Paneth cells

**Location and histology:** Paneth cells sit at the base of the crypts of Lieberkühn, most numerous in the distal small intestine (ileum). They are pyramidal cells with prominent apical eosinophilic (bright pink/red) secretory granules on H&E and abundant rough ER. They are long-lived (about 20 days), unlike most intestinal epithelial cells, which turn over in 3-5 days.

**Secretory products:** - Alpha-defensins (cryptdins; human HD5 and HD6). These disrupt microbial membranes. - Lysozyme, which cleaves bacterial peptidoglycan. - Phospholipase A2 and the C-type lectin REG3γ (RegIIIγ). - TNF-α and other factors.

**Functions:** 1. Innate immune defense. They shape the gut microbiota and protect against enteric pathogens. Secretion is triggered by bacterial products and cholinergic stimulation. 2. Stem cell niche. They sit next to Lgr5+ crypt base columnar stem cells and provide Wnt3, EGF, and Notch ligands (Dll4) that sustain stemness. 3. They may phagocytose some bacteria and help regulate mucosal homeostasis.

**Embryology and differentiation:** They derive from the intestinal stem cells. Wnt signaling drives their differentiation and positioning at the crypt base. Related transcription factors include Sox9 and Atoh1 (secretory lineage).

**Clinical associations:** - **Crohn disease:** Mutations in NOD2 (CARD15) and in the autophagy gene ATG16L1 impair Paneth cell function and defensin secretion. This leads to a defective antimicrobial barrier and the transmural inflammation of Crohn disease, which is most common in the terminal ileum. Paneth cell dysfunction is a classic high-yield link. - **Necrotizing enterocolitis (NEC):** Premature infants have immature Paneth cell function and decreased defensins, which may contribute to NEC. - **Metaplasia:** Paneth cell metaplasia (outside the small intestine, e.g., colon, stomach) occurs in chronic inflammation, such as ulcerative colitis and chronic gastritis. It is also seen in Barrett esophagus and gastric intestinal metaplasia. - **Graft-versus-host disease:** Paneth cell loss is a marker of severe gastrointestinal GVHD and is associated with poor prognosis. - **Cystic fibrosis and other conditions:** Altered Paneth cell function has been implicated in other conditions, but the evidence is less established.

**Comparison with other crypt/villus cells (high-yield):** - Goblet cells secrete mucus. - Enterocytes absorb nutrients. - Enteroendocrine cells (I, K, L, S, etc.) secrete hormones (CCK, GIP, GLP-1, secretin). - M cells overlie Peyer patches and sample antigens. - Tuft cells sense helminths and parasites (IL-25 → type 2 immunity). - Paneth cells make antimicrobial peptides and support stem cells.

**Boards pearl:** "Cell at the base of the intestinal crypt with bright eosinophilic granules containing lysozyme and defensins" = Paneth cell. Think Crohn disease (NOD2/ATG16L1) when the question asks about defective Paneth cell function.