title: Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*).
abstract: The autoinflammatory diseases are characterized by seemingly unprovoked episodes of inflammation, without high-titer autoantibodies or antigen-specific T cells. The concept was proposed ten years ago with the identification of the genes underlying hereditary periodic fever syndromes. This nosology has taken root because of the dramatic advances in our knowledge of the genetic basis of both mendelian and complex autoinflammatory diseases, and with the recognition that these illnesses derive from genetic variants of the innate immune system. Herein we propose an updated classification scheme based on the molecular insights garnered over the past decade, supplanting a clinical classification that has served well but is opaque to the genetic, immunologic, and therapeutic interrelationships now before us. We define six categories of autoinflammatory disease: IL-1beta activation disorders (inflammasomopathies), NF-kappaB activation syndromes, protein misfolding disorders, complement regulatory diseases, disturbances in cytokine signaling, and macrophage activation syndromes. A system based on molecular pathophysiology will bring greater clarity to our discourse while catalyzing new hypotheses both at the bench and at the bedside.
authors.affiliation: The National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. masterss@mail.nih.gov
authors.forename: Seth L
authors.initials: SL
authors.lastname: Masters
authors.forename: Anna
authors.initials: A
authors.lastname: Simon
authors.forename: Ivona
authors.initials: I
authors.lastname: Aksentijevich
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000145:classification* / Q000235:genetics / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000145:classification* / Q000235:genetics / Q000276:immunology*; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D053583:Interleukin-1beta; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D014409:Tumor Necrosis Factor-alpha; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase