The Cryopyrinopathies Familial Cold Autoinflammatory Syndrome Muckle Wells Syndrome and Neonatal Onset Multisystem Inflammatory Disease

Similar to pyrin and PSTPIP1, many other proteins involved in the regulation of innate immunity consist of multiple protein interaction domains. A second disease-associated molecule containing an N-terminal PYD is denoted cryopyrin (Hoffman et al. 2001b), so named for its N-terminal PYD and to reflect its association with cold-induced urticaria. This protein is also known as NALP3 (Aganna et al. 2002; Tschopp et al. 2003), PYPAF1 (Manji et al. 2002), or caterpiller 1.1 (Harton et al. 2002; O'Connor et al. 2003; Ting and Davis 2004). Mutations in this protein cause three separate disease entities that vary in severity. Familial cold autoinflammatory syndrome (FCAS, also known as familial cold urticaria, familial polymorphous cold eruption, and cold hypersensitivity) is a relatively mild febrile syndrome characterized by episodic fever, rash, and arthralgia, precipitated by exposure to cold temperature. The rash resembles urticaria, but biopsies show a neutrophilic infiltrate and the absence of mast cells (Hoffman et al. 2001b). Muckle-Wells syndrome (MWS) is a more severe illness with more prominent joint involvement, bilateral progressive hearing loss, and increased risk of systemic amyloidosis. Febrile episodes are often longer than those with FCAS, and there is usually no association with cold temperature. Finally, neonatal onset multisystem inflammatory disease (NOMID; also called chronic infantile neurological, cutaneous, and articular syndrome, CINCA [Prieur et al. 1987]) is potentially the most serious cryopyrinopathy, with continuous symptoms fluctuating in intensity. Many patients with NOMID/CINCA develop a bilateral deforming arthropathy due to overgrowth of the epiphyses of the long bones (Prieur and Griscelli 1981; Hassink and Goldsmith 1983; Hashkes and Lovell 1997; Prieur 2001). Besides daily rash and fever, patients may have hepatosplenomegaly, aseptic meningitis, bilateral hearing loss, vision loss, and mental retardation. Growth retardation and reduced reproductive potential are common. Mortality has been estimated at 20% by age 20 (Prieur et al. 1987; Hashkes and Lovell 1997).

Although the cryopyrinopathies have been separated into three distinct conditions, there is a continuous spectrum of pathology from mild (FCAS) to severe (NOMID/CINCA), with some mutations associated with more than one syndrome and wide variation in manifestations among individuals with the same diagnosis. NOMID/CINCA patients in particular fall into various disease subgroups, with some experiencing severe joint disease and central nervous system involvement, and others with milder arthropathy and few or no mental disabilities. All three syndromes are inherited in an autosomal dominant fashion (Hoffman et al. 2001a; Aganna et al. 2002; Aksentijevich et al. 2002; Dode et al. 2002), although de novo mutations have been documented, especially in NOMID/CINCA, and it appears likely that additional modifier genes influence the observed phenotype, as is the case with FMF.

The cryopyrin protein, encoded on chromosome 1q44, consists of an N-terminal PYD, followed by a NACHT (neuronal apoptosis inhibitor protein, CIITA, HET-E, and TP1, also called NBS: nucleotide-binding site [Koonin and Aravind 2000]) domain, and 7-11 C-terminal leucine-rich repeats (LRR), depending on the splice isoform. Mutations associated with disease are missense substitutions mainly found in the NACHT domain (Neven et al. 2004). The NACHT contains various conserved motifs, including an ATP/GTPase-specific P loop and a Mg++ binding site (the Walker A and B domains, respectively) (Walker et al. 1982). The NACHT domain is homologous to a domain in APAF-1 (Zou et al. 1997), a protein that activates the pro-apoptotic enzyme, caspase-9, by oligomerization and ATP binding (Acehan et al. 2002).

To date four NOMID/CINCA-associated mutations cluster around the NACHT metal ion-binding site, and many others line the nucleotide-binding cleft (Albrecht et al. 2003; Neven et al. 2004), suggesting that this motif regulates the function of cryopyrin in inflammatory cells. Cryopyrin is expressed in polymorphonuclear cells, consistent with the principal role of neutrophils in the urticaria-like lesions, as well as in cultured chondrocytes, which may explain the arthropathy observed in NOMID/CINCA (Feldmann et al. 2002).

Similar to pyrin, cryopyrin has been shown to associate with ASC via PYD-PYD homotypic interactions (Manji et al. 2002), thus potentially implicating cryopyrin in the regulation of cytokine production (L. Wang et al. 2002), NF-kB activation (Manji et al. 2002; Stehlik et al. 2002; Dowds et al. 2003), and apoptosis (Dowds et al. 2003). Cryopyrin (NALP3) forms a proinflammatory molecular platform called the NALP3 inflammasome (Fig. 3) by complexing with ASC and another protein called Cardinal, thereby bringing two molecules of caspase-1 into close proximity to induce autocatalysis and consequent IL-ip and IL-18 activation (Agostini et al. 2004). Disease-associated mutations in CIAS1 cause spontaneous ILip production by patients' peripheral blood monocytes (Agostini et al. 2004) and transfected cell lines (Dowds et al. 2004). As noted above, under some conditions pyrin may compete with cryopyrin for ASC, thereby limiting IL-ip production.

As is the case for pyrin, cryopyrin's effect on NFkB activation is controversial. In the presence of ASC, cryopyrin may activate NF-kB (Manji et al. 2002; Dowds et al. 2003), inhibit TNF-induced NF-kB induction (O'Connor et al. 2003), exert a context-dependent effect on NF-kB activation (Stehlik et al. 2002), or have no effect on NF-kB (Yu et al. 2005). The possible ASC-dependent effect of cryopyrin on NF-kB may be mediated by the indirect interaction of ASC with the IKK complex through RICK/Rip2/CARDIAK (Inohara et al. 1998; McCarthy et al. 1998; Thome et al. 1998), or through a direct interaction of ASC with IKK (Stehlik et al. 2002). Transfected cryopyrin mutants have increased NF-kB stimulatory activity, but only if ASC is present (Dowds et al. 2004). Without ASC, cryopyrin and its mutants suppress NF-kB activity. The currently available data suggest a complex picture in which the stoichiomet-ric relationships of multiple interacting proteins may determine the effect of cryopyrin on NF-kB activation under varying conditions.

The molecular mechanism by which NACHT-domain mutations in cryopyrin lead to autoinflammatory disease is still under investigation. One attractive hypothesis is based on the possible intramolecular interaction of the NACHT domain and LRRs (Fig. 3). Deletion of the C-terminal LRRs is necessary to detect optimal association of cryopyrin with Cardinal, suggesting the possibility of an autoinhibitory effect of the LRRs on NACHT-mediated inflammasome assembly (Agostini et al. 2004). By this hypothesis, disease-associated mu-

ASC sequestered

pyrin

2b. procaspase-1

2a. ASC/cryopyrin complex

2a. ASC/cryopyrin complex

lb. Active cryopyrin

lb. Active cryopyrin

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