학술논문
Correlation of Secretory Activity of Neutrophils With Genotype in Patients With Familial Mediterranean Fever.
Document Type
Article
Author
Gohar, Faekah; Orak, Banu; Kallinich, Tilmann; Jeske, Marion; Lieber, Mareike; von Bernuth, Horst; Giese, Arnd; Weissbarth‐Riedel, Elisabeth; Haas, Johannes‐Peter; Dressler, Frank; Holzinger, Dirk; Lohse, Peter; Neudorf, Ulrich; Lainka, Elke; Hinze, Claas; Masjosthusmann, Katja; Kessel, Christoph; Weinhage, Toni; Foell, Dirk; Wittkowski, Helmut
Source
Subject
*BIOMARKERS
*C-reactive protein
*DOSE-response relationship in biochemistry
*FLOW cytometry
*GENETIC disorders
*INFLAMMATION
*INTERLEUKINS
*GENETIC mutation
*NEUTROPHILS
*RESEARCH funding
*STATISTICS
*PHENOTYPES
*DATA analysis
*RETROSPECTIVE studies
*SEVERITY of illness index
*DESCRIPTIVE statistics
*IN vitro studies
*MANN Whitney U Test
*GENOTYPES
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Language
ISSN
2326-5191
Abstract
Objective 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. Methods 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. Results 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. Conclusion 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. [ABSTRACT FROM AUTHOR]