What is the pathophysiology of familial Mediterranean fever (FMF)?

Updated: May 14, 2018
  • Author: John O Meyerhoff, MD; Chief Editor: Herbert S Diamond, MD  more...
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Answer

Nonsense or missense mutations in the MEFV (Mediterranean fever) gene appear to cause the disease in many cases. MEFV produces a protein called pyrin (derived from the association with predominant fever); the protein is also called marenostrin (derived from the phrase "our sea," because of the Mediterranean heritage of most patients).

Pyrin is expressed mostly in neutrophils. To date, its main functions have been determined to involve the innate immune response, such as inflammasome assemblage and, as a part of the inflammasome, sensing intracellular danger signals, activating mediators of inflammation, and resolving inflammation by the autophagy of regulators of innate immunity. [2]

In patients with FMF, uninhibited pyrin activity results in uncontrolled production of interleukin-1 (IL-1), leading to episodes of inflammation (with accompanying fever) in the peritoneum, pleura, and joints; persistent subclinical inflammation is also common. [3, 4]

FMF attacks are also characterized by the release of neutrophil extracellular traps (NET), which are chromatin filaments ‘decorated’ with neutrophil granular and cytoplasmic proteins, including active IL-1β. NETs restrict their own generation by a negative feedback mechanism, which may help explain the self-limited nature of FMF attacks. [5, 6]

Presumably, the inflammatory episodes in persons with FMF lead to the excess production of amyloid A protein in the acute phase and reactant serum amyloid A with subsequent deposition in the kidneys. However, only patients with specific MEFV haplotypes develop amyloidosis. [7]


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