title: An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome.
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.
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute for Arthritis and Musculoskeletal and Skin Diseases (NIAMS), US National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Canna
authors.affiliation: Translational Autoinflammatory Disease Section, NIAMS, NIH, Bethesda, Maryland, USA.
authors.forename: Adriana A
authors.initials: AA
authors.lastname: de Jesus
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute for Arthritis and Musculoskeletal and Skin Diseases (NIAMS), US National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Sushanth
authors.initials: S
authors.lastname: Gouni
authors.affiliation: Biodata Mining and Discovery Section, Office of Science and Technology, NIAMS, NIH, Bethesda, Maryland, USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Brooks
authors.affiliation: Translational Autoinflammatory Disease Section, NIAMS, NIH, Bethesda, Maryland, USA.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Marrero
authors.affiliation: Translational Autoinflammatory Disease Section, NIAMS, NIH, Bethesda, Maryland, USA.
authors.forename: Yin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Laboratory of Structural Biology, NIAMS, NIH, Bethesda, Maryland, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: DiMattia
authors.affiliation: Light Imaging Section, Office of Science and Technology, NIAMS, NIH, Bethesda, Maryland, USA.
authors.forename: Kristien J M
authors.initials: KJ
authors.lastname: Zaal
authors.affiliation: 1] Translational Autoinflammatory Disease Section, NIAMS, NIH, Bethesda, Maryland, USA. [2] Office of the Clinical Director, NIAMS, NIH, Bethesda, Maryland, USA.
authors.forename: Gina A Montealegre
authors.initials: GA
authors.lastname: Sanchez
authors.affiliation: Translational Autoinflammatory Disease Section, NIAMS, NIH, Bethesda, Maryland, USA.
authors.forename: Hanna
authors.initials: H
authors.lastname: Kim
authors.affiliation: 1] Translational Autoinflammatory Disease Section, NIAMS, NIH, Bethesda, Maryland, USA. [2] Office of the Clinical Director, NIAMS, NIH, Bethesda, Maryland, USA.
authors.forename: Dawn
authors.initials: D
authors.lastname: Chapelle
authors.affiliation: 1] Translational Autoinflammatory Disease Section, NIAMS, NIH, Bethesda, Maryland, USA. [2] Office of the Clinical Director, NIAMS, NIH, Bethesda, Maryland, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Plass
authors.affiliation: Translational Autoinflammatory Disease Section, NIAMS, NIH, Bethesda, Maryland, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute for Arthritis and Musculoskeletal and Skin Diseases (NIAMS), US National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Alejandro V
authors.initials: AV
authors.lastname: Villarino
authors.affiliation: Center for Human Immunology, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
authors.forename: Angelique
authors.initials: A
authors.lastname: Biancotto
authors.affiliation: Department of Laboratory Medicine, NIH Clinical Center, Bethesda, Maryland, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Fleisher
authors.affiliation: Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Duncan
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute for Arthritis and Musculoskeletal and Skin Diseases (NIAMS), US National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Shea
authors.affiliation: Pediatric Rheumatology, Alberta Children's Hospital and University of Calgary, Calgary, Alberta, Canada.
authors.forename: Susanne
authors.initials: S
authors.lastname: Benseler
authors.affiliation: Pediatric Rheumatology, Cincinnati Children's Hospital and University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Alexei
authors.initials: A
authors.lastname: Grom
authors.affiliation: Biodata Mining and Discovery Section, Office of Science and Technology, NIAMS, NIH, Bethesda, Maryland, USA.
authors.forename: Zuoming
authors.initials: Z
authors.lastname: Deng
authors.affiliation: Pediatric Rheumatology, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Laxer
authors.affiliation: Translational Autoinflammatory Disease Section, NIAMS, NIH, Bethesda, Maryland, USA.
authors.forename: Raphaela
authors.initials: R
authors.lastname: Goldbach-Mansky
mesh_terms: D000595:Amino Acid Sequence; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002648:Child; D059472:Exome / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D058847:Inflammasomes / Q000235:genetics*; D007249:Inflammation / Q000097:blood / Q000235:genetics*; D020382:Interleukin-18 / Q000097:blood / Q000378:metabolism; D055501:Macrophage Activation Syndrome / Q000097:blood / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D020411:Oligonucleotide Array Sequence Analysis; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid
chemical_list: D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D058847:Inflammasomes; D020382:Interleukin-18; C435692:NLRC4 protein, human