Model of the three major myeloid dendritic cell populations and their hypothesized (dys)function in human inflammatory bowel disease (The majority of pathways were identified for Crohn’s disease and to a lesser degree for ulcerative colitis. See text and references for details. For clarity no distinction between Crohn’s disease and ulcerative colitis was made and to bring out cellular details this cartoon is not to scale.). (1) Peripheral blood myeloid dendritic cells: In IBD patients these cells display an activated phenotype and have been demonstrated to express HLA-DR, CCR6, CCR7(CD197), CCR8, CD80, CD83, CD86, CD40, ICAM-1 (CD49d), TLR2, and TLR4. In acute flares circulating dendritic cells evade the peripheral blood pool and probably migrate to the mucosal sites of the inflammation. Their secretion of chemokines like CXCL8 (IL-8) attracts innate immune cells such as granulocytes expressing its cognate receptor CXCR8 and homing CCR9⁺ α4β7⁺ T-lymphocytes that transmigrate into the tissue mediate, amplify and perpetuate the inflammation. (2) Mucosal myeloid dendritic cells: In IBD they show an activated phenotype as well. These cells inspect molecular microbial associated patterns (MAMP) of the intestinal microbiota with their own TLR2 and TLR4 receptors directly through their epithelial layer penetrating dendrites or are fed microbial antigens via M-cells in Peyer’s patches that transport them into the lamina propria. Moreover, antigens are recognized by intracellular NOD. In the small intestine this happens in the subepithelial dome area of Peyer’s patches or isolated lymph follicles in other parts of the small and large intestine. DC-SIGN and CD83 expressing myeloid dendritic cells have been described in isolated lymph follicles as well. Misinterpretation of MAMPs perhaps due to single nucleotide polymorphisms of TLR4 and NOD2 reported in IBD and absent tolerogenic effects of TGFβ and retinoid acid on mucosal dendritic cells normally secreted intestinal epithelia triggers immunity against the normally tolerated flora. The distinct pro-inflammatory cytokine profile (TNFα, IL-6, IL-17, IL-23, and IL-27) of myeloid mucosal dendritic cells in IBD promotes the development of inflammatory Th1 and Th17 T-lymphocytes and attracts other leukocytes to transmigrate through the endothelial layer into the lamina propria. (3) Mesenteric lymph node myeloid dendritic cells: Stromal cells and high endothelial venules (HEV) secrete the chemokine CCL21 and attract circulating dendritic cells that recognize it through their expression of its native receptor CCR7. Mucosal dendritic cells migrate along the chemokine gradient via efferent lymphatic vessels from the lamina propria into the afferent lymphatic of the mesenteric lymph node (MLN). In the paracortex mesenteric myeloid lymph node dendritic cell function depends on their expression of CD103. Once arrived in the T-cell zone CD103⁺ dendritic cells secrete CCL19 that increases via feedback loop the expression of CCR7^–—the CCL19 receptor on dendritic cells—and also attract CCR9⁺ α4β7⁺ T-lymphocytes to arrive through high endothelial venules from the blood. These T-cells start to proliferate once they recognize their cognate antigens presented by the mesenteric lymph node dendritic cells and leave the lymph node activated through the efferent lymphatic further aggravating inflammation. The expression of CCL19 and CCL21 suggests that B-cells are also attracted to mesenteric lymph nodes which may induce follicular dendritic cells that secrete CXCL13 (BCA-1 or BLC) that drives more B-cell migration. While the chemokine expression has been described in IBD, the interaction is speculative