Scientific Abstract
Proposal No. IBD-0007
Principal Investigator: Johan D. Söderholm, M.D., Ph.D.
Applicant Organization: Linköping University (Sweden)
Project Title: The role of the follicle-associated epithelium in the initiation of inflammatory bowel disease
Period of Award: November 1, 2002 – September 30, 2005
Inflammatory bowel disease (IBD) represents the outcome of the interaction between the predisposition of the host (genetic and environmental), the mucosal immune response, and the bacterial flora in the intestinal lumen. The earliest observable lesions in Crohn’s disease (CD) are microscopic erosions in the follicle-associated epithelium (FAE). In contrast to the villus epithelium, the FAE contains very few goblet and enteroendocrine cells, but contains specialized epithelial M (microfold or membranous) cells. The M cells are designed to deliver samples of luminal antigens to intra- and subepithelial immune cells by transepithelial vesicular transport. This sampling from the lumen is believed to be crucial for induction of protective mucosal immune responses, but also provides a route of entry into the mucosa for various pathogens: bacteria, viruses, as well as protozoa.
Despite the importance of FAE and M cells, studies of FAE function in the human intestine are lacking. Together with the co-applicants, my group is now one of the very few with the needed knowledge and methodology for functional studies of human FAE and M cells.
Our hypothesis is that a malfunction in the interaction between luminal antigens/microorganisms, epithelial cells, and immune cells that takes place in the FAE is a crucial step in the initiation of mucosal inflammation in CD. The aims of the proposed project are to elucidate initiating events in the inflammatory process of CD, by studying FAE and M-cells from patients with CD at various stages of inflammation.
Within this project, we will do the first functional characterization of FAE and M cells in human intestine. We will also be able to investigate the intestinal barrier to enteric bacteria, and compare the defense against epithelial invasion of luminal bacteria with different invasion characteristics in tissue from CD and control patients. Thereby, the project will be the first to study the actual process of bacterial uptake into the FAE in IBD, and will add important insights into what is thought to be a crucial step in the pathophysiology of intestinal inflammation.
Little is known about regulation of uptake of macromolecules and microorganisms via the human FAE and M cells. Concurrently with the planned comparative studies between CD and controls, mechanisms of regulation of normal FAE function by luminal and neuroimmune factors will be investigated. When we have acquired data from the planned studies, we will be able to study possible alterations in FAE regulation in CD. Also, we anticipate being able to study FAE gene expression in CD mucosa.