An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome

  • Nat Genet. 2014 Oct;46(10):1140-6. doi: 10.1038/ng.3089.
Scott W Canna  1 ,  Adriana A de Jesus  2 ,  Sushanth Gouni  1 ,  Stephen R Brooks  3 ,  Bernadette Marrero  2 ,  Yin Liu  2 ,  Michael A DiMattia  4 ,  Kristien J M Zaal  5 ,  Gina A Montealegre Sanchez  6 ,  Hanna Kim  2 ,  Dawn Chapelle  6 ,  Nicole Plass  6 ,  Yan Huang  2 ,  Alejandro V Villarino  1 ,  Angelique Biancotto  7 ,  Thomas A Fleisher  8 ,  Joseph A Duncan  9 ,  John J O'Shea  1 ,  Susanne Benseler  10 ,  Alexei Grom  11 ,  Zuoming Deng  3 ,  Ronald M Laxer  12 ,  Raphaela Goldbach-Mansky  2
Affiliations
  • 1. Molecular Immunology and Inflammation Branch, National Institute for Arthritis and Musculoskeletal and Skin Diseases (NIAMS), US National Institutes of Health (NIH), Bethesda, Maryland, USA.
  • 2. Translational Autoinflammatory Disease Section, NIAMS, NIH, Bethesda, Maryland, USA.
  • 3. Biodata Mining and Discovery Section, Office of Science and Technology, NIAMS, NIH, Bethesda, Maryland, USA.
  • 4. Laboratory of Structural Biology, NIAMS, NIH, Bethesda, Maryland, USA.
  • 5. Light Imaging Section, Office of Science and Technology, NIAMS, NIH, Bethesda, Maryland, USA.
  • 6. 1] Translational Autoinflammatory Disease Section, NIAMS, NIH, Bethesda, Maryland, USA. [2] Office of the Clinical Director, NIAMS, NIH, Bethesda, Maryland, USA.
  • 7. Center for Human Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
  • 8. Department of Laboratory Medicine, NIH Clinical Center, Bethesda, Maryland, USA.
  • 9. Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
  • 10. Pediatric Rheumatology, Alberta Children's Hospital and University of Calgary, Calgary, Alberta, Canada.
  • 11. Pediatric Rheumatology, Cincinnati Children's Hospital and University of Cincinnati, Cincinnati, Ohio, USA.
  • 12. Pediatric Rheumatology, Hospital for Sick Children, Toronto, Ontario, Canada.
PMID: 25217959 DOI: 10.1038/ng.3089
Abstract

Inflammasomes are innate immune sensors that respond to pathogen- and damage-associated signals with Caspase-1 activation, interleukin (IL)-1β and IL-18 secretion, and macrophage Pyroptosis. The discovery that dominant gain-of-function mutations in NLRP3 cause the cryopyrin-associated periodic syndromes (CAPS) and trigger spontaneous inflammasome activation and IL-1β oversecretion led to successful treatment with IL-1-blocking agents. Herein we report a de novo missense mutation (c.1009A > T, encoding p.Thr337Ser) affecting the nucleotide-binding domain of the inflammasome component NLRC4 that causes early-onset recurrent fever flares and macrophage activation syndrome (MAS). Functional analyses demonstrated spontaneous inflammasome formation and production of the inflammasome-dependent cytokines IL-1β and IL-18, with the latter exceeding the levels seen in CAPS. The NLRC4 mutation caused constitutive Caspase-1 cleavage in cells transduced with mutant NLRC4 and increased production of IL-18 in both patient-derived and mutant NLRC4-transduced Macrophages. Thus, we describe a new monoallelic inflammasome defect that expands the monogenic autoinflammatory disease spectrum to include MAS and suggests new targets for therapy.