Functional and structural characteristics of HLA-B*13:01-mediated specific T cells reaction in dapsone-induced drug hypersensitivity.
J Biomed Sci
; 29(1): 58, 2022 Aug 13.
Article
em En
| MEDLINE
| ID: mdl-35964029
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*1301 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*1301-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*1301 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*1301-beta-2-microglobulin (ß2M) complex at 1.5 Å resolution and performed mutation assays demonstrating that I118 or I119, and R121 of HLA-B*1301 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*1301-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*1301, DDS and the clonotype-specific TCR in DDS-DIHS.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Dapsona
/
Hipersensibilidade a Drogas
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article