Abstract
Primary Sjögren’s syndrome (pSS) is a systemic autoimmune rheumatic disease characterized by dryness of the eyes and mucous membranes, which can be accompanied by various extraglandular autoimmune manifestations. The majority of patients exhibit persistent systemic activation of the type I interferon (IFN) system, a feature that is shared with other systemic autoimmune diseases. Type I IFNs are integral to anti-viral immunity and are produced in response to stimulation of pattern recognition receptors, among which nucleic acid (NA) receptors. Dysregulated detection of endogenous NAs has been widely implicated in the pathogenesis of systemic autoimmune diseases. Stimulation of endosomal Toll-like receptors by NA-containing immune complexes are considered to contribute to the systemic type I IFN activation. Accumulating evidence suggest additional roles for cytosolic NA-sensing pathways in the pathogenesis of systemic autoimmune rheumatic diseases. In this review, we will provide an overview of the functions and signaling of intracellular RNA- and DNA-sensing receptors and summarize the evidence for a potential role of these receptors in the pathogenesis of pSS and the sustained systemic type I IFN activation.
Highlights
The immunogenicity of nucleic acids (NAs) and their shaping of the immune response has been recognized for many decades [1,2]
Knockout of STING has been reported to resolve autoimmunity in some animal autoimmune models [162,163,164], while exacerbating autoimmunity in other models [195]. The latter observations could at least in part be explained by the negative regulatory role of STING on TLR7 and/or TLR9 signaling in certain immune cells, which is potentially mediated through SOCS1/3 [172,195]
Knowledge from multiple disciplines has advanced our understanding of potential driving mechanisms of type I IFN activation in systemic autoimmune diseases
Summary
The immunogenicity of nucleic acids (NAs) and their shaping of the immune response has been recognized for many decades [1,2]. NA-sensing receptors induce the production of pro-inflammatory cytokines and type I interferons (IFNs) [4,7,8]. Persistent systemic type I IFN activation occurs in primary Sjögren’s syndrome (pSS) and other systemic autoimmune diseases and is considered to contribute to the ongoing loop of inflammation [12]. The majority of patients with pSS and related systemic autoimmune diseases have anti-nuclear antibodies, reflecting the exposure of nuclear components to the immune system. Internalization of immune complex-bound NAs and activation of endosomal PRRs is thought to represent a major type I IFN-stimulating mechanism in these patients [14,15,16].
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