Department of Neurology, Danish Multiple Sclerosis Center, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, Copenhagen, 2100, Denmark.
J Neuroinflammation. 2012 Sep 14;9:215. doi: 10.1186/1742-2094-9-215.
Numerous cytokines are implicated in the immunopathogenesis of multiple sclerosis (MS), but studies are often limited to whole blood (WB) or peripheral blood mononuclear cells (PBMCs), thereby omitting important information about the cellular origin of the cytokines. Knowledge about the relation between blood and cerebrospinal fluid (CSF) cell expression of cytokines and the cellular source of CSF cytokines is even more scarce.
We studied gene expression of a broad panel of cytokines in WB from relapsing-remitting multiple sclerosis (RRMS) patients in remission and healthy controls (HCs). Subsequently we determined the gene expression of the dysregulated cytokines in isolated PBMC subsets (CD4+, CD8+T-cells, NK-cells, B-cells, monocytes and dendritic cells) from RRMS patients and HCs and in CSF-cells from RRMS patients in clinical relapse and non-inflammatory neurological controls (NIND).
RRMS patients had increased expression of IFN-gamma (IFNG), interleukin (IL) 1-beta (IL1B), IL7, IL10, IL12A, IL15, IL23, IL27, lymphotoxin-alpha (LTA) and lymphotoxin-beta (LTB) in WB. In PBMC subsets the main sources of pro-inflammatory cytokines were T- and B-cells, whereas monocytes were the most prominent source of immunoregulatory cytokines. In CSF-cells, RRMS patients had increased expression of IFNG and CD19 and decreased expression of IL10 and CD14 compared to NINDs. CD19 expression correlated with expression of IFNG, IL7, IL12A, IL15 and LTA whereas CD14 expression correlated with IL10 expression.
Using a systematic approach, we show that expression of pro-inflammatory cytokines in peripheral blood primarily originates from T- and B-cells, with an important exception of IFNG which is most strongly expressed by NK-cells. In CSF-cell studies, B-cells appear to be enriched in RRMS and associated with expression of pro-inflammatory cytokines; contrarily, monocytes are relatively scarce in CSF from RRMS patients and are associated with IL10 expression. Thus, our findings suggest a pathogenetic role of B-cells and an immunoregulatory role of monocytes in RRMS.
许多细胞因子参与多发性硬化症（MS）的免疫发病机制，但研究通常仅限于全血（WB）或外周血单核细胞（PBMCs），从而忽略了细胞因子的细胞起源的重要信息。关于血液和脑脊液（CSF）细胞中细胞因子表达之间的关系以及 CSF 细胞因子的细胞来源的知识就更加匮乏。
我们研究了缓解期复发型多发性硬化症（RRMS）患者和健康对照者（HCs）的 WB 中广泛细胞因子的基因表达。随后，我们确定了 RRMS 患者和 HCs 中分离的 PBMC 亚群（CD4+、CD8+T 细胞、NK 细胞、B 细胞、单核细胞和树突状细胞）以及 RRMS 患者处于临床复发期和非炎症性神经学对照者（NIND）的 CSF 细胞中失调细胞因子的基因表达。
RRMS 患者的 WB 中 IFN-γ（IFNG）、白细胞介素（IL）1-β（IL1B）、IL7、IL10、IL12A、IL15、IL23、IL27、淋巴毒素-α（LTA）和淋巴毒素-β（LTB）表达增加。在 PBMC 亚群中，促炎细胞因子的主要来源是 T 细胞和 B 细胞，而单核细胞是免疫调节细胞因子的最主要来源。与 NIND 相比，RRMS 患者的 CSF 细胞中 IFNG 和 CD19 表达增加，而 IL10 和 CD14 表达减少。CD19 的表达与 IFNG、IL7、IL12A、IL15 和 LTA 的表达相关，而 CD14 的表达与 IL10 的表达相关。
通过系统的方法，我们发现外周血中促炎细胞因子的表达主要来源于 T 细胞和 B 细胞，IFNG 是一个例外，它主要由 NK 细胞表达。在 CSF 细胞研究中，B 细胞在 RRMS 中似乎更为丰富，并与促炎细胞因子的表达相关；相反，RRMS 患者的 CSF 中单核细胞相对较少，与 IL10 的表达相关。因此，我们的研究结果表明 B 细胞在 RRMS 中具有致病作用，而单核细胞具有免疫调节作用。
