Development of myelin oligodendrocyte glycoprotein autoreactive transgenic B lymphocytes:: Receptor editing in vivo after encounter of a self-antigen distinct from myelin oligodendrocyte glycoprotein

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 K (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 kappa (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 expressings solely the transgenic Ig H-chain, In fact, in TH kappa (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 TH kappa (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 TH kappa (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 kappa (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.