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IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations


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 RORgamma and RORgammaT isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from RORgamma- and RORgammaT-deficient individuals also displayed an impaired IFN-gamma response to Mycobacterium. This principally reflected profoundly defective IFN-gamma production by circulating gammadelta T cells and CD4(+)CCR6(+)CXCR3(+) alphabeta T cells. In humans, both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require RORgamma, RORgammaT, or both.

Type Journal
ISBN 1095-9203 (Electronic) 0036-8075 (Linking)
Authors Okada, S.; Markle, J. G.; Deenick, E. K.; Mele, F.; Averbuch, D.; Lagos, M.; Alzahrani, M.; Al-Muhsen, S.; Halwani, R.; Ma, C. S.; Wong, N.; Soudais, C.; Henderson, L. A.; Marzouqa, H.; Shamma, J.; Gonzalez, M.; Martinez-Barricarte, R.; Okada, C.; Avery, D. T.; Latorre, D.; Deswarte, C.; Jabot-Hanin, F.; Torrado, E.; Fountain, J.; Belkadi, A.; Itan, Y.; Boisson, B.; Migaud, M.; Arlehamn, C. S.; Sette, A.; Breton, S.; McCluskey, J.; Rossjohn, J.; de Villartay, J. P.; Moshous, D.; Hambleton, S.; Latour, S.; Arkwright, P. D.; Picard, C.; Lantz, O.; Engelhard, D.; Kobayashi, M.; Abel, L.; Cooper, A. M.; Notarangelo, L. D.; Boisson-Dupuis, S.; Puel, A.; Sallusto, F.; Bustamante, J.; Tangye, S. G.; Casanova, J. L.;
Responsible Garvan Author A/Prof Elissa Deenick
Publisher Name SCIENCE
Published Date 2015-01-01
Published Volume 349
Published Issue 6248
Published Pages 606-13
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version