Defining the role of vitamin D in multiple sclerosis

摘要 多发性硬化(MS)是一种中枢神经系统(CNS)炎性脱髓鞘疾病 这会导致进行性神经功能障碍，影响到美国的40万人。这是无法治愈的，终身的 疾病给医疗保健系统和社会带来了相当高的代价，保守估计全国每年 2007年的成本为200亿美元。多发性硬化症的患病率和发病率在全球范围内呈上升趋势。因此，需要 预防多发性硬化症的策略比以往任何时候都要重要。多发性硬化症的病因仍不清楚；人们普遍认为 遗传和环境因素的结合决定了疾病的易感性。维生素D 缺乏正在成为MS的一个重要环境风险。流行病学研究表明，MS 频率随着纬度的升高而增加，这与阳光和维生素D水平呈负相关。 此外，迁移和阳光暴露的研究表明，患多发性硬化症的易感性在 儿童时期，尽管疾病起病的时间较晚。在生命早期提供充足的维生素D可能有益于 预防多发性硬化症目前尚不清楚早期维生素D缺乏如何影响成人发病的易感性 没有研究调查早期缺乏维生素D是否会增加罹患癌症的风险 成年期的自身免疫性脱髓鞘疾病。维生素D受体在两种免疫系统中都很普遍 和中枢神经系统(CNS)，使得这两个系统在早期由于维生素D不足而潜在地改变 生活。MS是一种与阳光/维生素D水平关系最密切的自身免疫性疾病，这表明 中枢神经系统特有的与维生素D信号有关的成分，可能导致发生MS的风险。 这项研究的长期目标是了解早期生命中充足的维生素D印记的机制 对晚年多发性硬化症发展的保护。拟议项目的总体目标是比较 免疫系统或中枢神经系统维生素D信号受损的小鼠对EAE的易感性 在生命的早期。我们的主要假设是，早期生命中维生素D信号的减少会使中枢神经系统 易受炎症影响，增加自身免疫性脱髓鞘疾病的易感性。其基本原理是 这项研究的基础是，一旦早期生活中维生素D缺乏与多发性硬化症易感性的相关性 完全定义，这将是制定公共卫生政策以操纵这一点很容易修改的基础 MS的危险因素具体目标如下：1)确定免疫系统中是否存在维生素D不足 幼鼠体内的维生素D系统增强了对EAE的易感性，以及2)确定中枢神经系统中是否存在维生素D缺乏 在幼年小鼠中增加了对EAE的易感性。维生素D信号在免疫中的相对作用 要了解维生素D在多发性硬化症风险中扮演的角色，以及数据是如何 可能适用于其他自身免疫性疾病和神经退行性疾病。了解这是如何 影响多发性硬化症风险的环境因素将是朝着最终目标-预防多发性硬化症迈出的重要一步。

Abstract Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that causes progressive neurological deficits, which affects 400,000 people in the USA. This incurable, life-long disease is quite costly to the health care system and society with a conservative estimate of a national annual cost of $20 billion in 2007. The prevalence and incidence of MS are increasing worldwide. Thus, the need for strategies to prevent MS is greater than ever. The cause of MS remains unknown; it is generally accepted that the combination of genetic and environmental factors determines the disease susceptibility. Vitamin D deficiency is emerging as an important environmental risk of MS. Epidemiological studies have shown that MS frequency increases with higher latitude, which is inversely correlated with sunlight and vitamin D levels. Furthermore, studies of migration and sun exposure indicate susceptibility to develop MS is determined in childhood, although disease onset is later in life. Providing sufficient vitamin D in early life may be beneficial to prevent MS. What is not known is how early life vitamin D deficiency influences the susceptibility to adult-onset MS. No studies have investigated whether low vitamin D during early life enhances the risk of developing autoimmune demyelinating disease in adulthood. Vitamin D receptors are prevalent in both the immune system and central nervous system (CNS), making both systems potentially altered due to low vitamin D during early life. MS is the autoimmune disease most closely linked to sunlight/vitamin D levels suggesting that there is a CNS-specific component related to vitamin D signals that may contribute to the risk of developing MS. The longterm goal of this study is to understand the mechanism by which sufficient vitamin D in early life imprints the protection against MS development later in life. The overall objective of the proposed project is to compare the susceptibility of mice to EAE in which there is impaired vitamin D signaling in the immune system or CNS during early life. Our main hypothesis is that reduced vitamin D signaling during early life makes the CNS more vulnerable to inflammation, enhancing the susceptibility to autoimmune demyelinating disease. The rationale that underlies this study is that, once the correlation of early life vitamin D deficiency and MS susceptibility is fully defined, this will be the foundation for making a public health policy to manipulate this easily modifiable risk factor for MS. The specific aims are as follows: 1) determine if vitamin D insufficiency in the immune system in juvenile mice enhances susceptibility to EAE, and 2) determine if vitamin D insufficiency in the CNS in juvenile mice enhances susceptibility to EAE. The relative contribution of vitamin D signaling in the immune system versus the CNS is necessary to understand the role that vitamin D plays in MS risk, and how the data may be applicable to other autoimmune diseases and neurodegenerative diseases. Understanding how this environmental factor influence MS risks will be a significant step towards the ultimate goal - preventing MS.