The A946T variant of the RNA sensor IFIH1 mediates an interferon program that limits viral infection but increases the risk for autoimmunity

Jacquelyn A Gorman et al., Nat. Immunology 2017 Jul;18(7):744-752.

Speaker: Jia-Bao Chen (陳家寶)                              Time: 14:00~15:00, Oct. 25, 2017

Commentator: Chia-Yi Yu (余佳益 老師)           Place: Room 601

Abstract:

 IFIH1, also known as MDA5, is a cytosolic sensor of dsRNA that induces an anti-viral type I interferon state. The single-nucleotide polymorphism variants of IFIH1 have been associated with various autoimmune phenotypes, most particularly type 1 diabetes (T1D)^1.2. The authors investigated the rs1990760 allele, which results in an amino-acid change (A946T). Family-based single-marker analysis indicated that presence of IFIH1^T946 (or simply IFIH1^R) increased risk for T1D. To study the effect of such polymorphisms, the author found that PBMCs from healthy donors expressing IFIH1^R exhibited increased ligand-triggered production of type I interferons. Next, the author overexpressed risk and non-risk proteins and showed that IFIH1^R exhibited heightened basal and ligand-triggered interferon activity. Then, to investigate the effect of variant in vivo, the authors developed a knock-in mouse model and report that either mice carried heterozygous or homozygous risk gene expressed higher interferon-β mRNA and interferon-stimulated genes than Ifih1^NR mice. Besides, Ifih1^R mice exhibited protection from an IFIH1-specific viral challenge. To sum up the above results, the authors futher investigated how interferon signature lead to automimmune disease. They established mouse model of autoimmune diabetes by treating streptozotocin to injure pancreatic β-cells and data shown that the Ifih1^R mice was prone to elicit disease than Ifih1^NR mice with low dose of streptozotocin. These findings indicated that IFIH1^R can promote an autoimmune state. In previous experiments, the authors observed a significant embryonic survival defect in their homozygous Ifih1^R mice, which they hypothesized might be due to enhanced sensitivity of the IFIH1^R variant for self dsRNA ligands. To prove the hypothesis, the authors tested condition in vitro cell study and found that IFIH1^R was hypersensitive to the RNA self ligands in ADAR1-null cells and thereby generated a stronger type I interferon signal. In conclusion, the risk variant of IFIH1 increases basal and ligand-triggered interferon and protects against viral challenge, which probably accounts for its selection within human populations but provides this advantage at the cost of modestly promoting the risk of autoimmunity.

References：

1.      Smyth, D.J. et al. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat. Genet. 38, 617–619 (2006).

2.      Rice, G.I. et al. Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat. Genet. 46, 503–509 (2014).