Mauf Sabrina, Penna-Martinez Marissa, Jentzsch Thorsten, Ackermann Hanns, Henrich Dirk, Radeke Heinfried H, Brück Patrick, Badenhoop Klaus, Ramos-Lopez Elizabeth
Division of Endocrinology & Metabolism, Department of Internal Medicine, Goethe-University Hospital, Theodor-Stern-Kai, Frankfurt am Main, Germany.
Division of Trauma Surgery, Department of Surgery, University Hospital Zürich, Switzerland.
J Steroid Biochem Mol Biol. 2015 Mar;147:17-23. doi: 10.1016/j.jsbmb.2014.11.001. Epub 2014 Nov 7.
Preventive measures and a causal therapy for type 1 diabetes (T1D) remain elusive. An imbalance between different dendritic cells (DC) with increased immunogenic DC and decreased tolerogenic DC (tDC) may lead to T1D. Furthermore, 25(OH)D3 is associated with less adverse effects than 1,25(OH)2D3.
The present study was performed to clarify the remaining issues about the cellular effects of 25(OH)D3 in patients with T1D and the role of genetic polymorphisms of the vitamin D3 (VD3) metabolism on a functional cellular level.
Twelve patients with T1D were case-matched to twelve healthy controls (HC). Monocytes (MC) were either not supplemented or supplemented with 25(OH)D3 in vitro and phenotyped with fluorescence-activated cell sorting. In vitro synthesis and plasma levels of 25(OH)D3 and 1,25(OH)2D3 were analyzed as well as twelve gene polymorphisms of the VD3 metabolism.
25(OH)D3 significantly inhibited differentiation of MC into DC and led to an increase of intermediate cells (IC), which show a similar phenotype as tDC. The patient with a recent onset of T1D showed a higher increase in MC and IC compared to patients with long-standing T1D. There were significant differences for the increase of IC with supplementation of 25(OH)D3 between different genotypes within the polymorphisms of VDR-BsmI-rs1544410, VDR-TaqI-rs731236 and CYP24A1-rs927650.
This study suggests that 25(OH)D3 shows immunomodulatory effects on a cellular level in patients with T1D and HC by inhibiting the differentiation of MC into DC and promoting the formation of IC, which are similar to tDC, thereby shifting immunity to self-tolerance. The potency of 25(OH)D3 did not differ between patients with T1D and HC. Increased plasma levels of 25(OH)D3 may inhibit a proinflammatory cell milieu. Despite of the limited patient number, this study generates the hypothesis that the immunmodulatory effects may be influenced by genotypes of the VDR and CYP24A1 illustrating their functional role in T1D susceptibility, which is worth further investigation.
1型糖尿病（T1D）的预防措施和病因疗法仍然难以捉摸。不同树突状细胞（DC）之间的失衡，即具有增强免疫原性的DC增加而具有耐受性的DC（tDC）减少，可能导致T1D。此外，与1,25(OH)2D3相比，25(OH)D3的不良反应更少。
本研究旨在阐明T1D患者中25(OH)D3的细胞效应以及维生素D3（VD3）代谢的基因多态性在功能细胞水平上的作用等遗留问题。
12例T1D患者与12例健康对照（HC）进行病例匹配。单核细胞（MC）在体外不添加或添加25(OH)D3，并通过荧光激活细胞分选进行表型分析。分析了25(OH)D3和1,25(OH)2D3的体外合成及血浆水平，以及VD3代谢的12个基因多态性。
25(OH)D3显著抑制MC向DC的分化，并导致中间细胞（IC）增加，这些中间细胞表现出与tDC相似的表型。与长期患T1D的患者相比，近期发病的T1D患者的MC和IC增加更高。在VDR - BsmI - rs1544410、VDR - TaqI - rs731236和CYP24A1 - rs927650多态性的不同基因型中，添加25(OH)D3后IC的增加存在显著差异。
本研究表明，25(OH)D3通过抑制MC向DC的分化并促进IC（类似于tDC）的形成，在T1D患者和HC的细胞水平上显示出免疫调节作用，从而将免疫转向自身耐受。25(OH)D3在T1D患者和HC之间的效力没有差异。25(OH)D3血浆水平升高可能抑制促炎细胞环境。尽管患者数量有限，但本研究提出了一个假设，即免疫调节作用可能受VDR和CYP24A1基因型的影响，阐明了它们在T1D易感性中的功能作用，值得进一步研究。
