Abnormal B-Cell Cytokine Responses A Trigger of T-Cell Mediated Disease in MS?
Abnormal B-Cell Cytokine Responses A Trigger of T-Cell Mediated Disease in MS?
复制标题
DOI：
10.1002/ana.21939
复制
发表时间：
2010-04-01
影响因子：
11.2
通讯作者：
Smith, Craig H.
中科院分区：
文献类型：
--
作者：
Bar-Or, Amit;Fawaz, Lama;Smith, Craig H.
目的：研究B细胞对多发性硬化症（MS）患者炎症性疾病活动的抗体不依赖性贡献，以及利妥昔单抗B细胞耗竭的免疫后果。方法：采用3信号激活模型比较MS患者和对照组的b细胞效应-细胞因子反应。b细胞消耗对MS患者Th1/Th17 CD4和CD8 t细胞反应的影响在体内和体外进行了评估，并作为2项利妥昔单抗治疗复发缓解型MS临床试验的一部分进行了药代动力学/药效学研究。MS患者的B细胞表现出异常的促炎细胞因子反应，当在病原体相关的tlr9配体CpG-DNA或Th1细胞因子干扰素γ的背景下激活时，分别包括淋巴素（LT）：白细胞介素-10比率增加，LT和肿瘤坏死因子(TNF)- α分泌增加。体外和体内的b细胞消耗导致CD4和CD8 T细胞的促炎（Th1和Th17）反应显著降低。未经治疗的MS患者活化B细胞的可溶性产物重建了相同患者体内B细胞耗尽后观察到的t细胞反应减弱，这种效应似乎主要由B细胞LT和TNF α介导。解释：我们提出，间歇性触发异常的b细胞细胞因子反应介导了疾病相关的促炎T细胞的“旁观者激活”，导致新的复发性MS疾病活动。我们的研究结果为长期以来公认的感染与多发性硬化症复发之间的关联指出了一种合理的机制，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（包括多发性硬化症）中的治疗作用提供了新的见解。67:452 - 461
Objective: 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).Methods: 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.Results: 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 TNF alpha.Interpretation: 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. ANN NEUROL 2010;67:452-461