Development of myelin oligodendrocyte glycoprotein autoreactive transgenicB 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 auto antigens in a double-transgenic mouse model carrying the Ig H-chain (introd uced 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-specif ic Ig H-chain differentiate without tolerogenic censure. We show now that d ouble-transgenic (TH kappa (mog)) B cells expressing transgenic Ig H- and L -chains are subjected to receptor editing. We show that in adult mice carry ing both MOG-specific Ig H- and L-chains, the frequency of MOG-binding B ce lls 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 recepto r editing. In rearrangement-deficient RAG-2(-) mice, differentiation of TH kappa (mog) B cells is blocked at an immature stage (defined by the B220(lo w)IgM(low)IgD(-) phenotype), reflecting interaction of the autoreactive B c ells with a local self-determinant, The tolerogenic structure in the bone m arrow 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 prop ortion 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 c ells without affecting the pathogenic potential of the remaining MOG-specif ic B cells, This phenomenon represents a particular form of chain-specific split tolerance.