Myasthenia gravis (MG) is a chronic and severe disease of the skeletal neuromuscular junction (NMJ) in which the effects of neurotransmitters are attenuated, leading to muscle weakness. In the most common forms of autoimmune MG, antibodies attack components of the postsynaptic membrane, including the acetylcholine receptor (AChR) or muscle-specific kinase (MuSK). MuSK, a master regulator of NMJ development, associates with the low-density lipoprotein-related receptor 4 (Lrp4) to form the signaling receptor for neuronal Agrin, a nerve-derived synaptic organizer. Pathogenic antibodies to MuSK interfere with binding between MuSK and Lrp4, inhibiting the differentiation and maintenance of the NMJ. MuSK MG can be debilitating and refractory to treatments that are effective for AChR MG. We show here that recombinant antibodies, derived from MuSK MG patients, cause severe neuromuscular disease in mice. The disease can be prevented by a MuSK agonist antibody, presented either prophylactically or after disease onset. These findings suggest a therapeutic alternative to generalized immunosuppression for treating MuSK MG by selectively and directly targeting the disease mechanism.

中文翻译：

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MuSK 激动剂抗体可保护小鼠免受 MuSK 重症肌无力的侵害


重症肌无力 （MG） 是一种慢性和严重的骨骼神经肌肉接头 （NMJ） 疾病，其中神经递质的作用减弱，导致肌肉无力。在最常见的自身免疫性 MG 中，抗体攻击突触后膜的成分，包括乙酰胆碱受体 （AChR） 或肌肉特异性激酶 （MuSK）。MuSK 是 NMJ 发育的主要调节因子，与低密度脂蛋白相关受体 4 （Lrp4） 结合，形成神经元 Agrin 的信号受体，Agrin 是一种神经来源的突触组织者。MuSK 的致病性抗体会干扰 MuSK 和 Lrp4 之间的结合，从而抑制 NMJ 的分化和维持。MuSK MG 可能使人衰弱，并且对对 AChR MG 有效的治疗无效。我们在这里表明，源自 MuSK MG 患者的重组抗体会导致小鼠出现严重的神经肌肉疾病。该疾病可通过预防性或在疾病发作后出现的 MuSK 激动剂抗体来预防。这些发现为通过选择性和直接靶向疾病机制来治疗 MuSK MG 提供了一种全身免疫抑制的替代疗法。