Vitamin D Fluctuations and the Mucosal Immune Response

描述（由申请人提供）：美国和加拿大北方地区的人群中炎症性肠病（IBD）的发病率最高。维生素D的状态已被证明会随着季节的变化而变化，这是由于减少阳光照射而在皮肤中产生维生素D。此外，饮食是维生素D的相对较差的来源。实验性IBD在维生素D缺乏小鼠中更严重，维生素D的活性形式（1，25（OH）2D 3）抑制疾病。我们推测，户外活动减少、污染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状况的大幅波动，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，特别是产前和儿童期的改变，会影响免疫反应的发展和IBD等疾病的发展。我们的初步数据显示，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，这导致肠道中的粘膜CD 8aa调节性T细胞很少。我们认为CD 8aa 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CD 8aa T细胞减少。我们假设维生素D是粘膜CD 8aa T细胞受体a <$IEL的发展所必需的。所涉及的机制可能包括对肠道T细胞归巢、胸腺中CD 8aa前体的发育和/或诱导CD 8aa表达的胸腺外信号的影响。维生素D和VDR调节CD 8aa T细胞的机制将被确定。这些实验产生的数据对于理解维生素D对免疫力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。 公共卫生相关性：目前在公共论坛上有大量关于维生素D和维生素D补充剂作为免疫系统调节剂的错误信息。确定维生素D在免疫系统中的细胞和分子靶点非常重要，这样就可以做出关于健康个体以及患有炎症性肠病等自身免疫性疾病的患者使用维生素D补充剂的合理决定。

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.