Lu Ming, Shi Hui, Taylor Bruce V, Körner Heinrich
Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China; Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China.
Cytokine. 2022 May;153:155866. doi: 10.1016/j.cyto.2022.155866. Epub 2022 Mar 23.
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)D 1-alpha-hydroxylase) and CYP24A1 (1,25(OH)D 24-alpha-hydroxylase). Therefore, we hypothesize that the MS risk alleles around gene CYP27B1 and CYP24A1 are associated with the altered inflammatory profile of peripheral Th cells in PBMCs both ex vivo and in vitro potentially 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 gene CYP24A1) 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 gene CYP27B1) 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.
辅助性T细胞在多发性硬化症（MS）的病因学中起重要作用。维生素D对辅助性T细胞具有抗炎作用，并可影响MS的发病和发病机制。全基因组关联研究已将活化的辅助性T（Th）细胞表达的维生素D代谢途径的两个基因鉴定为MS风险基因，即CYP27B1（25（OH）D 1-α-羟化酶）和CYP24A1（1,25（OH）D 24-α-羟化酶）。因此，我们假设基因CYP27B1和CYP24A1周围的MS风险等位基因与外周血单个核细胞（PBMC）中Th细胞的炎症谱改变相关，这在体内外都可能影响MS的发病机制。收集了MS患者（41例缓解期复发缓解型MS患者和4例继发进展型MS患者）和12名健康对照者的PBMC，分别通过流式细胞术和细胞计数珠阵列（CBA）检测PBMC中Th细胞亚群和细胞因子谱。通过等位基因特异性PCR分析对MS风险单核苷酸多态性（SNP）进行基因分型。使用非参数检验和线性回归分析数据以调整多种因素。Th17.1、Th17和Th1细胞的比例均与MS相关，而Th2细胞（显著）和Th17细胞（接近显著）的比例与MS患者的扩展残疾量表评分相关。此外，我们发现刀豆球蛋白A刺激的PBMC中Th细胞的IL-6和TNF产生存在MS特异性失调。此外，风险等位基因rs2248359-C（靠近基因CYP24A1）对Th1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（靠近基因CYP27B1）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均影响PBMC中辅助性T细胞的炎症谱。
