תרומתי לרפואה

תהליכים המשפיעים על FMF או משתתפים בהתהוות FMF

עבודות מחקר בנושא פתוגנזה של FMF ניתן למצוא ברשימת המאמרים המלאה, במאמרים הבאים: 22, 36, 46, 164, 217, 282, 288, 303, 408, 462,  (לרשימת המאמרים המלאה). להלן, מובאים תקצירים של 5 מאמרים נבחרים:

1. Am J Med. 1991 Apr;90(4):434-8.

Tumor necrosis factor in familial Mediterranean fever.

Schattner A(1), Lachmi M, Livneh A, Pras M, Hahn T.

Abstract

PURPOSE: The pleiotropic inflammatory effects of tumor necrosis factor (TNF) prompted a study of this cytokine in familial Mediterranean fever (FMF), a recurrent polyserositis of unknown etiology.

PATIENTS AND METHODS: Thirty-six asymptomatic and 24 patients with acute FMF were studied and compared with 20 matched healthy subjects. TNF levels were measured by bioassay in the plasma and in supernatants of peripheral blood mononuclear cells (PBMC) incubated alone or with an inducer (lipopolysaccharide, phytohemagglutinin

, or Sendai virus). Cytotoxicity could be abolished in all cases by preincubation with monoclonal anti-TNF-alpha antibodies.

RESULTS: No TNF was found in plasma and non-induced PBMC supernatants. Induced TNF production was markedly decreased in patients with acute FMF and increased in asymptomatic FMF patients to levels over those of control subjects (p less than 0.05). Thus, PHA-induced TNF levels were 4 U/mL in patients with acute FMF, 25 U/mL in asymptomatic patients, and 14 U/mL in healthy control subjects (median values), and the other inducers gave similar results. Retesting of patients first studied during an acute episode when their disease was quiescent also revealed a fivefold increase in TNF production. These results were independent of the use of colchicine, which also had no effect on TNF levels when taken by volunteers (1 mg/day) or when added to the PBMC cultures (10(-7) M).

CONCLUSIONS: Since TNF has a very short half-life in plasma, the capacity of PBMC to respond to TNF inducers may more accurately reflect its synthesis. A marked decrease in this response in acute FMF suggests "exhaustion" of cells that are already highly activated to produce TNF and the possible participation of TNF in the pathogenesis of FMF.

2. J Rheumatol. 1991 Apr;18(4):606-8.
Determination of autoantibodies in patients with familial Mediterranean fever and their first degree relatives.
Swissa M, Schul V, Korish S, Livneh A, Pras M, Shoenfeld Y.

Abstract
Sera samples of 168 patients with familial Mediterranean fever (FMF) and their 184 first degree relatives were analyzed for the presence of autoantibodies to ssDNA, dsDNA, poly (I), poly (G), cardiolipin, histones, RNP and Ro(SSA), using an enzyme linked immunosorbent assay (ELISA). A similar analysis was employed on  culture fluids of Epstein-Barr virus (EBV) transformed B lymphocytes derived from patients with FMF and healthy controls. No increased incidence of these antibodies was observed among patients with FMF and their relatives compared to healthy controls. It is possible that autoimmune features observed in FMF are the result of nonspecific changes occurring in inflammation and not due to autoimmune mechanisms.

3. J Rheumatol. 1999 Apr;26(4):890-7.
Activation of the cytokine network in familial Mediterranean fever.
Gang N(1), Drenth JP, Langevitz P, Zemer D, Brezniak N, Pras M, van der Meer JW, Livneh A.

Abstract
OBJECTIVE: To elucidate the role of cytokines in the pathogenesis of familial Mediterranean fever (FMF), an inherited disease characterized by attacks of serosal membrane inflammation.
METHODS: Blood samples were obtained from patients with FMF during attacks and remission. The cytokine concentrations in plasma and in supernatants from whole blood stimulated by bacterial lipopolysaccharide (LPS) were determined.
RESULTS: There were 27 patients with FMF, of whom 8 were studied during attacks, 9 during remission and 10 during both attack and remission. FMF attacks did not affect levels of plasma tumor necrosis factor-alpha (TNF-alpha) or interleukin 1beta (IL-1beta). In contrast, compared to remission, FMF attacks were associated with significantly higher mean levels of plasma IL-6 [8.4 pg/ml, 95% confidence interval (CI) 7.8-8.9 in remission vs 59 pg/ml, CI 21.4-96.7 during attacks; p=0.0005], sTNFr p55 (1.3 ng/ml, CI 1.2-1.4, vs 1.98 ng/ml, CI 1.6-2.3; p=0.005), and sTNFr p75 (2.9 ng/ml, CI 2.5-3.3, vs 4.09 ng/ml, CI 3.2-4.9; p=0.0249). The TNF-alpha, IL-1beta, and IL-6 content in supernatants derived from LPS stimulated blood cells was not modified by the attacks of FMF. Significant lower TNF-alpha release in LPS stimulated whole blood was detected in patients who were sampled in a later stage of the attacks (r=-0.54, p=0.047).
CONCLUSION: Our results suggest that the cytokine network is activated during attacks of FMF. IL-6 appears to play an important role in the evolution of FMF attacks. Whether TNF-alpha or IL-1beta has a function in initiating the attacks remains to be established.

4. J Investig Med. 2004 Jan;52(1):58-61. doi: 10.1136/jim-52-01-28.
Neutrophil adhesion molecule expression in familial Mediterranean fever: discordance between the intravascular regulation of beta2 integrin and L-selectin expression in acute attack.
Molad Y, Fridenberg A, Bloch K, Langevitz P, Mukamel M, Sulkes J, Pras M, Livneh A.

Abstract
BACKGROUND: To determine the surface expression of neutrophil beta2 integrin (CD11b/CD18) and L-selectin (LS) adhesion molecules in patients with familial Mediterranean fever (FMF) and to investigate the in vitro regulation of their expression in response to chemoattractant stimuli. 
METHODS: Neutrophil surface expression of CD11b and LS molecules was analyzed by 
flow cytometry in anticoagulated whole blood drawn from FMF patients and normal controls, and the in vitro regulation of these molecules induced by the chemoattractant N-formyl-methionyl-leucyl-phenylalanine (FMLP) was assayed. 
RESULTS: Patients during acute FMF attacks showed a statistically significant increased neutrophil surface CD11b compared with normal controls (mean fluorescence intensity: 22.8 +/- 13.7 vs 12.8 +/- 10.41, respectively; p = .03). There was no difference in LS expression between the groups. Neutrophils of FMF patients regulate CD11b and LS expression induced by chemoattractant (FMLP) stimulation to a degree similar to that in controls.
CONCLUSIONS: beta2 Integrin is up-regulated during an acute attack of FMF in dissociation with LS expression, suggesting a unique nonchemoattractant-mediated  neutrophil activation.

5. Clin Exp Rheumatol. 2004 Jul-Aug;22(4 Suppl 34):S56-8.
Urine leukotriene B4 in familial Mediterranean fever.
Bentancur AG, Naveh N, Lancri J, Selah BA, Livneh A.

Abstract
OBJECTIVE: To determine urinary leukotriene B4 (LTB4) levels and their role in FMF:
METHODS: Urinary LTB4 levels were studied using a commercial ELISA kit in 12 FMF 
patients during abdominal attacks, and 20 FMF patients during remission.
RESULTS: Urinary LTB4 levels in FMF patients during attacks were comparable to those during remission, but higher than normal levels (p = 0.03). 
CONCLUSIONS: These findings suggest a persistent activation of the leukotriene pathway in FMF. Whether elevated LTB4 levels are the cause or the effect of inflammation is yet to be determined.

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