Neuroimmunology Unit, Montreal Neurological Institute and Hospital, McGill University, Montreal Quebec, Canada.
Ann Neurol. 2010 Apr;67(4):452-61. doi: 10.1002/ana.21939.
To study antibody-independent contributions of B cells to inflammatory disease activity, and the immune consequences of B-cell depletion with rituximab, in patients with multiple sclerosis (MS).
B-Cell effector-cytokine responses were compared between MS patients and matched controls using a 3-signal model of activation. The effects of B-cell depletion on Th1/Th17 CD4 and CD8 T-cell responses in MS patients were assessed both ex vivo and in vivo, together with pharmacokinetic/pharmacodynamic studies as part of 2 rituximab clinical trials in relapsing-remitting MS.
B Cells of MS patients exhibited aberrant proinflammatory cytokine responses, including increased lymphotoxin (LT):interleukin-10 ratios and exaggerated LT and tumor necrosis factor (TNF)-alpha secretion, when activated in the context of the pathogen-associated TLR9-ligand CpG-DNA, or the Th1 cytokine interferon-gamma, respectively. B-Cell depletion, both ex vivo and in vivo, resulted in significantly diminished proinflammatory (Th1 and Th17) responses of both CD4 and CD8 T cells. Soluble products from activated B cells of untreated MS patients reconstituted the diminished T-cell responses observed following in vivo B-cell depletion in the same patients, and this effect appeared to be largely mediated by B-cell LT and TNFalpha.
We propose that episodic triggering of abnormal B-cell cytokine responses mediates 'bystander activation' of disease-relevant proinflammatory T cells, resulting in new relapsing MS disease activity. Our findings point to a plausible mechanism for the long-recognized association between infections and new MS relapses, and provide novel insights into B-cell roles in both health and disease, and into mechanisms contributing to therapeutic effects of B-cell depletion in human autoimmune diseases, including MS.
研究 B 细胞在多发性硬化症（MS）患者炎症疾病活动中的抗体非依赖性作用，以及利妥昔单抗耗竭 B 细胞的免疫后果。
采用三信号激活模型比较 MS 患者与匹配对照者的 B 细胞效应细胞因子应答。评估 B 细胞耗竭对 MS 患者 Th1/Th17 CD4 和 CD8 T 细胞应答的影响，包括在体外和体内，并结合药代动力学/药效学研究，作为两项利妥昔单抗治疗复发缓解型 MS 的临床试验的一部分。
MS 患者的 B 细胞表现出异常的促炎细胞因子应答，包括在病原体相关 TLR9 配体 CpG-DNA 或 Th1 细胞因子干扰素-γ的背景下激活时，淋巴毒素（LT）：白细胞介素-10 比值增加，以及 LT 和肿瘤坏死因子（TNF）-α分泌增加。无论是在体外还是在体内，B 细胞耗竭都会导致 CD4 和 CD8 T 细胞的促炎（Th1 和 Th17）应答显著减弱。未治疗的 MS 患者激活的 B 细胞的可溶性产物重建了在同一患者体内 B 细胞耗竭后观察到的减弱的 T 细胞应答，并且这种作用似乎主要由 B 细胞 LT 和 TNFalpha 介导。
我们提出，异常 B 细胞细胞因子应答的偶发触发介导了疾病相关促炎 T 细胞的“旁观者激活”，导致新的复发型 MS 疾病活动。我们的研究结果为感染与新的 MS 复发之间的长期公认关联提供了合理的机制，并为 B 细胞在健康和疾病中的作用以及 B 细胞耗竭在人类自身免疫性疾病（包括 MS）中的治疗效果的机制提供了新的见解。
