title: Correlation of Secretory Activity of Neutrophils With Genotype in Patients With Familial Mediterranean Fever.
abstract: Familial Mediterranean fever (FMF) is an autoinflammatory disorder caused by pyrin-encoding MEFV mutations. Patients present with recurrent but self-limiting episodes of acute inflammation and often have persistent subclinical inflammation. The pathophysiology is only partially understood, but neutrophil overactivation is a hallmark of the disease. S100A12 is a neutrophil-derived proinflammatory danger signal that is strongly elevated in active FMF. This study was undertaken to characterize the secretory activity of neutrophils in vitro and investigate the association of S100A12 with disease activity and genotype in patients with FMF.
  
  
  
  Neutrophils from FMF patients carrying the p.M694V mutation (1 compound heterozygous and 5 homozygous) and neutrophils from 4 healthy control subjects were purified and stimulated in vitro. Neutrophil secretion of S100A12, interleukin-18 (IL-18), IL-1β, and caspase 1 was determined. Based on these in vitro analyses, serum concentrations of S100A12, IL-18, and IL-1β were also analyzed in 128 clinically and genetically characterized patients with FMF.
  
  
  
  In vitro, unstimulated neutrophils from p.M694V-positive patients spontaneously secreted more S100A12, IL-18, and caspase 1 compared to neutrophils from healthy controls. Serum concentrations of S100A12 correlated with disease activity and genotype, with the levels being highest in homozygous patients and with compound heterozygotes displaying higher levels than heterozygotes. Compared to individuals negative for the p.M694V mutation, heterozygous, compound heterozygous, or homozygous p.M694V-positive patients had higher serum levels of S100A12 and IL-18 during inactive and subclinical disease.
  
  
  
  The FMF phenotype is known to be more severe in patients carrying the p.M694V mutation. This report describes 2 molecules secreted by unconventional secretory pathways, S100A12 and IL-18, whose concentrations correlated with clinical disease activity and genotype in patients with FMF. In this clinically and genetically heterogeneous disease, management of these surrogate markers might help to improve patient care and outcomes.
authors.affiliation: University Children's Hospital, Muenster, Germany.
authors.forename: Faekah
authors.initials: F
authors.lastname: Gohar
authors.affiliation: Charité University Medicine, Berlin, Germany.
authors.forename: Banu
authors.initials: B
authors.lastname: Orak
authors.affiliation: Charité University Medicine, Berlin, Germany.
authors.forename: Tilmann
authors.initials: T
authors.lastname: Kallinich
authors.affiliation: University of Duisburg-Essen, Essen, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Jeske
authors.affiliation: Charité University Medicine, Berlin, Germany.
authors.forename: Mareike
authors.initials: M
authors.lastname: Lieber
authors.affiliation: Labor Berlin-Charité Vivantes GmbH and Charité University Medicine, Berlin, Germany.
authors.forename: Horst
authors.initials: H
authors.lastname: von Bernuth
authors.affiliation: St. Josef-Hospital, Ruhr University, Bochum, Germany.
authors.forename: Arnd
authors.initials: A
authors.lastname: Giese
authors.affiliation: University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Weissbarth-Riedel
authors.affiliation: German Centre for Child and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany.
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Haas
authors.affiliation: Hannover Medical School, Hannover, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Dressler
authors.affiliation: University Children's Hospital, Muenster, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Holzinger
authors.affiliation: Center for Genomics and Transcriptomics, Tuebingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lohse
authors.affiliation: University of Duisburg-Essen, Essen, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Neudorf
authors.affiliation: University of Duisburg-Essen, Essen, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Lainka
authors.affiliation: University Children's Hospital, Muenster, Germany.
authors.forename: Claas
authors.initials: C
authors.lastname: Hinze
authors.affiliation: University Children's Hospital, Muenster, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Masjosthusmann
authors.affiliation: University Children's Hospital, Muenster, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kessel
authors.affiliation: University Children's Hospital, Muenster, Germany.
authors.forename: Toni
authors.initials: T
authors.lastname: Weinhage
authors.affiliation: University Children's Hospital, Muenster, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Foell
authors.affiliation: University Children's Hospital, Muenster, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Wittkowski
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D020170:Caspase 1 / Q000097:blood / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D010505:Familial Mediterranean Fever / Q000097:blood / Q000235:genetics* / Q000276:immunology; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D066298:In Vitro Techniques; D020382:Interleukin-18 / Q000097:blood / Q000378:metabolism*; D053583:Interleukin-1beta / Q000097:blood / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D000071198:Pyrin / Q000235:genetics*; D000067616:S100A12 Protein / Q000097:blood / Q000378:metabolism*; D055815:Young Adult
chemical_list: C508585:IL1B protein, human; D020382:Interleukin-18; D053583:Interleukin-1beta; C000604192:MEFV protein, human; D000071198:Pyrin; D000067616:S100A12 Protein; C090441:S100A12 protein, human; D020170:Caspase 1