ReviewAnti-MOG antibody: The history, clinical phenotype, and pathogenicity of a serum biomarker for demyelination
Introduction
Myelin oligodendrocyte glycoprotein (MOG) is a member of the immunoglobulin superfamily and a component of myelin, making up less than 0.05% of total myelin proteins [1], [2], [3], [4]. Full length human MOG is made up of 218 amino acids and is expressed exclusively in the central nervous system (CNS). Its relatively late expression in neural development suggests that it may serve as an important surface marker of oligodendrocyte maturation, as well as playing a role in myelin integrity, adhesion and cell surface interactions [3], [5]. MOG has been studied as a target CNS autoantigen for both humoral and cell-mediated immune responses. The putative role of MOG and antibodies to MOG in CNS demyelination has been explored for decades, with immunization using MOG inducing experimental autoimmune encephalomyelitis (EAE), an important animal model of multiple sclerosis (MS). MOG is sequestered to the external surface of myelin and the plasma membranes of oligodendrocytes [1], with its highest antigen density in the outermost lamellae of myelin sheaths, thereby serving as a biologically plausible and accessible antigen target for the action of autoantibodies [1], [6]. Herein we explore the evolution of MOG as a candidate CNS autoantigen in demyelination, the methodological complexities of MOG antibody detection, and its role as a potential biomarker in human disease. Furthermore, we highlight the existing deficiencies in our understanding of the pathophysiological mechanisms and classification of MOG antibody-associated autoimmunity.
Section snippets
The evolution of MOG as a candidate autoantigen in demyelination
In order to evaluate anti-MOG antibodies in the context of the extensive published literature on MOG and demyelination, several factors need to be considered. Firstly, it has been animal studies, particularly the EAE model, which have led the way to identify MOG as a candidate autoantigen. The EAE model is a complex system with a strong T cell driven component in which anti-MOG antibodies are produced, but do not necessarily transfer disease. Secondly, it is important to note that while
MOG antibody detection in MS
Given the interest in MOG antibody-associated demyelination in animal studies, the evaluation of anti-MOG antibodies in patients with MS has been of interest for many years. Using Western blots and ELISA, a number of early studies found the presence of antibodies to recombinant human MOG or native full length mouse MOG in the serum and CSF of patients with MS [33], [34], [35], [36], [37], [38], [39]. One study [40] evaluated 103 patients with clinically isolated syndrome (CIS). Using
Introduction of cell-based assays
In cell-based assays, native human MOG is transfected or transduced in mammalian cell lines. Surface MOG expressing cells are incubated with the sample to be tested, and then with a secondary anti-human IgG antibody, followed by microscopy or flow cytometry to qualitatively or quantitatively analyze antibody binding [55]. The MOG antigen is therefore presented to the autoantibody repertoire in its native state, with positive antibodies identified using this methodology more likely to have
The MOG antibody binding epitope in human demyelination using conformational MOG
Based on the evidence gathered to highlight the importance of utilizing native MOG in its conformational state, the epitope determination of native human MOG is likely to provide more insights than using linear MOG peptides. Importantly, the epitope binding site in rodents and humans may be different. Mayer et al. [122] identified that the amino acids (H103;S104) bound by the 8-18C5 mAb were in fact not the most frequently recognized residues in humans. However, this study also showed that the
Insights into possible pathogenic mechanisms of anti-MOG antibodies
It is yet to be established whether anti-MOG antibodies have a pathogenic role in demyelinating disease, or whether their presence is an epiphenomenon secondary to myelin destruction. The difference between epitopes in humans and rodents raises the question of whether human anti-MOG antibodies are indeed pathogenic as much of the evidence in animal studies supportive of pathogenicity has been obtained using the 8-18C5 mAb, which binds to an epitope that most human anti-MOG antibodies do not
Detection of anti-MOG antibodies in CSF versus serum
MOG antibody detection has been found to be more sensitive in serum when compared to CSF. One study found that, in anti-MOG IgG seronegative patients, the corresponding CSF samples were negative; in the low titer range anti-MOG antibodies were only present in the serum but not in the CSF; but in patients with serum titer values greater than or equal to 1:640, there was detectable reactivity to MOG in the CSF, suggesting a peripheral production of MOG specific autoantibodies [64]. Similarly in
The nomenclature of MOG and AQP4 antibody-associated demyelination
The recent finding of MOG antibodies in patients with the clinical syndrome of NMO/NMOSD has led to some controversy regarding the nomenclature and classifications of these patients. Using the revised diagnostic criteria for NMO [81], it is possible for a patient to be diagnosed with “definite NMO” without being AQP4 antibody-positive. As a consequence, both MOG and AQP4 antibody-positive patients, who frequently present with prominent ON and/or TM, are intuitively distinguished from MS and
Take-home messages
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Animal models of experimental autoimmune encephalomyelitis have been crucial in establishing the importance of MOG as an autoantigen in demyelination. However, due to differences in epitope binding between species, the pathogenicity of these autoantibodies in humans requires further exploration.
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Live cell-based assays using full length human MOG as the antigen have been shown to be the gold standard for the detection of biologically relevant MOG antibodies in human demyelination.
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In adults,
Acknowledgements
This work was supported by Multiple Sclerosis Research Australia, the Trish MS Research Foundation (Australia), the Star Scientific Foundation (Australia), the Petre Foundation (Australia), and the National Health and Medical Research Council (Australia).
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