Multiple Sclerosis: Lipids, Lymphocytes, and Vitamin D.
Multiple Sclerosis: Lipids, Lymphocytes, and Vitamin D.
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DOI：
10.20900/immunometab20200019
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发表时间：
2020-01-01
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影响因子：
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通讯作者：
Ntambi, James M
中科院分区：
文献类型：
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作者：
Hayes, Colleen E;Ntambi, James M
多发性硬化症（MS）是一种中枢神经系统的炎症性脱髓鞘疾病。我们回顾了MS的两个核心特征，髓磷脂不稳定、碎片化和髓鞘再生失败，以及致病性CD4+ Th17细胞优于保护性CD4+ Treg细胞。为了更好地理解髓磷脂病理学，我们描述了髓磷脂的生物合成、结构和功能，然后重点介绍了硬脂酰辅酶a去饱和酶（SCD）在神经酸生物合成中的作用以及神经酸对髓磷脂稳定性的贡献。注意到维生素D缺乏会降低外周细胞的SCD，我们认为它也会降低少突胶质细胞的SCD，破坏神经酸的供应，导致髓磷脂不稳定和断裂。为了更好地理解扭曲的Th17/Treg细胞平衡，我们总结了Th17细胞在MS发病中的作用，然后强调了从小胶质细胞到CD4+ T细胞的1,25-二羟基维生素D3信号如何恢复Treg细胞的优势。该信号通过蛋氨酸循环迅速增加通量，去除同型半胱氨酸，补充s -腺苷基蛋氨酸，并改善表观遗传标记。注意到MS患者CD4+ T细胞中存在DNA低甲基化和DRB1*1501不适当表达，我们提出维生素D缺乏阻碍DRB1*1501和Th17细胞特征基因的表观遗传下调，以及Treg细胞特征基因的上调，导致CD4+ T细胞区室内的失调。我们解释了肥胖如何降低维生素D水平，以及雌激素和维生素D如何协同促进女性Treg细胞的优势。最后，我们讨论了这一新知识对髓磷脂和Th17/Treg细胞平衡的影响，并倡导努力解决肥胖和维生素D缺乏症的全球流行，以期减少MS的影响。
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. We review the two core MS features, myelin instability, fragmentation, and remyelination failure, and dominance of pathogenic CD4+ Th17 cells over protective CD4+ Treg cells. To better understand myelin pathology, we describe myelin biosynthesis, structure, and function, then highlight stearoyl-CoA desaturase (SCD) in nervonic acid biosynthesis and nervonic acid's contribution to myelin stability. Noting that vitamin D deficiency decreases SCD in the periphery, we propose it also decreases SCD in oligodendrocytes, disrupting the nervonic acid supply and causing myelin instability and fragmentation. To better understand the distorted Th17/Treg cell balance, we summarize Th17 cell contributions to MS pathogenesis, then highlight how 1,25-dihydroxyvitamin D3 signaling from microglia to CD4+ T cells restores Treg cell dominance. This signaling rapidly increases flux through the methionine cycle, removing homocysteine, replenishing S-adenosyl-methionine, and improving epigenetic marking. Noting that DNA hypomethylation and inappropriate DRB1*1501 expression were observed in MS patient CD4+ T cells, we propose that vitamin D deficiency thwarts epigenetic downregulation of DRB1*1501 and Th17 cell signature genes, and upregulation of Treg cell signature genes, causing dysregulation within the CD4+ T cell compartment. We explain how obesity reduces vitamin D status, and how estrogen and vitamin D collaborate to promote Treg cell dominance in females. Finally, we discuss the implications of this new knowledge concerning myelin and the Th17/Treg cell balance, and advocate for efforts to address the global epidemics of obesity and vitamin D deficiency in the expectation of reducing the impact of MS.