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Human IFNAR2 deficiency: lessons for antiviral immunity

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Christopher J. A. Duncan, Siti M. B. Mohamad, Dan Frushard Young, Andrew J. Skelton, T. Ronan Leahy, Diane Carolyn Munday, Karina M. Butler, Sofia Morfopoulou, Julianne R. Brown, Mike Hubank, Jeff Connell, Patrick J. Gavin, Cathy McMahon, Eugene Dempsey, Niamh E. Lynch, Thomas S. Jacques, Manoj Valappil, Andrew J. Cant, Judith Breuer, Karin R. Engelhardt & 2 more Richard Edward Randall, Sophie Hambleton

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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.


Original languageEnglish
Article number307ra154
Number of pages7
JournalScience Translational Medicine
Issue number307
Publication statusPublished - 30 Sep 2015

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