Combinations of PYD, CARD, NACHT, and/or LRR domains are found in over 20 other proteins encoded in the human genome (Tschopp et al. 2003; Ting and Davis 2004; Martinon and Tschopp 2005), many of which are expressed in immune tissues. One such molecule is the NOD2/CARD15 protein, which contains two N-terminal CARD domains, followed by a NACHT domain and ten LRR motifs (Fig. 4). Mutations in the LRR of NOD2/CARD15 were first associated with Crohn's disease, one of two common forms of inflammatory bowel disease (Hugot et al. 2001; Ogura et al. 2001). Crohn's disease is a multifactorial disorder characterized by fever, diarrhea, abdominal pain, granulomatous lesions in the gastrointestinal tract, and, at times, extraintestinal manifestations in the skin, joints, and eyes. Subsequently, LRR variants of NOD2/CARD15 were associated with psoriatic arthritis (Rahman et al. 2003), another genetically complex inflammatory disorder.
In contrast, mutations in the NACHT domain of NOD2/CARD15 have been shown to cause Blau syndrome (BS) (Miceli-Richard et al. 2001), a rare autosomal dominant disorder characterized by early-onset granulomatous arthritis, rash, and uveitis with camptodactyly (permanent contractures of the digits) (Blau 1985; Jabs et al. 1985; Miller 1986; Raphael et al. 1993). More recently, mutations in the NACHT domain of NOD2/CARD15 have been found to cause a clinically similar disorder, early-onset sarcoidosis (EOS) (Kanazawa et al. 2005).
Even though they share a common underlying gene, BS/EOS and CD exhibit important clinical differences. BS/EOS patients present with granulomatous lesions in sterile sites such as the eye and the joints, and, as such, BS/EOS is clearly autoinflammatory. In contrast, although CD patients sometimes develop arthritis, uveitis, or even pyoderma gangrenosum, the primary lesion of CD is in the intestine, and the clinical phenotype may well be influenced by intestinal flora.
NOD2/CARD15 is expressed primarily in myeloid cells, as well as Paneth cells in the small intestine, and activated intestinal epithelial cells (Eckmann and Karin 2005). As is the case for cryopyrin, MDP stimulates NOD2/CARD15-mediated NF-kB activation (Girardin et al. 2003; Inohara et al. 2003), and a common CD-associated mutation of the LRR abrogates this effect, suggesting that NOD2/CARD15 also senses intracellular bacteria through this domain. NOD2/CARD15-mediated NF-kB activation occurs through several pathways (Eckmann and Karin 2005), including the induction of CARD-CARD cognate interactions with RICK/Rip2/CARDIAK, leading to IKK activation (Abbott et al. 2004).
The physiologic role of NOD2/CARD15 and the consequent effects of CD-associated mutations, remain unclear. Recent studies of Nod2/Card15-deficient mice demonstrated increased susceptibility to orally administered bacterial pathogens and a deficiency in cryptdins, a subgroup of intestinal anti-microbial peptides (Kobayashi et al. 2005). Moreover, mice harboring a CD-associated Nod2/Card15 mutant exhibited increased NF-kB activation in response to MDP and accentuated secretion of IL-1ß (Maeda et al. 2005). These data suggest a proinflammatory role for NOD2/CARD15, with CD mutations representing activating, "gain-of-function" variants. Nevertheless, yet another study of Nod2-deficient mice suggested an anti-inflammatory role for normal NOD2/CARD15, inhibiting TLR-2-stimulated NF-kB activation, with CD-associated mutations representing a loss of this negative regulatory function (Watanabe et al. 2004). Although both models predict increased inflammatory activation in peripheral blood monocytes from CD patients, in fact the opposite has been observed (Li et al. 2004).
Consistent with the autosomal dominant pattern of inheritance for BS, and with the presence of BS lesions in aseptic sites, BS-associated NOD2/CARD15 mutations are gain-of-function variants that result in MDP-independent constitutive activation of NF-kB (Chamaillard et al. 2003a, b; Tanabe et al. 2004). It is interesting to note that the NOD2/CARD15 codon at which two different BS mutations have been identified is in a position in the NACHT domain homologous to the location of the MWS/FCAS-associated R260W mutation in cryopyrin (Chamaillard et al. 2003a). Similarly, EOS-associated NOD2/CARD15 mutations are also associated with increased basal NF-kB activity (Kanazawa et al. 2005).
Was this article helpful?
Thank you for deciding to learn more about the disorder, Osteoarthritis. Inside these pages, you will learn what it is, who is most at risk for developing it, what causes it, and some treatment plans to help those that do have it feel better. While there is no definitive “cure” for Osteoarthritis, there are ways in which individuals can improve their quality of life and change the discomfort level to one that can be tolerated on a daily basis.