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首页> 外文期刊>Journal of Neuroimmunology: Official Bulletin of the Research Committee on Neuroimmunology of the World Federation of Neurology >Vitamin D and estrogen synergy in Vdr-expressing CD4(+) T cells is essential to induce Helios(+)FoxP3(+) T cells and prevent autoimmune demyelinating disease
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Vitamin D and estrogen synergy in Vdr-expressing CD4(+) T cells is essential to induce Helios(+)FoxP3(+) T cells and prevent autoimmune demyelinating disease

机译：Vdr表达CD4（+）T细胞中的维生素D和雌激素协同作用对于诱导Helios（+）FoxP3（+）T细胞和预防自身免疫性脱髓鞘疾病至关重要

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Multiple sclerosis (MS) is a neurodegenerative disease resulting from an autoimmune attack on the axon-myelin unit. A female MS bias becomes evident after puberty and female incidence has tripled in the last half-century, implicating a female sex hormone interacting with a modifiable environmental factor. These aspects of MS suggest that many female MS cases may be preventable. Mechanistic knowledge of this hormone-environment interaction is needed to devise strategies to reduce female MS risk. We previously demonstrated that vitamin D-3 (D3) deficiency increases and D3 supplementation decreases experimental autoimmune encephalomyelitis (EAE) risk in a female-biased manner. We also showed that D3 acts in an estrogen (E2)-dependent manner, since ovariectomy eliminated and E2 restored D3-mediated EAE protection. Here we probed the hypothesis that E2 and D3 interact synergistically within CD4(+) T cells to control T cell fate and prevent demyelinating disease. The E2 increased EAE resistance in wild-type (WT) but not T-Vdr(0) mice lacking Vdr gene function in CD4(+) T cells, so E2 action depended entirely on Vdr(+)CD4(+) T cells. The E2 levels were higher in WT than T-Vdr(0) mice, suggesting the Vdr CD4+ T cells produced E2 or stimulated its production. The E2 decreased Cyp24a1 and increased Vdr transcripts in T cells, prolonging the calcitriol half-life and increasing calcitriol responsiveness. The E2 also increased CD4(+)Helios(+)FoxP3(+) T regulatory (Treg) cells in a Vdr-dependent manner. Thus, CD4+ T cells have a cooperative amplification loop involving E2 and calcitriol that promotes CD4(+)Helios(+)FoxP3(+) Treg cell development and is disrupted when the D3 pathway is impaired. The global decline in population D3 status may be undermining a similar cooperative E2-D3 interaction controlling Treg cell differentiation in women, causing a breakdown in T cell self tolerance and a rise in MS incidence. (C) 2015 Elsevier B.V. All rights reserved.
机译：多发性硬化症（MS）是一种神经退行性疾病，是由对轴突-髓鞘单位的自身免疫攻击引起的。青春期后，女性的MS偏见变得明显，并且在过去的半个世纪中，女性的发病率增加了两倍，这意味着女性性激素与可调节的环境因素相互作用。 MS的这些方面表明，许多女性MS病例是可以预防的。需要有关激素与环境相互作用的机制知识，以制定降低女性MS风险的策略。我们以前证明维生素D-3（D3）缺乏症增加，而D3补充剂则以女性偏见的方式降低了实验性自身免疫性脑脊髓炎（EAE）的风险。我们还显示，D3以雌激素（E2）依赖性方式起作用，因为卵巢切除术消除了，E2恢复了D3介导的EAE保护。在这里，我们探讨了CD4（+）T细胞内E2和D3协同相互作用以控制T细胞命运并预防脱髓鞘疾病的假说。 E2增加了野生型（WT）的EAE抵抗力，但没有在CD4（+）T细胞中缺乏Vdr基因功能的T-Vdr（0）小鼠，因此E2的作用完全取决于Vdr（+）CD4（+）T细胞。 WT中的E2水平高于T-Vdr（0）小鼠，表明Vdr CD4 + T细胞产生了E2或刺激了它的产生。 E2减少Cyp24a1并增加T细胞中的Vdr转录本，从而延长了骨化三醇的半衰期并增加了骨化三醇的响应能力。 E2还以Vdr依赖性方式增加CD4（+）Helios（+）FoxP3（+）T调节（Treg）细胞。因此，CD4 + T细胞具有涉及E2和骨化三醇的协同扩增环，可促进CD4（+）Helios（+）FoxP3（+）Treg细胞发育，并在D3途径受损时被破坏。全球人口D3地位的下降可能正在破坏控制妇女Treg细胞分化的类似的合作E2-D3相互作用，从而导致T细胞自我耐受性下降和MS发病率上升。 （C）2015 Elsevier B.V.保留所有权利。

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