Functional and structural characteristics of HLA-B*13:01-mediated specific T cells reaction in dapsone-induced drug hypersensitivity

Abstract

Background Severe cutaneous adverse drug reactions (SCARs) are a group of serious clinical conditions caused by immune reaction to certain drugs. The allelic variance of human leukocyte antigens of HLA-B*13:01 has been strongly associated with hypersensitivities induced by dapsone (DDS). T-cell receptor mediated activation of cytotoxic T lymphocytes (CTLs) has also been suggested to play an essential role in pathogenesis of SCARs. However, HLA-B*13:01-DDS-TCR immune synapse that plays role in drug-induced hypersensitivity syndrome (DIHS) associated T cells activation remains uncharacterized. Methods To investigate the molecular mechanisms for HLA-B*13:01 in the pathogenesis of Dapsone-induced drug hypersensitivity (DDS-DIHS), we performed crystallization and expanded drug-specific CTLs to analyze the pathological role of DDS-DIHS. Results Results showed the crystal structure of HLA-B*13:01-beta-2-microglobulin (β2M) complex at 1.5 Å resolution and performed mutation assays demonstrating that I118 or I119, and R121 of HLA-B*13:01 were the key residues that mediate the binding of DDS. Subsequent single-cell TCR and RNA sequencing indicated that TCRs composed of paired TRAV12-3/TRBV28 clonotype with shared CDR3 region specifically recognize HLA-B*13:01-DDS complex to trigger inflammatory cytokines associated with DDS-DIHS. Conclusion Our study identified the novel p-i-HLA/TCR as the model of interaction between HLA-B*13:01, DDS and the clonotype-specific TCR in DDS-DIHS. Graphical Abstract

Advances in understanding of the pathogenesis and therapeutic implications of drug reaction with eosinophilia and systemic symptoms: an updated review

“…No intracellular antigen processing was involved in the HLA presentation of carbamazepine ( 77 ). Similar interaction was also seen in the hypersensitivity reaction induced by dapsone ( 78 ). The concept of the altered peptide repertoire model was demonstrated in the case of abacavir hypersensitivity syndrome in HLA-B*57:01-positive individuals ( 79 – 81 ).…”

An association study of HLA with levofloxacin-induced severe cutaneous adverse drug reactions in Han Chinese

“…In the present study, we identified that LEV could hydrophobically bind to the A-E subpocket of the antigen-binding groove in HLA-B∗13:01, while dapsone and salazosulfapyridine have been reported to bind toward the F pocket of the same groove. 25 , 26 , 27 , 28 The differences in binding site may be attributed to their different chemical scaffolds. LEV has a bigger structure compared to dapsone and salazosulfapyridine, which was not suitable in the narrow F pocket and, therefore, favorably located in the larger cleft consisting of A-E pocket.…”

“…demonstrated that three different amino acids in the antigen-binding site (I94, I95, and R97 in HLA-B∗13:01, and T94, W95, and T97 in HLA-B∗13:02) played important roles in dapsone selectivity through creating steric hindrance, changing van der Waals interactions and affecting the electrostatic properties of the dapsone-binding pocket. 26 …”

Current understanding of genetic associations with delayed hypersensitivity reactions induced by antibiotics and anti-osteoporotic drugs

“… Zhao et al (2021) investigated that dapsone and its metabolite nitroso-dapsone are selectively interacted with HLA-B*13:01 to activate CTLs related cytotoxicity. Recently, Jiang et al (2022) demonstrated that HLA-B*13:01-dapsone-TCR immune molecular mechanism is formed according to pharmacological-interaction model.…”