[New aspects of the pathogenesis of gout. Danger signals, autoinflammation and beyond].
Gout is caused by monosodium urate (MSU) crystal-induced inflammation of the joints and periarticular tissues. MSU crystals activate the NOD-like receptor (NLR) NALP3, which functions as a pattern recognition receptor (PRR). Activated NALP3 mediates interleukin-1b (IL-1b) generation from its inactive pro-form, resulting in the activation of further cells and an IL-8-mediated neutrophil influx into the joint. Based on these new findings on the pathophysiology of gout, an open pilot study has recently demonstrated successful treatment of gout with the soluble IL-1R antagonist anakinra in 10 patients. The physiological role of MSU crystals might be that of a danger signal in peripheral tissues, where they stimulate dendritic cell maturation. The role of PRRs such as the NLR is underlined by NALP3 mutations causing hereditary autoinflammatory syndromes and NOD2 polymorphisms as genetic risk factors for Crohn's disease. In addition to the recognition of danger-associated molecular patterns (e.g. MSU), PRRs confer autoantigen recognition and activation of the innate and adaptive immune system in autoimmune diseases. Detection of RNA and DNA-containing immune complexes by toll-like receptors inducing B-cell activation in systemic lupus erythematosus and of proteinase 3 by the protease-activated receptor-2 inducing dendritic cell maturation in Wegener's granulomatosis have recently been reported.
Lamprecht
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Poliklinik für Rheumatologie, Universität zu Lübeck, Vaskulitiszentrum - Universitätsklinikum Schleswig-Holstein (UKSH) und Rheumaklinik Bad Bramstedt, Lübeck, Deutschland. peter.lamprecht@rheuma.uni-luebeck.de
Till
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Kabelitz
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D001168:Arthritis / Q000175:diagnosis / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D002352:Carrier Proteins / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D006073:Gout / Q000175:diagnosis / Q000276:immunology*; D006801:Humans; D018448:Models, Immunological; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D053472:Nod Signaling Adaptor Proteins / Q000276:immunology*; D011379:Prognosis; D018570:Risk Assessment; D015398:Signal Transduction / Q000276:immunology
D002352:Carrier Proteins; D016207:Cytokines; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D053472:Nod Signaling Adaptor Proteins