Selective Unresponsiveness to Conformational B Cell Epitopes of the Myelin Oligodendrocyte Glycoprotein in H-2b Mice

Bourquin, Carole; Schubart, Anna; Tobollik, Stephanie; Mather, Ian H.; Ogg, Sherry; Liblau, Roland; Linington, Christopher

doi:10.4049/jimmunol.171.1.455

Cited by 40 publications

(46 citation statements)

References 31 publications

(45 reference statements)

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“…It was therefore not possible to control for possible differences in lesion burden at the time of transfer, or in the rate of lesion formation induced by the two antibody populations. Nevertheless, the broad conclusions of this study -demyelinating antibody responses are directed against discontinuous, rather than linear epitopes -are in agreement with results obtained in other species [46].Von Büdingen et al point out that although antibodies to linear peptide epitopes did not induce extensive demyelination, the burden of CNS lesions in the animals injected with these antibodies was higher than in the two controls that received naive marmoset Ig ‹ . The sample size is too small to make any definitive conclusions but this observation does raise the possibility that antibodies bind to MOG epitopes that are generated during the MBP-induced inflammatory response.…”

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confidence: 79%

“…As demonstrated in Fig. 2 this technique differentiates between responses to linear (non-pathogenic), and discontinuous (demyelinating) epitopes in the rat, and was also used to identify cytolytic antibody response to MOG in murine models of MOG-induced EAE [46]. Using this approach it may also be possible to confirm the association between demyelination in MBP/PLP-induced EAE in the marmoset with the development of a MOG-specific antibody response [53].…”

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confidence: 88%

“…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].…”

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confidence: 99%

“…However, the composition of the MOG-reactive antibody repertoire is also clearly influenced by both genetic [46,51] and environmental influences [47,52].…”

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confidence: 99%

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

et al. 2004

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Myelin oligodendrocyte glycoprotein (MOG) is the only myelin protein known to initiate a demyelinating autoantibody response in EAE, an animal model for multiple sclerosis (MS). The pathophysiological significance of MOG-specific autoantibodies in MS is, however, controversial, as high titer antibody responses to MOG are also found in many patients with nondemyelinating neurological diseases. In this issue of the European Journal of Immunology, von Büdingen et al. demonstrate that demyelination in a primate model of MOG-induced EAE is mediated by MOG-specific antibodies directed against discontinuous, rather than linear, MOG epitopes. This functional segregation of pathogenic vs. non-pathogenic autoantibodies in terms of epitope specificity may be crucial to understand the relevance of MOGspecific responses in human disease. This commentary discusses these findings in the context of the structure and immunobiology of MOG, and their implications with respect to antibody-mediated demyelination in MS. Humoral responses in the pathogenesis of multiple sclerosisLoss of immunological self-tolerance to myelin antigens in genetically susceptible individuals plays a major role in the pathogenesis of multiple sclerosis (MS), a complex inflammatory demyelinating disease of the central nervous system (CNS) [1]. MS is often discussed as a purely T cell mediated disease, but there is increasing indirect evidence that antibody-dependent mechanisms are also involved in disease pathogenesis. Immunopathological studies identified immunoglobulins and complementactivation products deposited on the surface of intact myelin sheaths at the active edge of demyelinating lesions, as well as the presence of opsonized myelin debris that is cleared from the lesions by activated macrophages [2][3][4][5][6][7]. Plasma exchange can also dramatically reduce clinical disease activity in a subset of MS patients [8,9]. This provides further circumstantial evidence that humoral factors can be involved in disease pathogenesis, but their mode of action remains obscure.The tacit assumption made on the basis of immunopathological findings is that this mode of action involves autoantibodies recognizing determinants exposed on the surface of the myelin sheath. Immunopathological studies indicate that the clinical significance of antibodymediated demyelination in this response varies between patients. There is no evidence at all that antibody is involved in lesion formation in 20-40% of patients [5,6], whilst in some subtypes of MS such as Devic's disease (neuromyelitis optica) antibody-mediated effects may play a dominant role in disease pathogenesis [7]. There is also a wide variation in the clinical response of MS Eur. J. Immunol. 2004. 34: 2065-2071 patients to plasma exchange [8,9]. This supports the concept that the effector mechanisms involved in disease pathogenesis can vary significantly between patients, but its relationship to antibody-mediated demyelination remains unproven.It is obvious that if we were able to identify those patients in who...

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confidence: 79%

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confidence: 88%

mentioning

confidence: 99%

“…However, the composition of the MOG-reactive antibody repertoire is also clearly influenced by both genetic [46,51] and environmental influences [47,52].…”

mentioning

confidence: 99%

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

et al. 2004

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“…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.…”

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confidence: 99%

Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein

Breithaupt

Schubart

Zander

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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M ultiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) associated with autoaggressive T and B cell responses to various myelin proteins. Myelin oligodendrocyte glycoprotein (MOG) was identified as a candidate autoantigen in MS because it induces a demyelinating antibody response in laboratory animals with experimental autoimmune encephalomyelitis (EAE), an animal model of MS (1). MOG is a quantitatively minor type I transmembrane CNS protein of unknown function with a single extracellular Ig-like domain (2). In contrast to other CNS proteins, MOG is found only in mammals and is highly conserved across species. It is expressed exclusively in the CNS by myelin-forming oligodendrocytes and is preferentially localized at the outermost surface of the myelin sheath thus directly exposed to autoantibodies in the extracellular milieu. MOG is the only antigen that can induce both a pathogenic demyelinating autoantibody response and an encephalitogenic T cell response in experimental animals (3). In MOG-induced EAE this combination of immune effector mechanisms reproduces the demyelinating pathology seen in the majority of patients with MS. The clinical relevance of autoimmune responses to MOG in MS is supported by reports that MS is associated with enhanced MOG-specific T and B cell responses and by the identification of MOG-specific antibodies associated with myelin debris in actively demyelinating MS lesions (4). Experimental evidence indicates that the autoantibody response to MOG is heterogeneous; demyelinating MOG-specific autoantibodies recognize purely conformation-dependent epitopes whereas MOG peptide-specific antibodies fail to recognize the native protein (5-7). To examine the structural basis of the pathogenic autoantibody response to MOG we determined the crystal structures of the extracellular domain of rat MOG (residues 1-126, MOG Igd ) and a complex of MOG Igd with the chimeric antigen-binding fragment (Fab) of the demyelinating MOG-specific monoclonal antibody 8-18C5 (8). Materials and Methods Preparation of Recombinant MOG Igd and the MOG Igd -(8-18C5)-FabComplex. The cDNA of the extracellular domain of rat MOG (residues 1-125) was subcloned into the His-tag expression vector pQE-12. The protein was overexpressed in inclusion bodies in Escherichia coli, refolded, and further purified by nickel-nitrilotriacetic acid affinity chromatography and gel filtration. Selenomethionine (SeMet)-labeled protein was produced in the methionine-auxotrophic E. coli strain B834(DE3) and grown in minimal medium with SeMet (0.3 mM) substituted for methionine. The cDNA of the variable domains of the mouse monoclonal antibody 8-18C5 was subcloned into the expression vector pASK107, yielding the chimeric (8-18C5)-Fab composed of the 8-18C5 variable domains, the human IgG constant domains, and the Strep tag II fused to the C terminus of the heavy chain (9, 10). (8-18C5)-Fab was produced by periplasmic secretion in E. coli and purified by streptavidin affinity chromatogr...

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Frontline: Epitope recognition on the myelin/oligodendrocyte glycoprotein differentially influences disease phenotype and antibody effector functions in autoimmune demyelination

et al. 2004

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Preliminary observations of humoral immunity against the myelin oligodendrocyte glycoprotein (MOG) in experimental allergic encephalomyelitis (EAE) and human multiple sclerosis (MS) suggest that a subset of anti-MOG autoantibodies directed against conformational epitopes is of pathogenic predominance. Here, we provide proof that in marmoset EAE, autoantibodies reactive against conformational epitopes of MOG are not only responsible for aggravating demyelination, but also an essential factor for disease dissemination in space within the central nervous system, a hallmark for typical forms of human MS. In terms of effector mechanisms, IgG deposition and complement activation occur exclusively in association with presence of these conformational antibodies, while microglial/macrophage activation appears to be a common immunopathological finding regardless of the fine determinant specificity of anti-MOG antibodies. These findings highlight for the first time the complex heterogeneity of function and pathogenicity in the polyclonal anti-MOG antibody repertoire of outbred species. Because the linear and conformational antibody determinants of MOG are shared between marmosets and humans, these results are directly relevant to understanding effector mechanisms of organ damage in MS. See accompanying Commentary http://dx

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Selective Unresponsiveness to Conformational B Cell Epitopes of the Myelin Oligodendrocyte Glycoprotein in H-2b Mice

Cited by 40 publications

References 31 publications

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

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

Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein

Frontline: Epitope recognition on the myelin/oligodendrocyte glycoprotein differentially influences disease phenotype and antibody effector functions in autoimmune demyelination

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