Neuroimmunology Unit, Montreal Neurological Institute, McGill University, 3801 University Street, Room 111, Montréal , QC, H3A 2B3, Canada.
Department of Neurology and Center for NeuroInflammation and Experimental Therapeutics (CNET), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
J Neuroinflammation. 2018 Apr 19;15(1):114. doi: 10.1186/s12974-018-1136-2.
The success of clinical trials of selective B cell depletion in patients with relapsing multiple sclerosis (MS) indicates B cells are important contributors to peripheral immune responses involved in the development of new relapses. Such B cell contribution to peripheral inflammation likely involves antibody-independent mechanisms. Of growing interest is the potential that B cells, within the MS central nervous system (CNS), may also contribute to the propagation of CNS-compartmentalized inflammation in progressive (non-relapsing) disease. B cells are known to persist in the inflamed MS CNS and are more recently described as concentrated in meningeal immune-cell aggregates, adjacent to the subpial cortical injury which has been associated with progressive disease. How B cells are fostered within the MS CNS and how they may contribute locally to the propagation of CNS-compartmentalized inflammation remain to be elucidated.
We considered whether activated human astrocytes might contribute to B cell survival and function through soluble factors. B cells from healthy controls (HC) and untreated MS patients were exposed to primary human astrocytes that were either maintained under basal culture conditions (non-activated) or pre-activated with standard inflammatory signals. B cell exposure to astrocytes included direct co-culture, co-culture in transwells, or exposure to astrocyte-conditioned medium. Following the different exposures, B cell survival and expression of T cell co-stimulatory molecules were assessed by flow cytometry, as was the ability of differentially exposed B cells to induce activation of allogeneic T cells.
Secreted factors from both non-activated and activated human astrocytes robustly supported human B cell survival. Soluble products of pre-activated astrocytes also induced B cell upregulation of antigen-presenting cell machinery, and these B cells, in turn, were more efficient activators of T cells. Astrocyte-soluble factors could support survival and activation of B cell subsets implicated in MS, including memory B cells from patients with both relapsing and progressive forms of disease.
Our findings point to a potential mechanism whereby activated astrocytes in the inflamed MS CNS not only promote a B cell fostering environment, but also actively support the ability of B cells to contribute to the propagation of CNS-compartmentalized inflammation, now thought to play key roles in progressive disease.
选择性 B 细胞耗竭在复发性多发性硬化症（MS）患者中的临床试验的成功表明 B 细胞是参与新复发的外周免疫反应的重要贡献者。这种 B 细胞对外周炎症的贡献可能涉及非抗体依赖性机制。越来越多的人关注的是，B 细胞在多发性硬化症的中枢神经系统（CNS）中，也可能有助于进展性（非复发）疾病中中枢神经系统分隔性炎症的传播。B 细胞已知存在于炎症性 MS 中枢神经系统中，最近被描述为集中在脑膜免疫细胞聚集体中，与皮质下损伤相邻，该损伤与进展性疾病有关。B 细胞如何在 MS 中枢神经系统中得到促进，以及它们如何局部有助于中枢神经系统分隔性炎症的传播，仍有待阐明。
我们考虑了激活的人星形胶质细胞是否可以通过可溶性因子促进 B 细胞的存活和功能。将来自健康对照（HC）和未经治疗的 MS 患者的 B 细胞暴露于基础培养条件下维持的原代人星形胶质细胞（非激活）或用标准炎症信号预先激活的原代人星形胶质细胞。B 细胞暴露于星形胶质细胞包括直接共培养、Transwell 共培养或暴露于星形胶质细胞条件培养基。在不同的暴露后，通过流式细胞术评估 B 细胞的存活和 T 细胞共刺激分子的表达，以及不同暴露的 B 细胞诱导同种异体 T 细胞激活的能力。
来自非激活和激活的人星形胶质细胞的分泌因子均强烈支持人 B 细胞的存活。预激活星形胶质细胞的可溶性产物还诱导 B 细胞上调抗原呈递细胞机制，而这些 B 细胞反过来又能更有效地激活 T 细胞。星形胶质细胞可溶性因子可支持 MS 中涉及的 B 细胞亚群的存活和激活，包括来自复发和进展形式疾病的患者的记忆 B 细胞。
我们的研究结果表明了一种潜在的机制，即炎症性 MS 中枢神经系统中的激活星形胶质细胞不仅促进了 B 细胞的培育环境，而且还积极支持 B 细胞有助于中枢神经系统分隔性炎症传播的能力，现在认为这在进展性疾病中发挥着关键作用。
