Neuroimmunology Research, Portland VA Medical Center, R&D-31, 3710 SW US Veterans Hospital Rd., Portland, OR 97239 ; Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97201 ; Department of Anesthesiology and Peri-Operative Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239.
Transl Stroke Res. 2012 Sep;3(3):324-30. doi: 10.1007/s12975-012-0187-4. Epub 2012 May 9.
Although inflammatory immune cells clearly contribute to the development of middle cerebral artery occlusion (MCAO) in mice, the failure to block neutrophil-associated injury in clinical stroke trials has discouraged further development of immunotherapeutic approaches. However, there is renewed interest in a possible protective role for regulatory T- and B-cells that can suppress inflammation and limit central nervous system damage induced by infiltrating pro-inflammatory cells. Our failure to implicate CD4(+)FoxP3(+) T-cells in limiting brain lesion volume after MCAO turned our focus towards regulatory B-cells known to mediate protection against other inflammatory CNS conditions. Our results clearly demonstrated that B-cell deficient mice developed larger infarct volumes, higher mortality and more severe functional deficits compared to wild-type mice, and had increased numbers of activated T-cells, macrophages, microglial cells, and neutrophils in the affected brain hemisphere. These MCAO-induced changes were completely prevented in B-cell-restored mice after transfer of highly purified WT B-cells but not IL-10-deficient B-cells. Our novel observations are the first to implicate IL-10-secreting B-cells as a major regulatory cell type in stroke and suggest that enhancement of regulatory B-cells might have application as a novel therapy for this devastating neurologic condition.
尽管炎症免疫细胞显然有助于小鼠大脑中动脉闭塞（MCAO）的发展，但在临床中风试验中未能阻止中性粒细胞相关损伤的发生，这阻碍了免疫治疗方法的进一步发展。然而，人们对调节性 T 细胞和 B 细胞可能具有保护作用重新产生了兴趣，这些细胞可以抑制炎症并限制浸润性促炎细胞引起的中枢神经系统损伤。我们未能在 MCAO 后暗示 CD4(+)FoxP3(+)T 细胞限制脑损伤体积，这促使我们将注意力转向调节性 B 细胞，已知其可针对其他炎症性中枢神经系统疾病提供保护。我们的研究结果清楚地表明，与野生型小鼠相比，B 细胞缺陷小鼠的梗死体积更大、死亡率更高、功能缺陷更严重，并且在受影响的大脑半球中，活化的 T 细胞、巨噬细胞、小胶质细胞和中性粒细胞数量增加。在 B 细胞恢复小鼠中，通过转移高度纯化的 WT B 细胞而非 IL-10 缺陷 B 细胞完全预防了这些 MCAO 诱导的变化。我们的新发现首次表明，IL-10 分泌 B 细胞是中风的主要调节细胞类型，并表明增强调节性 B 细胞可能作为这种毁灭性神经疾病的一种新疗法具有应用前景。
