Patients suffering from myasthenia gravis (MG) have debilitating muscle weakness and fatigue. MG is the result of neuromuscular junction (NMJ) dysfunction and is frequently associated with the presence of autoantibodies that target the acetylcholine receptor (AChR) or the kinase MuSK, which are critical for NMJ formation. Subsets of MG patients do not produce autoantibodies against either AChR or MuSK and little is know about how MG develops in these individuals. Recently, autoantibodies against the low-density lipoprotein receptor-related protein 4 (LRP4) were identified in a cohort of three patients with MG. To determine if LRP4 autoantibodies contribute to MG, Chengyong Shen, Yisheng Lu, Bin Zhang, and colleagues from Georgia Regents University developed a mouse model of LRP4 autoantibody-induced MG. Immunization of mice with the extracellular domain of LRP4 induced the production of anti-LRP4 antibodies and MG-like symptoms. Furthermore, transfer of anti-LRP4 sera into mice also resulted in MG phenotypes. NMJs from these mice were fragmented and not fully formed. This study demonstrates that LRP4 antibodies promote MG, and that LRP4 is required to maintain NMJ function. The companion image depicts the NMJ. Neurofilaments are green, AchRs are red, and nuclei are stained blue. These structures are disrupted in MG.
Myasthenia gravis (MG) is the most common disorder affecting the neuromuscular junction (NMJ). MG is frequently caused by autoantibodies against acetylcholine receptor (AChR) and a kinase critical for NMJ formation, MuSK; however, a proportion of MG patients are double-negative for anti-AChR and anti-MuSK antibodies. Recent studies in these subjects have identified autoantibodies against low-density lipoprotein receptor–related protein 4 (LRP4), an agrin receptor also critical for NMJ formation. LRP4 autoantibodies have not previously been implicated in MG pathogenesis. Here we demonstrate that mice immunized with the extracellular domain of LRP4 generated anti-LRP4 antibodies and exhibited MG-associated symptoms, including muscle weakness, reduced compound muscle action potentials (CMAPs), and compromised neuromuscular transmission. Additionally, fragmented and distorted NMJs were evident at both the light microscopic and electron microscopic levels. We found that anti-LRP4 sera decreased cell surface LRP4 levels, inhibited agrin-induced MuSK activation and AChR clustering, and activated complements, revealing potential pathophysiological mechanisms. To further confirm the pathogenicity of LRP4 antibodies, we transferred IgGs purified from LRP4-immunized rabbits into naive mice and found that they exhibited MG-like symptoms, including reduced CMAP and impaired neuromuscular transmission. Together, these data demonstrate that LRP4 autoantibodies induce MG and that LRP4 contributes to NMJ maintenance in adulthood.
Chengyong Shen, Yisheng Lu, Bin Zhang, Dwight Figueiredo, Jonathan Bean, Jiung Jung, Haitao Wu, Arnab Barik, Dong-Min Yin, Wen-Cheng Xiong, Lin Mei