title: Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis.
abstract: OBJECTIVE
  To determine whether patients with myasthenia gravis (MG) have serum antibodies to lipoprotein-related protein 4 (LRP4), a newly identified receptor for agrin that is essential for neuromuscular junction formation, and to establish whether such antibodies contribute to MG pathogenesis.
  
  
  METHODS
  Serum samples from patients with MG with known status of serum antibodies to the acetylcholine receptor (AChR) and muscle-specific kinase (MuSK) and serum samples from control subjects (healthy individuals and individuals with other diseases) were tested for antibodies to LRP4. Serum samples with such antibodies were tested to determine whether they had the ability to inhibit 2 different functions of LRP4 at the neuromuscular junction.
  
  
  METHODS
  Serum samples were collected at the Hellenic Pasteur Institute and Wayne State University. Samples were tested for LRP4 autoantibodies at Georgia Health Sciences University. Other immunoreactivities of the samples were tested at the Hellenic Pasteur Institute, Athens, Greece, or processed through University Laboratories of the Detroit Medical Center, Michigan. Patients  The study included 217 patients with MG, 76 patients with other neurologic or psychiatric diseases, and 45 healthy control subjects.
  
  
  RESULTS
  Anti-LRP4 antibodies were detected in 11 of 120 patients with MG without detectable anti-AChR or anti-MuSK antibodies (double seronegative) and in 1 of 36 patients without anti-AChR antibodies but with anti-MuSK antibodies, but they were not detected in any of the 61 patients with anti-AChR antibodies. No healthy control subjects and only 2 of the 76 control patients with neurologic disease had anti-LRP4 antibodies. Serum samples from patients with MG with anti-LRP4 antibodies were able to inhibit the LRP4-agrin interaction and/or alter AChR clustering in muscle cells.
  
  
  CONCLUSIONS
  Anti-LRP4 antibodies were detected in the serum of approximately 9.2% of patients with double-seronegative MG. This frequency is intermediate compared with 2 recent studies showing anti-LRP4 antibodies in 2% and 50% of patients with double-seronegative MG from different geographic locations. Together, these observations indicate that LRP4 is another autoantigen in patients with MG, and anti-LRP4 autoantibodies may be pathogenic through different immunopathogenic processes.
authors.affiliation: Department of Neurology, Institute of Molecular Medicine and Genetics, Georgia Health Sciences University, 1120 15th St, Augusta, GA 30912, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: John S
authors.initials: JS
authors.lastname: Tzartos
authors.forename: Maria
authors.initials: M
authors.lastname: Belimezi
authors.forename: Samia
authors.initials: S
authors.lastname: Ragheb
authors.forename: Beverly
authors.initials: B
authors.lastname: Bealmear
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lewis
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Xiong
authors.forename: Robert P
authors.initials: RP
authors.lastname: Lisak
authors.forename: Socrates J
authors.initials: SJ
authors.lastname: Tzartos
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
mesh_terms: D018171:Agrin / Q000378:metabolism; D001323:Autoantibodies / Q000097:blood* / Q000494:pharmacology; D002461:Cell Line, Transformed; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D026502:LDL-Receptor Related Proteins / Q000737:chemistry / Q000276:immunology*; D008297:Male; D009103:Multiple Sclerosis / Q000097:blood / Q000276:immunology; D009157:Myasthenia Gravis / Q000097:blood* / Q000276:immunology*; D009471:Neuromyelitis Optica / Q000097:blood / Q000276:immunology; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology; D011950:Receptors, Cholinergic / Q000276:immunology; D012559:Schizophrenia / Q000097:blood / Q000276:immunology; D012701:Serotonin / Q000378:metabolism*; D014162:Transfection
chemical_list: D018171:Agrin; D001323:Autoantibodies; D026502:LDL-Receptor Related Proteins; C551781:LRP4 protein, human; D011950:Receptors, Cholinergic; D012701:Serotonin; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases