Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the Arctic

被引：51

作者：

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

Skouboe, Morten K. ^{[3
,4
]}

Howarth, Sophie ^{[1
]}

Hollensen, Anne K. ^{[3
,4
]}

Chen, Rui ^{[1
]}

Borresen, Malene L. ^{[5
,6
]}

Thompson, Benjamin J. ^{[1
]}

Spegarova, Jarmila Stremenova ^{[1
]}

Hatton, Catherine F. ^{[1
]}

Staeger, Frederik F. ^{[7
]}

Andersen, Mette K. ^{[8
]}

Whittaker, John ^{[1
]}

Paludan, Soren R. ^{[3
]}

Jorgensen, Sofie E. ^{[3
,4
]}

Thomsen, Martin K. ^{[3
]}

Mikkelsen, Jacob G. ^{[3
]}

Heilmann, Carsten ^{[5
,9
]}

Buhas, Daniela ^{[10
,11
]}

Obro, Nina F. ^{[12
]}

Bay, Jakob T. ^{[12
]}

Marquart, Hanne, V ^{[12
]}

de la Morena, M. Teresa ^{[13
,14
]}

Klejka, Joseph A. ^{[15
]}

Hirschfeld, Matthew ^{[16
]}

Borgwardt, Line ^{[17
]}

Forss, Isabel ^{[17
]}

Masmas, Tania ^{[5
]}

Poulsen, Anja ^{[5
]}

Noya, Francisco ^{[18
]}

Rouleau, Guy ^{[19
]}

Hansen, Torben ^{[8
]}

Zhou, Sirui ^{[11
]}

Albrechtsen, Anders ^{[7
]}

Alizadehfar, Reza ^{[18
]}

Allenspach, Eric J. ^{[12
,13
,20
,21
]}

Hambleton, Sophie ^{[1
,2
]}

Mogensen, Trine H. ^{[3
,4
]}

机构：

[1] Newcastle Univ, Clin & Translat Res Inst, Immun & Inflammat Theme, Newcastle Upon Tyne, Tyne & Wear, England

[2] Newcastle Upon Tyne Hosp NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England

[3] Aarhus Univ, Dept Biomed, Aarhus, Denmark

[4] Aarhus Univ Hosp, Dept Infect Dis, Aarhus, Denmark

[5] Copenhagen Univ Hosp, Rigshosp, Dept Paediat & Adolescent Med, Copenhagen, Denmark

[6] Statens Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark

[7] Univ Copenhagen, Dept Biol, Sect Computat & RNA Biol, Copenhagen, Denmark

[8] Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Fac Hlth & Med Sci, Copenhagen, Denmark

[9] Dronning Ingrid Hosp, Med Dept, Pediat Sect, Nuuk, Greenland

[10] McGill Univ, Hlth Ctr, Dept Specialized Med, Div Genet, Montreal, PQ, Canada

[11] McGill Univ, Dept Human Genet, Montreal, PQ, Canada

[12] Copenhagen Univ Hosp, Dept Clin Immunol, Copenhagen, Denmark

[13] Seattle Childrens Hosp, Seattle, WA USA

[14] Univ Washington, Dept Pediat, Seattle, WA 98195 USA

[15] Yukon Kuskokwim Hlth Corp, Bethel, AK USA

[16] Alaska Native Med Ctr, Anchorage, AK USA

[17] Copenhagen Univ Hosp, Rigshosp, Ctr Genom Med, Copenhagen, Denmark

[18] McGill Univ, Montreal Childrens Hosp, Montreal Gen Hosp, Div Allergy & Clin Immunol, Montreal, PQ, Canada

[19] McGill Univ, Dept Neurol & Neurosurg, Neuro, Montreal, PQ, Canada

[20] Seattle Childrens Res Inst, Ctr Immun & Immunotherapies, Seattle, WA USA

[21] Brotman Baty Inst Precis Med, Seattle, WA USA

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2022年 / 219卷 / 06期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

I INTERFERON RECEPTOR; HERPES-SIMPLEX ENCEPHALITIS; MICRORNA SUPPRESSION; STAT1; DEFICIENCY; INBORN-ERRORS; ALPHA; RESPONSES; GENE; TLR3; ACTIVATION;

D O I：

10.1084/jem.20212427

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Type I interferons (IFN-I) play a critical role in human antiviral immunity, as demonstrated by the exceptionally rare deleterious variants of IFNAR1 or IFNAR2. We investigated five children from Greenland, Canada, and Alaska presenting with viral diseases, including life-threatening COVID-19 or influenza, in addition to meningoencephalitis and/or hemophagocytic lymphohistiocytosis following live-attenuated viral vaccination. The affected individuals bore the same homozygous IFNAR2 c.157T>C, p.Ser53Pro missense variant. Although absent from reference databases, p.Ser53Pro occurred with a minor allele frequency of 0.034 in their Inuit ancestry. The serine to proline substitution prevented cell surface expression of IFNAR2 protein, small amounts of which persisted intracellularly in an aberrantly glycosylated state. Cells exclusively expressing the p.Ser53Pro variant lacked responses to recombinant IFN-I and displayed heightened vulnerability to multiple viruses in vitro-a phenotype rescued by wild-type IFNAR2 complementation. This novel form of autosomal recessive IFNAR2 deficiency reinforces the essential role of IFN-I in viral immunity. Further studies are warranted to assess the need for population screening.

引用

页数：26

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