title: The systemic autoinflammatory diseases: inborn errors of the innate immune system.
abstract: The autoinflammatory syndromes are a newly recognized group of immune disorders that lack the high titers of self-reactive antibodies and T cells characteristic of classic autoimmune disease. Nevertheless, patients with these illnesses experience unprovoked inflammatory disease in the absence of underlying infection. Here we discuss recent advances in eight Mendelian autoinflammatory diseases. The causative genes and the proteins they encode play a critical role in the regulation of innate immunity. Both pyrin and cryopyrin, the proteins mutated in familial Mediterranean fever and the cryopyrinopathies, respectively, are involved in regulation of the proinflammatory cytokine, IL-1beta, and may influence the activity of the transcription factor, NFkappaB. NOD2, the Blau syndrome protein, shares certain domains with cryopyrin and appears to be a sensor of intracellular bacteria. PSTPIP1, mutated in the syndrome of pyogenic arthritis with pyoderma gangrenosum and acne, interacts both with pyrin and a protein tyrosine phosphatase to regulate innate and adaptive immune responses. Somewhat unexpectedly, mutations in the p55 TNF receptor lead not to immunodeficiency but to dramatic inflammatory disease, the mechanisms of which are still under investigation. Finally, the discovery of the genetic basis of the hyperimmunoglobulinemia D with periodic fever syndrome has provided a fascinating but incompletely understood link between cholesterol biosynthesis and autoinflammation. In this manuscript, we summarize the current state of the art with regard to the diagnosis, pathogenesis, and treatment of these inborn errors of the innate immune system.
authors.affiliation: Genetics and Genomics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892-1820, USA. brydgess@mail.nih.gov
authors.forename: S
authors.initials: S
authors.lastname: Brydges
authors.forename: D L
authors.initials: DL
authors.lastname: Kastner
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000502:physiology; D010505:Familial Mediterranean Fever / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D006801:Humans; D006942:Hypergammaglobulinemia / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate; D007072:Immunoglobulin D / Q000032:analysis*; D007249:Inflammation / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017511:Pyoderma Gangrenosum / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D000071198:Pyrin; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D007072:Immunoglobulin D; C000604192:MEFV protein, human; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C486382:PSTPIP1 protein, human; D000071198:Pyrin; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; C069521:recombinant human tumor necrosis factor-binding protein-1