Insights into IBD Pathogenesis

Abstract

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder caused by dysregulated immune responses in a genetically predisposed individual. Recent accumulating data, including genome-wide association studies, have identified more than 50 distinct genetic loci that confer susceptibility. We highlight the role of microbial-host interaction, particularly with respect to the overlap of common genetic and pathophysiologic mechanisms of CD and UC, interleukin-22-producing natural killer cells, autophagy, and TL1A, a member of the tumor necrosis factor (TNF) family, in gut homeostasis and IBD pathogenesis. This article focuses on the recent advances in understanding of IBD from the past year, including advances in genetics and immunobiology.

Figure 1

Working hypothesis of inflammatory bowel disease. Intestinal immune system is in close apposition to luminal antigen/bacteria, which are separated by a single layer of epithelial cells. Goblet cells contribute to the formation of the protective mucus layer, and M cells and dendritic cells (DC) sample intestinal luminal contents. Overresponse to antigens, either through Toll-like receptors (TLR), intracellular sensor NOD2, or antigen processing via autophagy, results in stimulated DC that recruit and generate T-cell (Th1, Th2, and Th17) and NK-cell subtypes. One subpopulation of RORγt⁺NKp46⁺ NK cells that resides in gut cryptopatches is found to readily produce IL-22 in response to IL-23, likely released by DC. IL-22 may play an important role in epithelial homeostasis, bacteria clearance, and tissue repair. TL1A appears to be a critical factor important in generating Th1, Th2, and Th17 cells. For each T-helper cell differentiation program, specific transcription factors and cytokine milieu are required (indicated in the figure). Terminally differentiated T-helper cells are characterized by a specific combination of effector cytokines (indicated in the figure) that orchestrate effector function of the adaptive immune system. Crohn’s disease is a predominantly Th1- and Th17-mediated process, whereas ulcerative colitis appears to be mediated by Th2 and possibly Th17.