Compromised fidelity of B-cell tolerance checkpoints in AChR and MuSK myasthenia gravis.
Compromised fidelity of B-cell tolerance checkpoints in AChR and MuSK myasthenia gravis.
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DOI：
10.1002/acn3.311
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发表时间：
2016-06
影响因子：
5.3
通讯作者：
O'Connor KC
中科院分区：
文献类型：
--
作者：
Lee JY;Stathopoulos P;Gupta S;Bannock JM;Barohn RJ;Cotzomi E;Dimachkie MM;Jacobson L;Lee CS;Morbach H;Querol L;Shan JL;Vander Heiden JA;Waters P;Vincent A;Nowak RJ;O'Connor KC
重症肌无力 (MG) 是一种自身免疫性疾病，其中自身抗体与乙酰胆碱受体 (AChR) 或少数患者中与肌肉特异性激酶 (MuSK) 的结合导致神经传递受损。两种 MG 亚型（AChR 或 MuSK）之间的主要 IgG 亚类、致病机制和治疗反应存在差异。这些抗体被认为是 T 细胞依赖性的，但其产生的机制尚不清楚。先前未描述的一个方面是，在两种或任一形式的 MG 中是否发现中枢和外周耐受检查点的缺陷，这些缺陷允许自身反应性 B 细胞在初始库中积累。一套既定的测定方法可测量初始人群中多反应性和自身反应性 B 细胞受体 (BCR) 的频率，并将其应用于从 AChR 或 MuSK MG 患者和健康对照中收集的标本。使用放射免疫和基于细胞的测定来测量 BCR 与 AChR 和 MuSK 的结合。 AChR 和 MuSK MG 患者的多反应性和自身反应性 BCR 频率 (n = 262) 均高于健康对照。 MG 衍生的 BCR 均不结合 AChR 或 MuSK。结果表明，这两种 MG 亚型都存在中枢和外周 B 细胞耐受检查点的缺陷。 B 细胞耐受缺陷可能是 MG 自身免疫的一个根本因素，在考虑重症肌无力治疗策略（尤其是消除 B 细胞的生物制剂）的持久性时尤为重要。
Myasthenia gravis (MG) is an autoimmune condition in which neurotransmission is impaired by binding of autoantibodies to acetylcholine receptors (AChR) or, in a minority of patients, to muscle specific kinase (MuSK). There are differences in the dominant IgG subclass, pathogenic mechanisms, and treatment responses between the two MG subtypes (AChR or MuSK). The antibodies are thought to be T‐cell dependent, but the mechanisms underlying their production are not well understood. One aspect not previously described is whether defects in central and peripheral tolerance checkpoints, which allow autoreactive B cells to accumulate in the naive repertoire, are found in both or either form of MG. An established set of assays that measure the frequency of both polyreactive and autoreactive B cell receptors (BCR) in naive populations was applied to specimens collected from patients with either AChR or MuSK MG and healthy controls. Radioimmuno‐ and cell‐based assays were used to measure BCR binding to AChR and MuSK. The frequency of polyreactive and autoreactive BCRs (n = 262) was higher in both AChR and MuSK MG patients than in healthy controls. None of the MG‐derived BCRs bound AChR or MuSK. The results indicate that both these MG subtypes harbor defects in central and peripheral B cell tolerance checkpoints. Defective B cell tolerance may represent a fundamental contributor to autoimmunity in MG and is of particular importance when considering the durability of myasthenia gravis treatment strategies, particularly biologics that eliminate B cells.