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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2017

Open Access 01-12-2017 | Research

Human antibodies against the myelin oligodendrocyte glycoprotein can cause complement-dependent demyelination

Authors: Patrick Peschl, Kathrin Schanda, Bleranda Zeka, Katherine Given, Denise Böhm, Klemens Ruprecht, Albert Saiz, Andreas Lutterotti, Kevin Rostásy, Romana Höftberger, Thomas Berger, Wendy Macklin, Hans Lassmann, Monika Bradl, Jeffrey L. Bennett, Markus Reindl

Published in: Journal of Neuroinflammation | Issue 1/2017

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Abstract

Background

Antibodies to the myelin oligodendrocyte glycoprotein (MOG) are associated with a subset of inflammatory demyelinating diseases of the central nervous system such as acute disseminated encephalomyelitis and neuromyelitis optica spectrum disorders. However, whether human MOG antibodies are pathogenic or an epiphenomenon is still not completely clear. Although MOG is highly conserved within mammals, previous findings showed that not all human MOG antibodies bind to rodent MOG. We therefore hypothesized that human MOG antibody-mediated pathology in animal models may only be evident using species-specific MOG antibodies.

Methods

We screened 80 human MOG antibody-positive samples for their reactivity to mouse and rat MOG using either a live cell-based assay or immunohistochemistry on murine, rat, and human brain tissue. Selected samples reactive to either human MOG or rodent MOG were subsequently tested for their ability to induce complement-mediated damage in murine organotypic brain slices or enhance demyelination in an experimental autoimmune encephalitis (EAE) model in Lewis rats. The MOG monoclonal antibody 8-18-C5 was used as a positive control.

Results

Overall, we found that only a subset of human MOG antibodies are reactive to mouse (48/80, 60%) or rat (14/80, 18%) MOG. Purified serum antibodies from 10 human MOG antibody-positive patients (8/10 reactive to mouse MOG, 6/10 reactive to rat MOG), 3 human MOG-negative patients, and 3 healthy controls were tested on murine organotypic brain slices. Purified IgG from one patient with high titers of anti-human, mouse, and rat MOG antibodies and robust binding to myelin tissue produced significant, complement-mediated myelin loss in organotypic brain slices, but not in the EAE model. Monoclonal 8-18-C5 MOG antibody caused complement-mediated demyelination in both the organotypic brain slice model and in EAE.

Conclusion

This study shows that a subset of human MOG antibodies can induce complement-dependent pathogenic effects in a murine ex vivo animal model. Moreover, a high titer of species-specific MOG antibodies may be critical for demyelinating effects in mouse and rat animal models. Therefore, both the reactivity and titer of human MOG antibodies must be considered for future pathogenicity studies.
Appendix
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Metadata
Title
Human antibodies against the myelin oligodendrocyte glycoprotein can cause complement-dependent demyelination
Authors
Patrick Peschl
Kathrin Schanda
Bleranda Zeka
Katherine Given
Denise Böhm
Klemens Ruprecht
Albert Saiz
Andreas Lutterotti
Kevin Rostásy
Romana Höftberger
Thomas Berger
Wendy Macklin
Hans Lassmann
Monika Bradl
Jeffrey L. Bennett
Markus Reindl
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2017
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-017-0984-5

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