Severe cutaneous adverse drug reactionsare life-threatening diseases,which are associated with human leukocyte antigenrisk variants.However,the low positive predictive values of HLA variants suggest additional factors influence disease susceptibility.Using dapsone hypersensitivity syndromeas a paradigm for SCARs,we show that the DHS patients harbor a sex-related global reduction in blood NK cells,contributing to the higher incidence of reactions in females.Single-cell RNA sequencing revealed a d...更多
Severe cutaneous adverse drug reactionsare life-threatening diseases,which are associated with human leukocyte antigenrisk variants.However,the low positive predictive values of HLA variants suggest additional factors influence disease susceptibility.Using dapsone hypersensitivity syndromeas a paradigm for SCARs,we show that the DHS patients harbor a sex-related global reduction in blood NK cells,contributing to the higher incidence of reactions in females.Single-cell RNA sequencing revealed a decrease in the immunoregulatory CD56low XCL1/2low NK cell subset and an expansion of CD56high XCL1/2high NK cell subsets with an effector phenotype in DHS patients compared to dapsone-tolerant individuals.Functionally,interleukin-15 superagonist-induced activation of NK cells exacerbated SCARs-like symptoms in a murine model.Mechanistically,TSC22 domain family member 3deficiency enhanced NK cell effector function,shifting the immune response from CD4+T cell to CD8+T cell function.These results demonstrate that TSC22D3-regulated NK cells play a critical role in predisposing to drug hypersensitivity reactions,bridging innate and adaptive immune dysregulation in SCARs pathogenesis.Our study highlights the importance of NK cell heterogeneity and TSC22D3 in immune-mediated hypersensitivity disorders,offering potential therapeutic targets for SCARs and related conditions.收起
