How loss-of-function mutations in IFIH1 contribute to infectious and/or inflammatory disease – a systematic review

The <i>IFIH1</i> gene encodes for the cytoplasmic innate immune receptor <i>Melanoma Differentiation-Associated protein 5</i> (MDA5) that detects viral double-stranded RNA to initiate type I interferon (IFN) responses. While gain-of-function mutations in <i>IFIH1</i> have been linked with systemic inflammatory diseases, loss-of-function remains less well understood. This systematic review, following <i>Preferred Reporting Items for Systematic reviews and Meta-Analyses</i> (PRISMA) guidance, explored how <i>IFIH1</i>/MDA5 loss-of-function affects susceptibility to virus infections and/or contributes to inflammatory diseases. Sixteen loss-of-function variants affecting <i>IFIH1</i> were discussed across 33 studies. Loss-of-function variants were consistently associated with increased susceptibility and/or severity of <b>virus infections</b>, including severe acute respiratory syndrome coronavirus (SARS-CoV2) and human immunodeficiency virus (HIV). Several rare biallelic <i>IFIH1</i> mutations lead to profound immunodeficiency, while heterozygous mutations associate with milder clinical presentations. Likely through dampening IFN responses, several variants <b>protect from the development of inflammatory diseases, including</b> type 1 diabetes and hypothyroidism. However, <i>IFIH1</i> deficiency is also implicated in the development of inflammatory diseases, including i<b>nflammatory bowel disease. Moreover,</b> the presence of <b>inactivating</b> anti-MDA5 antibodies may alter the clinical phenotypes and prognosis of dermatomyositis and infections with SARS-CoV2. Though their exact impact on MDA5 function has not been confirmed experimentally, anti-MDA5 antibodies may result in loss-of-function and impaired host defence against viruses. Loss of <i>IFIH1</i>/MDA5 activity has diverse effects on anti-viral immunity, associated damage and susceptibility to inflammatory disease, but also protection against organ-specific immune-mediated pathology. Findings highlight the importance of <i>IFIH1</i> in immune regulation and warrant future studies exploring its potential as a diagnostic and therapeutic target.