Figure 3.

Possible genetic and environmental factors involved in the anti-MDA5 dermatomyositis. Viral double stranded RNA (dsRNA) activates MDA5 in infected cells, leading to type I interferon (IFN-I) production and increased levels of MDA5. Altered WDFY4 impairs antigen cross-presentation by CD1c+ dendritic cells (DCs), favoring an inefficient elimination of infected cells and further activation of MDA5. In parallel, altered WDFY4 also enhances MDA5-mediated nuclear factor-kappa B (NF-κB) pathway leading to the apoptosis of infected cells, and the release of MDA5. Local dysfunctional mitochondrial polynucleotide phosphorylase (PNPase) could lead to intracellular accumulation of endogenous dsRNA, fueling uncontrolled activation and expression of MDA5. Abnormal accumulation of MDA5 may favor a loss of tolerance to MDA5 in an individual with proper genetic background, leading to anti-MDA5 antibodies (Abs).