Ahn Julie J, Islam Yusra, Clarkson-Paredes Cheryl, Karl Molly T, Miller Robert H
The George Washington University School of Medicine and Health Sciences, Department of Anatomy and Cell Biology, Ross Hall, 2300 I St NW, Washington, DC 20037, United States of America.
The George Washington University School of Medicine and Health Sciences, Nanofabrication and Imaging Center, Science and Engineering Hall, 800 22(nd) St NW, Washington, DC 20037, United States of America.
Neurobiol Dis. 2023 Oct 15;187:106290. doi: 10.1016/j.nbd.2023.106290. Epub 2023 Sep 13.
Multiple sclerosis (MS) is characterized by a compromised blood-brain barrier (BBB) resulting in central nervous system (CNS) entry of peripheral lymphocytes, including T cells and B cells. While T cells have largely been considered the main contributors to neuroinflammation in MS, the success of B cell depletion therapies suggests an important role for B cells in MS pathology. Glial cells in the CNS are essential components in both disease progression and recovery, raising the possibility that they represent targets for B cell functions. Here, we examine astrocyte and microglia responses to B cell depleting treatments in an animal model of MS, experimental autoimmune encephalomyelitis (EAE). B cell depleted EAE animals had markedly reduced disease severity and myelin damage accompanied by reduced microglia and astrocyte reactivity 20 days after symptom onset. To identify potential initial mechanisms mediating functional changes following B cell depletion, astrocyte and microglia transcriptomes were analyzed 3 days following B cell depletion. In control EAE animals, transcriptomic analysis revealed astrocytic inflammatory pathways were activated and microglial influence on neuronal function were inhibited. Following B cell depletion, initial functional recovery was associated with an activation of astrocytic pathways linked with restoration of neurovascular integrity and of microglial pathways associated with neuronal function. These studies reveal an important role for B cell depletion in influencing glial function and CNS vasculature in an animal model of MS.
多发性硬化症（MS）的特征是血脑屏障（BBB）受损，导致外周淋巴细胞（包括T细胞和B细胞）进入中枢神经系统（CNS）。虽然T细胞在很大程度上被认为是MS神经炎症的主要促成因素，但B细胞清除疗法的成功表明B细胞在MS病理过程中发挥着重要作用。CNS中的神经胶质细胞是疾病进展和恢复的重要组成部分，这增加了它们可能是B细胞功能靶点的可能性。在这里，我们在MS动物模型实验性自身免疫性脑脊髓炎（EAE）中研究了星形胶质细胞和小胶质细胞对B细胞清除治疗的反应。症状出现20天后，B细胞清除的EAE动物疾病严重程度和髓鞘损伤明显减轻，同时小胶质细胞和星形胶质细胞反应性降低。为了确定B细胞清除后介导功能变化的潜在初始机制，在B细胞清除3天后分析了星形胶质细胞和小胶质细胞的转录组。在对照EAE动物中，转录组分析显示星形胶质细胞炎症途径被激活，小胶质细胞对神经元功能的影响受到抑制。B细胞清除后，最初的功能恢复与与神经血管完整性恢复相关的星形胶质细胞途径以及与神经元功能相关的小胶质细胞途径的激活有关。这些研究揭示了B细胞清除在影响MS动物模型中的神经胶质细胞功能和CNS脉管系统方面的重要作用。
