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Development of Myelin Oligodendrocyte Glycoprotein Autoreactive Transgenic B Lymphocytes: Receptor Editing In Vivo After Encounter of a Self-Antigen Distinct from Myelin Oligodendrocyte Glycoprotein

Tobias Litzenburger^*, Horst Blüthmann, Patricia Morales, Danielle Pham-Dinh^§, André Dautigny^§, Hartmut Wekerle^* and Antonio Iglesias^1,*

^* Max-Planck-Institut für Neurobiologie, Martinsried, Germany; Roche AG, Basel, Switzerland; CBM, Universidad Autónoma, Cantoblanco, Madrid, Spain; and ^§ Unité Mixte de Recherche, Centre National de la Recherche Scientifique 7624, University of Paris, Paris, France

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 (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 (TH^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 TH^mog double-transgenic mice, the transgenic ^mog L-chain was commonly replaced by endogenous L-chains, i.e., by receptor editing. In rearrangement-deficient RAG-2^- mice, differentiation of TH^mog B cells is blocked at an immature stage (defined by the B220^lowIgM^lowIgD^- 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 TH^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 TH^mog B cell receptor and induces editing of the transgenic ^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.

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