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

Büdingen, Hans‐Christian von; Hauser, Stephen L.; Ouallet, J.-C.; Tanuma, Naoyuki; Menge, Til; Genain, Claude P.

doi:10.1002/eji.200425050

Cited by 100 publications

(102 citation statements)

References 41 publications

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“…However, it is possible that the epitopes recognized by MS-mAb may depend on their intact conformation and/or posttranslational modifications. In the case of anti-MOG antibodies, for example, it has been shown that demyelinating anti-MOG antibodies recognize conformational epitopes [7] or glycosylated MOG [28]. Furthermore, epitopes of lipids, which have also been described to be target antigens of humoral immune responses in MS [39,40], would not be appropriately represented by Western blotting or phage display techniques.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, clonally restricted Ig genes suggesting the presence of an antigendriven immune response have been found in MS lesion tissue [4]. In animal models of MS, namely experimental autoimmune encephalomyelitis in rodents and primates, CNS myelin-specific autoantibodies against myelin oligodendrocyte glycoprotein (MOG) have been demonstrated to possess myelin-destructive potential [5][6][7]. Antibody responses against MOG and other myelin proteins (e.g.…”

Section: Introductionmentioning

confidence: 99%

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Clonally expanded plasma cells in the cerebrospinal fluid of MS patients produce myelin‐specific antibodies

et al. 2008

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Clonally expanded plasma cells (cePC) and their presumed products, oligoclonal immunoglobulin G bands (OCB), are characteristic findings in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS). While cePC and OCB strongly suggest an involvement of B cell-dependent immune mechanisms in the pathogenesis of MS, their actual pathological relevance and target antigens remain unknown. To further understand the potential role played by cePC, we generated a panel of monoclonal antibodies (MS-mAb) from CSF-derived cePC from four patients with early or definite MS. Single-cell RT-PCR of correctly paired heavy and light chain immunoglobulin genes from individual cePC ensured the subsequent resurrection of their original antigen specificity. Immunofluorescence stainings of MS lesion tissue with MS-mAb revealed myelin reactivity in the cePC repertoire of all four patients and intracellular filament reactivity in one patient. While myelin staining by MS-mAb was only rarely detectable in non-MS CNS white matter tissue, it was greatly enhanced at the edge of demyelinating lesions in MS brain tissue. Our findings provide conclusive evidence for the presence of an antigen-driven B cell response in the CSF of MS patients directed against epitopes present in areas of myelin degradation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Clonally expanded plasma cells in the cerebrospinal fluid of MS patients produce myelin‐specific antibodies

et al. 2008

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“…Recent studies suggest that this lack of concordance between different studies is due to the inability of most assay methods to differentiate between pathogenic (demyelinating) and nonpathogenic MOG-specific Abs. Experimental animals mount a complex Ab response to the extracellular domain of MOG (MOG ex ) that targets both linear as well as discontinuous, conformational epitopes (22)(23)(24). Crucially, only conformation-dependent MOG-specific Abs are able to initiate demyelination in EAE (22)(23)(24).…”

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confidence: 99%

“…Experimental animals mount a complex Ab response to the extracellular domain of MOG (MOG ex ) that targets both linear as well as discontinuous, conformational epitopes (22)(23)(24). Crucially, only conformation-dependent MOG-specific Abs are able to initiate demyelination in EAE (22)(23)(24). In contrast, Abs directed against linear MOG ex -peptide epitopes are unable to bind to the native protein at the membrane surface and fail to induce any significant pathology in vivo.…”

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confidence: 99%

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

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Pellkofer

et al. 2008

The Journal of Immunology

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Conformational epitopes of myelin oligodendrocyte glycoprotein (MOG) provide a major target for demyelinating autoantibodies in experimental autoimmune encephalomyelitis and recent studies indicate that a similar situation may exist in multiple sclerosis. We recently solved the crystal structure of the extracellular domain of MOG (MOGex) in complex with a Fab derived from the demyelinating mAb 8-18C5 and identified the conformational 8-18C5 epitope on MOG that is dominated by the surface exposed FG loop of MOG. To determine the importance of this epitope with regard to the polyclonal Ab response to MOGex we investigated the effects of mutating His103 and Ser104, the two central amino acids of the FG loop, on Ab binding. Mutation of these two residues reduced binding of a panel of eight demyelinating conformation-dependent mAbs to <20% compared with binding to wild-type MOGex, whereas substitution of amino acids that do not contribute to the 8-18C5 epitope had only a minor effect on Ab binding. The same restriction was observed for the polyclonal MOG-specific Ab response of MOG DNA-vaccinated BALB/c and SJL/J mice. Our data demonstrate that the pathogenic anti-MOG Ab response primarily targets one immunodominant region centered at the FG loop of MOG. Comparison of the structure of MOGex with the structures of related IgV-like domains yields a possible explanation for the focused Ab response.

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“…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. If this is the case, this antibody response (together with antibodies recognizing other exposed determinants) may influence lesional pathology by accelerating the clearance of myelin debris from the lesions by activated macrophages.However, the MOG-specific antibody response in patients with MS recognizes a far more complex repertoire of linear epitopes [33,47] than marmosets [36] or rodents [26-28, 46, 48] do. This peptide-specific response in man does not recognize the native protein [33] and is therefore unlikely to mediate demyelination in vivo, but further studies are required to determine whether or not these responses have any other pathological significance.…”

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confidence: 99%

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

Cited by 100 publications

References 41 publications

Clonally expanded plasma cells in the cerebrospinal fluid of MS patients produce myelin‐specific antibodies

Clonally expanded plasma cells in the cerebrospinal fluid of MS patients produce myelin‐specific antibodies

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

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

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