Crohn’s disease: Evidence for involvement of unregulated transcytosis in disease etio-pathogenesis

Abstract

Crohn's disease (CD) is a chronic inflammatory bowel disease. Research has identified genetic predisposition and environmental factors as key elements in the development of the disease. However, the precise mechanism that initiates immune activation remains undefined. One pathway for luminal antigenic molecules to enter the sterile lamina propria and activate an immune response is via transcytosis. Transcytosis, although tightly regulated by the cell, has the potential for transepithelial transport of bacteria and highly antigenic luminal molecules whose uncontrolled translocation into the lamina propria can be the source of immune activation. Viewed as a whole, the evidence suggests that unregulated intestinal epithelial transcytosis is involved in the inappropriate presentation of immunogenic luminal macromolecules to the intestinal lamina propria. Thus fulfilling the role of an early pre-morbid mechanism that can result in antigenic overload of the lamina propria and initiate an immune response culminating in chronic inflammation characteristic of this disease. It is the aim of this paper to present evidence implicating enterocyte transcytosis in the early etio-pathogenesis of CD.

Intestinal deletion ofClaudin-7enhances paracellular organic solute flux and initiates colonic inflammation in mice

“…This result was distinct from the previous finding that fMLP, acting as a neutrophil chemoattractant, is taken into epithelial cells via PEPT1, an H + -coupled oligopeptide transporter and/or by endocytosis pathways to cause inflammatory responses 26 27 35. Our findings reveal that paracellular permeability in addition to transcellular permeability plays a role in initiating inflammation.…”

Disruption of the epithelial barrier during intestinal inflammation: Quest for new molecules and mechanisms

“…This phenomenon, observed in both CD and UC patients, is called ‘rapid antigen uptake into the cytosol of enterocytes’ (RACE). RACE is a characteristic feature of both inflamed and non-inflamed intestinal mucosa of IBD patients, and it was proposed to play an important role in the disease by increasing transcytosis of luminal antigens and their presentation to the lamina propria immune system [114]. Since TJs and AJs are located in the close proximity to the apical plasma membrane, the increased formation and internalization of apical membrane vesicles may destabilize junctional complexes and shift their trafficking cycle toward endocytosis.…”

Mechanisms of Intestinal Epithelial Barrier Dysfunction by Adherent-Invasive Escherichia coli

“…46, 47 AIEC translocation through the epithelial barrier is dependent on type 1 pili and binding of LPF to glycoprotein 2 (GP2) to AIEC Disruption of Epithelial Junctions microfold cells (M-cells) 39, 43, 48. M-cells are required for the development of host immunity, 49 are involved in bacterial sampling,50, 51, 52, 53 and can serve as an alternative gateway for AIEC39, 54 into and through the epithelium (reviewed by Pravda 55 ). The AIEC-containing endosome can mature into a phagosome and exit basolaterally from the IEC, where it can be processed by macrophages (Figure 1).…”