Correlation of Secretory Activity of Neutrophils With Genotype in Patients With Familial Mediterranean Fever

被引：28

作者：

Gohar, Faekah ^{[1
]}

Orak, Banu ^{[2
]}

Kallinich, Tilmann ^{[2
]}

Jeske, Marion ^{[3
]}

Lieber, Mareike ^{[2
]}

von Bernuth, Horst ^{[2
,4
]}

Giese, Arnd ^{[5
]}

Weissbarth-Riedel, Elisabeth ^{[6
]}

Haas, Johannes-Peter ^{[7
]}

Dressler, Frank ^{[8
]}

Holzinger, Dirk ^{[1
]}

Lohse, Peter ^{[9
]}

Neudorf, Ulrich ^{[3
]}

Lainka, Elke ^{[3
]}

Hinze, Claas ^{[1
]}

Masjosthusmann, Katja ^{[1
]}

Kessel, Christoph ^{[1
]}

Weinhage, Toni ^{[1
]}

Foell, Dirk ^{[1
]}

Wittkowski, Helmut ^{[1
]}

机构：

[1] Univ Childrens Hosp, Munster, Germany

[2] Charite, Berlin, Germany

[3] Univ Duisburg Essen, Essen, Germany

[4] Labor Berlin Charite Vivantes GmbH, Berlin, Germany

[5] Ruhr Univ, St Josef Hosp, Bochum, Germany

[6] Univ Hosp Hamburg Eppendorf, Hamburg, Germany

[7] German Ctr Child & Adolescent Rheumatol, Garmisch Partenkirchen, Germany

[8] Hannover Med Sch, Hannover, Germany

[9] Ctr Genom & Transcript, Tubingen, Germany

来源：

Arthritis & Rheumatology | 2016年 / 68卷 / 12期

关键词：

JUVENILE IDIOPATHIC ARTHRITIS; AUTOINFLAMMATORY DISEASES; IL-1-BETA PRODUCTION; NLRP3; INFLAMMASOME; MEFV MUTATIONS; COLCHICINE; AMYLOIDOSIS; ACTIVATION; CHILDREN; PROTEIN;

D O I：

10.1002/art.39784

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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-1 beta, and caspase 1 was determined. Based on these in vitro analyses, serum concentrations of S100A12, IL-18, and IL-1 beta 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 markersmight help to improve patient care and outcomes.

引用

页码：3010 / 3022

页数：13