2. Academic Validation
  3. Human IFNAR2 deficiency: Lessons for antiviral immunity

Human IFNAR2 deficiency: Lessons for antiviral immunity

  • Sci Transl Med. 2015 Sep 30;7(307):307ra154. doi: 10.1126/scitranslmed.aac4227.
Christopher J A Duncan 1,  Siti M B Mohamad 2,  Dan F Young 3,  Andrew J Skelton 4,  T Ronan Leahy 5,  Diane C Munday 3,  Karina M Butler 5,  Sofia Morfopoulou 6,  Julianne R Brown 7,  Mike Hubank 8,  Jeff Connell 9,  Patrick J Gavin 5,  Cathy McMahon 10,  Eugene Dempsey 11,  Niamh E Lynch 12,  Thomas S Jacques 13,  Manoj Valappil 14,  Andrew J Cant 15,  Judith Breuer 16,  Karin R Engelhardt 17,  Richard E Randall 3,  Sophie Hambleton 18
Affiliations

Affiliations

  • 1 Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE1 4LP, UK. Department of Infectious Diseases and Tropical Medicine, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK. christopher.duncan@ncl.ac.uk sophie.hambleton@ncl.ac.uk.
  • 2 Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE1 4LP, UK. Advanced Medical and Dental Institute, Universiti Sains Malaysia, 11800 Penang, Malaysia.
  • 3 School of Biology, University of St. Andrews, St. Andrews KY16 9ST, UK.
  • 4 Bioinformatics Support Unit, Newcastle University, Newcastle upon Tyne NE1 4LP, UK.
  • 5 Department of Pediatric Infectious Diseases and Immunology, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
  • 6 Division of Infection and Immunity, University College London, London WC1E 6BT, UK.
  • 7 Virology Department, Great Ormond Street Hospital for Children National Health Service (NHS) Foundation Trust, London WC1N 3JH, UK. National Institutes of Health Research Biomedical Research Centre, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
  • 8 Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College London, London WC1E 6BT, UK.
  • 9 National Virus Reference Laboratory, University College Dublin, Belfield, Dublin 4, Ireland.
  • 10 Department of Pediatric Intensive Care and Anaesthetics, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
  • 11 INFANT Centre, Cork University Maternity Hospital, University College Cork, Ireland.
  • 12 Department of Pediatrics, Bon Secours Hospital, Cork, Ireland.
  • 13 Developmental Biology and Cancer Programme, University College London Institute of Child Health, London WC1N 1EH, UK.
  • 14 Public Health England, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK.
  • 15 Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE1 4LP, UK. Pediatric Immunology Service, Great North Children's Hospital, Newcastle upon Tyne NE1 4LP, UK.
  • 16 Division of Infection and Immunity, University College London, London WC1E 6BT, UK. Virology Department, Great Ormond Street Hospital for Children National Health Service (NHS) Foundation Trust, London WC1N 3JH, UK.
  • 17 Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE1 4LP, UK.
  • 18 Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE1 4LP, UK. Pediatric Immunology Service, Great North Children's Hospital, Newcastle upon Tyne NE1 4LP, UK. christopher.duncan@ncl.ac.uk sophie.hambleton@ncl.ac.uk.
PMID: 26424569 DOI: 10.1126/scitranslmed.aac4227
Abstract

Type I interferon (IFN-α/β) is a fundamental Antiviral defense mechanism. Mouse models have been pivotal to understanding the role of IFN-α/β in immunity, although validation of these findings in humans has been limited. We investigated a previously healthy child with fatal encephalitis after inoculation of the live attenuated measles, mumps, and rubella (MMR) vaccine. By targeted resequencing, we identified a homozygous mutation in the high-affinity IFN-α/β receptor (IFNAR2) in the proband, as well as a newborn sibling, that rendered cells unresponsive to IFN-α/β. Reconstitution of the proband's cells with wild-type IFNAR2 restored IFN-α/β responsiveness and control of IFN-attenuated viruses. Despite the severe outcome of systemic live vaccine challenge, the proband had previously shown no evidence of heightened susceptibility to respiratory viral pathogens. The phenotype of IFNAR2 deficiency, together with similar findings in STAT2-deficient patients, supports an essential but narrow role for IFN-α/β in human Antiviral immunity.

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