Chan Andrew, Seguin Rosanne, Magnus Tim, Papadimitriou Christina, Toyka Klaus V, Antel Jack P, Gold Ralf
Department of Neurology, Julius-Maximilians-University, Würzburg, Germany.
Glia. 2003 Sep;43(3):231-42. doi: 10.1002/glia.10258.
Apoptosis of autoaggressive T-cells in the CNS is an effective, noninflammatory mechanism for the resolution of T-cell infiltrates, contributing to clinical recovery in T-cell-mediated neuroinflammatory diseases. The clearance of apoptotic leukocytes by tissue-specific phagocytes is critical in the resolution of the inflammatory infiltrate and leads to a profound downregulation of phagocyte immune functions. Adult human microglia from surgically removed normal brain tissue was used in a standardized, light-microscopic in vitro phagocytosis assay of apoptotic autologous peripheral blood-derived mononuclear cells (MNCs). Microglia from five different patients had a high capacity for the uptake of apoptotic MNCs in contrast to nonapoptotic target cells with the phagocytosis rate for nonapoptotic MNCs amounting to only 61.6% of the apoptotic MNCs. A newly described phosphatidylserine receptor, critical in the phagocytosis of apoptotic cells by macrophages, is also expressed at similar levels on human microglia. The effects of the therapeutically used immunomodulatory agent interferon-beta (IFNbeta) were investigated using Lewis rat microglia and apoptotic, encephalitogenic, myelin basic protein-specific autologous T-cells. Also, rat microglia had a high capacity to phagocytose apoptotic T-cells specifically. IFNbeta increased the phagocytosis of apoptotic T-cells to 36.8% above the untreated controls. The enhanced phagocytic activity was selective for apoptotic T-cells and was not mediated by increased IL-10 secretion. Apoptotic inflammatory cells may be efficiently and rapidly removed by microglial cells in the autoimmune-inflamed human CNS. The in vitro increase of phagocytosis by IFNbeta merits further investigations whether this mechanism could also be therapeutically exploited.
中枢神经系统中自身攻击性T细胞的凋亡是清除T细胞浸润的一种有效、非炎症性机制，有助于T细胞介导的神经炎症性疾病的临床恢复。组织特异性吞噬细胞清除凋亡白细胞对于炎症浸润的消退至关重要，并导致吞噬细胞免疫功能的显著下调。在一项标准化的光学显微镜体外吞噬试验中，使用了从手术切除的正常脑组织中获取的成人人类小胶质细胞，以吞噬凋亡的自体外周血来源单核细胞（MNCs）。与非凋亡靶细胞相比，来自五名不同患者的小胶质细胞对凋亡MNCs具有较高的摄取能力，非凋亡MNCs的吞噬率仅为凋亡MNCs的61.6%。一种新描述的磷脂酰丝氨酸受体，对巨噬细胞吞噬凋亡细胞至关重要，在人类小胶质细胞上也以相似水平表达。使用Lewis大鼠小胶质细胞和凋亡的、致脑炎性的、髓鞘碱性蛋白特异性自体T细胞，研究了治疗用免疫调节剂干扰素-β（IFNβ）的作用。此外，大鼠小胶质细胞具有特异性吞噬凋亡T细胞的高能力。IFNβ使凋亡T细胞的吞噬作用比未处理的对照增加了36.8%。增强的吞噬活性对凋亡T细胞具有选择性，且不是由IL-10分泌增加介导的。在自身免疫性炎症的人类中枢神经系统中，小胶质细胞可能有效地快速清除凋亡炎性细胞。IFNβ在体外增加吞噬作用值得进一步研究这种机制是否也可用于治疗。
