title: Molecular mechanisms in genetically defined autoinflammatory diseases: disorders of amplified danger signaling.
abstract: Patients with autoinflammatory diseases present with noninfectious fever flares and systemic and/or disease-specific organ inflammation. Their excessive proinflammatory cytokine and chemokine responses can be life threatening and lead to organ damage over time. Studying such patients has revealed genetic defects that have helped unravel key innate immune pathways, including excessive IL-1 signaling, constitutive NF-κB activation, and, more recently, chronic type I IFN signaling. Discoveries of monogenic defects that lead to activation of proinflammatory cytokines have inspired the use of anticytokine-directed treatment approaches that have been life changing for many patients and have led to the approval of IL-1-blocking agents for a number of autoinflammatory conditions. In this review, we describe the genetically characterized autoinflammatory diseases, we summarize our understanding of the molecular pathways that drive clinical phenotypes and that continue to inspire the search for novel treatment targets, and we provide a conceptual framework for classification.
authors.affiliation: Translational Autoinflammatory Diseases Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland 20892; email: goldbacr@mail.nih.gov.
authors.forename: Adriana Almeida
authors.initials: AA
authors.lastname: de Jesus
authors.forename: Scott W
authors.initials: SW
authors.lastname: Canna
authors.forename: Yin
authors.initials: Y
authors.lastname: Liu
authors.forename: Raphaela
authors.initials: R
authors.lastname: Goldbach-Mansky
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D015551:Autoimmunity; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006801:Humans; D007113:Immunity, Innate; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007372:Interferons / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018836:Inflammation Mediators; D007375:Interleukin-1; D016328:NF-kappa B; D007372:Interferons
keywords: IFN-mediated autoinflammatory diseases; IL-1-mediated autoinflammatory diseases; autoinflammatory diseases; cryopyrin-associated periodic syndromes; hereditary fever syndromes; inflammasomes in human disease; macrophage activation syndrome; proteasome-associated autoinflammatory syndromes