In Crohn's disease, NOD2/CARD15 mutations on chromosome 16 are the strongest known genetic risk factor, particularly for ileal disease. NOD2 is an intracellular PRR expressed in Paneth cells and macrophages. How do loss-of-function NOD2 mutations paradoxically lead to MORE inflammation rather than less, in the intestinal mucosa?

• A Mutant NOD2 gains constitutive activity, directly activating NLRP3 inflammasome and causing IL-18 hypersecretion
• B Loss of NOD2 causes Paneth cell apoptosis, depleting defensin-α secretion and allowing bacterial translocation that triggers systemic SIRS
• C Loss of NOD2 allows uncontrolled TLR2/TLR4 (cell-surface PRR) signaling by commensal microbes, because NOD2 normally acts as a negative regulator of TLR-mediated NF-κB activation; without NOD2 feedback, sustained NF-κB drives excess IL-12, TNF-α and IL-1β production ✓
• D NOD2 mutations cause upregulation of RIPK2, which phosphorylates IκB to constitutively activate NF-κB

Explanation

NOD2 plays dual roles: it activates NF-κB in response to muramyl dipeptide (MDP) from bacterial peptidoglycan, but it also cross-inhibits TLR-mediated signaling by promoting ubiquitin-dependent degradation of RIP2 and sequestering TRAF6. Loss-of-function NOD2 mutations (e.g., 3020insC, R702W) result in failure of this negative regulatory function, leading to disinhibition of TLR2-mediated NF-κB activation by luminal commensal bacteria. In Paneth cells, reduced defensin output also impairs innate mucosal defense, allowing deeper bacterial invasion. The net result is dysregulated mucosal innate immunity, excess IL-12, TNF-α, and subsequent Th1 polarization driving granulomatous ileitis.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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Written and medically reviewed by the StethoPrep medical team.