2. Academic Validation
  3. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome

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

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.

Figures