title: Anti-LRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis.
abstract: Myasthenia gravis (MG) is an autoimmune disorder characterized by a defect in synaptic transmission at the neuromuscular junction causing fluctuating muscle weakness with a decremental response to repetitive nerve stimulation or altered jitter in single-fiber electromyography (EMG). Approximately 80% of all myasthenia gravis patients have autoantibodies against the nicotinic acetylcholine receptor in their serum. Autoantibodies against the tyrosine kinase muscle-specific kinase (MuSK) are responsible for 5-10% of all myasthenia gravis cases. The autoimmune target in the remaining cases is unknown. Recently, low-density lipoprotein receptor-related protein (LRP4) has been identified as the agrin receptor. LRP4 interacts with agrin, and the binding of agrin activates MuSK, which leads to the formation of most if not all postsynaptic specializations, including aggregates containing acetylcholine receptors (AChRs) in the junctional plasma membrane. In the present study we tested if autoantibodies against LRP4 are detectable in patients with myasthenia gravis. To this end we analyzed 13 sera from patients with generalized myasthenia gravis but without antibodies against AChR or MuSK. The results showed that 12 out of 13 antisera from double-seronegative MG patients bound to proteins concentrated at the neuromuscular junction of adult mouse skeletal muscle and that approximately 50% of the tested sera specifically bound to HEK293 cells transfected with human LRP4. Moreover, 4 out of these 13 sera inhibited agrin-induced aggregation of AChRs in cultured myotubes by more than 50%, suggesting a pathogenic role regarding the dysfunction of the neuromuscular endplate. These results indicate that LRP4 is a novel target for autoantibodies and is a diagnostic marker in seronegative MG patients.
authors.affiliation: Department of Physiological Genomics, Institute for Physiology, Ludwig-Maximilians University, Pettenkoferstrasse 12, 80336, Munich, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Pevzner
authors.forename: Benedikt
authors.initials: B
authors.lastname: Schoser
authors.forename: Katja
authors.initials: K
authors.lastname: Peters
authors.forename: Nicoleta-Carmen
authors.initials: NC
authors.lastname: Cosma
authors.forename: Andromachi
authors.initials: A
authors.lastname: Karakatsani
authors.forename: Berthold
authors.initials: B
authors.lastname: Schalke
authors.forename: Arthur
authors.initials: A
authors.lastname: Melms
authors.forename: Stephan
authors.initials: S
authors.lastname: Kröger
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018171:Agrin / Q000378:metabolism; D000818:Animals; D001323:Autoantibodies / Q000097:blood* / Q000494:pharmacology; D002038:Bungarotoxins / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects; D009157:Myasthenia Gravis / Q000097:blood* / Q000276:immunology* / Q000473:pathology; D009460:Neurologic Examination; D009469:Neuromuscular Junction / Q000378:metabolism / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology; D011978:Receptors, Nicotinic / Q000276:immunology / Q000378:metabolism; D014162:Transfection; D055815:Young Adult
chemical_list: D018171:Agrin; D001323:Autoantibodies; D002038:Bungarotoxins; D026502:LDL-Receptor Related Proteins; C551781:LRP4 protein, human; D011978:Receptors, Nicotinic; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D020794:Receptor Protein-Tyrosine Kinases