Carbamazepine-modified HLA-A*24:02-bound peptidome: Implication of CORO1A in skin rash.

BACKGROUND

Previous studies have demonstrated that human leukocyte antigen (HLA)-A*24:02 is a common genetic risk factor for antiepileptic drug-induced skin rash, while HLA-B*15:02 is a specific risk factor for carbamazepine (CBZ)-induced Stevens Johnson syndrome and toxin epidermal necrolysis. The HLA-B*15:02 allele can alter the repertoire of endogenous peptides to trigger CBZ-induced hypersensitivity. However, it is uncertain whether HLA-A*24:02 could produce alterations in the peptide repertoire during treatment with antiepileptic drugs.

METHODS

We generated stable HMy2.C1R cells expressing HLA-A*24:02 and HLA-B*15:02, clarified into 4 groups according to with or without CBZ treatment. We employed LC/MSto detect the HLA-bound peptides in 4 groups. Furthermore, we conducted in silico analysis to seek th differential expressed genes (DEGs) associated with HLA-A*24:02 and HLA-B*15:02. Finally, we verify the DEGs via qRT-PCR and Western blotting.

RESULTS

A total of 134 peptides were identified from the four groups, mainly comprising<15 mer peptides. In CBZ-treated groups, 29 and 30 peptides showed significantly increased respectively in HLA-A*24:02 and HLA-B*15:02 positive cells comprising Lysine in PΩ, but the sources of these lysine peptides are different. Three peptides were exclusively detected in the HLA-A*24:02 positive cells treated with CBZ, of which 'SRQVVRSSK' was derived from the immune associated protein coronin 1A (CORO1A). CORO1A and its mRNA were significantly expressed in HLA-A*24:02 positive cells treated with CBZ. Additionally, this significantly high expression was identified in HLA-A*24:02 positive cells that were treated with lamotrigine (LTG). Nonetheless, CORO1A were not decreased in HLA-B*15:02 positive cells with or without CBZ or LTG treatment.

CONCLUSIONS

These findings confirmed that the alteration in the endogenous peptidome was a general mechanism of HLA-linked skin rashes and suggests that CORO1A is involved in HLA-A*24:02-associated skin rash.