Figure 1. Type I IFN-centric view of SLE pathogenesis.
Numerous polymorphisms in genes encoding regulators of nucleic acid degradation or mediators of pathways involved in induction of or response to IFN-I, along with environmental factors that lead to cellular stress or oxidative damage, generate a host endowed with enhanced capacity to activate the IFN-I pathway. A favored view is that stimulatory endogenous nucleic acids activate cytoplasmic nucleic acid sensors and induce IFN-I, possibly enriched in IFN-β, although an exogenous viral trigger remains possible. A recent study suggests that this early event might occur in nonhematopoietic cells (82). The resulting IFN-I will prime an adaptive immune response, and in a host enriched in gene variants that lower the threshold for lymphocyte activation, a self-reactive immune response may be favored. When autoantibodies target nucleic acids or nucleic acid-binding proteins, immune complexes form and strongly amplify IFN-I production, predominantly IFN-α, through Fc receptor-dependent activation of pDCs mediated by endosomal TLRs. The adjuvant activity of the immune complex also amplifies the autoimmune response to the associated nucleic acid-binding proteins. Neutrophils can respond to exposure to IFN-I and immune complexes with extrusion of nucleic acids and associated proteins, in the form of mitochondria or neutrophil extracellular traps (NETs), produce IFN-I and contribute to disease flares. Neutrophils and pDCs can each amplify production of IFN-I by the other cell type, modify function of adaptive immune system cells and amplify autoimmunity. The immunologic consequences of this sustained viral-like response result in broad immune dysregulation, inflammation and tissue damage.