Duddy Martin, Niino Masaaki, Adatia Femina, Hebert Sherry, Freedman Mark, Atkins Harry, Kim Ho Jin, Bar-Or Amit
Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, and Department of Neurology, Ottawa General Hospital, Canada.
J Immunol. 2007 May 15;178(10):6092-9. doi: 10.4049/jimmunol.178.10.6092.
Although recent animal studies have fuelled growing interest in Ab-independent functions of B cells, relatively little is known about how human B cells and their subsets may contribute to the regulation of immune responses in either health or disease. In this study, we first confirm that effector cytokine production by normal human B cells is context dependent and demonstrate that this involves the reciprocal regulation of proinflammatory and anti-inflammatory cytokines. We further report that this cytokine network is dysregulated in patients with the autoimmune disease multiple sclerosis, whose B cells exhibit a decreased average production of the down-regulatory cytokine IL-10. Treatment with the approved chemotherapeutic agent mitoxantrone reciprocally modulated B cell proinflammatory and anti-inflammatory cytokines, establishing that the B cell cytokine network can be targeted in vivo. Prospective studies of human B cells reconstituting following in vivo depletion suggested that different B cell subsets produced distinct effector cytokines. We confirmed in normal human B cell subsets that IL-10 is produced almost exclusively by naive B cells while the proinflammatory cytokines lymphotoxin and TNF-alpha are largely produced by memory B cells. These results point to an in vivo switch in the cytokine "program" of human B cells transitioning from the naive pool to the memory pool. We propose a model that ascribes distinct and proactive roles to memory and naive human B cell subsets in the regulation of memory immune responses and in autoimmunity. Our findings are of particular relevance at a time when B cell directed therapies are being applied to clinical trials of several autoimmune diseases.
尽管最近的动物研究激发了人们对B细胞非抗体依赖性功能的兴趣，但对于人类B细胞及其亚群如何在健康或疾病状态下调节免疫反应，我们知之甚少。在本研究中，我们首先证实正常人B细胞产生效应细胞因子是依赖于环境的，并证明这涉及促炎细胞因子和抗炎细胞因子的相互调节。我们进一步报告，在自身免疫性疾病多发性硬化症患者中，这种细胞因子网络失调，其B细胞下调调节性细胞因子IL-10的平均产生量降低。使用已批准的化疗药物米托蒽醌进行治疗可相互调节B细胞的促炎和抗炎细胞因子，证明B细胞细胞因子网络可在体内被靶向作用。对体内耗竭后重建的人类B细胞进行的前瞻性研究表明，不同的B细胞亚群产生不同的效应细胞因子。我们在正常人B细胞亚群中证实，IL-10几乎完全由初始B细胞产生，而促炎细胞因子淋巴毒素和TNF-α主要由记忆B细胞产生。这些结果表明，人类B细胞的细胞因子“程序”在体内从初始细胞库向记忆细胞库转变时发生了转换。我们提出了一个模型，该模型赋予记忆性和初始性人类B细胞亚群在调节记忆免疫反应和自身免疫中独特且积极的作用。在B细胞定向疗法正应用于多种自身免疫性疾病的临床试验之际，我们的发现具有特别的相关性。
