Autoinflammatory Disease Reloaded: A Clinical Perspective

Laboratory of Clinical Investigation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Cell (Impact Factor: 32.24). 03/2010; 140(6):784-90. DOI: 10.1016/j.cell.2010.03.002
Source: PubMed


Our understanding of the etiology of autoinflammatory disease is growing rapidly. Recent advances offer new opportunities for therapeutic intervention and suggest that the definition of what constitutes an autoinflammatory disease should be reassessed.

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Available from: Ivona Aksentijevich
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    • "The innate immune system with its cellular components (e.g., granulocytes, monocyte/macrophages , dendritic cells, NK cells), PRRs, and soluble mediators (e.g., interleukins, chemokines) dominates the pathogenesis of autoinflammatory diseases. Currently, both BS and gout are included in the classification schemes of autoinflammatory diseases [32] [33]. Gout is a prevalent disease with a still increasing prevalence [34]. "
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    ABSTRACT: C-type lectin domain family 12, member A (CLEC12A) is a C-type lectin-like pattern recognition receptor capable of recognizing monosodium urate crystals. Monosodium urate crystals, the causative agents of gout are also among the danger-associated molecular patterns reflecting cellular injury/cell death. In response to monosodium urate crystals, CLEC12A effectively inhibits granulocyte and monocyte/macrophage functions and hence acts as a negative regulator of inflammation. Behçet's syndrome and gout are autoinflammatory disorders sharing certain pathological (neutrophilic inflammation), clinical (exaggerated response to monosodium urate crystals) and therapeutic (colchicine) features. We propose the hypothesis that decreased expression of CLEC12A is a common denominator in the hyperinflammatory responses observed in Behçet's syndrome and gout. Major lines of evidence supporting this hypothesis are: (1) Downregulation/deficiency of CLEC12A is associated with hyperinflammatory responses. (2) CLEC12A polymorphisms with functional and clinical implications have been documented in other inflammatory diseases. (3) Colchicine, a fundamental therapeutic agent used both in Behçet's syndrome and gout is shown to oppose the downregulation of CLEC12A. (4) Behçet's syndrome and gout are characterized by a hyperinflammatory response to monosodium urate crystals and other than gout, Behçet's syndrome is the only inflammatory condition exhibiting this exaggerated response. (5) Genomewide linkage and association studies of Behçet's syndrome collectively point to 12p12-13, the chromosomal region harboring CLEC12A. (6) Patients with severe forms of Behçet's syndrome underexpress CLEC12A with respect to patients with mild forms of the disease. If supported by well-designed, rigorous experiments, the forementioned hypothesis pertinent to CLEC12A will carry important implications for therapy, designing experimental models, and uncovering immunopathogenic mechanisms in Behçet's syndrome and gout. Copyright © 2015 Elsevier Ltd. All rights reserved.
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    • "Shortly thereafter , it was discovered that de novo mutations in NLRP3 also cause neonatal-onset multisystem inflammatory disease (NOMID), which is also known as chronic infantile neurological cutaneous and articular syndrome (CINCA) (Aksentijevich et al. 2002; Feldmann et al. 2002). These disorders are collectively referred to as Cryopyrin-Associated Periodic syndromes (CAPS) and are considered to be autoinflammatory rather than autoimmune because they are mediated primarily by cytokines of the innate immune system, most notably IL-1b (Kastner et al. 2010; Dinarello et al. 2012). Mice engineered to contain human mutant NLRP3 also show a CAPS-like disorder, and macrophages from these mice activate caspase-1 and secrete IL-1b directly in response to microbial PAMPs without the need for signal 2 (e.g., ATP) (Meng et al. 2009). "
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    ABSTRACT: Inflammasomes are large cytosolic multiprotein complexes that assemble in response to detection of infection- or stress-associated stimuli and lead to the activation of caspase-1-mediated inflammatory responses, including cleavage and unconventional secretion of the leaderless proinflammatory cytokines IL-1β and IL-18, and initiation of an inflammatory form of cell death referred to as pyroptosis. Inflammasome activation can be induced by a wide variety of microbial pathogens and generally mediates host defense through activation of rapid inflammatory responses and restriction of pathogen replication. In addition to its role in defense against pathogens, recent studies have suggested that the inflammasome is also a critical regulator of the commensal microbiota in the intestine. Finally, inflammasomes have been widely implicated in the development and progression of various chronic diseases, such as gout, atherosclerosis, and metabolic syndrome. In this perspective, we discuss the role of inflammasomes in infectious and noninfectious inflammation and highlight areas of interest for future studies of inflammasomes in host defense and chronic disease.
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    • "Autoinflammatory conditions include the classic periodic fever syndromes, as well as some newer conditions described such as DIRA (deficiency of the IL-1 receptor antagonist). Many autoinflammatory conditions have been reported to have hypergammaglobulinemia (Kastner et al. 2010). These conditions are well known to have high IgG and not classic primary immunodeficiencies, so they will not be discussed in detail. "

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