Myelin oligodendrocyte glycoprotein autoantibodies (MOG-Ab) have been identified in patients with various central nervous system (CNS) demyelinating diseases, including single or recurrent optic neuritis (ON), transverse myelitis (TM), acute disseminated encephalomyelitis (ADEM), encephalitis, and brainstem encephalitis (1, 2). MOG-Ab-associated disease (MOGAD) is considered a distinct condition from multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD), yet the factors contributing to its clinical diversity remain unclear. The age at onset of MOGAD was known to be a relevant clinical factor that children can have ADEM-like brain lesions more frequently, whereas adult patients tend to present with optic neuritis (3). Further, MOG-Ab positivity has been linked to the clinical course of MOGAD; children with a monophasic clinical course become MOG-Ab negative earlier than those with relapsing courses (4).

The detection of MOG-Ab is commonly performed using a live cell-based immunoassay with full-length human MOG by indirect immunofluorescence or flow cytometry methods (5). Given that these methods allow for the expression of MOG in its native conformation, the conformational epitopes of MOG could be important for the detection of specific human MOG-Ab (1, 6). The epitope most frequently recognized by MOG-Ab is known to be Proline42 (P42) within the CC’-loop of the extracellular MOG domain (6), however, the clinical implications of different epitopes recognized by MOG-Ab are largely unknown.

In this study, we aimed to establish an in-house cell-based immunoassay for the detection of different epitopes of MOG-Ab and evaluate the clinical characteristics of patients with MOGAD in relation to epitope reactivity.

In this study, we developed an in-house cell-based immunoassay to identify distinct epitopes of MOG-Ab. We also analyzed the clinical characteristics of patients with MOG-Ab who had varying binding reactivity to the epitopes of the MOG protein. This is the first study to investigate the epitopes of MOG-Ab in Korean patients with MOG-associated disorder (MOGAD) and examine the relationship between MOG-Ab epitopes and the clinical characteristics of MOGAD.

The clinical significance of MOG-Ab has been studied thoroughly with the discovery of reliable cell-based immunoassay for MOG-Ab using full-length human MOG protein and IgG1 antibody (9). The detection of MOG-Ab became an essential part of the differential diagnosis of CNS demyelinating diseases (5, 10), and it has helped to expand our understanding of the clinical diversity of MOGAD; the clinical syndromes of MOGAD include single/recurrent or bilateral ON, TM, ADEM, brain or brainstem syndrome, and cortical encephalitis (2, 5, 11–13). In our study, patients with MOGAD also showed diverse clinical syndromes, and ON was the most common presenting clinical syndrome (38/55, 69.1%), which was in line with the results of previous studies (3, 14, 15). Double seropositive cases, where patients have both aquaporin-4 autoantibody and MOG-Ab are rarely reported (16, 17), but there were no such cases in our study. The preventive treatment profiles in our patients were consistent with previous international expert survey reports, with azathioprine and mycophenolate mofetil being the most commonly used drugs for maintenance (18). The MOG-Ab antibody titer may indicate severe relapses, but it is not necessarily indicative of long-term prognosis. Instead, it may be correlated with the time interval between the recent relapse and blood sampling. Negative seroconversion of MOG-Ab may indicate a lower activity of the disease (4, 19, 20).

In terms of the epitope of MOG-Ab, the P42 position in the MOG protein is known to be a major target of human MOG-Ab (21, 22). However, the clinical diversity associated with different MOG-Ab epitopes has not been extensively studied. One large study found that adults with relapsing ON were less reactive to the P42 position, while most MOG-Ab in pediatric patients recognized the P42 position. Our study also found that the P42 position in the MOG protein was the most frequently targeted by MOG-Ab, and patients with a monophasic clinical course and childhood-onset patients were only present in the group that showed reactivity to the P42 position (21). These findings are in line with previous reports; other clinical characteristics, including the total number of attacks, clinical presentation at onset, and phenotype of MOGAD, were not different according to the presence of reactivity to the P42 site. However, in our study, 41.7% of the samples showed no decreased reactivity to human MOG variants, which is a higher proportion than in previous reports conducted in Western countries (6). This may be due to the low affinity of MOG-Ab to certain epitopes, and the possibility of human leukocyte antigen (HLA) variation across different ethnic groups; there was no strong association with MOG-Ab in UK population, but the study conducted in the Chinese pediatric-onset cohort suggested the association between DQB1*05:02–DRB1*16:02 haplotype and MOGAD (23, 24).

The identification of epitopes in autoimmune disorders could be important. Knowledge of the autoantibody epitope target could lead to better diagnosis with precise testing and the development of epitope-specific medicines (25). Further large-scale studies that include clinical analysis of MOG-Ab and their epitopes are necessary to fully understand the clinical significance of MOG-Ab epitopes in patients with MOGAD.

Our study has several limitations that should be considered when interpreting our findings. First, the demographic profiles of enrolled patients were not controlled, as patients were recruited from a neurology clinic, which may have influenced the clinical characteristics of the MOGAD in this study and limited the number of childhood-onset patients. This limits the generalizability of our results. Second, a limited number of samples were collected due to patient consent, which may have restricted the ability to draw concrete conclusions about the relationship between the epitope and clinical features. Despite these limitations, this is the first study to examine the clinical significance of MOG-Ab epitopes in Korean patients, which is a strength of this study. However, further large-scale studies of MOG-Ab epitopes in Korean patients are needed. Third, this study is a cross-sectional analysis of MOG-Ab epitopes, and we did not evaluate the temporal stability of the epitopes or the change in the titer of MOG-IgG. Although a previous study showed that reactivity to P42 remained unchanged after 9 years of follow-up, temporal changes in the titers could be a crucial factor for predicting the clinical course of the disease (21, 26). Fourth, this study did not evaluate the radiological phenotypes and their correlation with P42 binding reactivity, although radiological features are one of the crucial clinical aspects of patients with MOGAD. Additionally, two of the patients included in the analysis met the diagnostic criteria of MS and were receiving DMT treatment at the time of sampling. Although MOG antibodies can be found in patients who have been diagnosed with MS, the antibodies tend to be more prevalent in children than in adults and can wane over time (27). Given the lack of subsequent antibody monitoring, our results should be approached with caution. Lastly, this study only evaluated MOG-Ab epitopes using serum samples, but recent studies have reported that some patients with MOGAD are positive for MOG-Ab only in their cerebrospinal fluid (CSF) samples, and an intra-individual heterogeneity of epitopes targeted by MOG-Ab from MOG-specific B cells was reported (28, 29). This suggests that there may be different sources of the production of MOG-Ab. Therefore, evaluations of MOG-Ab epitopes using both serum and CSF samples in patients with MOGAD may be necessary.

In conclusion, we developed an in-house cell-based immunoassay to analyze the epitopes of MOG-Ab in Korean patients with MOGAD. The results showed that the P42 site on the MOG protein is the primary target of MOG-Ab in Korean patients, and may have a correlation with the childhood-onset and monophasic clinical course of MOGAD. Further studies are needed to determine the predictive value of MOG-Ab and its epitopes.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the institutional review board of the Samsung Medical Center. The patients/participants provided their written informed consent to participate in this study.

JS: conceptualization, data investigation and analysis, visualization, and manuscript writing and editing. MJ: data curation and methodology. YC, HJ, HL, SK, and J-HM: data collection. E-SK: supervision and methodology. BK: conceptualization, data collection, data analysis, supervision, and manuscript review and editing. All authors contributed to the article and approved the submitted version.

This research was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Korean government (NRF-2019R1F1A1062978) and Soonchunhyang University Research Fund.

J-HM is funded by and has received research support from the National Research Foundation of Korea and SMC Research and Development Grant. She has lectured, consulted, and received honoraria from Bayer Schering Pharma, Merk, Biogen Idec, Sanofi, UCB, Samsung Bioepis, Mitsubishi Tanabe, Celltrion, Roche, and Janssen. BK has received honoraria and/or consulting fees from Bayer, Genzyme, Merk, Celltrion, Astellas, Genuv, and Corestem.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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