Molecular Level Characterization of Circulating Aquaporin-4 Antibodies in Neuromyelitis Optica Spectrum Disorder.
Molecular Level Characterization of Circulating Aquaporin-4 Antibodies in Neuromyelitis Optica Spectrum Disorder.
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DOI：
10.1212/nxi.0000000000001034
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Ippolito GC
中科院分区：
文献类型：
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作者：
Li J;Bazzi SA;Schmitz F;Tanno H;McDaniel JR;Lee CH;Joshi C;Kim JE;Monson N;Greenberg BM;Hedfalk K;Melamed E;Ippolito GC
为了确定不同的水通道蛋白-4 (AQP4)-IgG谱系是否在视神经脊髓炎谱系障碍（NMOSD）发病机制中发挥作用，我们对2例NMOSD患者的AQP4-IgG多克隆血清库进行了分析，并对循环中的不同AQP4-IgG谱系进行了鉴定、量化和功能表征。我们结合高通量测序和定量免疫蛋白组学，同时测定了NMOSD患者外周血中b细胞受体（BCR）和血清抗aqp4抗体库的成分。通过该平台鉴定的单克隆抗体在体外进行了重组表达和功能鉴定。多种抗体谱系包括血清AQP4-IgG谱。然而，它们的分布在极化（多克隆与少克隆）上可能有显著不同。在2例患者血清中鉴定的4种AQP4-IgG单克隆抗体中，3种在模型哺乳动物细胞系中诱导补体依赖性细胞毒性（p < 0.01）。AQP4-IgG抗体库的组成和极化可能在NMOSD的发病机制和临床表现中起重要作用。在这里，我们提出了一种结合细胞（BCR）和血清学（IgG）抗体库分析的方法，这在NMOSD中以前没有进行过。我们的分析可以在未来应用于NMOSD患者的临床管理，以监测疾病活动随时间的变化，以及应用于其他自身免疫性疾病，以促进对自身抗体克隆相关疾病发病机制的更深入了解。
To determine whether distinct aquaporin-4 (AQP4)-IgG lineages play a role in neuromyelitis optica spectrum disorder (NMOSD) pathogenesis, we profiled the AQP4-IgG polyclonal serum repertoire and identified, quantified, and functionally characterized distinct AQP4-IgG lineages circulating in 2 patients with NMOSD. We combined high-throughput sequencing and quantitative immunoproteomics to simultaneously determine the constituents of both the B-cell receptor (BCR) and the serologic (IgG) anti-AQP4 antibody repertoires in the peripheral blood of patients with NMOSD. The monoclonal antibodies identified by this platform were recombinantly expressed and functionally characterized in vitro. Multiple antibody lineages comprise serum AQP4-IgG repertoires. Their distribution, however, can be strikingly different in polarization (polyclonal vs pauciclonal). Among the 4 serum AQP4-IgG monoclonal antibodies we identified in 2 patients, 3 induced complement-dependent cytotoxicity in a model mammalian cell line (p < 0.01). The composition and polarization of AQP4-IgG antibody repertoires may play an important role in NMOSD pathogenesis and clinical presentation. Here, we present a means of coupling both cellular (BCR) and serologic (IgG) antibody repertoire analysis, which has not previously been performed in NMOSD. Our analysis could be applied in the future to clinical management of patients with NMOSD to monitor disease activity over time as well as applied to other autoimmune diseases to facilitate a deeper understanding of disease pathogenesis relative to autoantibody clones.