title: Human IFNAR2 deficiency: Lessons for antiviral immunity.
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.
authors.affiliation: 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.
authors.forename: Christopher J A
authors.initials: CJ
authors.lastname: Duncan
authors.affiliation: 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.
authors.forename: Siti M B
authors.initials: SM
authors.lastname: Mohamad
authors.affiliation: School of Biology, University of St. Andrews, St. Andrews KY16 9ST, UK.
authors.forename: Dan F
authors.initials: DF
authors.lastname: Young
authors.affiliation: Bioinformatics Support Unit, Newcastle University, Newcastle upon Tyne NE1 4LP, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Skelton
authors.affiliation: Department of Pediatric Infectious Diseases and Immunology, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
authors.forename: T Ronan
authors.initials: TR
authors.lastname: Leahy
authors.affiliation: School of Biology, University of St. Andrews, St. Andrews KY16 9ST, UK.
authors.forename: Diane C
authors.initials: DC
authors.lastname: Munday
authors.affiliation: Department of Pediatric Infectious Diseases and Immunology, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
authors.forename: Karina M
authors.initials: KM
authors.lastname: Butler
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6BT, UK.
authors.forename: Sofia
authors.initials: S
authors.lastname: Morfopoulou
authors.affiliation: 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.
authors.forename: Julianne R
authors.initials: JR
authors.lastname: Brown
authors.affiliation: Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College London, London WC1E 6BT, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Hubank
authors.affiliation: National Virus Reference Laboratory, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Jeff
authors.initials: J
authors.lastname: Connell
authors.affiliation: Department of Pediatric Infectious Diseases and Immunology, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Gavin
authors.affiliation: Department of Pediatric Intensive Care and Anaesthetics, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
authors.forename: Cathy
authors.initials: C
authors.lastname: McMahon
authors.affiliation: INFANT Centre, Cork University Maternity Hospital, University College Cork, Ireland.
authors.forename: Eugene
authors.initials: E
authors.lastname: Dempsey
authors.affiliation: Department of Pediatrics, Bon Secours Hospital, Cork, Ireland.
authors.forename: Niamh E
authors.initials: NE
authors.lastname: Lynch
authors.affiliation: Developmental Biology and Cancer Programme, University College London Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Jacques
authors.affiliation: Public Health England, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK.
authors.forename: Manoj
authors.initials: M
authors.lastname: Valappil
authors.affiliation: 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.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Cant
authors.affiliation: 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.
authors.forename: Judith
authors.initials: J
authors.lastname: Breuer
authors.affiliation: Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE1 4LP, UK.
authors.forename: Karin R
authors.initials: KR
authors.lastname: Engelhardt
authors.affiliation: School of Biology, University of St. Andrews, St. Andrews KY16 9ST, UK.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Randall
authors.affiliation: 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.
authors.forename: Sophie
authors.initials: S
authors.lastname: Hambleton
mesh_terms: D017809:Fatal Outcome; D005808:Genes, Recessive; D005816:Genetic Complementation Test; D006801:Humans; D007109:Immunity; D007223:Infant; D007372:Interferons / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C508033:IFNAR2 protein, human; D053633:Receptor, Interferon alpha-beta; D007372:Interferons