Functional characterization of reappearing B cells after anti-CD20 treatment of CNS autoimmune disease.
Functional characterization of reappearing B cells after anti-CD20 treatment of CNS autoimmune disease.
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DOI：
10.1073/pnas.1810470115
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发表时间：
2018-09-25
影响因子：
11.1
通讯作者：
Weber MS
中科院分区：
文献类型：
--
作者：
Häusler D;Häusser-Kinzel S;Feldmann L;Torke S;Lepennetier G;Bernard CCA;Zamvil SS;Brück W;Lehmann-Horn K;Weber MS
通过抗CD 20单克隆抗体去除B细胞是一种新型的、高效的多发性硬化症（MS）治疗方法。在小鼠MS模型中，我们研究了三个在人类中无法解决的机制问题。首先，我们确定了脾脏中的一部分成熟B细胞对抗CD20具有抗性。第二，我们确定，在停止治疗后，脾和骨髓B细胞平行重建，基本上先于B细胞在血液中重新出现。第三，我们观察到，在涉及活化B细胞的模型中，抗CD20后的B细胞库中含有分化的髓鞘反应性B细胞的频率升高。总之，我们的研究结果揭示了致病性B细胞在抗CD20治疗中可能持续存在的机制。抗CD20抗体ocrelizumab被批准用于治疗多发性硬化症，导致血液中B细胞的快速消除。B细胞耗竭的程度和它们在不同免疫区室中恢复的动力学在很大程度上是未知的。在此，我们研究了抗CD20治疗如何影响实验性自身免疫性脑脊髓炎（EAE）模型中骨髓、血液、淋巴结和脾脏中的B细胞。抗CD20减少了检查的所有隔室中的成熟B细胞，尽管抗原经历的B细胞亚群持续存在于脾滤泡中。治疗停止后，CD 20 + B细胞在血液中重新出现之前同时在骨髓和脾脏中重新增殖。在由天然髓鞘少突胶质细胞糖蛋白（MOG）诱导的EAE中，B细胞被激活的模型，B细胞恢复的特征在于成熟分化细胞的扩增，所述成熟分化细胞含有高频率的髓鞘反应性B细胞，具有受限的B细胞受体基因多样性。这些B细胞作为有效的抗原呈递细胞（APC）激活髓鞘特异性T细胞。在MOG肽诱导的EAE中，不需要B细胞的纯T细胞介导的模型，相比之下，重构B细胞表现出幼稚表型而没有有效的APC能力。我们的研究结果表明，不同的B细胞亚群的抗CD20治疗的敏感性不同，并表明，分化的B细胞持续在次级淋巴器官有助于恢复B细胞池。
B cell depletion via anti-CD20 monoclonal antibodies is a novel, highly efficient therapy for multiple sclerosis (MS). In a murine MS model, we investigated three mechanistic questions that cannot be addressed in humans. First, we established that a fraction of mature B cells in the spleen is resistant to anti-CD20. Second, we determined that, after cessation of treatment, splenic and bone-marrow B cells reconstitute in parallel, substantially preceding B cell reappearance in blood. Third, we observed that, in a model involving activated B cells, the post–anti-CD20 B cell pool contained an elevated frequency of differentiated, myelin-reactive B cells. Together, our findings reveal mechanisms by which pathogenic B cells may persist in anti-CD20 treatment. The anti-CD20 antibody ocrelizumab, approved for treatment of multiple sclerosis, leads to rapid elimination of B cells from the blood. The extent of B cell depletion and kinetics of their recovery in different immune compartments is largely unknown. Here, we studied how anti-CD20 treatment influences B cells in bone marrow, blood, lymph nodes, and spleen in models of experimental autoimmune encephalomyelitis (EAE). Anti-CD20 reduced mature B cells in all compartments examined, although a subpopulation of antigen-experienced B cells persisted in splenic follicles. Upon treatment cessation, CD20+ B cells simultaneously repopulated in bone marrow and spleen before their reappearance in blood. In EAE induced by native myelin oligodendrocyte glycoprotein (MOG), a model in which B cells are activated, B cell recovery was characterized by expansion of mature, differentiated cells containing a high frequency of myelin-reactive B cells with restricted B cell receptor gene diversity. Those B cells served as efficient antigen-presenting cells (APCs) for activation of myelin-specific T cells. In MOG peptide-induced EAE, a purely T cell-mediated model that does not require B cells, in contrast, reconstituting B cells exhibited a naive phenotype without efficient APC capacity. Our results demonstrate that distinct subpopulations of B cells differ in their sensitivity to anti-CD20 treatment and suggest that differentiated B cells persisting in secondary lymphoid organs contribute to the recovering B cell pool.
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多发性硬化症中的利妥昔单抗：一项关于安全性和功效的回顾性观察研究。
影响因子：
9.9
作者：
Salzer J;Svenningsson R;Alping P;Novakova L;Björck A;Fink K;Islam-Jakobsson P;Malmeström C;Axelsson M;Vågberg M;Sundström P;Lycke J;Piehl F;Svenningsson A
通讯作者：
Svenningsson A
影响因子：
--
作者：
Jacob, Anu;Weinshenker, Brian G.;Cree, Bruce A. C.
通讯作者：
Cree, Bruce A. C.
影响因子：
11.2
作者：
Weber, Martin S.;Prod'homme, Thomas;Patarroyo, Juan C.;Molnarfi, Nicolas;Karnezis, Tara;Lehmann-Horn, Klaus;Danilenko, Dimitry M.;Eastham-Anderson, Jeffrey;Slavin, Anthony J.;Linington, Christopher;Bernard, Claude C. A.;Martin, Flavius;Zamvil, Scott S.
通讯作者：
Zamvil, Scott S.
影响因子：
15.9
作者：
Chamberlain, Nicolas;Massad, Christopher;Meffre, Eric
通讯作者：
Meffre, Eric
影响因子：
11.2
作者：
Hawker, Kathleen;O'Connor, Paul;Smith, Craig H.
通讯作者：
Smith, Craig H.