title: Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange.
abstract: Antibodies play a central role in immunity by forming an interface with the innate immune system and, typically, mediate proinflammatory activity. We describe a novel posttranslational modification that leads to anti-inflammatory activity of antibodies of immunoglobulin G, isotype 4 (IgG4). IgG4 antibodies are dynamic molecules that exchange Fab arms by swapping a heavy chain and attached light chain (half-molecule) with a heavy-light chain pair from another molecule, which results in bispecific antibodies. Mutagenesis studies revealed that the third constant domain is critical for this activity. The impact of IgG4 Fab arm exchange was confirmed in vivo in a rhesus monkey model with experimental autoimmune myasthenia gravis. IgG4 Fab arm exchange is suggested to be an important biological mechanism that provides the basis for the anti-inflammatory activity attributed to IgG4 antibodies.
authors.affiliation: Sanquin Research-AMC Landsteiner Laboratory, Department of Immunopathology, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands.
authors.forename: Marijn
authors.initials: M
authors.lastname: van der Neut Kolfschoten
authors.forename: Janine
authors.initials: J
authors.lastname: Schuurman
authors.forename: Mario
authors.initials: M
authors.lastname: Losen
authors.forename: Wim K
authors.initials: WK
authors.lastname: Bleeker
authors.forename: Pilar
authors.initials: P
authors.lastname: Martínez-Martínez
authors.forename: Ellen
authors.initials: E
authors.lastname: Vermeulen
authors.forename: Tamara H
authors.initials: TH
authors.lastname: den Bleker
authors.forename: Luus
authors.initials: L
authors.lastname: Wiegman
authors.forename: Tom
authors.initials: T
authors.lastname: Vink
authors.forename: Lucien A
authors.initials: LA
authors.lastname: Aarden
authors.forename: Marc H
authors.initials: MH
authors.lastname: De Baets
authors.forename: Jan G J
authors.initials: JG
authors.lastname: van de Winkel
authors.forename: Rob C
authors.initials: RC
authors.lastname: Aalberse
authors.forename: Paul W H I
authors.initials: PW
authors.lastname: Parren
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology; D018951:Antigens, CD20 / Q000276:immunology; D052179:Antigens, Plant; D001323:Autoantibodies / Q000276:immunology; D066246:ErbB Receptors / Q000276:immunology; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000737:chemistry; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D007074:Immunoglobulin G / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D007143:Immunoglobulin Heavy Chains; D008253:Macaca mulatta; D051379:Mice; D009154:Mutation; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000276:immunology / Q000517:prevention & control; D011499:Protein Processing, Post-Translational; D011950:Receptors, Cholinergic / Q000276:immunology
chemical_list: D000485:Allergens; D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D052179:Antigens, Plant; D001323:Autoantibodies; D006023:Glycoproteins; D007127:Immunoglobulin Constant Regions; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D011950:Receptors, Cholinergic; D066246:ErbB Receptors; C059296:Fel d 1 protein, Felis domesticus