Vitamin D Fluctuations and the Mucosal Immune Response

描述（由申请人提供）：居住在美国北部和加拿大的人群中，炎症性肠病（IBD）的发病率最高。维生素D的状态随着季节的变化而变化，这是由于皮肤中产生维生素D的阳光照射减少的结果。此外，饮食中维生素D的来源相对较差。实验性IBD在维生素D缺乏的小鼠中更为严重，而活性形式的维生素D （1,25(OH)2D3）抑制了这种疾病。我们假设，户外活动的减少、污染的增加以及缺乏足够维生素D的饮食，共同造成了发达国家维生素D水平的大幅波动，尤其是在经历冬季的人群中。我们认为，产前和产后维生素D暴露会改变免疫功能，从而导致IBD。维生素D假说提出，维生素D调节免疫系统的发育和功能，维生素D状态的变化，特别是产前和儿童时期的变化，会影响由此产生的免疫反应的发展和IBD等疾病的发展。我们的初步数据表明，维生素D受体（VDR） KO小鼠对实验性IBD的易感性增加是T细胞归巢改变的结果，导致肠道粘膜CD8aa调节性T细胞减少。我们提出CD8aa T细胞需要维生素D，即使是短暂的低维生素D状态也会导致上皮内淋巴细胞（IEL）的CD8aa T细胞减少。我们假设维生素D是粘膜CD8aa T细胞受体a¿IEL发育所必需的。所涉及的机制可能包括对肠道T细胞归巢的影响，胸腺中CD8aa前体的发育，和/或诱导CD8aa表达的胸腺外信号。维生素D和VDR调节CD8aa T细胞的机制将被确定。从这些实验中产生的数据对于了解维生素D对免疫的影响以及高剂量维生素D作为预防或治疗IBD等疾病的替代方法的潜在用途至关重要。

DESCRIPTION (provided by applicant): The incidence of inflammatory bowel disease (IBD) is highest for people that live in the Northern parts of the United States and Canada. Vitamin D status has been shown to change with season as a result of decreased sunlight exposure that produces vitamin D in the skin. In addition, the diet is a relatively poor source of vitamin D. Experimental IBD is more severe in vitamin D deficient mice and the active form of vitamin D (1,25(OH)2D3) suppresses the disease. We hypothesize that decreased outdoor activity and increased pollution and diets that lack adequate vitamin D have combined to create large fluctuations in vitamin D status in developed countries and especially in populations that experience winter. We propose that vitamin D exposure prenatally as well as postnatally alters immune function and as a result IBD. The vitamin D hypothesis proposes that vitamin D regulates the development and function of the immune system and that changes in vitamin D status especially prenatal as well as childhood alterations affect the development of the resultant immune response and the development of diseases like IBD. Our preliminary data show that the increased susceptibility of the vitamin D receptor (VDR) KO mice to experimental IBD is a result of altered T cell homing that results in few mucosal CD8aa regulatory T cells in the gut. We propose that CD8aa T cells require vitamin D and that even transient periods of low vitamin D status result in decreases in the CD8aa T cells of the intraepithelial lymphocytes (IEL). We hypothesize that vitamin D is required for the development of the mucosal CD8aa T cell receptor a¿ IEL. The mechanisms involved might include an effect on gut T cell homing, development of CD8aa precursors in the thymus, and/or extrathymic signals that induce expression of CD8aa. The mechanisms by which vitamin D and the VDR regulate the CD8aa T cells will be determined. The data generated from these experiments is critical to the understanding of the effects of vitamin D on immunity and the potential use of high dose vitamin D as an alternative way to prevent or treat diseases like IBD. Public Health Relevance: There is at present a great deal of misinformation about vitamin D and vitamin D supplements as immune system modulators in the public forum. Identifying the cellular and molecular targets of vitamin D in the immune system is important so that rational decisions about the use of vitamin D supplements for healthy individuals as well as patients with autoimmune diseases like inflammatory bowel disease can be made.