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

Satoshi Okada; Janet G Markle; Elissa K Deenick; Federico Mele; Dina Averbuch; Macarena Lagos; Mohammed Alzahrani; Saleh Al-Muhsen; Rabih Halwani; Cindy S Ma; Natalie Wong; Claire Soudais; Lauren A Henderson; Hiyam Marzouqa; Jamal Shamma; Marcela Gonzalez; Rubén Martinez-Barricarte; Chizuru Okada; Danielle T Avery; Daniela Latorre; Caroline Deswarte; Fabienne Jabot-Hanin; Egidio Torrado; Jeffrey Fountain; Aziz Belkadi; Yuval Itan; Bertrand Boisson; Mélanie Migaud; Cecilia S Lindestam Arlehamn; Alessandro Sette; Sylvain Breton; James McCluskey; Jamie Rossjohn; Jean-Pierre de Villartay; Despina Moshous; Sophie Hambleton; Sylvain Latour; Peter D Arkwright; Capucine Picard; Olivier Lantz; Dan Engelhard; Masao Kobayashi; Laurent Abel; Andrea M Cooper; Luigi D Notarangelo; Stéphanie Boisson-Dupuis; Anne Puel; Federica Sallusto; Jacinta Bustamante; Stuart G Tangye; Jean-Laurent Casanova

doi:10.1126/science.aaa4282

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. Epub 2015 Jul 9.

Authors

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 Halwani¹⁰, Cindy S Ma^{3

4}, Natalie Wong^{3

4}, Claire Soudais¹¹, Lauren A Henderson¹², Hiyam Marzouqa¹³, Jamal Shamma¹³, Marcela Gonzalez^{7

6}, Rubén Martinez-Barricarte¹, Chizuru Okada¹, Danielle T Avery^{3

4}, Daniela Latorre⁵, Caroline Deswarte^{14

15}, Fabienne Jabot-Hanin^{14

15}, Egidio Torrado¹⁶, Jeffrey Fountain¹⁶, Aziz Belkadi^{14

15}, Yuval Itan¹, Bertrand Boisson¹, Mélanie Migaud^{14

15}, Cecilia S Lindestam Arlehamn¹⁷, Alessandro Sette¹⁷, Sylvain Breton¹⁸, James McCluskey¹⁹, Jamie Rossjohn^{20

21

22}, Jean-Pierre de Villartay²³, Despina Moshous^{23

24}, Sophie Hambleton²⁵, Sylvain Latour²⁶, Peter D Arkwright²⁷, Capucine Picard^{1

14

15

24

28}, Olivier Lantz¹¹, Dan Engelhard⁶, Masao Kobayashi², 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Animals
Candida albicans / immunology*
Candidiasis, Chronic Mucocutaneous / complications
Candidiasis, Chronic Mucocutaneous / genetics*
Candidiasis, Chronic Mucocutaneous / immunology
Cattle
Child
Child, Preschool
DNA Mutational Analysis
Exome / genetics
Female
Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor
Humans
Immunity / genetics*
Interferon-gamma / immunology
Interleukin-17 / immunology
Mice
Mutation
Mycobacterium bovis / immunology
Mycobacterium bovis / isolation & purification
Mycobacterium tuberculosis / immunology
Mycobacterium tuberculosis / isolation & purification
Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics*
Pedigree
Receptors, Antigen, T-Cell, alpha-beta / genetics
Receptors, Antigen, T-Cell, alpha-beta / immunology
Receptors, Antigen, T-Cell, gamma-delta / genetics
Receptors, Antigen, T-Cell, gamma-delta / immunology
Severe Combined Immunodeficiency / genetics*
T-Lymphocytes / immunology
Thymus Gland / abnormalities
Thymus Gland / immunology
Tuberculosis, Bovine / genetics*
Tuberculosis, Bovine / immunology
Tuberculosis, Pulmonary / genetics*
Tuberculosis, Pulmonary / immunology

Substances

Interleukin-17
Nuclear Receptor Subfamily 1, Group F, Member 3
RORC protein, human
Receptors, Antigen, T-Cell, alpha-beta
Receptors, Antigen, T-Cell, gamma-delta
Interferon-gamma

Abstract

Publication types

MeSH terms

Substances

Grants and funding