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Impaired endotoxin tolerance induction in patients with familial Mediterranean fever
Tigran K Davtyan1, Gagik S Hakopyan, Samvel A Avetisyan
1Laboratory of Immunology and Virology, Armenicum Research Center, Yerevan State Medical University, Republic of Armenia. tigdav@excite.com
Objective:
To investigate periodic disturbances in proinflammatory activation of neutrophils and monocytes in patients with familial Mediterranean fever (FMF) both during an attack and in remission.
Methods:
20 FMF patients, who were naive to colchicine treatment and did not have amyloidosis, and 10 patients with Behçet's disease (BD) were enrolled in this study. Phagocytosis, respiratory burst, CD11a/CD18 expression and intracellular cytokine synthesis were determined by flow cytometry. Endotoxin tolerance induction was defined by a reduced capacity of monocytes to respond to lipopolysaccharide (LPS) activation following a first exposure to LPS.
Results:
In FMF patients, we observed upregulation of neutrophil and monocyte phagocytic activity and oxidative burst during remission and downregulation of phagocytic activity and stimulus-dependent oxidative burst during an attack. A comparative analysis of oxidative burst has revealed that while the neutrophil population shows a certain periodicity in the increase (during remission) and decrease (during attacks) in the spontaneous and inducible respiratory burst, periodicity in the monocyte population is very poor. In addition, LPS-induced oxidative burst and CD11a/CD18 integrin surface expression is higher in patients during an attack compared to patients in remission. The induction of homologous tolerance of monocytes to the repeated action of LPS is observed in FMF patients during an attack, normal donors and patients with BD, whereas monocytes from patients in remission failed to induce LPS homologous tolerance and exhibited heightened sensitivity to bacterial endotoxin. We found that colchicine is able to restore impaired LPS homologous tolerance induction in FMF patients in remission upon increased synthesis of IL-4 in FMF patient monocytes.
Conclusion:
Chronic inflammation during FMF is characterized by periodic changes in monocyte and neutrophil activation and heightened sensitivity to endotoxin, which is associated with the episodic nature of FMF. Increased endotoxin sensitivity in the period of remission could result from a shift in the monocyte activation program from 'alternatively' into 'classically' activated monocytes, which may have important implications for the treatment of FMF.
Insights
Familial Mediterranean Fever (FMF) involves periodic immune cell changes, with heightened endotoxin sensitivity during remission. Colchicine may restore normal immune responses in FMF patients.
Area of Science:
- Immunology
- Rheumatology
- Genetics
Background:
- Familial Mediterranean Fever (FMF) is a chronic autoinflammatory disorder characterized by recurrent febrile attacks.
- Neutrophil and monocyte activation are key components of the inflammatory response in FMF.
Purpose of the Study:
- To investigate periodic disturbances in proinflammatory activation of neutrophils and monocytes in FMF patients during attacks and remission.
- To compare immune cell activation in FMF patients with Behçet's disease (BD) patients and healthy controls.
Main Methods:
- Flow cytometry was used to assess phagocytosis, respiratory burst, CD11a/CD18 expression, and intracellular cytokine synthesis in 20 FMF patients and 10 BD patients.
- Endotoxin tolerance induction was evaluated by measuring monocyte response to lipopolysaccharide (LPS) after initial exposure.
Main Results:
- FMF patients showed increased neutrophil and monocyte phagocytic activity and oxidative burst during remission, and decreased activity during attacks.
- Monocytes from FMF patients in remission failed to induce LPS tolerance, exhibiting heightened endotoxin sensitivity, unlike during attacks.
- Colchicine treatment restored LPS tolerance induction in remission by increasing IL-4 synthesis in FMF patient monocytes.
Conclusions:
- Chronic inflammation in FMF involves periodic immune cell activation changes and heightened endotoxin sensitivity, correlating with the disease's episodic nature.
- Increased endotoxin sensitivity during remission may stem from a shift to 'classically' activated monocytes, impacting FMF treatment strategies.
