Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018099 (gout)
 5,192 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nucleotide-binding domain, leucine-rich repeat containing family (NLR) network has provided pivotal genetic and molecular insights into diseases that were hitherto regarded as autoimmune. The NLR-related disorders include rare monogenic autoinflammatory diseases collectively termed cryopyrin-associated periodic syndromes, Crohn's disease which is a common polygenic disease and also an association at the mechanistic level with gout and pseudogout. Unlike the classical autoimmune diseases where disease immunopathogenesis is played out primarily in the primary and secondary lymphoid organs, the immunopathogenesis of the NLR-related disorders is played out in the tissues where inflammation arises. As the genetic mutations or molecular cascades associated with the NLR-related disorders have a widespread cellular distribution, it has been somewhat enigmatic why these disorders attack certain territories, but not others. This implies that tissue-specific factors in the target organs themselves contribute to disease expression. Such examples include the high abundance of NOD2 expressing cells in the part of the gut most typically afflicted by Crohn's disease and the preferential deposition of crystals in the joints to where inflammation localises in gout and pseudogout. The NLR network is associated principally with increases in TNF or IL-1 production, both of which are key players in innate immunity. Therefore, the NLR network identifies at the genetic and molecular level a robust paradigm for innate immune activation against self. This tissue-specific-factor-associated inflammation is the diametric opposite of classical autoimmunity. Of note, the MHC class-I-associated diseases including psoriasis (HLA-Cw6) and ankylosing spondylitis (HLA-B27) show striking clinical overlaps with Crohn's disease and also some rare monogenic diseases. Thus, the NLR innate immune pathway allows the full spectrum of inflammation against self to be viewed along an immunological disease continuum with autoantibody-associated disease at one end, innate immune diseases at the other and MHC class-1-related disorders as an intermediate.
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PMID:The NLR network and the immunological disease continuum of adaptive and innate immune-mediated inflammation against self. 1780 42

Inflammasomes are large, multimeric protein complexes that link the sensing of microbial products and metabolic stress to the proteolytic processing of prointerleukin (pro-IL)-1beta to its active form. NALP1 and NALP2 are founding members of the Nod-like receptor family. Other Nod-like receptors, including NALP3 and NOD2, which are associated with inflammatory disorders, have also been described. The NALP1 and NALP3 inflammasomes are located in the cytoplasm and can, therefore, detect intracellular infection through recognition of microbial pathogen-associated molecular patterns. The inflammasome pathways cooperate with Toll-like receptor pathways to mediate a rapid and appropriate response to pathogens and genotoxic stress. Mutations in both pyrin and NALP3 components of inflammasomes are associated with innate-immune-mediated diseases (familial Mediterranean fever and the 'cryopyrinopathies'), and aberrant IL-1beta processing has been reported in several autoinflammatory conditions, including Muckle-Wells syndrome, chronic infantile neurologic, cutaneous and articular syndrome/neonatal onset multisystem inflammatory disease, and gout. The effectiveness of IL-1beta blockade in treating many of these conditions has transformed the understanding and management of these disorders and also highlighted the role of aberrant IL-1beta signaling in other conditions, such as adult-onset Still's disease and systemic juvenile idiopathic arthritis.
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PMID:Primer: inflammasomes and interleukin 1beta in inflammatory disorders. 1817 47

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.
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PMID:[New aspects of the pathogenesis of gout. Danger signals, autoinflammation and beyond]. 1829 53