Article Text

SP0155 New genes in autoinflammation ... provide new insights into disease pathogenesis beyond IL-1
  1. R. Goldbach-Mansky
  1. Translational Autoinflammatory Disease Section, National Institute of Arthritis, Musculoskeletal and Skin diseases (NIAMS)/NIH, Bethesda, United States


The rapid discovery of the molecular basis of a growing number of autoinflammatory diseases presenting early in childhood with fever and systemic and sterile organ inflammation, is providing us with novel insights into the workings of the innate immune system in coordinating inflammatory responses and their resolution. These discoveries have not only provided insights into the phenotypic disease expression and provided novel treatments of these rare disorders, but the principles learnt are suggesting hypotheses of how inflammatory processes can be triggered in common likely polygenic diseases such as gout, and those that were not considered inflammatory in the past, including diabetes, coronary artery diseases and Alzheimer’s disease.

The discovery that missense mutations in CIAS1/NLRP3, cause the clinical spectrum of the cryopyrin associated periodic syndromes (CAPS), which includes FCAS, MWS and NOMID/CINCA, has revealed an intracellular sensor of “danger”, the NLRP3 inflammasome, that couples pathogen and cell stress recognition with IL-1 activation to coordinate an immune response to these danger signals. The finding that the inflammasome leads to caspase-1 activation and cleavage and activation of IL-1β, spurred early proof of concept studies that tested IL-1 blocking strategies and revealed the pivotal role of the proinflammatory cytokine IL-1 in the pathogenesis of CAPS. These studies led to the establishment of anticytokine therapy with IL-1 blocking agents, that have changed patients life and disease outcomes, as standard of care therapies for these conditions. The discovery that the accumulation of molecular stress molecules in specific organs in gout, Type II diabetes and endothelial plaques in coronary artery disease can stimulate the inflammasome to produce IL-1, has led to the hypothesis that inflammasome activation may contribute to the inflammatory manifestations of metabolic diseases and provided the rationale to explore IL-1 blocking therapies in these conditions.

However, a growing number of patients with autoinflammatory conditions are unresponsive to IL-1 blocking therapy and force the exploration of additional pathways beyond IL-1. The discovery of novel, IL-1 independent autoinflammatory disorders with systemic and organ specific inflammation has provided insights into additional inflammatory pathways that may shed light on molecular causes of fat, muscle, and pustular skin inflammation. Mutations in proteasome genes, i.e. PSMB8, cause a spectrum of proteasome-associated autoinflammatory conditions termed: Joint contracture, muscle atrophy and panniculitis induced lipodystrophy (JMP) syndrome, Nakajo-Nishimura syndrome and Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures, (CANDLE). Recent mutation in genes that encode proteins that are mainly expressed in the skin, are providing new insights into pathways that regulate skin inflammation and reveal novel targets for therapy.

Learning Objectives At the end of the session the listener will be able to:

  • Recognize clinical signs and symptoms of autoinflammatory diseases

  • Understand pathogenesis of the inflammasome mediated cryopyrin associated periodic syndromes (CAPS), and recognize disease pathology mediated by IL-1.

  • Understand the presumed role of inflammasome mediated IL-1 release on the inflammatory manifestations of gout, and metabolic conditions such as diabetes, atherosclerosis and obesity and know the rational for the development of studies that treat patients with diabetes and coronary artery diseases with IL-1 blocking agents.

  • Recognize a number of monogenic disorders that are not IL-1 responsive and provide us novel innate immune pathways that regulate inflammation including the proteasome associated autoinflammatory syndromes.

Disclosure of Interest None Declared

Statistics from

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.