Human inborn errors of immunity mediated by the cytokines interleukin-17A and interleukin-17F (IL-17A/F) underlie mucocutaneous candidiasis, whereas inborn errors of interferon-gamma (IFN-gamma) 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 ROR gamma and ROR gamma T isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from ROR gamma- and ROR gamma T-deficient individuals also displayed an impaired IFN-gamma response to Mycobacterium. This principally reflected profoundly defective IFN-gamma production by circulating gamma delta T cells and CD4+CCR6+CXCR3+ alpha beta T cells. In humans, both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require ROR gamma, ROR gamma T, or both.
Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations / 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. - In: SCIENCE. - ISSN 0036-8075. - 349:6248(2015), pp. 606-613. [10.1126/science.aaa4282]
Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations
Latorre D;
2015-01-01
Abstract
Human inborn errors of immunity mediated by the cytokines interleukin-17A and interleukin-17F (IL-17A/F) underlie mucocutaneous candidiasis, whereas inborn errors of interferon-gamma (IFN-gamma) 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 ROR gamma and ROR gamma T isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from ROR gamma- and ROR gamma T-deficient individuals also displayed an impaired IFN-gamma response to Mycobacterium. This principally reflected profoundly defective IFN-gamma production by circulating gamma delta T cells and CD4+CCR6+CXCR3+ alpha beta T cells. In humans, both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require ROR gamma, ROR gamma T, or both.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
