Artikel
Comparison of Neutrophilic Activation and Secretion of Cytokines derived from Patients with Familial Mediterranean Fever and other Acute and Chronic Inflammatory Diseases
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Autoren
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Iris Stoler
- Charité - Universitätsmedizin Berlin, Klinik für Pädiatrie mit Schwerpunkt Pneumologie und Immunologie, Sektion Rheumatologie, Berlin
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Judith Freytag
- Charité - Universitätsmedizin Berlin, Klinik für Pädiatrie mit Schwerpunkt Pneumologie und Immunologie, Sektion Rheumatologie, Berlin
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Banu Orak
- Charité - Universitätsmedizin Berlin, Klinik für Pädiatrie mit Schwerpunkt Pneumologie und Immunologie, Sektion Rheumatologie, Berlin
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Christine Seib
- Charité - Universitätsmedizin Berlin, Charité - Universitätsmedizin Berlin, Berlin
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Lars Esmann
- Department of Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin, Berlin
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Eva C. D. Seipelt
- Immanuel Krankenhaus Berlin, Klinik für Innere Medizin, Abteilung Rheumatologie und Klinische Immunologie, Berlin
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Faekah Gohar
- Department of Paediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster
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Dirk Foell
- Department of Paediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster
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Helmut Wittkowski
- Department of Paediatric Rheumatology and Immunology, University Children's Hospital Münster, Münster
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Tilmann Kallinich
- Charité - Universitätsmedizin Berlin, Klinik für Pädiatrie mit Schwerpunkt Pneumologie und Immunologie, Sektion Rheumatologie, Berlin
| Veröffentlicht: | 29. August 2016 |
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Gliederung
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Background: In Familiar Mediterranean Fever (FMF), the most common monogenic autoinflammatory disorder, gain-of-function mutations lead to an increased activation of the inflammasome. Neutrophils play a key role in the pathogenesis of FMF.
Objectives: (i) To identify a FMF-specific genotype-dependent activation of neutrophilic surface markers and (ii) to describe an ex vivo activation of the inflammasome and the secretion of cytokines and S-100 molecules. (iii) To compare the observed activation patterns to changes in neutrophils from patients with other inflammatory diseases.
Methods: 6 FMF patients, 6 healthy heterozygous carriers and 4-6 patients with active Crohn’s disease, cystic fibrosis, rheumatoid arthritis / spondylarthritis, immundeficiencies with autoinflammation, other autoinflammatory diseases and acute infections as well as healthy controls were analyzed. CRP, IL-18, S100A12 und Caspase-1 were determined in serum. After neutrophil seperation by density gradient, neutrophils were cultivated. The kinetics of the surface expression of CD62L and CD11b was measured at 0h, 1/2h, 1h, 2h, 3h, 4h and 5h. Furthermore, the cells from the FMF patients were stimulated (LPS 4h + ATP 30 min) and treated with colchicine. S100A12, IL-18 and Caspase-1 were measured in the cell culture supernatants at the correspondent time-points. The effect of an IL-1 inhibition on the secretion of the specified parameters was evaluated by treatment with Anakinra.
Results: Compared to healthy controls, neutrophil granulocytes from FMF patients show a spontaneous hypersecretion of IL-18, Caspase-1, S100A12 and S100A8/9. Neutrophils from homozygous FMF patients showed a strong spontaneous activation measured by means of CD62L expression (MIF 1736 [SD 453] before cultivation; MIF 22 [SD 33] after 5 hours). Neutrophils from healthy heterozygous FMF subjects exhibited lower activation levels (MIF 1216 [382] vs. 709 [208]). In contrast, neutrophils from patients with other inflammatory diseases (2093 [661] vs. 1734 [579]) and healthy controls (1766 [512] vs. 1478 [345]) showed low activation levels. Patients with acute infections showed an inhomogenous activation pattern. Blockade of IL-1 did not alter spontaneous neutrophilc activation.
Conclusion: The spontaneous activation of neutrophils from patients with FMF is a disease specific genotype-dependent phenomenon.
