Elevated N-Linked Glycosylation of IgG V Regions in Myasthenia Gravis Disease Subtypes.
Elevated N-Linked Glycosylation of IgG V Regions in Myasthenia Gravis Disease Subtypes.
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DOI：
10.4049/jimmunol.2100225
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发表时间：
2021-10-15
期刊：
影响因子：
--
通讯作者：
O'Connor KC
中科院分区：
文献类型：
--
作者：
Mandel-Brehm C;Fichtner ML;Jiang R;Winton VJ;Vazquez SE;Pham MC;Hoehn KB;Kelleher NL;Nowak RJ;Kleinstein SH;Wilson MR;DeRisi JL;O'Connor KC
免疫球蛋白G可变区的N-连接糖基化升高（IgG-VN-Glyc）是一种与自身免疫性疾病相关的新兴分子表型。为了测试IgG-VN-Glyc升高的更广泛的特异性，我们研究了具有不同亚型的重症肌无力（MG）（一种B细胞介导的自身免疫性疾病）的患者。我们的实验设计集中于检查B细胞库和总IgG。具体包括适应性免疫受体库测序（用于定量和表征循环B细胞受体库中的N-连接糖基化位点）、蛋白质组学（用于检查总循环IgG的糖基化模式）和人源性重组自身抗体的探索（采用质谱和抗原结合试验研究，分别确认糖基化位点的占用并确定其是否改变结合）。我们发现，与健康供体相比，MG患者的总B细胞受体库中IgG-VN-Glyc基序的频率增加。升高的频率归因于两个偏向V基因片段的使用和体细胞超突变。IgG-VN-Glyc可在MG患者亚组的总循环IgG中观察到。自身抗原结合，由四个患者来源的MG自身抗原特异性单克隆抗体与实验证实存在的IgG-VN-Glyc，没有改变的糖基化。我们的研究结果扩展了先前关于MG亚型自身免疫中免疫球蛋白可变区N-连接糖基化模式的工作。
Elevated N-linked glycosylation of immunoglobulin G variable regions (IgG-VN-Glyc) is an emerging molecular phenotype associated with autoimmune disorders. To test the broader specificity of elevated IgG-VN-Glyc, we studied patients with distinct subtypes of myasthenia gravis (MG), a B cell-mediated autoimmune disease. Our experimental design focused on examining the B cell repertoire and total IgG. It specifically included adaptive immune receptor repertoire sequencing to quantify and characterize N-linked glycosylation sites in the circulating B cell receptor repertoire, proteomics to examine glycosylation patterns of the total circulating IgG, and an exploration of human-derived recombinant autoantibodies, which were studied with mass spectrometry and antigen binding assays to respectively confirm occupation of glycosylation sites and determine whether they alter binding. We found that the frequency of IgG-VN-Glyc motifs was increased in the total B cell receptor repertoire of MG patients when compared to healthy donors. The elevated frequency was attributed to both biased V gene segment usage and somatic hypermutation. IgG-VN-Glyc could be observed in the total circulating IgG in a subset of MG patients. Autoantigen binding, by four patient-derived MG autoantigen-specific monoclonal antibodies with experimentally confirmed presence of IgG-VN-Glyc, was not altered by the glycosylation. Our findings extend prior work on patterns of immunoglobulin variable region N-linked glycosylation in autoimmunity to MG subtypes.
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DOI：
10.1084/jem.20200513
发表时间：
2020-12-07
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fichtner ML;Vieni C;Redler RL;Kolich L;Jiang R;Takata K;Stathopoulos P;Suarez PA;Nowak RJ;Burden SJ;Ekiert DC;O'Connor KC
通讯作者：
O'Connor KC
影响因子：
82.9
作者：
Hoch, W;McConville, J;Vincent, A
通讯作者：
Vincent, A
DOI：
10.1212/nxi.0000000000000547
发表时间：
2019-05-01
影响因子：
8.8
作者：
Huijbers, Maartje G.;Vergoossen, Dana L.;Verschuuren, Jan J.
通讯作者：
Verschuuren, Jan J.
影响因子：
4.4
作者：
Anil, Rahul;Kumar, Aditya;Nowak, Richard J.
通讯作者：
Nowak, Richard J.
影响因子：
4.4
作者：
Koers, Jana;Derksen, Ninotska I. L.;Rispens, Theo
通讯作者：
Rispens, Theo