title: Reduced serpinB9-mediated caspase-1 inhibition can contribute to autoinflammatory disease.
abstract: Patients who suffer from autoinflammatory disease (AID) exhibit seemingly uncontrolled release of interleukin (IL)-1β. The presence of this inflammatory cytokine triggers immune activation in absence of pathogens and foreign material. The mechanisms that contribute to 'sterile inflammation' episodes in AID patients are not fully understood, although for some AIDs underlying genetic causes have been identified. We show that the serine protease inhibitor B9 (serpinB9) regulates IL-1β release in human monocytes. SerpinB9 function is more commonly known for its role in control of granzyme B. SerpinB9 however also serves to restrain IL-1β maturation through caspase-1 inhibition. We here describe an autoinflammatory disease-associated serpinB9 (c.985G>T, A329S) variant, which we discovered in a patient with unknown AID. Using patient cells and serpinB9 overexpressing monocytic cells, we show the A329S variant of serpinB9 exhibits unobstructed granzyme B inhibition, but compromised caspase-1 inhibition. SerpinB9 gene variants might contribute to AID development.
authors.affiliation: Department of Pediatric Immunology, Wilhelmina Children's Hospital, UMC Utrecht, EA, Utrecht, Netherlands.|Laboratory of Translational Immunology, University Medical Center Utrecht, CX, Utrecht, Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: van der Burgh
authors.affiliation: Department of Pathology, University Medical Center Utrecht, CX, Utrecht, Netherlands.|Laboratory of Translational Immunology, University Medical Center Utrecht, CX, Utrecht, Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Meeldijk
authors.affiliation: Department of Pediatric Immunology, Wilhelmina Children's Hospital, UMC Utrecht, EA, Utrecht, Netherlands.|Laboratory of Translational Immunology, University Medical Center Utrecht, CX, Utrecht, Netherlands.
authors.forename: Lieneke
authors.initials: L
authors.lastname: Jongeneel
authors.affiliation: Department of General Pediatrics, Wilhelmina Children's Hospital, UMC Utrecht, EA, Utrecht, Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Frenkel
authors.affiliation: Department of Pathology, University Medical Center Utrecht, CX, Utrecht, Netherlands.|Laboratory of Translational Immunology, University Medical Center Utrecht, CX, Utrecht, Netherlands.
authors.forename: Niels
authors.initials: N
authors.lastname: Bovenschen
authors.affiliation: Department of Genetics, University Medical Center Utrecht, EA, Utrecht, Netherlands.
authors.forename: Mariëlle
authors.initials: M
authors.lastname: van Gijn
authors.affiliation: Department of Pediatric Immunology, Wilhelmina Children's Hospital, UMC Utrecht, EA, Utrecht, Netherlands.|Laboratory of Translational Immunology, University Medical Center Utrecht, CX, Utrecht, Netherlands.
authors.forename: Marianne
authors.initials: M
authors.lastname: Boes
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001327:Autoimmune Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001483:Base Sequence; D020170:Caspase 1 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002648:Child; D005192:Family Health; D005260:Female; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism*; D008297:Male; D009000:Monocytes / Q000378:metabolism; D009154:Mutation; D017386:Sequence Homology, Amino Acid; D015843:Serpins / Q000235:genetics / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; C102316:SERPINB9 protein, human; D015843:Serpins; D020170:Caspase 1
keywords: Immune response; Immunity; Immunology and Microbiology Section; autoinflammation; caspase-1; granzyme B; interleukin 1β; serpinB9