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

Science. 2015 Aug 7;349(6248):606-613. doi: 10.1126/science.aaa4282.

Satoshi Okada ^# ¹ ², Janet G Markle ^# ¹, Elissa K Deenick ^# ³ ⁴, Federico Mele ^# ⁵, Dina Averbuch ^# ⁶, Macarena Lagos ^# ⁷ ⁸, Mohammed Alzahrani ^# ⁹, Saleh Al-Muhsen ^# ⁹ ¹⁰, Rabih Halwani ¹⁰, Cindy S Ma ³ ⁴, Natalie Wong ³ ⁴, Claire Soudais ¹¹, Lauren A Henderson ¹², Hiyam Marzouqa ¹³, Jamal Shamma ¹³, Marcela Gonzalez ⁷ ⁶, Rubén Martinez-Barricarte ¹, Chizuru Okada ¹, Danielle T Avery ³ ⁴, Daniela Latorre ⁵, Caroline Deswarte ¹⁴ ¹⁵, Fabienne Jabot-Hanin ¹⁴ ¹⁵, Egidio Torrado ¹⁶, Jeffrey Fountain ¹⁶, Aziz Belkadi ¹⁴ ¹⁵, Yuval Itan ¹, Bertrand Boisson ¹, Mélanie Migaud ¹⁴ ¹⁵, Cecilia S Lindestam Arlehamn ¹⁷, Alessandro Sette ¹⁷, Sylvain Breton ¹⁸, James McCluskey ¹⁹, Jamie Rossjohn ²⁰ ²¹ ²², Jean-Pierre de Villartay ²³, Despina Moshous ²³ ²⁴, Sophie Hambleton ²⁵, Sylvain Latour ²⁶, Peter D Arkwright ²⁷, Capucine Picard ¹ ¹⁴ ¹⁵ ²⁴ ²⁸, Olivier Lantz ¹¹, Dan Engelhard ⁶, Masao Kobayashi ², Laurent Abel ¹ ¹⁴ ¹⁵, Andrea M Cooper ^# ¹⁶, Luigi D Notarangelo ^# ¹² ²⁹, Stéphanie Boisson-Dupuis ^# ¹ ¹⁴ ¹⁵, Anne Puel ^# ¹ ¹⁴ ¹⁵, Federica Sallusto ^# ⁵ ³⁰, Jacinta Bustamante ^# ¹ ¹⁴ ¹⁵ ²⁸, Stuart G Tangye ^# ³ ⁴, Jean-Laurent Casanova ¹ ¹⁴ ¹⁵ ²⁴ ³¹

Affiliations

1 St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.
2 Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
3 Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
4 St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
5 Institute for Research in Biomedicine, University of Italian Switzerland, Bellinzona, Switzerland.
6 Department of Pediatrics, Hadassah University Hospital, Jerusalem, Israel.
7 Department of Immunology, School of Medicine, Universidad de Valparaíso, Santiago, Chile.
8 Department of Pediatrics, Padre Hurtado Hospital and Clinica Alemana, Santiago, Chile.
9 Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
10 Department of Pediatrics, Prince Naif Center for Immunology Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
11 Institut Curie, INSERM U932, Paris, France.
12 Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA.
13 Caritas Baby Hospital, Post Office Box 11535, Jerusalem, Israel.
14 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France.
15 Paris Descartes University, Imagine Institute, Paris, France.
16 Trudeau Institute, Saranac Lake, NY 12983, USA.
17 La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
18 Department of Radiology, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Hospital for Sick Children, Paris, France.
19 Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia.
20 Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.
21 Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia.
22 Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
23 Laboratoire Dynamique du Génome et Système Immunitaire, INSERM UMR 1163, Université Paris Descartes-Sorbonne Paris Cité, Imagine Institute, Paris, France.
24 Pediatric Hematology-Immunology Unit, AP-HP, Necker Hospital for Sick Children, Paris, France.
25 Institute of Cellular Medicine, Newcastle University and Great North Children's Hospital, Newcastle upon Tyne NE4 6BE, UK.
26 Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Université Paris Descartes-Sorbonne Paris Cité, Imagine Institute, Paris, France.
27 Department of Paediatric Allergy Immunology, University of Manchester, Royal Manchester Children's Hospital, Manchester, UK.
28 Center for the Study of Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, Paris, France.
29 Manton Center for Orphan Disease Research, Children's Hospital, Boston, MA 02115, USA.
30 Center of Medical Immunology, Institute for Research in Biomedicine, University of Italian Switzerland, Bellinzona, Switzerland.
31 Howard Hughes Medical Institute, New York, NY 10065, USA.
# Contributed equally.

PMID: 26160376 DOI: 10.1126/science.aaa4282

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-γ (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, RORγT, or both.

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