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Abstract
Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders that affects many individuals throughout their lives. Ulcerative colitis (UC) and Crohn’s disease (CD) are two major forms of IBD. Until the early 1990s, a murine model of spontaneous chronic colitis was unavailable. As a major breakthrough in the basic research field of IBD, three genetically manipulated murine chronic colitis models, including interleukin (IL)-2 knockout (KO), IL-10 KO, and T cell receptor alpha chain (TCRα) KO models, were established in 1993. Since then, complicated immunobiological mechanisms during the development of UC have been gradually discovered by utilizing a wide variety of murine models of IBD, including the TCRα KO mouse model. In particular, it has been recognized that four major factors, including enteric, environmental, and immunological factors as well as enteric microbiota are highly and mutually involved in the pathogenesis of UC. As a pioneer of the TCRα KO murine model of UC, our group has identified that the interactions between the unique TCRα-β+ T cell population and antigen-presenting cells, including dendritic cells and B cells, play a key role for the development and regulation of UC-like chronic colitis, respectively. Here we have summarized clinically proven pathogenic and regulatory factors which have been identified by this novel TCRα KO murine model of UC in the past nearly three decades.
Highlights
It is apparent that animal models are indispensable to analyze the pathogenesis of Inflammatory bowel disease (IBD) efficiently and mechanistically
In 1993, the first genetically manipulated murine models of spontaneous chronic colitis including IL-2 KO, IL-10 KO, and T cell receptor alpha chain (TCRα) KO mice were established in the same issue of Cell [1,2,3]
The severity of colitis in TCRα KO mice changes depending on the animal facilities; under germ-free conditions, but not specific-pathogen free (SPF) conditions, the onset of chronic colitis was completely suppressed in those mice [5,6]
Summary
It is apparent that animal models are indispensable to analyze the pathogenesis of IBD efficiently and mechanistically. In 2011, Morgan et al found for the first time that there were patients with homozygous G-to-A mutations in the exon 3 region of TRAC (TCRα subunit constant gene) [16] This suggests that T cells expressing TCRα−β+, which are found in TCRα KO mice that spontaneously develop colitis with aging, are present in humans, and that clonal expansion of T cells expressing only the TCRβ chain is one of the causes of the pathogenesis. These patients have been found to develop complex immunodeficiency diseases, such as respiratory infections, otitis media, candidiasis, diarrhea, and stunted growth in infancy [16]. A gap in the repertoire of TCRs expressed on T cells, one of the many immune cells, may affect intestinal homeostasis, but may contribute to an exaggerated response of intestinal epithelial cells [20]
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