| Abstract |
Background: FMF is the prototype hereditary autoinflammatory disorder. Although the inflammatory cytokine interleukin-1b (IL-1b) has been implicated in the pathophysiology of FMF, there is scarce evidence of dysregulated IL-1b production by FMF patients.
Objectives: To report on the clinical manifestations, genotyping variation, genotype-phenotype correlation, respond to treatment in FMF patients and to assess the protein expression and function of NLRP3 inflammasome in WBCs from FMF patients and healthy individuals.
Materials and methods: 106 patients were diagnosed with FMF. The clinical, laboratory and genetic characteristics of FMF patients were reviewed. We isolated peripheral white blood cells (WBCs) from 20 symptoms-free FMF patients and 21 healthy individuals. Intracellular protein expression of NLRP3, caspase-1, IL-1b at baseline and after LPS/ATP sequential treatment for NLRP3 activation was assessed by immunoblotting. Secreted IL-1b was quantified by ELISA. THP-1 cells were transfected with wild-type or mutant pyrin and IL-1b secretion was measured.
Results: 106 patients (50% women) were diagnosed with FMF with an average age 23.5 years at the time of first attack. Combined MEFV heterozygosity and homozygosity was found in 30.1% of the patients, while 19.9% of patients carried no mutation. 2 patients started on IL1-blockade (anakinra) due to colchicine failure. Amyloidosis developed in 2 patients both homozygotes for M694V mutation. There were no differences in clinical manifestations, response to treatment or expression and function of NALP3-inflammasome among patients with 1, 2, or no MEFV mutations. FMF WBCs exhibited lower NLRP3 and active caspase-1 protein expression compared to healthy individuals, and LPS/ATP treatment resulted in significantly lower intracellular IL-1b levels in FMF patients. Consistently, THP-1 cells transfected with FMF-associated M694V mutant pyrin displayed lower LPS/ATP-induced IL-1b compared with wild-type pyrin-transfected cells.
Conclusion: In a cohort of Cretan FMF patients, all but two patients had excellent prognosis on colchicine therapy. Genotype did not correlate with clinical manifestations or response to treatment. WBCs from FMF patients demonstrate reduced protein expression of NLRP3 and reduced NLRP3-mediated IL-1b production.
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Η ενεργοποίηση του φλεγμονοσώματος στον οικογενή μεσογειακό πυρετό : κλινική και εργαστηριακή μελέτη
