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Type I interference with self-tolerance

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Science Immunology  07 Jul 2017:
Vol. 2, Issue 13, eaao2061
DOI: 10.1126/sciimmunol.aao2061

Abstract

Common variant of the RNA sensor IFIH1 enhances antiviral responses but also increases the risk of autoimmune disease.

Type I interferons are critical in antiviral immune responses, but increased type I interferons have also been associated with autoimmune diseases, including type I diabetes and systemic lupus erythematosus (SLE). The RNA sensing molecule interferon induced with helicase C domain 1 (IFIH1) is a cytosolic receptor that recognizes single and double-stranded RNAs (dsRNAs) and confers protection in the context of RNA virus infection. When activated by its RNA ligands, IFIH1 induces production of type I interferons and interferon-stimulated genes. Activating mutations in IFIH1 have been documented in early onset auto-inflammatory disorders, whereas loss-of-function variants of IFIH1 have been associated with decreased susceptibility to autoimmunity. Gorman et al. focused their studies on the rs1990760, a risk allele of IFIH1 associated with multiple autoimmune disorders that has a frequency of ~57% in European populations. The variant causes a single amino acid change, A946T, in the C-terminal regulatory domain of the protein.

The authors found that blood cells from healthy donors homozygous for the IFIH1 rs1990760 variant allele produced more interferon-β (IFN-β) both at baseline and after stimulation with the artificial dsRNA ligand poly (I:C) than donors expressing nonrisk alleles. Cell lines transduced to express the IFIH1 rs1990760 allele had higher basal and induced IFN-β and were more efficient in fighting off West Nile virus. Knock-in mice carrying the human variant gene had increased basal and induced production of IFN-β in blood cells and survived an otherwise lethal challenge with encephalomyocarditis virus. However, this variant also enhanced the development of autoimmune disease in multiple diabetes and lupus mouse models. Lastly, the authors showed that the rs1990760 allele makes cells more sensitive to endogenous RNA. These studies suggest that the increased level of IFN-β induced by the rs1990760 allele is a double-edged sword, providing protection from viral infections but conferring an increased risk of autoimmune disease.

This study by Gorman et al. is an elegant example of how a risk allele identified by genome wide association studies can be sequentially studied in human patients, isolated human cells, and finally, engineered mouse models to identify its functional effects, and its contribution to human health and disease.

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