Peggy and Gary Edwards ALS Laboratory, Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas, USA.
Department of Surgery, University of Florida, Gainesville, Florida, USA.
JCI Insight. 2017 Mar 9;2(5):e89530. doi: 10.1172/jci.insight.89530.
Neuroinflammation is a pathological hallmark of ALS in both transgenic rodent models and patients, and is characterized by proinflammatory T lymphocytes and activated macrophages/microglia. In ALS mouse models, decreased regulatory T lymphocytes (Tregs) exacerbate the neuroinflammatory process, leading to accelerated motoneuron death and shortened survival; passive transfer of Tregs suppresses the neuroinflammation and prolongs survival. Treg numbers and FOXP3 expression are also decreased in rapidly progressing ALS patients. A key question is whether the marked neuroinflammation in ALS can be attributed to the impaired suppressive function of ALS Tregs in addition to their decreased numbers. To address this question, T lymphocyte proliferation assays were performed. Compared with control Tregs, ALS Tregs were less effective in suppressing responder T lymphocyte proliferation. Although both slowly and rapidly progressing ALS patients had dysfunctional Tregs, the greater the clinically assessed disease burden or the more rapidly progressing the patient, the greater the Treg dysfunction. Epigenetically, the percentage methylation of the Treg-specific demethylated region was greater in ALS Tregs. After in vitro expansion, ALS Tregs regained suppressive abilities to the levels of control Tregs, suggesting that autologous passive transfer of expanded Tregs might offer a novel cellular therapy to slow disease progression.
神经炎症是转(transgenic)基因(transgenic)啮齿动物模型和患者中 ALS 的病理标志之一，其特征为促炎 T 淋巴细胞和活化的巨噬细胞/小胶质细胞。在 ALS 小鼠模型中，调节性 T 淋巴细胞(Tregs)减少会加重神经炎症过程，导致运动神经元更快死亡和生存时间缩短；Tregs 的被动转移可抑制神经炎症并延长生存时间。在快速进展的 ALS 患者中，Treg 数量和 FOXP3 表达也减少。一个关键问题是，除了数量减少之外，ALS Tregs 抑制功能受损是否导致 ALS 中明显的神经炎症。为了解决这个问题，进行了 T 淋巴细胞增殖测定。与对照 Tregs 相比，ALS Tregs 抑制应答 T 淋巴细胞增殖的效果较差。虽然缓慢和快速进展的 ALS 患者均存在功能失调的 Tregs，但临床评估的疾病负担越大或患者进展越快，Treg 功能障碍越大。表观遗传上，ALS Tregs 中 Treg 特异性去甲基化区域的甲基化百分比更大。体外扩增后，ALS Tregs 恢复了对对照 Tregs 的抑制能力，表明扩增的 Tregs 的自体被动转移可能为减缓疾病进展提供一种新的细胞治疗方法。
