Mechanisms underlying B cell immune dysregulation and autoantibody production in MuSK myasthenia gravis.
Mechanisms underlying B cell immune dysregulation and autoantibody production in MuSK myasthenia gravis.
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DOI：
10.1111/nyas.13535
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发表时间：
2018-01
影响因子：
5.2
通讯作者：
O'Connor KC
中科院分区：
文献类型：
--
作者：
Stathopoulos P;Kumar A;Heiden JAV;Pascual-Goñi E;Nowak RJ;O'Connor KC
在没有检测到乙酰胆碱受体（AChR）抗体的重症肌无力（MG）患者中可以发现针对肌肉特异性酪氨酸激酶（MuSK）的致病性自身抗体。虽然自身抗体介导的病理已被很好地理解，但关于细胞免疫学对自身抗体产生的贡献仍有待了解。为此，我们的实验室研究了与麝香MG细胞免疫病理相关的特定成分。首先，我们发现B细胞耐受性缺陷导致幼稚库的异常发育，这表明失调发生在自身抗体产生之前。其次，我们通过应用高通量适应性免疫受体库测序（AIRR-seq）检查了原始和抗原经历记忆B细胞库，包括健康对照中未发现的异常。这凸显了广泛的免疫失调。第三，使用互补方法，包括生产人类单克隆抗体，我们确定循环质母细胞直接促进B细胞耗竭治疗后复发的患者产生musk特异性自身抗体。这些共同的发现有助于定义一个描述麝香MG免疫发病机制的机制模型。
Pathogenic autoantibodies to muscle-specific tyrosine kinase (MuSK) can be found in patients with myasthenia gravis (MG) who do not have detectable antibodies to the acetylcholine receptor (AChR). Although the autoantibody-mediated pathology is well understood, much remains to be learned about the cellular immunology that contributes to autoantibody production. To that end, our laboratory has investigated particular components associated with the cellular immunopathology of MuSK MG. First, we found that B cell tolerance defects contribute to the abnormal development of the naive repertoire, which indicates that dysregulation occurs before the production of autoantibodies. Second, both the naive and antigen-experienced memory B cell repertoire, which we examined through the application of high-throughput adaptive immune receptor repertoire sequencing (AIRR-seq), include abnormalities not found in healthy controls. This highlights a broad immune dysregulation. Third, using complementary approaches, including production of human monoclonal antibodies, we determined that circulating plasmablasts directly contribute to the production of MuSK-specific autoantibodies in patients experiencing relapse following B cell depletion therapy. These collective findings contribute to defining a mechanistic model that describes MuSK MG immunopathogenesis.
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影响因子：
11.2
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Bennett, Jeffrey L.;Lam, Chiwah;Kalluri, Sudhakar Reddy;Saikali, Philippe;Bautista, Katherine;Dupree, Cecily;Glogowska, Magdalena;Case, David;Antel, Jack P.;Owens, Gregory P.;Gilden, Don;Nessler, Stefan;Stadelmann, Christine;Hemmer, Bernhard
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Hemmer, Bernhard
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通讯作者：
Meffre, Eric
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作者：
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通讯作者：
Joly, Pascal
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作者：
Blum, Stefan;Gillis, David;Wong, Richard
通讯作者：
Wong, Richard
影响因子：
27.4
作者：
Della-Torre E;Feeney E;Deshpande V;Mattoo H;Mahajan V;Kulikova M;Wallace ZS;Carruthers M;Chung RT;Pillai S;Stone JH
通讯作者：
Stone JH