Human IFNAR2 deficiency: Lessons for antiviral immunity

被引：174

作者：

Duncan, Christopher J. A. ^{[1
,2
]}

Mohamad, Siti M. B. ^{[1
,3
]}

Young, Dan F. ^{[4
]}

Skelton, Andrew J. ^{[5
]}

Leahy, T. Ronan ^{[6
]}

Munday, Diane C. ^{[4
]}

Butler, Karina M. ^{[6
]}

Morfopoulou, Sofia ^{[7
]}

Brown, Julianne R. ^{[8
,9
]}

Hubank, Mike ^{[10
]}

Connell, Jeff ^{[11
]}

Gavin, Patrick J. ^{[6
]}

McMahon, Cathy ^{[12
]}

Dempsey, Eugene ^{[13
]}

Lynch, Niamh E. ^{[14
]}

Jacques, Thomas S. ^{[15
]}

Valappil, Manoj ^{[16
]}

Cant, Andrew J. ^{[1
,17
]}

Breuer, Judith ^{[7
,8
]}

Engelhardt, Karin R. ^{[1
]}

Randall, Richard E. ^{[4
]}

Hambleton, Sophie ^{[1
,17
]}

机构：

[1] Newcastle Univ, Inst Cellular Med, Primary Immunodeficiency Grp, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England

[2] Royal Victoria Infirm, Dept Infect Dis & Trop Med, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England

[3] Univ Sains Malaysia, Adv Med & Dent Inst, George Town 11800, Malaysia

[4] Univ St Andrews, Sch Biol, St Andrews KY16 9ST, Fife, Scotland

[5] Newcastle Univ, Bioinformat Support Unit, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England

[6] Our Ladys Childrens Hosp, Dept Pediat Infect Dis & Immunol, Dublin 12, Ireland

[7] UCL, Div Infect & Immun, London WC1E 6BT, England

[8] Great Ormond St Hosp Children Natl Hlth Serv NHS, Dept Virol, London WC1N 3JH, England

[9] Great Ormond St Hosp Children NHS Fdn Trust, NIH, Res Biomed Res Ctr, London WC1N 3JH, England

[10] UCL, Inst Child Hlth, Mol Haematol & Canc Biol Unit, London WC1E 6BT, England

[11] Univ Coll Dublin, Virus Reference Lab, Dublin 4, Ireland

[12] Our Ladys Childrens Hosp, Dept Pediat Intens Care & Anaesthet, Dublin 12, Ireland

[13] Natl Univ Ireland Univ Coll Cork, Matern Hosp, Univ Coll Cork, INFANT Ctr, Cork, Ireland

[14] Bon Secours Hosp, Dept Pediat, Cork, Ireland

[15] UCL, Inst Child Hlth, Dev Biol & Canc Programme, London WC1N 1EH, England

[16] Royal Victoria Infirm, Publ Hlth England, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England

[17] Great North Childrens Hosp, Pediat Immunol Serv, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2015年 / 7卷 / 307期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

PYOGENIC BACTERIAL-INFECTIONS; TARGETED DISRUPTION; INTERFERON; INDUCTION; INNATE; SUSCEPTIBILITY; ENCEPHALITIS; ALPHA/BETA; REVEALS; MYD88;

D O I：

10.1126/scitranslmed.aac4227

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Type I interferon (IFN-alpha/beta) is a fundamental antiviral defense mechanism. Mouse models have been pivotal to understanding the role of IFN-alpha/beta 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-alpha/beta receptor (IFNAR2) in the proband, as well as a newborn sibling, that rendered cells unresponsive to IFN-alpha/beta. Reconstitution of the proband's cells with wild-type IFNAR2 restored IFN-alpha/beta 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-alpha/beta in human antiviral immunity.

引用

页数：7

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