title: Autoantibodies to agrin in myasthenia gravis patients.
abstract: To determine if patients with myasthenia gravis (MG) have antibodies to agrin, a proteoglycan released by motor neurons and is critical for neuromuscular junction (NMJ) formation, we collected serum samples from 93 patients with MG with known status of antibodies to acetylcholine receptor (AChR), muscle specific kinase (MuSK) and lipoprotein-related 4 (LRP4) and samples from control subjects (healthy individuals and individuals with other diseases). Sera were assayed for antibodies to agrin. We found antibodies to agrin in 7 serum samples of MG patients. None of the 25 healthy controls and none of the 55 control neurological patients had agrin antibodies. Two of the four triple negative MG patients (i.e., no detectable AChR, MuSK or LRP4 antibodies, AChR-/MuSK-/LRP4-) had antibodies against agrin. In addition, agrin antibodies were detected in 5 out of 83 AChR+/MuSK-/LRP4- patients but were not found in the 6 patients with MuSK antibodies (AChR-/MuSK+/LRP4-). Sera from MG patients with agrin antibodies were able to recognize recombinant agrin in conditioned media and in transfected HEK293 cells. These sera also inhibited the agrin-induced MuSK phosphorylation and AChR clustering in muscle cells. Together, these observations indicate that agrin is another autoantigen in patients with MG and agrin autoantibodies may be pathogenic through inhibition of agrin/LRP4/MuSK signaling at the NMJ.
authors.affiliation: Department of Neuroscience and Regenerative Medicine and Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America; Department of Physiology, Basic Medical School, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei Province, P. R. China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience and Regenerative Medicine and Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America; Charlie Norwood VA Medical Center, Augusta, Georgia, United States of America.
authors.forename: Chengyong
authors.initials: C
authors.lastname: Shen
authors.affiliation: Department of Neurology, School of Medicine, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Beverly
authors.initials: B
authors.lastname: Bealmear
authors.affiliation: Department of Neurology, School of Medicine, Wayne State University, Detroit, Michigan, United States of America; Department of Biomedical Sciences, Oakland University William Beaumont School of Medicine, Rochester, Michigan, United States of America.
authors.forename: Samia
authors.initials: S
authors.lastname: Ragheb
authors.affiliation: Department of Neuroscience and Regenerative Medicine and Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America; Charlie Norwood VA Medical Center, Augusta, Georgia, United States of America.
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Xiong
authors.affiliation: Department of Neurology, School of Medicine, Wayne State University, Detroit, Michigan, United States of America; Department of Neurology, Cedars-Sinai Medical Center, West Hollywood, California, United States of America.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lewis
authors.affiliation: Department of Neurology, School of Medicine, Wayne State University, Detroit, Michigan, United States of America; Department of Immunology and Microbiology, School of Medicine, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Lisak
authors.affiliation: Department of Neuroscience and Regenerative Medicine and Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America; Charlie Norwood VA Medical Center, Augusta, Georgia, United States of America.
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
mesh_terms: D018171:Agrin / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D006801:Humans; D009157:Myasthenia Gravis / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000276:immunology / Q000378:metabolism
chemical_list: D018171:Agrin; D001323:Autoantibodies; D001324:Autoantigens; D011950:Receptors, Cholinergic; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases