title: MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4.
abstract: 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.
authors.affiliation: Department of Neurology, Department of Human Genetics and Department of Molecular Cell Biology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
authors.forename: Maartje G
authors.initials: MG
authors.lastname: Huijbers
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Rinse
authors.initials: R
authors.lastname: Klooster
authors.forename: Erik H
authors.initials: EH
authors.lastname: Niks
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Friese
authors.forename: Kirsten R
authors.initials: KR
authors.lastname: Straasheijm
authors.forename: Peter E
authors.initials: PE
authors.lastname: Thijssen
authors.forename: Hans
authors.initials: H
authors.lastname: Vrolijk
authors.forename: Jaap J
authors.initials: JJ
authors.lastname: Plomp
authors.forename: Pauline
authors.initials: P
authors.lastname: Vogels
authors.forename: Mario
authors.initials: M
authors.lastname: Losen
authors.forename: Silvère M
authors.initials: SM
authors.lastname: Van der Maarel
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Burden
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Verschuuren
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018171:Agrin / Q000276:immunology; D000818:Animals; D001323:Autoantibodies / Q000276:immunology* / Q000494:pharmacology; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D000939:Epitopes / Q000276:immunology; D005260:Female; D006801:Humans; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000276:immunology* / Q000494:pharmacology; D026502:LDL-Receptor Related Proteins / Q000037:antagonists & inhibitors / Q000276:immunology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D055503:Protein Multimerization / Q000187:drug effects / Q000276:immunology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology*; D011950:Receptors, Cholinergic / Q000276:immunology*; D011973:Receptors, LDL / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D018171:Agrin; D001323:Autoantibodies; D000939:Epitopes; D007074:Immunoglobulin G; D026502:LDL-Receptor Related Proteins; C551781:LRP4 protein, human; C116415:Lrp4 protein, mouse; D011950:Receptors, Cholinergic; D011973:Receptors, LDL; C095714:MUSK protein, human; C511695:MuSK protein, mouse; D020794:Receptor Protein-Tyrosine Kinases
keywords: Dok7; Rapsyn; activation loop; insulin receptor; neuromuscular junction