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 κ (conventional transgenic) of the mAb 8.18 C5, 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 (THκ 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 THκ mog double-transgenic mice, the transgenic κ mog L-chain was commonly replaced by endogenous L-chains, ie, by receptor editing. In rearrangement-deficient RAG-2− mice, differentiation of THκ 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 THκ 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 THκ mog B cell receptor and induces editing of the transgenic κ 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.