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NOD2 signalling can both positively and negatively regulate Toll-like receptor (TLR) responses. Previous studies have shown that lack of NOD2 signalling (in NOD2 knockout mice) leads to increased peptidoglycan induction of interleukin (IL)-12 via TLR2. Studies in this issue of Gut show that lack of NOD2 signalling (in patients with NOD2 mutations) leads to decreased CpG induction of tumour necrosis factor and IL-8 via TLR9. The first type of abnormality suggests that NOD2 mutations act by enhancing effector T cell function and the second that NOD2 mutations act by impairing regulatory T cell function. We weigh these possibilities.
Several years ago it was discovered that homozygous (or compound heterozygous) mutations of CARD15, a gene encoding NOD2 (nucleotide oligomerisation domain 2), are a major susceptibility factor underlying a significant subgroup of patients with Crohn’s disease in Western countries.1,2,3,4 More recently it has been shown that mutations of this gene are also associated with diseases that are immunologically related to Crohn’s disease, such as early onset sarcoidosis.5 Thus it has become increasingly clear that these mutations offer an extraordinary window on the function of the mucosal immune system and how defects in such function lead to disease.
The road to understanding the consequences of NOD2 mutations begins with knowledge of how NOD2 functions in normal individuals. NOD2 is now known to be a member of a large and somewhat heterogeneous protein family known as the NOD-LRR (leucine-rich repeat) protein family that are grouped together because they more or less share the same structural regions: an LRR domain, a NOD domain, and a CARD (caspase recruitment domain) (as in the case of NOD2) or PYRIN domain.6 The LRR domain is a cognate of a similar domain found in all members of the Toll-like receptor (TLR) family …
Conflict of interest: I am an advisor and speaker for Bristol Myers Squibb, makers of Enetecavir.
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