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

Figure 1 Antigenic exposure (a) of luminal antigens to the immune system can occur through either transcellular (through cells) or paracellular (between cells) pathways. Transcellular transport is mediated via transcytosis of processed antigen within discrete intracellular vesicles, termed endosomes, which are transported from apical to basal membrane prior to undergoing exocytosis, where immune recognition may occur within the lamina propria. Bacteria and macromolecules are transported in this fashion as they are too large to penetrate the tight intercellular space (paracellular pathway) maintained by tight junctional proteins. An immune response (b) can ensue subsequent to antigenic penetration into the lamina propria. Continuous unregulated transcytosis of luminal antigens and Mycobacterium avium paratuberculosis (MAP) into the lamina propria can initiate a chronic immune reaction. Inhibition of immune response (b) with immunosuppressive agents may temporarily restore epithelial integrity, but will not prevent transcytosis of luminal antigen, which continues upon discontinuation of immunosuppressive therapy. Mitigation of luminal antigenic exposure via restrictive diets or parenteral therapy cannot prevent subsequent transcytosis and relapse once normal dietary activity is resumed. A three pronged approach for acute therapy consisting of: (1) reduction of antigenic exposure via temporary dietary restriction; (2) temporary immunosuppression to inhibit immune mediated tissue damage and speed epithelial healing; and (3) Inhibition of transcytosis via endocytosis blocking agents to prevent future immune activation, may offer a therapeutic paradigm on which to base clinical decision making. Anti-MAP antibiotics may additionally be utilized to speed systemic removal of this bacterium and hasten downregulation of the immune response. Limited evidence suggests that inhibition of transcytosis may reduce intestinal antigenic exposure sufficiently to allow long term dietary activity with minimal restrictions. Maintenance therapy with endocytosis inhibiting agents may provide a safe and effective means of inducing long-term remission and interrupting the natural history of Crohn’s disease. TNF: Tumor necrosis factor.