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: 9.85).
02/2010; 6(3):146-56. DOI: 10.1038/nrrheum.2009.278
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.
Available from: ncbi.nlm.nih.gov
- "BXSB mice develop anti-nuclear autoantibodies (ANA), including anti-dsDNA, -ssDNA, -RNP, and -ssRNA, as well as splenomegaly and lymphadenopathy. Disease susceptibility in BXSB is linked to several genetic loci, particularly the telomeric region of chromosome 1, which encodes Fcr2b, Ifi202, and SLAM/ CD2 family members (Morel et al., 2001; Lauwerys and Wakeland, 2005; Fairhurst et al., 2006; Haywood et al., 2006; Theofilopoulos et al., 2010). Moreover, BXSB mice express the Y chromosome–linked autoimmune accelerator gene Yaa. "
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ABSTRACT: Plasmacytoid dendritic cells (pDCs) have long been implicated in the pathogenesis of lupus. However, this conclusion has been largely based on a correlative link between the copious production of IFN-α/β by pDCs and the IFN-α/β "signature" often seen in human lupus patients. The specific contribution of pDCs to disease in vivo has not been investigated in detail. For this reason, we generated a strain of BXSB lupus-prone mice in which pDCs can be selectively depleted in vivo. Early, transient ablation of pDCs before disease initiation resulted in reduced splenomegaly and lymphadenopathy, impaired expansion and activation of T and B cells, reduced antibodies against nuclear autoantigens and improved kidney pathology. Amelioration of pathology coincided with decreased transcription of IFN-α/β-induced genes in tissues. PDC depletion had an immediate impact on the activation of immune cells, and importantly, the beneficial effects on pathology were sustained even though pDCs later recovered, indicating an early pDC contribution to disease. Together, our findings demonstrate a critical function for pDCs during the IFN-α/β-dependent initiation of autoimmune lupus and point to pDCs as an attractive therapeutic target for the treatment of SLE.
Available from: Ronel Talker
- "Such direct interactions between virus-encoded and host-encoded nucleic acids provide another dimension to innate immunity . 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) , 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.
Available from: Kenneth Michael Pollard
- "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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