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

Lookup NU author(s): Professor Sophie HambletonORCiD

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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.


Publication metadata

Author(s): 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

Publication type: Article

Publication status: Published

Journal: Science

Year: 2015

Volume: 349

Issue: 6248

Pages: 606-613

Print publication date: 07/08/2015

Online publication date: 09/07/2015

Acceptance date: 29/06/2015

ISSN (print): 0036-8075

ISSN (electronic): 1095-9203

Publisher: American Association for the Advancement of Science

URL: http://dx.doi.org/10.1126/science.aaa4282

DOI: 10.1126/science.aaa4282


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Funding

Funder referenceFunder name
INSERM
Rheumatology Research Foundation's Scientist Development Award
Rockefeller University
St. Giles Foundation
Universite Paris Descartes
AXA Research Fund
Canadian Institutes of Health Research
European Molecular Biology Organization
Helmut Horten Foundation
Laboratory of Human Genetics of Infectious Diseases
National Center for Research Resources, NIH
National Health and Medical Research Council (NHMRC)
11-BSV3-005-01French National Research Agency (ANR)
13-ISV3-0001-01French National Research Agency (ANR)
149475Swiss National Science Foundation
25670477Japan Society for the Promotion of Science
25713039Japan Society for the Promotion of Science
323183 PREDICTEuropean Research Council
8UL1TR000043National Center for Advancing Sciences, NIH
ANR-10-IAHU-01French National Research Agency (ANR)
ANR-10-LABX-62-IBEIDLaboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases
HHSN272200900044CNIH
R37AI095983National Institute of Allergy and Infectious Diseases

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