Familial Mediterranean Fever

Familial Mediterranean fever (FMF) is a recessively inherited periodic fever syndrome with carrier rates as high as 1:3 to 1:5 among individuals of Armenian, Jewish, Arab, or Turkish descent (Aksentijevich et al. 1999; Stoffman etal. 2000; Gershoni-Baruch et al. 2001;Koganetal. 2001; Touitou 2001; Yilmaz et al. 2001; Al-Alami et al. 2003), thus raising the possibility of heterozygote selection. FMF is characterized by 1- to3-day febrile episodes with abdominal pain, pleurisy, arthritis, or a characteristic erysipeloid rash. Between attacks, patients feel comparatively well, despite evidence of subclinical inflammation (Tunca et al. 1999; Korkmaz et al. 2002; Duzova et al. 2003). Although sometimes debilitating during flares, the arthritis is usually nondeforming and none of the febrile symptoms are life-threatening. However, continuous elevation of inflammatory markers during and between attacks may lead to the tissue deposition of a misfolded fragment of the acute phase protein, serum amyloid A. This type of systemic amyloidosis frequently resulted in renal failure and early death before the era of colchicine prophylaxis.

Both the acute attacks and the amyloidosis of FMF can usually be prevented with colchicine (Dinarello et al. 1974; Zemer et al. 1974,1986,1991). Although colchicine is known to destabilize microtubules at high doses in vitro, the mechanism by which it prevents FMF attacks is incompletely understood. Colchicine is concentrated in granulocytes (Ben-Chetrit and Levy 1998), the major effector cells in acute FMF attacks, and its therapeutic benefit in FMF may be related to its effects on cell-surface adhesion molecules (Cronstein et al. 1995), leukocyte migration (Dinarello et al. 1976), or even the fact that the protein mutated in FMF can bind microtubules (Mansfield et al. 2001).

FMF is caused by over 50 mutations in the MEFV (Mediterranean Fever) gene, which are available online at http://fmf.igh.cnrs.fr/infevers/ (Touitou et al. 2004). Although most mutations show recessive inheritance patterns, a sizable percentage of patients with single identifiable mutations evince symptoms of FMF. In rare cases, dominant inheritance within families has been documented (Booth et al. 2000), and it is possible that modifier genes may sometimes allow the expression of the FMF phenotype in other patients harboring a single mutation.

The coding sequence of MEFV subsumes ten exons, oriented 5' ^ 3', centromere ^ telomere, covering approximately 15 kb on chromosome 16p13.3 (International FMF Consortium 1997). The approximately 3.7-kb transcript encodes a 781-amino acid protein called pyrin (International FMF Consortium 1997) or marenostrin (French FMF Consortium 1997). Pyrin is mainly expressed in granulocytes, cytokine-activated monocytes, dendritic cells, and in fibroblasts derived from skin, peritoneum, and synovium (Centola et al. 2000; Matzner et al. 2000; Diaz et al. 2004), consistent with the predominant role of granulocytes in (FMF)!FMF inflammation and the anatomic distribution of attacks. Endogenous pyrin is cytoplasmic in monocytes but predominantly nuclear in granulocytes, dendritic cells, and synovial fibroblasts (Diaz et al. 2004). Recent in vitro data suggest that the interaction of pyrin with the 14.3.3 protein may play a role in controlling subcellular localization of pyrin (Jeru et al. 2005).

The pyrin protein consists of a 92-amino acid N-terminal PYRIN domain (Bertin and DiStefano 2000), also denoted PYD (Martinon et al. 2001), PAAD (Pawlowski et al. 2001), or DAPIN (Staub et al. 2001), a B-box zinc finger, a coiled-coil region, and a C-terminal B30.2/rfp/SPRY domain (Ver-net et al. 1993; Henry et al. 1998; Seto et al. 1999). PYD is a member of the death domain fold superfamily (Fairbrother et al. 2001; Richards et al. 2001), which also includes death domains (DDs), death effector domains (DEDs), and caspase recruitment domains (CARDs). DD fold superfamily motifs have three-dimensional structures consisting of a specific orientation of six alpha helices, enabling homotypic protein interactions via electrostatic effects (Eliezer 2003; Hiller et al. 2003; Liepinsh et al. 2003; Liu et al. 2003). The B-box and coiled-coil regions also mediate protein-protein interactions (Centola et al. 1998; Shoham et al. 2003).

Consistent with the probable functions of its subunits, pyrin is capable of interacting with several other proteins. Through cognate N-terminal PYD interactions, pyrin binds the bipartite adaptor protein ASC (apoptosis-associated speck-like protein with a CARD) (Masumoto et al. 1999; Richards et al. 2001). ASC also contains a CARD domain and is able to bind caspase-1 (IL-1ß-converting enzyme [ICE]) via CARD-CARD homotypic interactions (Martinon et al. 2002; Srinivasula et al. 2002; L. Wang et al. 2002). In vitro, contact with ASC enables multimerization and autocatalysis of caspase-1 zymogen into its p20 and p10 enzymatic subunits. Caspase-1 then cleaves the inactive, 31-kDa IL-1ß precursor to its active, secreted 17-kDa form. Secreted IL-1ß is a potent proinflammatory mediator.

Studies of ASC-/- mice indicate that ASC is essential for activation of caspase-1 and IL-1ß secretion following stimulation with bacterial lipopolysaccharide or the intracellular bacterium Salmonella typhimurium (Mariathasan et al. 2004). In vivo, ASC participates in macromolecular complexes denoted inflammasomes to activate caspase-1 (Martinon and Tschopp 2004). The first inflammasome described contains ASC, a PYD and CARD-containing protein called NALP1, and caspases-1 and -5 (Martinon et al. 2002). A second inflammasome, to be discussed at greater length below, includes cryopyrin (also called NALP3), ASC, two molecules of caspase-1, and another protein denoted Cardinal (Agostini et al. 2004).

The effects of pyrin's interaction with ASC are complex and incompletely understood. In mice expressing a truncated form of pyrin, caspase-1 and IL-ip activation were shown to be increased, whereas ectopic expression of pyrin in mouse monocytic RAW cells led to suppression of IL-ip production, thus suggesting an inhibitory role for pyrin in caspase-1 activation, possibly by sequestering ASC (Fig. 1) (Chae et al. 2003). In contrast, in a more recent study of transfected human embryonic kidney cells, pyrin was found to potentiate ASC-dependent IL-1p production (Yu et al. 2005). In transfection systems in which ASC is not present, pyrin appears to suppress IL-1p production (Stehlik et al. 2003).

Pyrin has variously been found to have an inhibitory effect (Dowds et al. 2003; Masumoto et al. 2003), a context-dependent effect that could either be stimulatory or inhibitory (Stehlik et al. 2002), or no effect (Yu et al. 2005)

ASC sequestered

la. ASC

2. inflammasome ooo oo©

lb. Caspase-1

Other proteins







lb. Caspase-1

s. inflammation

Fig. 1 The sequestration hypothesis of pyrin function. Pyrin inhibits inflammatory signals by binding and sequestering ASC, which forms a multimolecular inflammasome complex by associating with caspase-1 and other proteins. The inflammasome allows activation of caspase-1 and subsequent cleavage of proIL-1p to its active, secreted form on NF-kB activation in cell lines, depending on the precise experimental conditions. Through its PYD, ASC has been shown to interact with the IkB kinase complex (IKK), an upstream regulator of NF-kB activation, and high levels of ASC suppress NF-kB activation (Stehlik et al. 2002). Possibly, the relative amounts of pyrin and ASC may affect their interactions with one another as well as with IKK, thereby tipping the balance either toward or against NF-kB activation.

Defective apoptosis may also play a role in the pathogenesis of FMF. Peritoneal macrophages from mice expressing the aforementioned truncated pyrin are deficient in apoptosis, possibly prolonging the inflammatory response by allowing activated cells to survive (Chae et al. 2003). Nevertheless, in some in vitro systems pyrin appears to exert an ASC-dependent anti-apoptotic effect (Richards et al. 2001; Dowds et al. 2003; Masumoto et al. 2003).

Although it appears that the impact of pyrin on various inflammatory pathways may depend on experimental if not physiologic conditions, it is clear that the interaction between pyrin and ASC is crucial for several of these effects. Perhaps reflecting the importance of PYD cognate interactions for pyrin's function, FMF-associated mutations in this N-terminal domain are very rare. In contrast, mutations in the C-terminal B30.2/rfp/SPRY domain are extremely common, and, given the high carrier frequency for FMF among certain human populations, appear to have been selected, perhaps by a pathogen or group of pathogens. Moreover, there is evidence that the wild-type sequence of the human B30.2/rfp/SPRY domain has been selected over primate evolution (Schaner et al. 2001). These observations have fueled speculation that the B30.2/rfp/SPRY domain of pyrin might bind certain intracellular pathogen-associated molecular patterns (PAMPs) (Schaneretal. 2001; Yu et al. 2005), although there is currently no direct experimental evidence to support this hypothesis. It is intriguing to note that the B30.2/rfp/SPRY domain of another protein, TRIM5a, blocks infection of certain retroviruses, and has undergone positive selection in primate evolution similar to pyrin (Perron et al. 2004; Song et al. 2005).

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