Recent advances in IBD pathogenesis: genetics and immunobiology

Abstract

The inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis, are chronic inflammatory disorders caused by dysregulated immune responses in genetically predisposed individuals. Although the precise etiology of IBD remains unclear, accumulating data, including genome-wide association studies, have advanced our understanding of its immunopathogenesis. This review highlights the role in gut homeostasis and IBD pathogenesis of autophagy, the interleukin (IL)-23/IL-17 axis, and a novel member of the tumor necrosis factor family, TL1A. It focuses on advances in our understanding of IBD from the past year, including advances in genetics and immunobiology.

Figure 1

Working hypothesis of inflammatory bowel disease. The intestinal immune system is in close apposition to luminal antigen/bacteria, separated by a single layer of epithelial cells. Goblet cells contribute to the formation of the protective mucus layer, M cells and dendritic cells (DCs) sample intestinal luminal contents. Over-response to antigens, either through the Toll-like receptors (TLR), the intracellular sensor NOD2, or antigen processing via autophagy, results in stimulated DCs that recruit and generate various T-helper-cell subtypes (Th1, Th2, and Th17). TL1A appears to be a critical factor in the generation of Th1, Th2, and Th17 cells. For each T-helper-cell differentiation program, specific transcription factors and cytokine milieu are required. Terminally differentiated T helper cells are characterized by a specific combination of effector cytokines that orchestrate the effector function of the adaptive immune system. Ulcerative colitis appears to be predominately Th2-mediated, whereas Crohn's disease is a predominately Th1- and Th17-mediated process. GATA—GATA binding protein; IFN—interferon; IL—interleukin; IRGM—immunity-related guanosine triphosphatase, M; MAPK—mitogen-activated protein kinase; MDP— muramyl dipeptide; MyD88—myeloid differentiation factor 88; NOD2—nucleotide-binding oligomerization domain containing 2; TGFβ—transforming growth factor β; TNF—tumor necrosis factor; RORγτ—retinoic acid-binding orphan receptor–γτ.