MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4

作者：Huijbers Maartje G^*; Zhang Wei; Klooster Rinse; Niks Erik H; Friese Matthew B; Straasheijm Kirsten R; Thijssen Peter E; Vrolijk Hans; Plomp Jaap J; Vogels Pauline; Losen Mario; Van der Maarel Silvere M; Burden Steven J; Verschuuren Jan J

来源：Proceedings of the National Academy of Sciences, 2013, 110(51): 20783-20788.

DOI：10.1073/pnas.1313944110

• neuromuscular junction
• Rapsyn
• Dok7
• activation loop
• insulin receptor

Myasthenia gravis (MG) is a severely debilitating autoimmune disease that is due to a decrease in the efficiency of synaptic transmission at neuromuscular synapses. MG is caused by antibodies against postsynaptic proteins, including (i) acetylcholine receptors, the neurotransmitter receptor, (ii) muscle-specific kinase (MuSK), a receptor tyrosine kinase essential for the formation and maintenance of neuromuscular synapses, and (iii) low-density lipoprotein receptor-related protein 4 (Lrp4), which responds to neural Agrin by binding and stimulating MuSK. Passive transfer studies in mice have shown that IgG4 antibodies from MuSK MG patients cause disease without requiring complement or other immune components, suggesting that these MuSK antibodies cause disease by directly interfering with MuSK function. Here we show that pathogenic IgG4 antibodies to MuSK bind to a structural epitope in the first Ig-like domain of MuSK, prevent binding between MuSK and Lrp4, and inhibit Agrin-stimulated MuSK phosphorylation. In contrast, these IgG4 antibodies have no direct effect on MuSK dimerization or MuSK internalization. These results provide insight into the unique pathogenesis of MuSK MG and provide clues toward development of specific treatment options.

• 出版日期2013-12-17