title: Antibody effector mechanisms in myasthenia gravis-pathogenesis at the neuromuscular junction.
abstract: Myasthenia gravis (MG) is an autoimmune disorder caused by autoantibodies that are either directed to the muscle nicotinic acetylcholine receptor (AChR) or to the muscle-specific tyrosine kinase (MuSK). These autoantibodies define two distinct subforms of the disease-AChR-MG and MuSK-MG. Both AChR and MuSK are expressed on the postsynaptic membrane of the neuromuscular junction (NMJ), which is a highly specialized region of the muscle dedicated to receive and process signals from the motor nerve. Autoantibody binding to proteins of the postsynaptic membrane leads to impaired neuromuscular transmission and muscle weakness. Pro-inflammatory antibodies of the human IgG1 and IgG3 subclass modulate the AChR, cause complement activation, and attract lymphocytes; together acting to decrease levels of the AChR and AChR-associated proteins and to reduce postsynaptic folding. In patients with anti-MuSK antibodies, there is no evidence of loss of junctional folds and no apparent loss of AChR density. Anti-MuSK antibodies are predominantly of the IgG4 isotype, which functionally differs from other IgG subclasses in its anti-inflammatory activity. Moreover, IgG4 undergoes a posttranslational modification termed Fab arm exchange that prevents cross-linking of antigens. These findings suggest that MuSK-MG may be different in etiological and pathological mechanisms from AChR-MG. The effector functions of IgG subclasses on synapse structure and function are discussed in this review.
authors.affiliation: Neuroimmunology Group, Department of Neuroscience, School of Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
authors.forename: Alejandro M
authors.initials: AM
authors.lastname: Gomez
authors.forename: Joost
authors.initials: J
authors.lastname: Van Den Broeck
authors.forename: Kathleen
authors.initials: K
authors.lastname: Vrolix
authors.forename: Sofie P
authors.initials: SP
authors.lastname: Janssen
authors.forename: Marijke A M
authors.initials: MA
authors.lastname: Lemmens
authors.forename: Eline
authors.initials: E
authors.lastname: Van Der Esch
authors.forename: Hans
authors.initials: H
authors.lastname: Duimel
authors.forename: Peter
authors.initials: P
authors.lastname: Frederik
authors.forename: Peter C
authors.initials: PC
authors.lastname: Molenaar
authors.forename: Pilar
authors.initials: P
authors.lastname: Martínez-Martínez
authors.forename: Marc H
authors.initials: MH
authors.lastname: De Baets
authors.forename: Mario
authors.initials: M
authors.lastname: Losen
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D018908:Muscle Weakness / Q000503:physiopathology; D009133:Muscular Atrophy / Q000503:physiopathology; D009157:Myasthenia Gravis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D009469:Neuromuscular Junction / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000276:immunology* / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000276:immunology* / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D011950:Receptors, Cholinergic; D011978:Receptors, Nicotinic; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases