B细胞耗竭疗法介导的麝香MG患者缓解和复发的免疫病理机制

K. OConnor, M. Fichtner
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摘要

反向转化医学的应用允许通过治疗干预了解免疫发病机制。我们将这种方法应用于重症肌无力的MuSK亚型。cd20特异性B细胞耗竭疗法(BCDT)治疗表明,MuSK MG患者的反应非常好;大多数患者总是在自身抗体水平显著下降的情况下达到缓解。循环抗体主要由不表达CD20的骨髓常驻浆细胞产生。那么,BCDT是如何减少MuSK自身抗体并诱导快速缓解的呢?我们建立了一个机制模型,该模型假设浆母细胞(一种短寿命的分泌抗体的B细胞群)产生了musk特异性自身抗体。抗CD20介导的BCDT预计会耗尽表达CD20的浆母细胞或表达CD20的记忆细胞,这些细胞供应浆母细胞群。为了验证这一假设,我们进行了一系列调查,这些调查在过去七年中被报道过,并在本文中进行了总结。首先,我们从患者身上分离出质母细胞,生成了与MuSK结合并具有致病能力的人重组单克隆自身抗体(mAb),证明该特异性细胞群可以产生MuSK自身抗体。单克隆抗体的表征表明,麝香自身抗体具有独特的性质,包括异常高的抗原结合亲和力,以及在其结合域中n -链糖基化的频率升高。进一步的表征表明,由于有缺陷的耐受性机制,在B细胞发育的早期阶段可能形成MuSK自身抗体产生细胞。最后,我们试图确定这些致病性B细胞克隆如何随时间变化。采用高通量B细胞受体测序技术对经抗cd20介导的BCDT治疗的患者纵向采集的样本进行研究。在超过5年的多个时间点检测到麝香特异性克隆变异,并在bcdt诱导的缓解后重新出现,比疾病复发提前几个月。这些集体调查提供了更详细的机制理解,包括通过循环质母细胞产生自身抗体,可被cd20特异性BCDT靶向,以及致病克隆可以在BCDT中存活并在临床复发之前重新出现。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The mechanisms of immunopathology underlying B cell depletion therapy-mediated remission and relapse in patients with MuSK MG
The application of reverse translational medicine allows for the understanding of immune pathogenesis via therapeutic intervention. We applied this approach to the MuSK subtype of myasthenia gravis. Treatment with the CD20-specific B cell depletion therapy (BCDT) demonstrated that MuSK MG patients respond remarkably well; the majority invariably reach remission accompanied by a remarkable drop in autoantibody levels. Circulating antibodies are primarily produced by bone marrow resident plasma cells, which do not express CD20. So, how does BCDT diminish MuSK autoantibodies and induce rapid remission? We developed a mechanistic model, which hypothesized that plasmablasts, which are short-lived antibody secreting B cell populations, produce MuSK-specific autoantibodies. Anti-CD20-mediated BCDT is expected to deplete CD20-expressing plasmablasts or CD20 expressing memory cells that supply the plasmablast population. To test this hypothesis, we performed a series of investigations, which were reported over the last seven years and are summarized in this review. First, we isolated plasmablasts from patients and generated human recombinant monoclonal autoantibodies (mAb) which bound MuSK and had pathogenic capacity, demonstrating that MuSK autoantibodies can be produced by this specific cell population. The characterization of the mAbs showed that MuSK autoantibodies can include unique properties including unusually high antigen binding affinity, and an elevated frequency of N-linked glycosylation in their binding domains. Further characterization suggested that MuSK autoantibody-producing cells may form in the early stages of B cell development due to defective tolerance mechanisms. Finally, we sought to determine how these pathogenic B cell clones behave over time. High throughput B cell receptor sequencing was applied to investigate longitudinally collected samples from patients treated with anti-CD20-mediated BCDT. MuSK-specific clonal variants were detected at multiple timepoints spanning more than five years and reemerged after BCDT-induced remission, predating disease relapse by several months. These collective investigations provide a more detailed mechanistic understanding that MuSK MG, the key features of which include production of autoantibodies by circulating plasmablasts that can be targeted by CD20-specific BCDT, and that pathogenic clones can survive BCDT and reemerge prior to manifestation of clinical relapse.
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