Depletion of B cells rejuvenates the peripheral B-cell compartment but is insufficient to restore immune competence in aging
Depletion of B cells rejuvenates the peripheral B-cell compartment but is insufficient to restore immune competence in aging
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DOI：
10.1111/acel.12959
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发表时间：
2019-08-01
期刊：
影响因子：
7.8
通讯作者：
Melamed, Doron
中科院分区：
文献类型：
--
作者：
Avivi, Irit;Zisman-Rozen, Simona;Melamed, Doron
衰老与骨髓(BM)淋巴细胞生成减少和B细胞多样性减少引起的感染的患病率和严重程度的增加有关。目前的研究提出了一种策略，通过在B细胞耗尽时恢复B血统来增强老龄小鼠和人类的免疫反应性。我们使用hCD20Tg小鼠去除老年和年轻小鼠的外周B细胞，分析了B细胞亚群、体外细胞功能和体内免疫应答。此外，老年患者以前接受过利妥昔单抗治疗，健康的老年人和年轻人在接受了详细的B细胞室分析后，接种了乙肝疫苗。老年小鼠的B细胞枯竭导致B细胞群体恢复活力，而B细胞群体来自于骨髓中的从头合成。再生后的B细胞在体外表现出“年轻”的能力和细胞对免疫刺激的反应性。然而，B细胞耗尽处理的小鼠并没有对体内免疫产生增强的抗体反应，也没有比对照组小鼠在“肮脏”的环境中存活更长时间。与这些结果一致的是，来自老年耗竭患者的外周B细胞显示出一种“年轻”样的谱系、种群动态和细胞对刺激的反应性。然而，老年枯竭和非枯竭受试者对乙肝疫苗的应答率是相似的，尽管枯竭患者的抗体滴度更高。这项研究提出了一个原理证明，在衰老过程中，通过B细胞耗尽来恢复外周B细胞的活力。有必要进行进一步的研究，以便将这种方法应用于提高老年人群的体液免疫反应性。
Aging is associated with increasing prevalence and severity of infections caused by a decline in bone marrow (BM) lymphopoiesis and reduced B-cell repertoire diversity. The current study proposes a strategy to enhance immune responsiveness in aged mice and humans, through rejuvenation of the B lineage upon B-cell depletion. We used hCD20Tg mice to deplete peripheral B cells in old and young mice, analyzing B-cell subsets, repertoire and cellular functions in vitro, and immune responsiveness in vivo. Additionally, elderly patients, previously treated with rituximab healthy elderly and young individuals, were vaccinated against hepatitis B (HBV) after undergoing a detailed analysis for B-cell compartments. B-cell depletion in old mice resulted in rejuvenated B-cell population that was derived from de novo synthesis in the bone marrow. The rejuvenated B cells exhibited a "young"-like repertoire and cellular responsiveness to immune stimuli in vitro. Yet, mice treated with B-cell depletion did not mount enhanced antibody responses to immunization in vivo, nor did they survive longer than control mice in "dirty" environment. Consistent with these results, peripheral B cells from elderly depleted patients showed a "young"-like repertoire, population dynamics, and cellular responsiveness to stimulus. Nevertheless, the response rate to HBV vaccination was similar between elderly depleted and nondepleted subjects, although antibody titers were higher in depleted patients. This study proposes a proof of principle to rejuvenate the peripheral B-cell compartment in aging, through B-cell depletion. Further studies are warranted in order to apply this approach for enhancing humoral immune responsiveness among the elderly population.