Defining the role of vitamin D in multiple sclerosis

摘要 多发性硬化（MS）是中枢神经系统（CNS）的炎性脱髓鞘疾病 会导致进行性神经功能缺损，在美国有40万人受到影响。这种不治之症， 疾病是相当昂贵的卫生保健系统和社会的保守估计， 2007年，耗资200亿元。MS的患病率和发病率在全球范围内不断增加。因此，需要 预防MS的策略比以往任何时候都更重要。MS的原因仍然未知;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，对迁移和阳光照射的研究表明，MS的易感性取决于 儿童期，虽然疾病发作是在生命的后期。在生命早期提供足够的维生素D可能有益于 目前尚不清楚的是，早期维生素D缺乏如何影响成年发病的易感性。 女士没有研究调查过早期维生素D水平低是否会增加患上糖尿病的风险。 自身免疫性脱髓鞘疾病维生素D受体普遍存在于免疫系统 和中枢神经系统（CNS），使这两个系统可能会改变，由于低维生素D在早期 生活MS是与阳光/维生素D水平最密切相关的自身免疫性疾病，这表明 与维生素D信号相关的CNS特异性组分，可能导致MS的风险。 这项研究的长期目标是了解早期生命印记中充足的维生素D的机制 防止MS在以后的生活中发展。拟议项目的总体目标是比较 小鼠对EAE的易感性，其中免疫系统或CNS中的维生素D信号传导受损 在生命的早期。我们的主要假设是，在生命早期，维生素D信号的减少使中枢神经系统更加脆弱。 易受炎症影响，增强自身免疫性脱髓鞘疾病的易感性。的理由 这项研究的基础是，一旦生命早期维生素D缺乏和MS易感性的相关性， 充分定义，这将是制定公共卫生政策的基础，以操纵这一容易修改的 MS的危险因素。具体目的如下：1）确定免疫中维生素D不足是否 系统在幼年小鼠中增强了对EAE的易感性，以及2）确定CNS中是否存在维生素D不足 增加了对EAE的易感性。维生素D信号在免疫系统中的相对贡献 系统与中枢神经系统的比较对于了解维生素D在MS风险中的作用以及数据如何影响MS风险是必要的。 可应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 环境因素对MS风险的影响将是朝着最终目标-预防MS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.