title: A functional inflammasome activation assay differentiates patients with pathogenic NLRP3 mutations and symptomatic patients with low penetrance variants.
abstract: Cryopyrin-associated periodic syndromes (CAPS) are characterized by recurrent episodes of systemic inflammation caused by mutations in the NLRP3 gene. Besides confirmed pathogenic NLRP3 mutations, patients with CAPS-like symptoms frequently show low penetrance variants in NLRP3. The disease relevance of these variants is inconsistent. In this study, we investigated if an inflammasome activation assay differentiates between patients with confirmed pathogenic CAPS mutations, patients with low penetrance NLRP3 variants (V198M and Q703K) and healthy controls. The release of mature IL-1β, IL-18, and caspase-1 into cell culture supernatants after 4h of inflammasome stimulation was significantly increased in patients with confirmed pathogenic CAPS mutations compared to low penetrance NLRP3 variants and controls. IL-1β secretion in CAPS patients correlated with disease severity. This inflammasome activation assay differentiates between autoinflammation patients with confirmed pathogenic CAPS mutations and patients with low penetrance NLRP3 variants, and points towards alternative pathophysiological mechanisms in low penetrance NLRP3 variants.
authors.affiliation: Department of Pediatrics I, University of Tuebingen, Tuebingen, Germany. Electronic address: nikolaus.rieber@med.uni-tuebingen.de.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Rieber
authors.affiliation: Department of Pediatrics I, University of Tuebingen, Tuebingen, Germany.
authors.forename: Alina
authors.initials: A
authors.lastname: Gavrilov
authors.affiliation: Department of Pediatrics I, University of Tuebingen, Tuebingen, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Hofer
authors.affiliation: Department of Pediatrics I, University of Tuebingen, Tuebingen, Germany.
authors.forename: Anurag
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Pediatrics I, University of Tuebingen, Tuebingen, Germany.
authors.forename: Hasan
authors.initials: H
authors.lastname: Öz
authors.affiliation: Department of Pediatrics I, University of Tuebingen, Tuebingen, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Endres
authors.affiliation: Department of Pediatrics I, University of Tuebingen, Tuebingen, Germany.
authors.forename: Iris
authors.initials: I
authors.lastname: Schäfer
authors.affiliation: Department of Pediatrics I, University of Tuebingen, Tuebingen, Germany.
authors.forename: Rupert
authors.initials: R
authors.lastname: Handgretinger
authors.affiliation: Department of Pediatrics I, University of Tuebingen, Tuebingen, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Hartl
authors.affiliation: Department of Pediatrics I, University of Tuebingen, Tuebingen, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Kuemmerle-Deschner
mesh_terms: D000328:Adult; D001681:Biological Assay / Q000379:methods*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D056587:Cryopyrin-Associated Periodic Syndromes / Q000235:genetics / Q000503:physiopathology; D005260:Female; D014644:Genetic Variation; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human
keywords: Autoinflammation; CAPS; IL-1β; NLRP3; TNF-α; Variants