Making Sense of Intracellular Nucleic Acid Sensing in Type I Interferon Activation in Sjögren’s Syndrome

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.

+3179G/A Insulin-Like Growth Factor-1 Receptor Polymorphism: A Novel Susceptibility Contributor in Anti-Ro/SSA Positive Patients with Sjögren’s Syndrome: Potential Clinical and Pathogenetic Implications

“…Given that other organs may also be affected, including joints, lungs, kidneys, liver, and nervous system, primary SS is considered a systemic disease [1,2], affecting mainly perimenopausal women with a female-to-male predominance about 9:1 [3]. Disease hallmarks include B-cell hyperactivity, oversecretion of serum autoantibodies such as anti-Ro/SSA, anti-La/SSB, and rheumatoid factor (RF), as well as the activation of type I and type II interferon (IFN) pathways [4][5][6][7]. The most severe disease complication is the development of non-Hodgkin's lymphoma (NHL), which occurs in 5-10% of primary SS patients and represents the leading cause of disease-related mortality [8][9][10].…”

Mitochondrial double-stranded RNAs as a pivotal mediator in the pathogenesis of Sjögren’s syndrome

“…CC-BY-NC-ND 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made detection of nucleic acids has been established as one of the autoimmune signatures (Huijser & Versnel, 2021). Taken together, dsRNA-sensing PRRs may play an important role in engendering autoimmune phenotypes, and investigating both the identity and the roles of PRR-activating dsRNAs in the pathogenesis of SS is critical to understand type I IFN signature in SS.…”

“…One of the most notable features of SS is the type I interferon (IFN) signature (Crow et al, 2019). The type I IFNs can be produced in response to stimulation of pattern recognition receptors (PRRs) such as Toll-Like Receptors (TLRs), Protein Kinase R (PKR), and Melanoma Differentiation-Associated Gene 5 (MDA5) that recognize double-stranded RNAs (dsRNAs) (Huijser & Versnel, 2021;Kiripolsky & Kramer, 2018). Indeed, the upregulation of TLRs is often accompanied by increased levels of IFN-stimulated genes (ISGs) and proinflammatory cytokines, including Tumor Necrosis Factor-α (TNF-α), various interleukins (ILs), and IFN-γ in SS patients (Bikker et al, 2010).…”

“…In particular, salivary glands with extensive mononuclear cell infiltration showed increased expression of type I IFNs and ISGs that are downstream targets of nucleic acidsensing PRRs (Greenwell-Wild et al, 2011;Min et al, 2019). Consequently, the dysregulated detection of nucleic acids has been established as one of the autoimmune signatures (Huijser & Versnel, 2021). Taken together, dsRNA-sensing PRRs may play an important role in engendering autoimmune phenotypes, and investigating both the identity and the roles of PRR-activating dsRNAs in the pathogenesis of SS is critical to understand type I IFN signature in SS.…”

Sjogren’s Syndrome: Recent Updates

“…The majority of patients exhibit persistent systemic activation of the type I interferon (IFN) system, a feature shared with other systemic autoimmune diseases [6]. In their comprehensive review, Huijser and Versnel highlight the role of deregulated intracellular sensing of viral or endogenous nucleic acids by RNA and DNA intracellular receptors in the sustained production of type I IFN in the setting of SS [10]. Moreover, Sebastian and colleagues report that SS patients positive for IFNγ (cut off = 36.57 pg/mL serum levels) are younger (<43 years) and display higher RF titers and EULAR Sjögren's syndrome disease activity index (ESSDAI) compared to IFNγ negative subjects [11].…”