Cross-Regulation of Innate and Adaptive Immunity: A New Perspective for the Pathogenesis of Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is characterized by chronic, relapsing inflammation, resulting from a pathological response in the gastrointestinal tract. The pathogenesis of IBD remains obscure; however, it has been suggested that IBD is caused in genetically susceptible host by an appropriate immune response against abnormal intestinal microflora. Abnormal innate and adaptive immune responses are regarded as the major components of IBD pathogenesis. For several decades, a majority of studies related to IBD have focused on the abnormal adaptive immune response as Crohn’s disease (CD) is considered to be associated with a Th1 response, while ulcerative colitis is driven by a Th2 response. Recent advances in IBD research, such as data from a genome-wide association study and the results of microbiome analyses, have helped unravel the complex innate immune responses in IBD, such as mucosal barrier function, microbial sensing, autophagy, and endoplasmic reticulum stress; these have indicated the importance of cross regulation of the innate and adaptive immune responses. The innate immune system, which provides nonspecific and rapid response, is at the head of host defense against intestinal pathogens. The innate immune system is composed of multiple factors such as antimicrobial peptides (such as β-defensin-2), and performs the diverse functions, including epithelial barrier function, autophagy, and unfolded protein response. In addition, this systems consists of phagocytic cells, such as dendritic cells, macrophages, and intestinal epithelial cells, which can recognize the intestinal microbial antigens, causing a rapid inflammatory response against abnormal pathogens. Furthermore, antigen presenting cells, such as dendritic cells, secrete cytokines that facilitate T cell differentiation, resulting in the activation of the adaptive immune systems. Unlike the innate immune system, the adaptive immune system is highly specific and confers long-lasting immunity. T cells are key players in the adaptive immune system. Naive T cells can differentiate into various effector T cells, such as Th1, Th2, or Th17 cells. These T cell subsets contribute to the removal of microbial organisms, such as bacteria, fungi, and parasites. However, the dysregulation of activated T cells results in the secretion of proinflammatory cytokines and chemokines, which leads to the onset of the chronic inflammation that characterizes IBD. The interplay between the innate and adaptive immune systems plays a central role in the pathogenesis of IBD. However, research into the pathogenesis of IBD has been largely focused on the two immune systems separately, some have focused on the adaptive immune system, especially T cells, whereas others have investigated the intestinal epithelial cells or phagocytic cells expressed in the lamina propria. The recent advances in molecular biology techniques, including sequencing, have aided in exploring the cross-talk between the innate and adaptive immune responses. For example, NOD2, a pattern recognition receptor belonging to the innate immune system, play a role in the regulation of adaptive immune responses. Despite this, the cross-regulation of the innate and adaptive immune systems remains largely unexplored. An article published in the latest issue of Gut and Liver has demonstrated the close association between the innate and adaptive immune systems. In this study, the authors investigated the frequency of expression of T cell immunoglobulinand mucin-domain-containing molecule-3 (TIM-3), human β-defensin-2 (HBD-2), forkhead box protein-3 (FOXP-3) and