Alterations of subset and cytokine profile of peripheral T helper cells in PBMCs from Multiple Sclerosis patients or from individuals with MS risk SNPs near genes CYP27B1 and CYP24A1
Alterations of subset and cytokine profile of peripheral T helper cells in PBMCs from Multiple Sclerosis patients or from individuals with MS risk SNPs near genes CYP27B1 and CYP24A1
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多发性硬化症患者或基因 CYP27B1 和 CYP24A1 附近具有 MS 风险 SNP 的个体的 PBMC 中外周 T 辅助细胞亚群和细胞因子谱的改变
DOI：
10.1016/j.cyto.2022.155866
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发表时间：
2022
期刊：
影响因子：
3.8
通讯作者：
Heinrich Korner
中科院分区：
文献类型：
--
作者：
Ming Lu;Hui Shi;Bruce V Taylor;Heinrich Korner
辅助性T细胞在多发性硬化（MS）的病因学中起重要作用。维生素D对T辅助细胞具有抗炎作用，并且可以影响MS的发作和发病机制。由活化的T辅助（Th）细胞表达的代谢维生素D途径的两个基因已经通过全基因组关联研究被鉴定为MS风险基因，CYP 27 B1（25（OH）D31-α-羟化酶）和CYP 24 A1（1，25（OH）2D 324-α-羟化酶）。因此，我们推测，MS风险基因CYP 27 B1和CYP 24 A1周围的等位基因与体内和体外PBMC中外周Th细胞的炎症特征改变相关，可能影响MS的发病机制。收集缓解期RRMS患者41例和SPMS患者4例，健康对照组12例，流式细胞术检测外周血单个核细胞（PBMC）中Th细胞亚群，流式细胞仪检测细胞因子谱。通过等位基因特异性PCR分析对MS风险SNPs进行基因分型。使用非参数检验和线性回归对数据进行分析，以调整多个因素。Th17.1、Th 17和Th 1细胞比例均与MS相关，而Th 2（显著）和Th 17（接近显著）细胞比例与MS患者扩展残疾量表评分相关。此外，我们还发现伴刀豆球蛋白A刺激的PBMC中Th细胞产生IL-6和TNF的MS特异性失调。此外，风险等位基因rs 2248359-C（接近CYP 24 A1基因）对Th 1和Th17.1细胞的比例显示出一致的抑制作用，纯合风险等位基因rs703842-AA（接近CYP 27 B1基因）的存在降低了IL-2的产生。总之，MS疾病及其维生素D代谢基因附近的风险等位基因影响PBMC中T辅助细胞的炎症特征。
T helper cells play an important role in the aetiology of Multiple Sclerosis (MS). Vitamin D has an anti-inflammatory effect on T helper cells and can affect onset and pathogenesis of MS. Two genes of the metabolic Vitamin D pathway expressed by activated T helper (Th) cells have been identified as MS risk genes by genome-wide association studies,CYP27B1(25(OH)D31-alpha-hydroxylase) and CYP24A1 (1,25(OH)2D324-alpha-hydroxylase). Therefore, we hypothesize that the MS risk alleles around geneCYP27B1andCYP24A1are associated with the altered inflammatory profile of peripheral Th cells in PBMCs bothex vivoandin vitropotentially influencing the pathogenesis of MS. PBMCs from MS patients (41 RRMS patients in their remitting stage and 4 SPMS patients) and 12 healthy controls were collected, subpopulation of Th cells in PBMCs and cytokine profile were tested by Flow cytometry and Cytometric Bead Array (CBA), respectively. MS risk SNPs were genotyped by allele-specific PCR analysis. Data were analysed using nonparametric tests and linear regression for adjusting multiple factors. The proportion of Th17.1, Th17 and Th1 cells were all associated with MS while the proportions of Th2 (significant) and Th17 (near significant) cells were correlated with the expanded disability scale score of MS patients. Additionally, we found a MS-specific dysregulation in the IL-6 and TNF production of Th cells in Concanavalin A-stimulated PBMCs. Furthermore, the risk allele rs2248359-C (near geneCYP24A1) showed a consistent inhibitory effect on the proportions of Th1 and Th17.1 cells, and the presence of the homozygous risk allele rs703842-AA (near geneCYP27B1) reduced the production of IL-2. In conclusion, both MS disease and its risk alleles near Vitamin D metabolism genes influence the inflammatory profile of T helper cells in PBMCs.