title: Update on genetics and pathogenesis of autoinflammatory diseases: the last 2 years.
abstract: Autoinflammatory diseases are a genetically heterogeneous group of rheumatologic diseases that are driven by abnormal activation of the innate immune system. Patients present with recurrent episodes of systemic inflammation and a spectrum of organ-specific comorbidities. These diseases are mediated by the overproduction of various inflammatory cytokines, such as IL-1, IL-18, IL-6, TNFα, and type I interferon. Treatments with biologic agents that inhibit these cytokines have been very efficient in most patients. During the past 2 years, remarkable progress has been made in the identification of disease-associated genes owing mostly to new technologies. Next generation sequencing technologies (NGS) have become instrumental in finding single-gene defects in undiagnosed patients with early onset symptoms. NGS has advanced the field of autoinflammation by identifying disease-causing genes that point to pathways not known to regulate cytokine signaling or inflammation. They include a protein that has a role in differentiation of myeloid cells, a ubiquitously expressed enzyme that catalyzes the addition of the CCA terminus to the 3-prime end of tRNA precursors, and an enzyme that catalyzes the oxidation of a broad range of substrates. Lastly, newly described mutations have informed a whole new dimension on genotype-phenotype relationships. Mutations in the same gene can give rise to a range of phenotypes with a common inflammatory component. This suggests greater than anticipated contributions by modifying alleles and environmental factors to disease expressivity.
authors: Inflammatory Disease Section, National Human Genome Research Institute, Bldg. 10/Rm. B2-5235, 10 Center Drive - MSC 1849, Bethesda, MD, 20892-1849, USA, aksentii@mail.nih.gov.
authors: Ivona
authors: I
authors: Aksentijevich
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics; D017668:Age of Onset; D001327:Autoimmune Diseases / Q000175:diagnosis / Q000209:etiology*; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D056726:Genetic Association Studies; D056660:Hereditary Autoinflammatory Diseases / Q000175:diagnosis / Q000209:etiology*; D006801:Humans; D007249:Inflammation / Q000175:diagnosis / Q000209:etiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics; D000099197:STING Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D053246:Receptor Activator of Nuclear Factor-kappa B; D014157:Transcription Factors; C435692:NLRC4 protein, human; C532857:STING1 protein, human; D000099197:STING Protein; C097695:TADA2A protein, human