A Common Form of Dominant Human Ifnar1 Deficiency Impairs Ifn-Α and -Ω But Not Ifn-Β-Dependent Immunity Publisher Pubmed



Al Qureshah F^{1, 2} ; Le Pen J³ ; De Weerd NA⁴ ; Moncadavelez M¹ ; Materna M⁵⁹ ; Lin D¹⁶ ; Milisavljevic B¹ ; Vianna F^{7, 8, 9, 10} ; Bizien L^{5, 6} ; Lorenzo L^{5, 6} ; Lecuit M^{6, 11, 12} ; Pommier JD^{12, 108, 116} ; Keles S¹³ ; Ozcelik T^{14, 80} Show All Authors Show Affiliations
Source: Journal of Experimental Medicine Published:2025

Abstract

Autosomal recessive deficiency of the IFNAR1 or IFNAR2 chain of the human type I IFN receptor abolishes cellular responses to IFN-α, -β, and -ω, underlies severe viral diseases, and is globally very rare, except for IFNAR1 and IFNAR2 deficiency in Western Polynesia and the Arctic, respectively. We report 11 human IFNAR1 alleles, the products of which impair but do not abolish responses to IFN-α and -ω without affecting responses to IFN-β. Ten of these alleles are rare in all populations studied, but the remaining allele (P335del) is common in Southern China (minor allele frequency ≈2%). Cells heterozygous for these variants display a dominant phenotype in vitro with impaired responses to IFN-α and -ω, but not -β, and viral susceptibility. Negative dominance, rather than haploinsufficiency, accounts for this dominance. Patients heterozygous for these variants are prone to viral diseases, attesting to both the dominance of these variants clinically and the importance of IFN-α and -ω for protective immunity against some viruses. © 2024 Al Qureshah et al.