title: Experimental autoimmune myasthenia gravis in mice expressing human immunoglobulin loci.
abstract: Antibodies (Abs) specifically directed against the muscular acetylcholine receptor (AChR) mediate the pathogenesis of myasthenia gravis (MG). The animal model experimental autoimmune MG (EAMG) can be induced by passive transfer or by active immunization of anti-AChR Abs. We report a new EAMG mouse model that generates human anti-AChR Abs upon immunization with Torpedo AChR (tAChR). Mice transgenic for human mu, gamma1, and kappa germ line genes (HuMAb-Mice) were immunized with tAChR. Serum titers of anti-tAChR Abs were in the nanomolar range, and anti-rodent AChR Abs were in picomolar range. Some HuMAb-Mice had signs of muscle weakness, clearly indicating their susceptibility to EAMG. Human Ab-mouse AChR complexes were found at the neuromuscular junction, while AChR loss was up to 65%. Spleen and lymph nodes were used for producing hybridomas. Of the anti-tAChR monoclonal Ab-producing hybridomas, 2% had cross-reactivity with rodent AChR and none with human AChR. Immunization with a fusion protein, Trx-Halpha1-210, displaying the human main immunogenic region did not result in EAMG or the generation of human anti-human AChR monoclonal Abs. These experiments show that the HuMAb-Mouse represents a suitable model to generate and study the effects of human anti-AChR Abs in vivo.
authors.affiliation: Department of Neurology, Brain and Behaviour Institute (Uns 50, Box 38), University of Maastricht, P.O. Box 616, 6200 MD, Maastricht, The Netherlands. m.stassen@np.unimass.nl
authors.forename: Maurice H W
authors.initials: MH
authors.lastname: Stassen
authors.forename: Fanping
authors.initials: F
authors.lastname: Meng
authors.forename: Eefje
authors.initials: E
authors.lastname: Melgert
authors.forename: Barbie M
authors.initials: BM
authors.lastname: Machiels
authors.forename: Sin-Hyeog
authors.initials: SH
authors.lastname: Im
authors.forename: Sara
authors.initials: S
authors.lastname: Fuchs
authors.forename: Arnout F
authors.initials: AF
authors.lastname: Gerritsen
authors.forename: Marc A
authors.initials: MA
authors.lastname: van Dijk
authors.forename: Jan G J
authors.initials: JG
authors.lastname: van de Winkel
authors.forename: Marc H
authors.initials: MH
authors.lastname: De Baets
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood; D005803:Genes, Immunoglobulin; D006801:Humans; D006825:Hybridomas / Q000276:immunology; D007114:Immunization; D051379:Mice; D008822:Mice, Transgenic; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D011950:Receptors, Cholinergic / Q000276:immunology*; D014101:Torpedo
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D011950:Receptors, Cholinergic