Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Medical School, New York, NY 10016.
Department of Neuroscience and Physiology, Neuroscience Institute, New York University School of Medicine, New York, NY 10016.
Proc Natl Acad Sci U S A. 2024 Sep 24;121(39):e2408324121. doi: 10.1073/pnas.2408324121. Epub 2024 Sep 17.
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.
重症肌无力（MG）是一种影响神经肌肉接头（NMJ）的慢性、严重疾病，导致神经递质作用减弱，从而引起肌肉无力。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 是一种神经衍生的突触组织者。致病性 MuSK 抗体干扰 MuSK 和 Lrp4 之间的结合，抑制 NMJ 的分化和维持。MuSK MG 可能导致衰弱，并对 AChR MG 有效的治疗方法产生抗药性。我们在这里表明，从 MuSK MG 患者中衍生的重组抗体在小鼠中引起严重的神经肌肉疾病。通过预防性或在疾病发作后使用 MuSK 激动剂抗体可以预防这种疾病。这些发现为治疗 MuSK MG 提供了一种替代方案，通过选择性和直接针对疾病机制，而不是进行全身性免疫抑制。
