title: Novel NLRP3/cryopyrin mutations and pro-inflammatory cytokine profiles in Behçet's syndrome patients.
abstract: Behçet's syndrome (BS) is a systemic inflammatory disorder with unknown etiology. Features of both innate and adaptive immunity have been claimed in the pathogenesis of BS. To test the possible dysregulation of the NLRP3/cryopyrin (Nod-like receptor with a pyrin domain 3) inflammasome, as a result of mutation(s), we performed single-strand conformation polymorphism analyses and/or sequencing of all the coding regions and intron-exon boundaries of NLRP3/cryopyrin and ASC (apoptosis-associated speck-like protein containing CARD) genes from Turkish BS patients and healthy controls. At the same time, we determined pro-inflammatory cytokine secretion profiles of peripheral blood cells in response to LPS treatment using ELISA. BS patients with vascular involvement showed significantly increased levels of TNF-α release at 2-, 4- and 8-h post-treatment and significantly increased IL-1β levels were detected at 2h (P = 0.005) and 4h (P = 0.025) (n = 10). We identified four mutations in the NLRP3/cryopyrin gene, V200M (n = 3/104) and T195M (n = 1/104), in BS patients but none in control samples. No mutations were detected in the ASC gene. The effect of these NLRP3/cryopyrin mutants on ASC speck assembly and IL-1β secretion was tested and the V200M mutant was shown to induce IL-1β secretion. Thus, it is likely that certain mutations in NLRP3/cryopyrin in combination with yet unknown other factors may contribute to the pro-inflammatory cytokine profiles in BS patients.
authors.affiliation: Molecular Biology and Genetics Department, Apoptosis and Cancer Immunology Laboratory (AKiL), Bogazici University, Bebek-Istanbul 34342, Turkey.
authors.forename: Şahru
authors.initials: Ş
authors.lastname: Yüksel
authors.forename: Elif
authors.initials: E
authors.lastname: Eren
authors.forename: Gülen
authors.initials: G
authors.lastname: Hatemi
authors.forename: Ali Can
authors.initials: AC
authors.lastname: Sahillioğlu
authors.forename: Yetiş
authors.initials: Y
authors.lastname: Gültekin
authors.forename: Duygu
authors.initials: D
authors.lastname: Demiröz
authors.forename: Cezmi
authors.initials: C
authors.lastname: Akdiş
authors.forename: İzzet
authors.initials: İ
authors.lastname: Fresko
authors.forename: Nesrin
authors.initials: N
authors.lastname: Özören
mesh_terms: D000328:Adult; D001528:Behcet Syndrome / Q000235:genetics / Q000276:immunology*; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D009154:Mutation / Q000235:genetics*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011110:Polymorphism, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014421:Turkey; D055815:Young Adult
chemical_list: D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C402202:PYCARD protein, human; D014409:Tumor Necrosis Factor-alpha
keywords: ASC; IL-1β; NLR; TNF-α; autoinflammation