Intestinal Dendritic Cells and Epithelial Barrier Dysfunction in Crohnʼs Disease

Abstract

Crohn's disease (CD) is a chronic gastrointestinal inflammatory disorder considered to be the result of an inappropriate and exaggerated mucosal immune reaction to yet undefined triggers from the gut flora in genetically predisposed individuals. This inflammatory phenomenon has been characterized by an adaptive T-cell response in addition to an abnormal function of the innate immune system. Dendritic cells (DCs) are constituents of this innate system, inducing T-cell activation via antigen presentation. In the gut, mucosal DCs are separated from the luminal milieu by a monolayer of cylindrical epithelial cells that forms an anatomical and physiological barrier that controls the normal traffic of antigens between both compartments. An imbalance of colonic and ileal DC distribution in tissues from CD patients as well as functional differences between DCs isolated from normal and diseased intestinal samples have been demonstrated. Moreover, a gut barrier defect in the para- and transepithelial routes in addition to a significant reduction in the intestinal secretion of epithelial products involved in barrier function has been well documented in CD. Therefore, this may expose the diseased mucosa to overwhelming amounts of antigens, resulting in abnormal DC activation and a subsequent imbalance in their distribution. In conclusion, this review provides a summary of relevant progress in CD, intestinal epithelial permeability, and DCs highlighting a potential relationship between increased epithelial permeability and abnormal DC distribution during the pathogenesis of intestinal inflammation.

Dendritic cells from human mesenteric lymph nodes in inflammatory and non‐inflammatory bowel diseases: subsets and function of plasmacytoid dendritic cells

“…28 In the PB of patients with IBD, increased numbers of DC expressing CD83 and CD86 have been found and matured DC generated from peripheral blood monocytes of IBD patients show raised immune-stimulating abilities when compared with those of healthy volunteers. 39 Activated DC found at the sites of inflammation in murine models of colitis might contribute to the pathogenesis, 11 and there is increasing evidence that mucosal DC accumulated within inflamed tissue might also play a role in human IBD. 16,40 Regarding DC in the peripheral blood of IBD patients, conflicting results have been reported.…”

“…8 Mucosal pDC and mDC have been investigated in only a few human studies, although accumulation of activated DC at the sites of inflammation may contribute to the pathogenesis of human inflammatory bowel disease (IBD). 6,[9][10][11][12] Reduced proportions of immature pDC have been found in the peripheral blood (PB) of patients with IBD, suggesting their recruitment to inflamed mucosal tissues. 13,14 Additionally, mesenteric lymph node (MLN) pDC express the chemokine receptor CCR6, which could explain musosal accumulation at inflamed tissue sites as a consequence of up-regulated mucosal addressines such as CCL20 or mucosal addressin cell adhesion molecule-1.…”

Crohn’s disease as an immunodeficiency

“…Components of the intestinal barrier are likely to play a more active role: an in vitro study has demonstrated the potential for cross-talk with, or recruitment of, inflammatory cells, particularly by dendritic cells [49,58]. Their role as antigen-presenting cells capable of influencing T-cell responses makes dendritic cell function in CD an intriguing avenue of study.…”

Interferon-γ Alters Downstream Signaling Originating from Epidermal Growth Factor Receptor in Intestinal Epithelial Cells

“…In health, a polarized monolayer of columnar intestinal epithelial cells normally forms a tight barrier to the access of toxic agents to the mucosal immune system (11). However, IFN-␥ disrupts tight junctions and thereby disturbs paracellular transport mechanisms.…”