Article

Sensors of the innate immune system: Their link to rheumatic diseases

Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Nature Reviews Rheumatology (Impact Factor: 10.25). 02/2010; 6(3):146-56. DOI: 10.1038/nrrheum.2009.278
Source: PubMed

ABSTRACT Evidence strongly suggests that excessive or protracted signaling, or both, by cell-surface or intracellular innate immune receptors is central to the pathogenesis of most autoimmune and autoinflammatory rheumatic diseases. The initiation of aberrant innate and adaptive immune responses in autoimmune diseases can be triggered by microbes and, at times, by endogenous molecules--particularly nucleic acids and related immune complexes--under sterile conditions. By contrast, most autoinflammatory syndromes are generally dependent on germline or de novo gene mutations that cause or facilitate inflammasome assembly. The consequent production of proinflammatory cytokines, principally interferon-alpha/beta and tumor necrosis factor in autoimmune diseases, and interleukin-1beta in autoinflammatory diseases, leads to the creation of autoamplification feedback loops and chronicity of these syndromes. These findings have resulted in a critical reappraisal of pathogenetic mechanisms, and provide a basis for the development of novel diagnostic and therapeutic modalities for these diseases.

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    • "Such direct interactions between virus-encoded and host-encoded nucleic acids provide another dimension to innate immunity [79]. Since viral infection has also been implicated in rheumatic disease onset or flare and Epstein-Barr virus is considered a major environmental risk factor for systemic lupus erythematosus (SLE) [83], the involvement of miRNA in host-virus interaction may also have some relevance to rheumatic disease pathogenesis. "
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    ABSTRACT: miRNAs have been shown to play essential regulatory roles in the innate immune system. They function at multiple levels to shape the innate immune response and maintain homeostasis by direct suppression of the expression of their target proteins, preferentially crucial signaling components and transcription factors. Studies in humans and in disease models have revealed that dysregulation of several miRNAs such as miR-146a and miR-155 in rheumatic diseases leads to aberrant production of and/or signaling by inflammatory cytokines and, thus, critically contributes to disease pathogenesis. In addition, the recent description of the role of certain extracellular miRNAs as innate immune agonist to induce inflammatory response would have direct relevance to rheumatic diseases.
    Arthritis research & therapy 04/2013; 15(2):210. DOI:10.1186/ar4194 · 3.75 Impact Factor
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    • "Failure to distinguish foreign from host, however, can result in the development of autoimmune diseases, including organ-specific disease with restricted tissue involvement, such as multiple sclerosis and type I diabetes, or more systemic involvement such as systemic lupus erythematosus (SLE). For most idiopathic autoimmune diseases, components of both the innate and adaptive immune responses are needed [3-5]. To varying extents, environmental factors also contribute to the development of autoimmunity. "
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    ABSTRACT: There is substantial evidence that environmental triggers in combination with genetic and stochastic factors play an important role in spontaneous autoimmune disease. Although the specific environmental agents and how they promote autoimmunity remain largely unknown, in part because of diverse etiologies, environmentally induced autoimmune models can provide insights into potential mechanisms. Studies of idiopathic and environmentally induced systemic autoimmunity show that they are mediated by common adaptive immune response genes. By contrast, although the innate immune system is indispensable for autoimmunity, there are clear differences in the molecular and cellular innate components that mediate specific systemic autoimmune diseases, suggesting distinct autoimmune-promoting pathways. Some of these differences may be related to the bifurcation of toll-like receptor signaling that distinguishes interferon regulatory factor 7-mediated type I interferon production from nuclear factor-κB-driven proinflammatory cytokine expression. Accordingly, idiopathic and pristane-induced systemic autoimmunity require both type I interferon and proinflammatory cytokines whereas the less aggressive mercury-induced autoimmunity, although dependent on nucleic acid-binding toll-like receptors, does not require type I interferon but needs proinflammatory cytokines. Scavenger receptors and the inflammasome may contribute to silica-induced autoimmunity. Greater understanding of the innate mechanisms responsible for idiopathic and environmentally induced autoimmunity should yield new information into the processes that instigate and drive systemic autoimmunity.
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    • "Since TLR9 exhibits higher affinity for this molecule, it is reasonable to suggest that the absence of TLR9 will result in increased trafficking of TLR7 and enhanced disease, as, in fact, occurred in the examples just given. Although it is still unclear why TLR7 is more pathogenic than TLR9, likely possibilities include differences in signaling intensity and/or higher availability of particles that contain TLR7-engaging ligands such as snRNPs (Theofilopoulos and others 2010). Thus, apart from minor incongruities, the published data strongly indicate that engagement of nucleic acid-specific TLRs is critical for the pathogenesis of lupus. "
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    ABSTRACT: A collection of molecular sensors has been defined by studies in the last decade that can recognize a diverse array of pathogens and initiate protective immune and inflammatory responses. However, if the molecular signatures recognized are shared by both foreign and self-molecules, as is the case of nucleic acids, then the responses initiated by these sensors may have deleterious consequences. Notably, this adverse occurrence may be of primary importance in autoimmune disease pathogenesis. In this case, microbe-induced damage or mishandled physiologic processes could lead to the generation of microparticles containing self-nucleic acids. These particles may inappropriately gain access to the cytosol or endolysosomes and, hence, engage resident RNA and DNA sensors. Evidence, as reviewed here, strongly indicates that these sensors are primary contributors to autoimmune disease pathogenesis, spearheading efforts toward development of novel therapeutics for these disorders.
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