Mechanisms associated with flares and remission in colitis

摘要 炎症性肠病(IBD)在全球范围内影响着数以百万计的人，其发病率还在不断增加。两者都有 遗传和环境因素似乎在IBD的发展中发挥了作用。对人类的基因研究已经 白介素23(IL-23)信号通路与IBD有关，但导致疾病的环境因素， 仍然难以捉摸。世界范围内IBD发病率的上升与饮食的西化有关 然而，几乎没有科学证据支持因果关系。在此应用程序中 我们将研究一组特殊的饮食添加剂，即食品着色剂，对 结肠炎。我们现在发现，食品着色剂红40，也被称为Allura Red AC，促进结肠炎 在有条件地表达低水平IL-23的小鼠(称为R23FR小鼠)中，但在野生型小鼠中不是。红色 40是世界上最丰富的食用着色剂，年产量超过230万公斤。它是广泛存在的 用作软饮料、樱桃味产品、糖果、乳制品、药品和化妆品中的红色着色剂。令人感兴趣的， 含有红40的饮料、酷爱和保湿溶液Pedialyte Cherry也会导致结肠炎 R23FR小鼠。红40诱导的R23FR小鼠结肠炎需要微生物区系和CD4T细胞。基于这些 和这里提出的其他结果，我们提出了一个中心假设，即红40或其代谢物半抗原 细菌或内源性蛋白在野生型小鼠中产生耐受性，或在IL-23感染的小鼠中产生结肠炎 表达是失调的。我们将在这项建议中研究与产生和预防有关的机制 在这些回应中。具体地说，我们将定义：1)红40及其代谢物ANSA是否为半抗原；2)红 40诱导对照组小鼠耐受；3)如果R23FR小鼠产生Red 40或ANSA特异性T细胞

Summary Inflammatory bowel diseases (IBD) affect millions of individuals worldwide and its incidence is increasing. Both genetic and environmental factors appear to play a role in IBD development. Genetic studies in humans have linked the interleukin-23 (IL-23) signaling pathway with IBD, but the environmental factors contributing to disease, have remained elusive. The rising incidence of worldwide IBD has been associated with westernization of dietary habits in developing countries, however there is little scientific evidence to support causality. In this application we will examine the role of a particular group of dietary additives, namely food colorants, to development of colitis. We have now discovered that the food colorant Red 40, also known as Allura Red AC, promotes colitis in mice that conditionally express low levels of IL-23 (referred to as R23FR mice), but not in wild type mice. Red 40 is the most abundant food colorant in the world, with annual production exceeding 2.3 million kg. It is widely used in as red colorant in soft drinks, cherry flavored products, candy, dairy, drugs, and cosmetics. Of interest, the Red 40-containing beverages, Kool-Aid and the hydrating solution Pedialyte Cherry can also cause colitis in R23FR mice. Red 40-induced colitis in R23FR mice requires the microbiota and CD4+ T cells. Based on these and other results presented here, we formulate a central hypothesis that the Red 40 or its metabolites haptenize bacterial or endogenous proteins to generate tolerance in wild type mice, or colitis in mice in which IL-23 expression is dysregulated. We will study in this proposal the mechanisms involved in generation and prevention of these responses. Specifically, we will define: 1) if Red 40 and its metabolite ANSA are haptens; 2) how Red 40 induces tolerance in control mice; and 3) if Red 40 or ANSA-specific T cells are generated in R23FR mice