A Novel Case of Homozygous Interferon Alpha/Beta Receptor Alpha Chain (IFNAR1) Deficiency With Hemophagocytic Lymphohistiocytosis

Gothe, Florian; Hatton, Christine; Truong, Linh; Klimova, Zofia; Kanderová, Veronika; Fejtková, Martina; Grainger, Angela; Perthen, Joanna E.; Mitra, Dipayan; Janda, Aleš; Froňková, Eva; Moravcikova, Dusana; Hambleton, Sophie; Duncan, Christopher J A

doi:10.1093/cid/ciaa1790

Cited by 28 publications

(27 citation statements)

References 13 publications

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“…No nonsynonymous variants of IFNAR1 , IFNAR2 , or the five genes controlling the type I IFN response pathway ( JAK1 , TYK2 , STAT1 , STAT2 , and IRF9 ; Bastard et al, 2020a ; Dupuis et al, 2003 ; Eletto et al, 2016 ; Gothe et al, 2020 ; Hambleton et al, 2013 ; Hernandez et al, 2018 ; Kreins et al, 2015 ; Watford and O’Shea, 2006 ) were found in the other six patients. We then hypothesized that these patients might have an autoimmune phenocopy of inborn errors of type I IFN immunity, as recently shown in patients with life-threatening COVID-19 pneumonia ( Bastard et al, 2020b ; Ku et al, 2020 ; Zhang et al, 2020a ; Zhang et al, 2020b ).…”

Section: Resultsmentioning

confidence: 89%

“…Auto-Abs against type I IFNs can therefore underlie severe COVID-19 or YFV-17D disease. Intriguingly, children with APS-1 and auto-Abs to type I IFNs have been vaccinated with MMR without any reported adverse reaction, despite the occurrence of MMR disease in several patients with inherited IFNAR1 or IFNAR2 deficiency ( Bastard et al, 2020a ; Duncan et al, 2015 ; Gothe et al, 2020 ; Hernandez et al, 2019 ). This may be due to the activity of IFN-β, IFN-κ, or IFN-ε in APS-1 patients, whose auto-Abs typically neutralize the 13 individual IFN-α2 and IFN-ω ( Bastard et al, 2020b ; Meager et al, 2006 ).…”

Section: Resultsmentioning

confidence: 99%

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Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine

Bastard

Michailidis

Hoffmann

et al. 2021

Journal of Experimental Medicine

178

145

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Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine–associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination.

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Section: Resultsmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine

Bastard

Michailidis

Hoffmann

et al. 2021

Journal of Experimental Medicine

178

145

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“…Only nine patients with autosomal recessive (AR) complete IFNAR1 deficiency from six unrelated kindreds have been described to date [45,[87][88][89] (Table 2). Most of the causal mutations are nonsense mutations or substitutions of essential splice sites, resulting in a premature stop codon and an absence of functional IFNAR1.…”

Section: Human Ar Ifnar1 Deficiencymentioning

confidence: 99%

Viral infections in humans and mice with genetic deficiencies of the type I IFN response pathway

Meyts

Casanova

2021

Eur J Immunol

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Type I IFNs are so‐named because they interfere with viral infection in vertebrate cells. The study of cellular responses to type I IFNs led to the discovery of the JAK‐STAT signaling pathway, which also governs the response to other cytokine families. We review here the outcome of viral infections in mice and humans with engineered and inborn deficiencies, respectively, of (i) IFNAR1 or IFNAR2, selectively disrupting responses to type I IFNs, (ii) STAT1, STAT2, and IRF9, also impairing cellular responses to type II (for STAT1) and/or III (for STAT1, STAT2, IRF9) IFNs, and (iii) JAK1 and TYK2, also impairing cellular responses to cytokines other than IFNs. A picture is emerging of greater redundancy of human type I IFNs for protective immunity to viruses in natural conditions than was initially anticipated. Mouse type I IFNs are essential for protection against a broad range of viruses in experimental conditions. These findings suggest that various type I IFN‐independent mechanisms of human cell‐intrinsic immunity to viruses have yet to be discovered.

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“…The MIS-C observed in this child is a novel phenotype associated with IFNAR1 deficiency. Intriguingly, progressive hemophagocytosis after MMR vaccine or cytomegalovirus infections was noted in two of the previously reported cases [ 43 , 44 ], as well as in patients with other defects in the type I IFN pathway including STAT1 [ 49 ], STAT2 [ 50 , 51 ], and IFNAR2 [ 9 , 52 ]. Despite exaggerated inflammation, our patient did not fulfill the diagnostic score of hemophagocytosis (Hscore [ 53 ]: 106).…”

Section: Discussionmentioning

confidence: 99%

Inherited IFNAR1 Deficiency in a Child with Both Critical COVID-19 Pneumonia and Multisystem Inflammatory Syndrome

et al. 2022

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Background Inborn errors of immunity (IEI) and autoantibodies to type I interferons (IFNs) underlie critical COVID-19 pneumonia in at least 15% of the patients, while the causes of multisystem inflammatory syndrome in children (MIS-C) remain elusive. Objectives To detect causal genetic variants in very rare cases with concomitant critical COVID-19 pneumonia and MIS-C. Methods Whole exome sequencing was performed, and the impact of candidate gene variants was investigated. Plasma levels of cytokines, specific antibodies against the virus, and autoantibodies against type I IFNs were also measured. Results We report a 3-year-old child who died on day 56 of SARS-CoV-2 infection with an unusual clinical presentation, combining both critical COVID-19 pneumonia and MIS-C. We identified a large, homozygous loss-of-function deletion in IFNAR1, underlying autosomal recessive IFNAR1 deficiency. Conclusions Our findings confirm that impaired type I IFN immunity can underlie critical COVID-19 pneumonia, while suggesting that it can also unexpectedly underlie concomitant MIS-C. Our report further raises the possibility that inherited or acquired dysregulation of type I IFN immunity might contribute to MIS-C in other patients.

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A Novel Case of Homozygous Interferon Alpha/Beta Receptor Alpha Chain (IFNAR1) Deficiency With Hemophagocytic Lymphohistiocytosis

Cited by 28 publications

References 13 publications

Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine

Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine

Viral infections in humans and mice with genetic deficiencies of the type I IFN response pathway

Inherited IFNAR1 Deficiency in a Child with Both Critical COVID-19 Pneumonia and Multisystem Inflammatory Syndrome

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