IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations.
IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations.
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DOI：
10.1126/science.aaa4282
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发表时间：
2015-08-07
期刊：
影响因子：
--
通讯作者：
Casanova JL
中科院分区：
文献类型：
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作者：
Okada S;Markle JG;Deenick EK;Mele F;Averbuch D;Lagos M;Alzahrani M;Al-Muhsen S;Halwani R;Ma CS;Wong N;Soudais C;Henderson LA;Marzouqa H;Shamma J;Gonzalez M;Martinez-Barricarte R;Okada C;Avery DT;Latorre D;Deswarte C;Jabot-Hanin F;Torrado E;Fountain J;Belkadi A;Itan Y;Boisson B;Migaud M;Arlehamn CSL;Sette A;Breton S;McCluskey J;Rossjohn J;de Villartay JP;Moshous D;Hambleton S;Latour S;Arkwright PD;Picard C;Lantz O;Engelhard D;Kobayashi M;Abel L;Cooper AM;Notarangelo LD;Boisson-Dupuis S;Puel A;Sallusto F;Bustamante J;Tangye SG;Casanova JL
由白细胞介素(IL)-17A/F细胞因子介导的人类先天性免疫错误是皮肤粘膜念珠菌病的基础，而干扰素(IFN)-γ免疫的先天性错误是分枝杆菌病的基础。我们报告了来自三种不同种族的7个患有念珠菌病和分枝杆菌病的个体的双等位基因RORC功能丧失突变的发现。在这些个体中，功能性RORγ和RORγT亚型的缺乏导致了IL-17A/ f生成T细胞的缺失，这可能是他们慢性念珠菌病的原因。出乎意料的是，来自RORγ-和RORγ t缺陷个体的白细胞也表现出对分枝杆菌的IFN-γ反应受损。这主要反映了循环中的γδ T细胞和CD4+CCR6+ CXCR3+ αβ T细胞产生IFN-γ的严重缺陷。在人类中，对念珠菌的粘膜免疫和对分枝杆菌的全身免疫都需要RORγ或RORγ t，或两者兼而有之。
Human inborn errors of immunity mediated by the cytokines interleukin (IL)-17A/F underlie mucocutaneous candidiasis, whereas inborn errors of interferon (IFN)-γ immunity underlie mycobacterial disease. We report the discovery of bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origins with both candidiasis and mycobacteriosis. The lack of functional RORγ and RORγT isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from RORγ- and RORγT-deficient individuals also displayed an impaired IFN-γ response to Mycobacterium. This principally reflected profoundly defective IFN-γ production by circulating γδ T cells and CD4+CCR6+ CXCR3+ αβ T cells. In humans, both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require RORγ, or RORγT, or both.