Systemic inflammation in progressive multiple sclerosis involves follicular T-helper, Th17- and activated B-cells and correlates with progression.
Systemic inflammation in progressive multiple sclerosis involves follicular T-helper, Th17- and activated B-cells and correlates with progression.
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DOI：
10.1371/journal.pone.0057820
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Sellebjerg F
中科院分区：
文献类型：
--
作者：
Romme Christensen J;Börnsen L;Ratzer R;Piehl F;Khademi M;Olsson T;Sørensen PS;Sellebjerg F
进行性多发性硬化症（MS）的病理学研究表明，炎症（包括Th 17细胞）和脑膜炎症（伴有异位淋巴滤泡、B细胞和浆细胞）的主要作用，后者表明新鉴定的滤泡辅助性T细胞（TFH）亚群的可能作用。尽管先前的研究报告了进展性MS中全身炎症的增加，但仍不清楚全身炎症是否有助于疾病进展和鞘内炎症。本研究旨在通过流式细胞术和CD 4+和CD 8 + T细胞、B细胞、单核细胞和树突状细胞的基因表达分析，研究进展型MS的全身炎症及其与疾病进展的关系。此外，研究了脑脊液细胞的基因表达。流式细胞术研究显示复发缓解型（RRMS）和继发性进展型（SPMS）MS患者外周血中ICOS+ TFH细胞的频率增加。所有MS亚型的Th 1 TFH-细胞的频率降低，而原发性进行性（PPMS）MS患者的Th 17 TFH-细胞的频率增加。Th 17亚群，白细胞介素-23受体+CD 4 + T细胞，在PPMS和SPMS中显著增加。在B细胞分析中，我们发现SPMS中浆母细胞和DC-SIGN+和CD 83 + B细胞显著增加。ICOS+ TFH细胞和DC-SIGN+ B细胞与SPMS患者的疾病进展相关。外周血细胞亚群的基因表达分析证实了流式细胞术的结果，证明增加表达IL 21，IL 21 R和ICOS的CD 4 + T细胞在进行性MS。脑脊液细胞从RRMS和进行性MS（合并SPMS和PPMS患者）有增加的表达TFH细胞和浆母细胞标志物。总之，本研究首次证明了活化的TFH细胞在MS中的潜在参与。Th 17细胞、活化的TFH细胞和B细胞的频率增加与病理学研究的结果平行，沿着活化的TFH细胞和B细胞与疾病进展之间的相关性，提示全身性炎症在进行性MS中的致病作用。这些观察结果可能对进行性MS的治疗有意义。
Pathology studies of progressive multiple sclerosis (MS) indicate a major role of inflammation including Th17-cells and meningeal inflammation with ectopic lymphoid follicles, B-cells and plasma cells, the latter indicating a possible role of the newly identified subset of follicular T-helper (TFH) cells. Although previous studies reported increased systemic inflammation in progressive MS it remains unclear whether systemic inflammation contributes to disease progression and intrathecal inflammation. This study aimed to investigate systemic inflammation in progressive MS and its relationship with disease progression, using flow cytometry and gene expression analysis of CD4+ and CD8+T-cells, B-cells, monocytes and dendritic cells. Furthermore, gene expression of cerebrospinal fluid cells was studied. Flow cytometry studies revealed increased frequencies of ICOS+TFH-cells in peripheral blood from relapsing-remitting (RRMS) and secondary progressive (SPMS) MS patients. All MS subtypes had decreased frequencies of Th1 TFH-cells, while primary progressive (PPMS) MS patients had increased frequency of Th17 TFH-cells. The Th17-subset, interleukin-23-receptor+CD4+T-cells, was significantly increased in PPMS and SPMS. In the analysis of B-cells, we found a significant increase of plasmablasts and DC-SIGN+ and CD83+B-cells in SPMS. ICOS+TFH-cells and DC-SIGN+B-cells correlated with disease progression in SPMS patients. Gene expression analysis of peripheral blood cell subsets substantiated the flow cytometry findings by demonstrating increased expression of IL21, IL21R and ICOS in CD4+T-cells in progressive MS. Cerebrospinal fluid cells from RRMS and progressive MS (pooled SPMS and PPMS patients) had increased expression of TFH-cell and plasmablast markers. In conclusion, this study is the first to demonstrate the potential involvement of activated TFH-cells in MS. The increased frequencies of Th17-cells, activated TFH- and B-cells parallel findings from pathology studies which, along with the correlation between activated TFH- and B-cells and disease progression, suggest a pathogenic role of systemic inflammation in progressive MS. These observations may have implications for the treatment of progressive MS.