title: Antibodies against low-density lipoprotein receptor-related protein 4 induce myasthenia gravis.
abstract: 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.
authors.forename: Chengyong
authors.initials: C
authors.lastname: Shen
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Lu
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Dwight
authors.initials: D
authors.lastname: Figueiredo
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bean
authors.forename: Jiung
authors.initials: J
authors.lastname: Jung
authors.forename: Haitao
authors.initials: H
authors.lastname: Wu
authors.forename: Arnab
authors.initials: A
authors.lastname: Barik
authors.forename: Dong-Min
authors.initials: DM
authors.lastname: Yin
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Xiong
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000276:immunology*; D051379:Mice; D008805:Mice, Inbred A; D009157:Myasthenia Gravis / Q000276:immunology*; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000276:immunology*; D009469:Neuromuscular Junction / Q000276:immunology* / Q000648:ultrastructure; D017434:Protein Structure, Tertiary; D011817:Rabbits; D051381:Rats; D011973:Receptors, LDL / Q000276:immunology* / Q000502:physiology
chemical_list: D001323:Autoantibodies; D026502:LDL-Receptor Related Proteins; C551781:LRP4 protein, human; C116415:Lrp4 protein, mouse; D011973:Receptors, LDL