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 κ (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 (THκmog) 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 THκmog double-transgenic mice, the transgenic κmog L-chain was commonly replaced by endogenous L-chains, i.e., by receptor editing. In rearrangement-deficient RAG-2− mice, differentiation of THκmog B cells is blocked at an immature stage (defined by the B220lowIgMlowIgD− 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 THκmog 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 THκmog B cell receptor and induces editing of the transgenic κmog 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.

Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein

“…2 a and b). This is consistent with the observation that in mice transgenic for the heavy chain of 8-18C5 MOG binding is maintained by pairing this heavy chain with different endogenous light chains (37).…”

“…MOG is expressed within the immunologically privileged environment of the CNS where it is sequestered from normal lymphocyte trafficking and unable to trigger antigen-specific B cell tolerance. The composition of the anti-MOG B cell repertoire, however, can be influenced by other self-antigens (37), which may include homologous proteins such as butyrophilin (41) or erythroid membrane-associated protein (42), the N-terminal IgV-like domains of which exhibit sequence identities to MOG Igd of 45-55% (43). Strikingly, those residues bound by 8-18C5, an antibody that has escaped this tolerogenic influence, are least conserved between MOG and its relatives (Fig.…”

Demyelinating Myelin Oligodendrocyte Glycoprotein-Specific Autoantibody Response Is Focused on One Dominant Conformational Epitope Region in Rodents

“…This leads to the obvious question of why then is the epitope specificity of conformation-dependent MOG ex -specific Abs focused on one main immunogenic region of the protein? Several observations suggest that this may be due to the deletion of certain epitope specificities from the Ab repertoire by components of self proteins that mimic the corresponding MOG epitopes (58,59).…”

Commentary: Sorting the wheat from the chaff: identifying demyelinating components of the myelin oligodendrocyte glycoprotein (MOG)‐specific autoantibody repertoire

“…This may explain the high frequency of antibody responses recognizing linear MOG peptides, but not the intact molecule, in patients with MS [23]. However, the composition of the MOG-reactive antibody repertoire is also clearly influenced by both genetic [46,51] and environmental influences [47,52].…”

“…This may explain the high frequency of antibody responses recognizing linear MOG peptides, but not the intact molecule, in patients with MS [23]. However, the composition of the MOG-reactive antibody repertoire is also clearly influenced by both genetic [46,51] and environmental influences [47,52].Genes within the MHC selectively censor the ability of H2-b mice to mount an antibody response to discontinuous (demyelinating) rat MOG Igd epitopes, whilst leaving the response to linear epitopes intact. This effect could involve protease activities encoded within the MHC, the selective deletion of MOG-reactive B cell clones mediated by structural homologues of MOG, or even strainspecific differences in the expression of MOG outside the CNS [46].…”