Neuroimmunology Laboratory and clinic, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
J Neuroimmunol. 2011 Mar;232(1-2):171-8. doi: 10.1016/j.jneuroim.2010.10.007. Epub 2010 Nov 26.
Multiple sclerosis (MS) plaques are characterized by neurodegeneration, astrogliolis, the presence of immature oligodendrocytes and infiltrating immune cells. Recent studies revealed a putative role for noggin in both neurogenesis and oligodenrocytes development. In order to study the potential of peripheral immune cells to contribute to neurogenesis in MS, we studied the mRNA expression, protein secretion and regulation profile of noggin in peripheral blood mononuclear cells (PBMCs) of untreated patients with relapsing-remitting MS (RR-MS), interferon-β (IFN-β) treated RR-MS patients compared to matched healthy controls (HC). Basal levels of noggin mRNA expression, determined by quantitative real-time PCR were lower in untreated patients than in HC. No differences were found between untreated patients and IFN-β treated patients. Similarly, the secreted levels of noggin, detected in 24h PBMCs supernatants by ELISA, were decreased in untreated RR-MS patients than in HC. Again no significant differences were found between untreated patients and IFN-β treated patients. Stimulation with anti-CD3/CD28 mAbs increased noggin mRNA expression in untreated patients but not in HC. However, noggin mRNA levels in untreated patients PBMCs stimulated with anti-CD3/CD28 did not reach noggin levels in unstimulated PBMCs of HC. Purification of monocytes (CD14+) and T cells (CD3+ cells) by magnet-activated cell separation has demonstrated that noggin mRNA is predominantly expressed in CD3(+) cells in both HC and in RR-MS patients. This pattern also appeared in protein level of noggin, tested by Western blot. The incubation of the PBMCs with TNF-α increased the expression of noggin only in HC group. In conclusion, T cells possess the potential to participate in the induction of neurogeneration by the production of noggin. This potential seems to be defective in immune cells of RR-MS patients as there is reduced mRNA expression and protein secretion levels of noggin, insufficient stimulatory effect of CD3/CD28 stimulation and unresponsiveness to TNF-α in these patients PBMCs.
多发性硬化症（MS）斑块的特征是神经退行性变、星形胶质细胞增生、未成熟少突胶质细胞和浸润免疫细胞的存在。最近的研究表明，noggin 在神经发生和少突胶质细胞发育中具有潜在作用。为了研究外周免疫细胞在 MS 中的神经发生中的潜在作用，我们研究了未经治疗的复发缓解型 MS（RR-MS）患者、干扰素-β（IFN-β）治疗的 RR-MS 患者与匹配的健康对照（HC）的外周血单核细胞（PBMC）中 noggin 的 mRNA 表达、蛋白分泌和调控谱。通过定量实时 PCR 确定的未治疗患者的 noggin mRNA 表达基础水平低于 HC。未治疗患者与 IFN-β 治疗患者之间未发现差异。同样，通过 ELISA 在 24 小时 PBMC 上清液中检测到的 noggin 分泌水平在未经治疗的 RR-MS 患者中低于 HC。同样，未治疗患者与 IFN-β 治疗患者之间也未发现显著差异。用抗 CD3/CD28 mAb 刺激可增加未经治疗患者的 noggin mRNA 表达，但 HC 中则不然。然而，未经治疗患者 PBMC 经抗 CD3/CD28 刺激后的 noggin mRNA 水平未达到 HC 未刺激 PBMC 中的 noggin 水平。通过磁激活细胞分离对单核细胞（CD14+）和 T 细胞（CD3+细胞）进行纯化表明，HC 和 RR-MS 患者中，noggin mRNA 主要在 CD3+细胞中表达。这种模式也出现在 noggin 的蛋白水平上，通过 Western blot 进行测试。在 HC 组中，TNF-α 的孵育仅增加 noggin 的表达。总之，T 细胞通过 noggin 的产生具有参与诱导神经发生的潜力。这种潜力在 RR-MS 患者的免疫细胞中似乎存在缺陷，因为 noggin 的 mRNA 表达和蛋白分泌水平降低，CD3/CD28 刺激的刺激作用不足，以及这些患者的 PBMC 对 TNF-α 无反应。
