Duncan Christopher J A, Mohamad Siti M B, Young Dan F, Skelton Andrew J, Leahy T Ronan, Munday Diane C, Butler Karina M, Morfopoulou Sofia, Brown Julianne R, Hubank Mike, Connell Jeff, Gavin Patrick J, McMahon Cathy, Dempsey Eugene, Lynch Niamh E, Jacques Thomas S, Valappil Manoj, Cant Andrew J, Breuer Judith, Engelhardt Karin R, Randall Richard E, Hambleton Sophie
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.
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.
Sci Transl Med. 2015 Sep 30;7(307):307ra154. doi: 10.1126/scitranslmed.aac4227.
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.
I型干扰素（IFN-α/β）是一种基本的抗病毒防御机制。小鼠模型对于理解IFN-α/β在免疫中的作用至关重要，尽管在人类中对这些发现的验证有限。我们调查了一名先前健康的儿童，其在接种减毒活麻疹、腮腺炎和风疹（MMR）疫苗后发生了致命性脑炎。通过靶向重测序，我们在先证者以及一名新生儿同胞中发现了高亲和力IFN-α/β受体（IFNAR2）中的纯合突变，该突变使细胞对IFN-α/β无反应。用野生型IFNAR2重建先证者的细胞可恢复IFN-α/β反应性并控制IFN减弱的病毒。尽管全身性活疫苗激发导致了严重后果，但先证者此前并未表现出对呼吸道病毒病原体易感性增加的证据。IFNAR2缺陷的表型以及STAT2缺陷患者的类似发现，支持了IFN-α/β在人类抗病毒免疫中起着重要但有限的作用。
