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

Type I IFNs (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 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 Ab response. Spontaneous MDA5 activation was not sufficient to initiate autoimmune or inflammatory pathology by itself, even though every immune cell population had signs of IFN activation. When combined with the lupus-susceptible background of the Fc gamma R2B deficiency, MDA5 overexpression did accelerate the production of switched autoantibodies, the incidence of glomerulonephritis, and early lethality. Thus, MDA5 transgenic 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. The Journal of Immunology, 2012, 188: 1451-1459.