Agonist antibody to MuSK protects mice from MuSK myasthenia gravis

• 成果类型: Article
• 署名作者: Oury, Julien; Gamallo-Lana, Begona; Santana, Leah; Steyaert, Christophe; Vergoossen, Dana L. E.; Mar, Adam C.; Vankerckhoven, Bernhardt; Silence, Karen; Vanhauwaert, Roeland; Huijbers, Maartje G.; Burden, Steven J.
• 署名单位: New York University; New York University; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Massachusetts General Hospital
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11579
• DOI: 10.1073/pnas.2408324121
• 发表日期: 2024-09-24
• 关键词: neuromuscular-junction formation; tyrosine kinase musk; receptor; lrp4; agrin; autoantibodies; domain; models; forms

摘要

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 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.