MDA5 is an essential double-stranded RNA (dsRNA) sensor to elicit antiviral interferon (IFN) upon viral infection. Recently, MDA5 has been implicated in autoimmune diseases, however how MDA5 triggers the onset of autoimmune disorders remains unclear.
We obtained a mouse line that spontaneously developed autoimmune symptoms such as lupus-like nephritis and found that this mouse has a missense mutation (G821S) in Ifih1 gene encoding MDA5. The onset of all symptoms was totally dependent on the signaling from MDA5 G821S via an essential signaling adaptor, MAVS. While IFNAR deficiency in MDA5 G821S mutant mice partially ameliorated the phenotypes, suggesting the involvement of NF-κB-dependent inflammatory cytokines in the pathogenesis. MDA5 G821S failed to respond to dsRNA, however it constitutively activated IFN promoter. In humans, missense mutations in IFIH1 gene encoding MDA5 were reported in patients of systemic lupus erythematosus, Aicardi-Goutieres syndrome and Singleton-Merten syndrome (SMS). In one SMS patient, mutation in DDX58 gene encoding another viral RNA sensor, RIG-I was reported. To examine the involvement of these mutations in autoimmune symptoms, we generated mutant mice expressing patient-related mutant of human MDA5 or RIG-I. We found that these mutant mice spontaneously developed various types of autoimmune symptoms, suggesting usefulness of these mice as human autoimmune disease models.
The involvement of signal transductions in autoimmune disease onset and possible preventions of the onset and treatments by inhibition of the signal transduction will be discussed.