Ifih1 Gene Dose Effect Reveals MDA5-Mediated Chronic Type I IFN Gene Signature, Viral Resistance, and Accelerated Autoimmunity

Abstract

Type I interferons (IFN-I) are normally produced during antiviral responses, yet high levels of chronic IFN-I expression correlate with autoimmune disease. A variety of viral sensors generate IFN-I in their response, but other than TLRs it is not fully known which pathways are directly involved in the development of spontaneous immune pathologies. To further explore the link between IFN-I induced by viral pathways and autoimmunity, we generated a new transgenic (Tg) mouse line containing multiple copies of Ifih1, a gene encoding the cytoplasmic dsRNA sensor MDA5 with proven linkage to diabetes and lupus. We show that MDA5 overexpression led to a chronic IFN-I state characterized by resistance to a lethal viral infection through rapid clearance of virus in the absence of a CD8+ or antibody response. Spontaneous MDA5 activation was not sufficient to initiate autoimmune or inflammatory pathology by itself even though every immune cell population had signs of interferon activation. When combined with the lupus-susceptible background of the FcγR2B deficiency, MDA5 overexpression did accelerate the production of switched autoantibodies, the incidence of glomerulonephritis and early lethality. Thus, MDA5 Tg mice provide evidence that chronic elevated levels of IFN-I are not sufficient to initiate autoimmunity or inflammation although they might exacerbate an ongoing autoimmune pathology.

Meta-analysis of STAT4 and IFIH1 polymorphisms in type 1 diabetes mellitus patients with autoimmune polyglandular syndrome type III

“…Despite this, on including our data in the meta-analysis study, the rs1990760 SNP in IFIH1 was found to be associated with T1D. The overexpression of IFIH1 in murine models is related to a chronic state of IFN-I production (Crampton et al, 2012). In multiple sclerosis (MS), which is an autoimmune disease, IFIH1 and Toll-like receptor 7 (TLR7) are overexpressed.…”

Cardiac-Specific Overexpression of Melanoma Differentiation–Associated Gene-5 Protects Mice From Lethal Viral Myocarditis

“…[32][33][34] Similarly, IFNγ transgenic mice also develop dilated cardiomyopathy and a reduction in fractional shortening that is mediated through increased production of TNF. 35 Interestingly, Crampton et al 36 recently reported that MDA5 transgenic mice have increased levels of type I IFN and ISGs and are resistant to infection with vesicular stomatitis virus, but do not spontaneously develop autoimmune or inflammatory pathology. These results are in agreement with what we have reported here, except that αMHC-MDA5 mice do show spontaneous production of cardiac inflammatory cytokines (TNF and interleukin 1) but do not develop myocardial dysfunction at 6 weeks of age.…”

Is Type 1 Diabetes “Going Viral”?

“…Protective variants in IFIH1 in patients who are otherwise genetically susceptible to diabetes exhibit reduced MDA5 expression and function (12). Further, recent data have also shown that mice with elevated expression of MDA5 exhibit increased systemic autoimmune disease (13,14). However, although identification of IFN I transcriptional signatures and increased IFN I expression has implicated a role for IFN I in diabetes in mice, loss of IFN I signaling did not affect diabetes induction (15).…”