and safe medications.
Highlights
The highly polymorphic human leukocyte antigen (HLA) system plays a central role within self-/non-self-recognition in adaptive immune responses through the presentation of peptides originating from self or pathogenic sources
Amino acid adverse drug reactions (ADRs) (AA) length of peptides presented by HLA-B∗15:02 is similar to other HLA class I molecules
Since severe CBZ-mediated ADRs are associated with the HLA allele B∗15:02, but the molecular mechanism still remains unclear, we aimed to compare the impact of CBZ and its main metabolite EPX on peptide presentation of B∗ 15:02
Summary
The highly polymorphic human leukocyte antigen (HLA) system plays a central role within self-/non-self-recognition in adaptive immune responses through the presentation of peptides originating from self or pathogenic sources. The peptide-binding region (PBR) of an HLA molecule can be subdivided into compartments of distinct amino acids (AAs) designated as pockets, where each pocket binds distinct AA side chains of a given peptide [1]. This dynamic binding between HLA pockets and peptides results in HLA allele-specific peptidebinding motifs, determining the pool of bound peptides. Certain HLA class I alleles are associated with hypersensitive reactions to drugs [5]. ADRs are defined as unintended and harmful reactions to drugs. They arise despite appropriate application, such as standard dosage, adequate route of administration, and usual range of application (WHO, 1972). The enormous relevance to assess the mechanisms of currently unpredictable ADRs becomes obvious
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