title: Development of myelin oligodendrocyte glycoprotein autoreactive transgenic B lymphocytes: receptor editing in vivo after encounter of a self-antigen distinct from myelin oligodendrocyte glycoprotein.
abstract: We explored mechanisms involved in B cell self-tolerance against brain autoantigens in a double-transgenic mouse model carrying the Ig H-chain (introduced by gene replacement) and/or the L-chain kappa (conventional transgenic) of the mAb 8.18C5, specific for the myelin oligodendrocyte glycoprotein (MOG). Previously, we demonstrated that B cells expressing solely the MOG-specific Ig H-chain differentiate without tolerogenic censure. We show now that double-transgenic (THkappa(mog)) B cells expressing transgenic Ig H- and L-chains are subjected to receptor editing. We show that in adult mice carrying both MOG-specific Ig H- and L-chains, the frequency of MOG-binding B cells is not higher than in mice expressing solely the transgenic Ig H-chain. In fact, in THkappa(mog) double-transgenic mice, the transgenic kappa(mog) L-chain was commonly replaced by endogenous L-chains, i.e., by receptor editing. In rearrangement-deficient RAG-2(-) mice, differentiation of THkappa(mog) B cells is blocked at an immature stage (defined by the B220(low)IgM(low)IgD(-) phenotype), reflecting interaction of the autoreactive B cells with a local self-determinant. The tolerogenic structure in the bone marrow is not classical MOG, because back-crossing THkappa(mog) mice into a MOG-deficient genetic background does not lead to an increase in the proportion of MOG-binding B cells. We propose that an as yet undefined self-Ag distinct from MOG cross-reacts with the THkappa(mog) B cell receptor and induces editing of the transgenic kappa(mog) L-chain in early immature B cells without affecting the pathogenic potential of the remaining MOG-specific B cells. This phenomenon represents a particular form of chain-specific split tolerance.
authors.affiliation: Max-Planck-Institut für Neurobiologie, Martinsried, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Litzenburger
authors.forename: H
authors.initials: H
authors.lastname: Blüthmann
authors.forename: P
authors.initials: P
authors.lastname: Morales
authors.forename: D
authors.initials: D
authors.lastname: Pham-Dinh
authors.forename: A
authors.initials: A
authors.lastname: Dautigny
authors.forename: H
authors.initials: H
authors.lastname: Wekerle
authors.forename: A
authors.initials: A
authors.lastname: Iglesias
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002469:Cell Separation; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D018985:Epitopes, B-Lymphocyte / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000276:immunology; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D007145:Immunoglobulin kappa-Chains / Q000096:biosynthesis / Q000235:genetics; D016130:Immunophenotyping; D007231:Infant, Newborn; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D009687:Nuclear Proteins; D017393:RNA Editing / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000096:biosynthesis / Q000235:genetics*; D017634:Self Tolerance / Q000235:genetics; D019076:Transgenes / Q000276:immunology
chemical_list: D001324:Autoantigens; D004268:DNA-Binding Proteins; D018985:Epitopes, B-Lymphocyte; D018398:Homeodomain Proteins; D007143:Immunoglobulin Heavy Chains; D007145:Immunoglobulin kappa-Chains; C571326:MOG protein, human; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; D011947:Receptors, Antigen, B-Cell; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein