Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies
Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies
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DOI：
10.1038/85520
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发表时间：
2001-03-01
期刊：
影响因子：
82.9
通讯作者：
Vincent, A
中科院分区：
文献类型：
--
作者：
Hoch, W;McConville, J;Vincent, A
重症肌无力（MG）是一种抗体介导的神经肌肉接头自身免疫性疾病。大约 80% 的患者存在针对肌肉烟碱乙酰胆碱受体 (AChR) 的自身抗体 (1)。这些抗体会导致 AChR 数量和功能丧失，并导致神经肌肉传递失败并伴有肌肉无力 (2)。 20% 的 AChR 抗体 (AChR-Ab) 血清阴性的全身性 MC 患者(3) 的致病机制尚未阐明，但有证据表明他们也患有抗体介导的疾病(4,5)，抗体针对另一个先前未识别的肌肉表面膜靶点 (6-8)。在这里，我们发现 70% 的 AChR-Ab 血清阴性 MC 患者（而非 AChR-Ab 血清阳性 MG 患者）具有针对肌肉特异性受体酪氨酸激酶 MUSK 的血清自身抗体。 MuSK 在突触形成过程中介导集聚蛋白诱导的 AChR 聚集，并且也在成熟的神经肌肉接头处表达 (9-12)。 MUSK 抗体对转染的 COS7 细胞中表达的 MUSK 胞外结构域具有特异性，并强烈抑制培养的肌管中的 MUSK 功能。我们的结果表明 MUSK 抗体参与了 AChR-Ab 血清阴性 MC 的发病机制，从而定义了该疾病的两种免疫学不同形式。 MUSK 抗体的测量将极大地帮助诊断和临床管理。
Myasthenia gravis (MG) is an antibody-mediated autoimmune disease of the neuromuscular junction. In approximately 80% of patients, auto-antibodies to the muscle nicotinic acetylcholine receptor (AChR) are present(1). These antibodies cause loss of AChR numbers and function, and lead to failure of neuromuscular transmission with muscle weakness(2). The pathogenic mechanisms acting in the 20% of patients with generalized MC who are seronegative for AChR-antibodies (AChR-Ab)(3) have not been elucidated, but there is evidence that they also have an antibody-mediated disorder(4,5), with the antibodies directed towards another, previously unidentified muscle-surface-membrane target(6-8). Here we show that 70% of AChR-Ab-seronegative MC patients, but not AChR-Ab-seropositive MG patients, have serum auto-antibodies against the muscle-specific receptor tyrosine kinase, MUSK. MuSK mediates the agrin-induced clustering of AChRs during synapse formation, and is also expressed at the mature neuromuscular junction(9-12). The MUSK antibodies were specific for the extracellular domains of MUSK expressed in transfected COS7 cells and strongly inhibited MUSK function in cultured myotubes. Our results indicate the involvement of MUSK antibodies in the pathogenesis of AChR-Ab-seronegative MC, thus defining two immunologically distinct forms of the disease. Measurement of MUSK antibodies will substantially aid diagnosis and clinical management.