1. NOD2 and Crohn’s Disease: Loss or Gain of Function?
Lars Eckmann, Michael Karin 
Immunity 
Volume 22, Issue 6, Pages (June 2005)
DOI: /j.immuni
Copyright © 2005 Elsevier Inc. Terms and Conditions

2. Figure 1 Structure of NOD2
NOD2 has a tripartite structure, with two caspase recruitment domains (CARD) at the N-terminal end, a centrally located nucleotide binding and oligomerization domain (NOD), and a C-terminal set of ten leucine-rich repeats (LRRs). The three major mutations associated with CD affect the C-terminal portion at sites that are depicted by arrows.
Immunity  , DOI: ( /j.immuni )
Copyright © 2005 Elsevier Inc. Terms and Conditions

3. Figure 2
Hypotheses for Explaining the Functions of CD-Associated NOD2 Variants
Three potential hypotheses were provided to explain the mechanisms by which NOD2 variants can promote intestinal inflammation. The top row shows the functions of normal NOD2 (green), whereas the bottom row depicts those of mutant NOD2 (NOD2m, blue). Hypothesis I (“Defective epithelial defense,” left column) envisions that normal NOD2 expressed in Paneth cells, or enterocytes upon stimulation, contributes to epithelial host defense against enteric bacteria (red rods) through induction of α-defensins (Def), which are released by Paneth cells and kill luminal microbes (gray rods with dashed outline), or through other unknown mechanisms in enterocytes. NOD2 variants fail to activate these defense mechanisms, leading to increased bacterial burden followed by mucosal inflammation. Hypothesis II (“IL-12 dysregulation,” middle column) suggests that normal NOD2 limits the TLR2-mediated macrophage response to peptidoglycan (PGN), whereas NOD2 variants fail to inhibit this process, causing enhanced activation of NF-κB, particularly c-Rel, and IL-12 p35 expression. Increased IL-12 release stimulates growth and differentiation of Th1 T cells, thereby promoting IFN-γ driven intestinal inflammation. Hypothesis III (“Enhanced IL-1β processing,” right column) holds that variant, but not normal, NOD2 can activate IL-1β-converting enzyme (ICE/caspase-1), which converts proIL-1β into mature 17 kDa IL-1β that is released by macrophages and contributes to intestinal inflammation through activation of a broad range of proinflammatory genes in an autocrine or paracrine fashion. In addition, CD-associated NOD2 variants are more effective activators of RIP2 and NF-κB.
Immunity  , DOI: ( /j.immuni )
Copyright © 2005 Elsevier Inc. Terms and Conditions