Immunoglobulin A Antibodies Against Myelin Oligodendrocyte Glycoprotein in a Subgroup of Patients With Central Nervous System Demyelination

Ana Beatriz Ayroza Galvão Ribeiro Gomes; Laila Kulsvehagen; Patrick Lipps; Alessandro Cagol; Nuria Cerdá-Fuertes; Tradite Neziraj; Julia Flammer; Jasmine Lerner; Anne-Catherine Lecourt; Nina de Oliveira S Siebenborn; Rosa Cortese; Sabine Schaedelin; Vinicius Andreoli Schoeps; Aline de Moura Brasil Matos; Natalia Trombini Mendes; Clarissa dos Reis Pereira; Mario Luiz Ribeiro Monteiro; Samira Luisa dos Apóstolos-Pereira; Patrick Schindler; Claudia Chien; Carolin Schwake; Ruth Schneider; Thivya Pakeerathan; Orhan Aktas; Urs Fischer; Matthias Mehling; Tobias Derfuss; Ludwig Kappos; Ilya Ayzenberg; Marius Ringelstein; Friedemann Paul; Dagoberto Callegaro; Jens Kuhle; Athina Papadopoulou; Cristina Granziera; Anne-Katrin Pröbstel

doi:10.1001/jamaneurol.2023.2523

. 2023 Aug 7;80(9):989–995. doi: 10.1001/jamaneurol.2023.2523

Immunoglobulin A Antibodies Against Myelin Oligodendrocyte Glycoprotein in a Subgroup of Patients With Central Nervous System Demyelination

Ana Beatriz Ayroza Galvão Ribeiro Gomes ^1,^2,^3,⁴, Laila Kulsvehagen ^1,^2,³, Patrick Lipps ^1,^2,³, Alessandro Cagol ^1,^3,⁶, Nuria Cerdá-Fuertes ¹, Tradite Neziraj ^1,^2,³, Julia Flammer ^1,^2,³, Jasmine Lerner ^1,^2,³, Anne-Catherine Lecourt ^1,^2,³, Nina de Oliveira S Siebenborn ^1,^3,^6,⁷, Rosa Cortese ⁸, Sabine Schaedelin ^1,^3,⁶, Vinicius Andreoli Schoeps ⁴, Aline de Moura Brasil Matos ^4,⁹, Natalia Trombini Mendes ⁴, Clarissa dos Reis Pereira ⁵, Mario Luiz Ribeiro Monteiro ⁵, Samira Luisa dos Apóstolos-Pereira ⁴, Patrick Schindler ^10,^11,¹², Claudia Chien ^10,^11,¹³, Carolin Schwake ¹⁴, Ruth Schneider ¹⁴, Thivya Pakeerathan ¹⁴, Orhan Aktas ¹⁵, Urs Fischer ¹, Matthias Mehling ^1,^2,³, Tobias Derfuss ^1,^2,³, Ludwig Kappos ^3,⁶, Ilya Ayzenberg ¹⁴, Marius Ringelstein ^15,¹⁶, Friedemann Paul ^10,^11,¹², Dagoberto Callegaro ⁴, Jens Kuhle ^1,^2,³, Athina Papadopoulou ^1,^3,⁶, Cristina Granziera ^1,^3,⁶, Anne-Katrin Pröbstel ^1,^2,^3,^✉

¹Department of Neurology, University Hospital Basel and University of Basel, Basel, Switzerland

²Departments of Biomedicine and Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland

³Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel and University of Basel, Basel, Switzerland

⁴Departamento de Neurologia, Instituto Central, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil

⁵Departamento de Oftalmologia e Laboratorio de Oftalmologia (LIM/33), Instituto Central, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil

⁶Translational Imaging in Neurology (ThINk) Basel, Department of Biomedical Engineering, University Hospital Basel and University of Basel, Basel, Switzerland

⁷Medical Imaging Analysis Center (MIAC), University of Basel, Basel, Switzerland

⁸Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy

⁹Instituto de Medicina Tropical de Sao Paulo, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil

¹⁰Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Neurocure Cluster of Excellence, Berlin, Germany

¹¹Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Max Delbrueck Center for Molecular Medicine, Experimental and Clinical Research Center, Berlin, Germany

¹²Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Psychiatry and Neurosciences, Berlin, Germany

¹³Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institut für Integrative Neuroanatomie, Berlin, Germany

¹⁴Department of Neurology, St Josef-Hospital, Ruhr University Bochum, Bochum, Germany

¹⁵Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

¹⁶Center for Neurology and Neuropsychiatry, LVR-Klinikum, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

Accepted for Publication: April 19, 2023.

Published Online: August 7, 2023. doi:10.1001/jamaneurol.2023.2523

^✉

Corresponding Author: Anne-Katrin Pröbstel, MD, University Hospital of Basel, Petersgraben 4, CH-4031 Basel, Switzerland (anne-katrin.proebstel@usb.ch).

Author Contributions: Dr Pröbstel had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr Ayroza Galvão Ribeiro Gomes and Ms Kulsvehagen contributed equally as co–first authors.

Concept and design: Ayroza Galvão Ribeiro Gomes, Kulsvehagen, Mehling, Derfuss, Papadopoulou, Pröbstel.

Acquisition, analysis, or interpretation of data: Ayroza Galvão Ribeiro Gomes, Kulsvehagen, Lipps, Cagol, Cerdá-Fuertes, Neziraj, Flammer, Lerner, Lecourt, de Oliveira S. Siebenborn, Cortese, Schaedelin, Andreoli Schoeps, de Moura Brasil Matos, Trombini Mendes, dos Reis Pereira, Ribeiro Monteiro, Apóstolos-Pereira, Schindler, Chien, Schwake, Schneider, Pakeerathan, Aktas, Fischer, Mehling, Kappos, Ayzenberg, Ringelstein, Paul, Callegaro, Kuhle, Papadopoulou, Granziera, Pröbstel.

Drafting of the manuscript: Ayroza Galvão Ribeiro Gomes, Kulsvehagen, Cerdá-Fuertes, Paul, Papadopoulou, Granziera, Pröbstel.

Critical review of the manuscript for important intellectual content: Ayroza Galvão Ribeiro Gomes, Kulsvehagen, Lipps, Cagol, Cerdá-Fuertes, Neziraj, Flammer, Lerner, Lecourt, de Oliveira S. Siebenborn, Cortese, Schaedelin, Andreoli Schoeps, de Moura Brasil Matos, Trombini Mendes, dos Reis Pereira, Ribeiro Monteiro, Apóstolos-Pereira, Schindler, Chien, Schwake, Schneider, Pakeerathan, Aktas, Fischer, Mehling, Derfuss, Kappos, Ayzenberg, Ringelstein, Callegaro, Kuhle, Papadopoulou, Granziera, Pröbstel.

Statistical analysis: Ayroza Galvão Ribeiro Gomes, Kulsvehagen, Cerdá-Fuertes, Schaedelin, Paul, Kuhle, Pröbstel.

Obtained funding: Apóstolos-Pereira, Callegaro, Kuhle, Granziera, Pröbstel.

Administrative, technical, or material support: Lipps, Lecourt, de Moura Brasil Matos, dos Reis Pereira, Apóstolos-Pereira, Schindler, Chien, Schneider, Ayzenberg, Ringelstein, Callegaro, Papadopoulou, Granziera, Pröbstel.

Supervision: Kulsvehagen, Ribeiro Monteiro, Apóstolos-Pereira, Mehling, Callegaro, Granziera, Pröbstel.

Other–managing clinical data: Lerner.

Other–image analysis: de Oliveira S. Siebenborn.

Conflict of Interest Disclosures: Dr Ayroza Galvão Ribeiro Gomes reported grants from Roche during the conduct of the study. Dr de Moura Brasil Matos reported grants from Hoffmann La Roche outside the submitted work. Dr Pereira reported grants from CNPq–Conselho Nacional de Desenvolvimento Científico e Tecnológico (308172/2018-3) during the conduct of the study. Dr Ribeiro Monteiro reported grants from CNPq–Conselho Nacional de Desenvolvimento Científico e Tecnológico during the conduct of the study. Dr Schindler reported nonfinancial support from UCB Pharma outside the submitted work. Dr Chien reported grants from Novartis and Alexion during the conduct of the study and nonfinancial support as a member from the Canadian Institutes of Health Research Standing Committee on Science outside the submitted work. Dr Schwake reported speaker honoraria from Alexion and travel support from Novartis and UCB outside the submitted work. Dr Schneider reported research grant support from Novartis and speaker honoraria from Roche and Alexion outside the submitted work. Dr Aktas reported personal fees from Alexion, Almirall, Horizon, Novartis, and Roche outside the submitted work and serving as steering committee member and co-coordinator of the German Neuromyelitis Optica Study Group (NEMOS). Dr Fischer reported grants to their institution from Medtronic, Stryker, Rapid Medical, Penumbra, and Phenox; consultant fees paid to their institution from Medtronic, Stryker, and CSL Behring outside the submitted work; participation in an advisory board for Alexion/Portola, Boehringer Ingelheim, Biogen, and Acthera (fees paid to institution); member of a clinical event committee of the COATING study (Phenox); member of the data and safety monitoring committee of the TITAN, LATE_MT, and IN EXTREMIS trials; and vice-presidency of the Swiss Neurological Society. Dr Mehling reported grants from the Swiss National Science Foundation, Roche, and Merck and fees for advisory board activities paid to their institution from Merck, Roche, Novartis, and Biogen outside the submitted work. Dr Derfuss reported grants from Alexion, Novartis, and Roche and fees paid to their institution for membership in advisory boards, data and safety monitoring boards, and/or steering committees from Actelion, Biogen, Celgene, Sanofi, GeNeuro, Merck, MedDay, Roche, Alexion, and Novartis outside the submitted work. Dr Kappos reported consultant, speaking, advisory board, and/or steering committee fees from Bayer, Biogen, Bristol Myers Squibb, Celltrion, df-mp Molnia & Pohlman, Eli Lilly (Suisse), EMD Serono, F&U confirm, Genentech, GlaxoSmithKline, Janssen, Japan Tobacco, Merck (Schweiz), Minoryx Therapeutics, Novartis, Roche, Santhera Pharmaceuticals, Shionogi, and Wellmera, grants from the European Union, Innosuisse, and Swiss National Science Foundation; and product license fees from Neurostatus outside the submitted work. Dr Ayzenberg reported personal fees from Roche, Alexion, Merck, Horison, and Sanofi and grants from Diamed from outside the submitted work. Dr Ringelstein reported personal fees from Alexion, Horizon, Roche, and Biogen outside the submitted work. Dr Callegaro reported being on the board of BCTRIMS, the Brazilian commitment for treatment and research in multiple sclerosis and related diseases, and serving as coordinator of the Neuroimmunology Center, Hospital das Clínicas, São Paulo University. Dr Kuhle reported grants from the Swiss MS Society, Swiss National Science Foundation, Novartis, Biogen, Merck, Bristol Myers Squibb, and Roche outside the submitted work. Dr Papadopoulou reported grants from University of Basel, grants from University Hospital of Basel, and grants from Swiss Multiple Sclerosis Society during the conduct of the study; advisory board and/or speaking fees to their institution from AbbVie, Eli Lilly, Lundbeck, and TEVA and conference travel support from TEVA outside the submitted work. Dr Pröbstel reported advisory board and/or consultant fees from Roche, Biogen, and Novartis outside the submitted work. No other disclosures were reported.

Funding/Support: The study was funded by an ECTRIMS Clinical Fellowship and a Swiss Government Excellence Scholarship (Dr Ayroza Galvão Ribeiro Gomes), an individual travel grant from the Amsterdam University Fund and a Trygve Tellefsens Legat Scholarship (Ms Kulsvehagen), a doctoral fellowship from the Goldschmidt-Jacobson Stiftung Foundation (Dr Lipps), a Young Talents in Clinical Research Fellowship from the Swiss Academy of Medical Sciences (Dr Flammer), the Swiss National Science Foundation (SNF Eccellenza Professorship: PCEFP3_194609), the National MS Society (FG-1708-28871), the Fondation Pierre Mercier pour la Science, the Propatient Foundation, the Goldschmidt Jacobson Foundation, and the Gottfried and Julia Bangerter Rhyner Foundation (all to Dr Pröbstel).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2.

Additional Contributions: We are grateful to Klaus Dornmair, PhD, Ludwig Maximilian University of Munich, Germany, for providing us with the humanized 8-18C5 antibody. We thank Christian G. Bien, MD, Laboratory Krone, Bad Salzuflen, Germany, for performing control testing for aquaporin-4 IgG antibodies in a subset of the samples (for which they were compensated), and Diagnósticos da America, São Paulo, Brazil, for processing the serum samples of the cohort from the University of São Paulo. We further thank Sebastian Thielemann, MD, and Bettina Fischer-Barnicol, MD, both University of Basel and University Hospital of Basel, and Jose Albino da Paz, MD, PhD, and Renata Barbosa Paolilo, MD, PhD, both University of São Paulo, for their help with patient recruitment, and Angeline Wettig, University of Basel and University Hospital of Basel, for her valuable aid in sample acquisition. Finally, we thank all patients for their participation.

^✉

Corresponding author.

PMCID: PMC10407763 PMID: 37548987

This cross-sectional study examines laboratory and imaging data for patients with demyelinating central nervous system disease to investigate the frequency of MOG-IgA and associated clinical features.

Key Points

Question

What is the frequency of immunoglobulin (Ig) A antibodies against myelin oligodendrocyte glycoprotein (MOG) in patients with central nervous system (CNS) demyelination, and do these antibodies associate with a distinct clinical phenotype?

Findings

In this longitudinal study, a subgroup of patients with demyelinating disorders was double-seronegative for aquaporin 4 (AQP4) IgG and MOG-IgG but seropositive for MOG-IgA. These patients presented with frequent myelitis and brainstem syndrome, infrequent optic nerve involvement, and a low percentage of cerebrospinal fluid–specific oligoclonal band positivity.

Meaning

The findings suggest that MOG-IgA may be a novel diagnostic biomarker in a distinct subgroup of AQP4-/MOG-IgG double-seronegative patients with CNS demyelination.

Abstract

Importance

Differential diagnosis of patients with seronegative demyelinating central nervous system (CNS) disease is challenging. In this regard, evidence suggests that immunoglobulin (Ig) A plays a role in the pathogenesis of different autoimmune diseases. Yet little is known about the presence and clinical relevance of IgA antibodies against myelin oligodendrocyte glycoprotein (MOG) in CNS demyelination.

Objective

To investigate the frequency of MOG-IgA and associated clinical features in patients with demyelinating CNS disease and healthy controls.

Design, Setting, and Participants

This longitudinal study comprised 1 discovery and 1 confirmation cohort derived from 5 centers. Participants included patients with suspected or confirmed demyelinating diseases and healthy controls. MOG-IgA, MOG-IgG, and MOG-IgM were measured in serum samples and cerebrospinal fluid (CSF) of patients, who were assessed from September 2012 to April 2022.

Main Outcomes and Measures

Frequency and clinical features of patients who were seropositive for MOG-IgA and double-seronegative for aquaporin 4 (AQP4) IgG and MOG-IgG.

Results

After the exclusion of 5 participants with coexisting AQP4-IgG and MOG-IgA, MOG-IgG, and/or MOG-IgM, 1339 patients and 110 healthy controls were included; the median follow-up time was 39 months (range, 0-227 months). Of included patients with isolated MOG-IgA, 11 of 18 were female (61%), and the median age was 31.5 years (range, 3-76 years). Among patients double-seronegative for AQP4-IgG and MOG-IgG (1126/1339; 84%), isolated MOG-IgA was identified in 3 of 50 patients (6%) with neuromyelitis optica spectrum disorder, 5 of 228 patients (2%) with other CNS demyelinating diseases, and 10 of 848 patients (1%) with multiple sclerosis but in none of the healthy controls (0/110). The most common disease manifestation in patients seropositive for isolated MOG-IgA was myelitis (11/17 [65%]), followed by more frequent brainstem syndrome (7/16 [44%] vs 14/75 [19%], respectively; P = .048), and infrequent manifestation of optic neuritis (4/15 [27%] vs 46/73 [63%], respectively; P = .02) vs patients with MOG-IgG. Among patients fulfilling 2017 McDonald criteria for multiple sclerosis, MOG-IgA was associated with less frequent CSF-specific oligoclonal bands (4/9 [44%] vs 325/351 [93%], respectively; P < .001) vs patients with multiple sclerosis who were MOG-IgG/IgA seronegative. Further, most patients with isolated MOG-IgA presented clinical attacks after recent infection or vaccination (7/11 [64%]).

Conclusion and Relevance

In this study, MOG-specific IgA was identified in a subgroup of patients who were double-seronegative for AQP4-/MOG-IgG, suggesting that MOG-IgA may be a novel diagnostic biomarker for patients with CNS demyelination.

Introduction

The identification of aquaporin 4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G (IgG) along with the description of their disease entities^1,2,3,4,5 has paved the way for serological diagnoses in patients with central nervous system (CNS) demyelination,⁶ including neuromyelitis optica spectrum disorder (NMOSD)^6,7 and MOG antibody–associated disease.^4,8 Yet the differential diagnosis and management of patients with AQP4-/MOG-IgG double-seronegative disease remains a challenge.

Recent evidence suggests that IgA may play a role in the pathogenesis of inflammatory disorders.^9,10 However, the role of autoreactive IgA antibodies in CNS demyelination is still unclear. Here, we conducted an observational, retrospective, longitudinal multicenter study to investigate the frequency of MOG-IgA and its association with clinical features in demyelinating CNS syndromes.

Methods

Study Participants

We cross-sectionally screened serum samples from 1344 patients with suspected or confirmed multiple sclerosis (MS),¹¹ MOG antibody–associated disease,⁸ or NMOSD⁷ at sampling and 110 healthy controls from 5 centers in a discovery and confirmation setup. Patients were assessed from September 2012 to April 2022 (median follow-up time, 39 months; range, 0-227 months). Both CSF and longitudinal serum samples were measured when available. Five patients were excluded from the study (eMethods in Supplement 1). This study was approved by the institutional review boards of the participating centers. All patients provided written informed consent.

Clinical and Imaging Data

Retrieval and analysis of available clinical and other data, magnetic resonance images, and retinal optical coherence tomography are described in the eMethods and eTable 1 in Supplement 1.

Live Cell-Based MOG Assay

Serum samples (1:100) and CSF (1:5) were examined for IgA/IgG/IgM reactivity against full-length human MOG using a live cell-based assay as previously described^3,5 (eMethods in Supplement 1). For each sample, the ratio of the geometric mean channel fluorescence intensity of the human MOG-transfected cell line divided by the geometric mean channel fluorescence intensity of the control cell line was calculated. Geometric mean channel fluorescence ratio cutoffs were set to 3 SDs and a 25% surplus above the mean values for the healthy controls of the discovery cohort (IgA ≥2.4, IgG ≥3, IgM ≥1.6).

Statistical Analysis

We used χ² and Fisher exact tests for categorical variables. For continuous variables, we used unpaired t tests. The significance cutoff was set at P < .05. For optical coherence tomography analyses, we performed linear mixed models at eye level with correction for age and sex (fixed effects) to account for intraparticipant, intereye dependencies. We used Prism 9 version 9.4.1 or R version 4.1.3 (packages: ellipsis, pastecs, readxl, ggplot2, car, lmerTest, MuMIn, Matrix, carData and lme4). Further details are described in the eMethods in Supplement 1.

Results

To assess the frequency of MOG-IgA seropositivity, we investigated MOG-IgA, MOG-IgG, and MOG-IgM in 1339 patients with CNS demyelination (MS, n = 865; NMOSD, n = 196; other demyelinating diseases, n = 278) (Figure 1A-C). Overall, MOG-IgG was present in 81 of 1339 patients (6%) (Figure 1C) of whom 18 of 81 (22%) presented either coexisting MOG-IgA (15/81 [19%]) or MOG-IgM (3/81 [14%]) (eFigure 1 and eTable 2 in Supplement 1). Isolated MOG-IgM was identified in 6 additional patients, and 1 patient presented with coexisting MOG-IgM and MOG-IgA. Isolated serum MOG-IgA was identified in 18 of 1126 patients (1.6%) who were double-seronegative for AQP4-/MOG-IgG (Figure 1C and eFigure 1 in Supplement 1) but in none of the available CSF samples (n = 25) or serum samples from controls (n = 110) (eFigure 1 in Supplement 1). MOG-IgA assay specificity was confirmed at 1:20 serum dilution (eFigure 1 in Supplement 1). Demographic and clinical features of patients with isolated MOG-IgA and MOG-IgG are summarized in the Table and eTables 2 and 3 in Supplement 1.

Figure 1. — A, Flowchart of patients in the discovery and confirmation cohort who were screened for MOG-IgA, MOG-IgG, and MOG-IgM. Aquaporin 4 (AQP4) was tested as part of the routine clinical diagnosis. B, Representative IgG and IgA binding of humanized 8-18C5 (h8-18C5) monoclonal antibody, MOG-Ig seropositive patient serum, and MOG-Ig seronegative control sample to human MOG–transfected or control cells. C, Individual patients’ geometric mean fluorescence intensity (MFI) ratio based on up to 4 measurements as XY plot for MOG-IgG and MOG-IgA, all cohorts combined. D, Antibody serostatus frequency according to clinical phenotype. Seronegative indicates AQP4-/MOG-IgG double-seronegative.

^aFive patients with neuromyelitis optica spectrum disorder (NMOSD) were excluded from downstream analysis: 3 with AQP4-IgG/MOG-IgG, 1 with AQP4-IgG/MOG-IgA, and 1 with AQP4-IgG/MOG-IgG/MOG-IgM.

Table. Demographic and Clinical Features of Patients Who Were Seropositive for MOG-IgA and MOG-IgG.

Characteristic	No./total No. (%)^a
Characteristic	Isolated MOG-IgA (n = 18)	MOG-IgG ± IgA/IgM (n = 81)^b
Sex
Female	11 (61)	40 (49)
Male	7 (39)	41 (51)
Age at disease onset, median (range), y	32.5 (3-76)	34 (3-68)
EDSS score at sampling, median (range)	2.75 (0-9.5)	2 (0-8.5)
No. of attacks at last follow-up, median (range)	2 (1-4)	2 (1-14)
Duration of follow-up, median (range), mo	25 (0-108)	43 (0-227)
CSF-specific OCBs	5/16 (31)	16/48 (33)
Untreated patients	7/16 (44)	14/69 (20)

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Abbreviations: EDSS, Expanded Disability Status Scale; Ig, immunoglobulin; MOG, myelin oligodendrocyte glycoprotein; OCBs, oligoclonal bands; CSF, cerebrospinal fluid.

^{^a}

All P values for comparisons of characteristics between groups were nonsignificant.

^{^b}

Patients who were seropositive for MOG-IgG regardless of coexistence of MOG-IgA and/or MOG-IgM.

MOG-IgA was positive in 3 of 50 patients (6%) with NMOSD, in 5 of 228 patients (2%) with other demyelinating diseases, and in 10 of 848 patients (1%) with MS who were double-seronegative for AQP4-/MOG-IgG (Figure 1D). Myelitis (11/17 [65%]) was the most frequent disease manifestation, followed by brainstem syndrome (7/16 [44%] vs 14/75 [19%], respectively; P = .048), which occurred at a higher frequency than in patients with MOG-IgG. Optic neuritis was less frequent in the isolated MOG-IgA group (4/15 [27%] vs 46/73 [63%] in the MOG-IgG group; P = .02) (Figure 2A and eFigure 2 in Supplement 1). Peripapillary retinal nerve fiber layer and ganglion cell–inner plexiform layer thicknesses in eyes of patients with isolated MOG-IgA and optic neuritis were not different from those of MOG-IgG patients with optic neuritis (eFigure 3 in Supplement 1). Additionally, no significant differences in the frequency of disease manifestations were detected in other MOG-Ig isotype groups (MOG-IgM, MOG-IgG/A, MOG-IgG/M), except for a difference in optic neuritis frequency comparing isolated MOG-IgA with isolated MOG-IgG (35/55 [64%]) (eFigure 2 in Supplement 1).

Figure 2. — A, Frequency of disease manifestations for patients with isolated MOG-IgA and MOG-IgG. B, Frequency of positive and negative cerebrospinal fluid (CSF)–specific oligoclonal bands (OCBs) in MOG-IgA seropositive multiple sclerosis (MS) compared with seronegative MS. C, Magnetic resonance imaging (MRI) of patients with MOG-IgA highlighting the following disease phenotypes: neuromyelitis optica spectrum disorder (NMOSD, often presenting with myelitis), atypical MS (often presenting with periventricular lesions), and atypical demyelination (often associated with brainstem syndrome or with tumor-mimic/atypical demyelination). D, Clinical features frequently observed in isolated MOG-IgA seropositive central nervous system demyelination. Arrows indicate high and low frequencies.

^aFisher exact test, P < .05.

^bFisher exact test, P < .001.

Interestingly, only 4 of 9 patients (44%) who were seropositive for isolated MOG-IgA and had a diagnosis of MS¹¹ presented CSF-specific OCBs, clearly less than in those with MOG-IgA/-IgG seronegative MS (4/9 [44%] vs 325/351 [93%], respectively; P < .001) (Figure 2B and eTable 3 in Supplement 1). Overall, patients with isolated MOG-IgA presented at least 1 of the following imaging features: (1) myelitis (short or longitudinally extensive); (2) periventricular lesion; (3) tumefactive deep white matter lesion; and (4) brainstem lesion, resembling NMOSD, atypical MS, and atypical demyelination phenotypes (Figure 2C and D and eFigure 4 in Supplement 1).

Investigating the frequency of patients with records of clinical attacks (onset or relapses) reported within 3 months following infection or vaccination, we observed no significant difference between the isolated MOG-IgA (7/11 [64%]) and MOG-IgG (7/19 [37%]) groups. No association with specific vaccines or pathogens was observed (eTable 3 in Supplement 1). Furthermore, there was no evidence of seroconversion from neither MOG-IgM/-IgG nor MOG-Ig seronegative to MOG-IgA in patients with available longitudinal samples (n = 90) (eMethods and eFigure 5 in Supplement 1).

Discussion

We identified isolated MOG-IgA in a small subset of patients presenting with myelitis, brainstem syndrome, and infrequent optic neuritis overlapping with core clinical features of NMOSD⁷ and MOG antibody–associated disease.⁸ While the coexistence of MOG-IgM and MOG-IgA has previously been described¹² in a similar frequency as detected in our cohort, we expand on the existing literature by reporting isolated MOG-IgA seropositivity in patients seronegative for MOG-IgG/-IgM and AQP4-IgG.

Unlike IgG, which is mounted systemically, IgA is mainly produced in mucosal tissues where it serves as a first-line barrier against pathogens and commensals, raising questions about the different mechanisms of immune activation that lead to divergent MOG-Ig responses. Although a high frequency of patients who were seropositive for isolated MOG-IgA showed records of attacks preceded by infections or vaccinations, we did not observe associations with specific triggers. An alternative explanation for the occurrence of isolated MOG-IgA could be subsequent seroconversion from MOG-IgM or MOG-IgG induced by the inflammatory milieu. While our longitudinal data of unchanged MOG-Ig isotype patterns over time argue against this, little is known about disease-specific induction of isolated IgA responses.⁹ Future studies are required to investigate the clinical relevance of both isolated and coexisting MOG-IgG/-IgA seropositivity.

In contrast to IgG, which is known for its proinflammatory role through complement activation,^4,6 the pathogenic potential of IgA is debated.⁹ Yet evidence suggests that IgA may target neuronal and myelin antigens^13,14 in CNS inflammation, and a proinflammatory role via IgA immune complex formation and subsequent immune activation has been described in several diseases.⁹ The distinct clinical syndrome in patients seropositive for isolated MOG-IgA, characterized by frequent inflammation of the brainstem and spinal cord, areas with high blood-brain barrier permeability,¹⁵ further suggests that IgA may have a pathogenic role in CNS inflammation. Prospective studies investigating immune activation mechanisms and transferring MOG-IgA into animals will be important steps to assess pathogenicity and clarify the etiology of MOG-IgA–associated disease.

Limitations

Our study has several limitations. First, the clinical data were mostly obtained retrospectively with some unavailable clinical variables; therefore, we cannot exclude the possibility of recollection bias. Second, serum samples were not always collected from untreated patients, possibly underestimating the detected frequency of MOG-IgA/-IgG/-IgM. Further, the small number of patients seropositive for isolated MOG-IgA may have underpowered the detection of additional clinical and other differences, compromising the generalizability of the findings.

Conclusions

In this study, MOG-specific IgA was identified in a subgroup of patients who were double-seronegative for AQP4-/MOG-IgG and presented with distinct clinical features. This finding suggests a potential use of MOG-IgA as a biomarker in AQP4-/MOG-IgG double-seronegative CNS demyelination. Further prospective studies are required to enhance the characterization of the syndrome and decipher underlying pathogenic mechanisms.

Supplement 1.

eMethods

eFigure 1. Serum and CSF (cerebrospinal fluid) myelin oligodendrocyte glycoprotein (MOG) immunoglobulin (Ig) levels

eFigure 2. Disease manifestations in MOG-Ig isotype subgroups

eFigure 3. Optical coherence tomography (OCT) stratified by optic neuritis (ON)

eFigure 4. Brain and spinal magnetic resonance imaging (MRI)

eFigure 5. Longitudinal MOG-Ig serolevels

eTable 1. Non-available data for clinical parameters

eTable 2. Demographic and clinical features of MOG-IgA and -IgG seropositive patients of the discovery, confirmation, and combined cohorts

eTable 3. Clinical characteristics of MOG-IgA seropositive patients

eReferences

Click here for additional data file.^{(1.5MB, pdf)}

Supplement 2.

Data sharing statement

Click here for additional data file.^{(14.6KB, pdf)}

References

1.Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364(9451):2106-2112. doi: 10.1016/S0140-6736(04)17551-X [DOI] [PubMed] [Google Scholar]
2.O’Connor KC, McLaughlin KA, De Jager PL, et al. Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. Nat Med. 2007;13(2):211-217. doi: 10.1038/nm1488 [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Pröbstel AK, Dornmair K, Bittner R, et al. Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis. Neurology. 2011;77(6):580-588. doi: 10.1212/WNL.0b013e318228c0b1 [DOI] [PubMed] [Google Scholar]
4.Marignier R, Hacohen Y, Cobo-Calvo A, et al. Myelin-oligodendrocyte glycoprotein antibody-associated disease. Lancet Neurol. 2021;20(9):762-772. doi: 10.1016/S1474-4422(21)00218-0 [DOI] [PubMed] [Google Scholar]
5.Pröbstel AK, Rudolf G, Dornmair K, et al. Anti-MOG antibodies are present in a subgroup of patients with a neuromyelitis optica phenotype. J Neuroinflammation. 2015;12(46):46. doi: 10.1186/s12974-015-0256-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
6.Sabatino JJ Jr, Pröbstel AK, Zamvil SS. B cells in autoimmune and neurodegenerative central nervous system diseases. Nat Rev Neurosci. 2019;20(12):728-745. doi: 10.1038/s41583-019-0233-2 [DOI] [PubMed] [Google Scholar]
7.Wingerchuk DM, Banwell B, Bennett JL, et al. ; International Panel for NMO Diagnosis . International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177-189. doi: 10.1212/WNL.0000000000001729 [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Banwell B, Bennett JL, Marignier R, et al. Diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease: International MOGAD Panel proposed criteria. Lancet Neurol. 2023;22(3):268-282. doi: 10.1016/S1474-4422(22)00431-8 [DOI] [PubMed] [Google Scholar]
9.Breedveld A, van Egmond M. IgA and FcαRI: pathological roles and therapeutic opportunities. Front Immunol. 2019;10:553. doi: 10.3389/fimmu.2019.00553 [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Pröbstel AK, Zhou X, Baumann R, et al. Gut microbiota-specific IgA⁺ B cells traffic to the CNS in active multiple sclerosis. Sci Immunol. 2020;5(53):eabc7191. doi: 10.1126/sciimmunol.abc7191 [DOI] [PMC free article] [PubMed] [Google Scholar]
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12.Pedreño M, Sepúlveda M, Armangué T, et al. Frequency and relevance of IgM, and IgA antibodies against MOG in MOG-IgG-associated disease. Mult Scler Relat Disord. 2019;28:230-234. doi: 10.1016/j.msard.2019.01.007 [DOI] [PubMed] [Google Scholar]
13.Schumacher H, Wenke NK, Kreye J, et al. IgA autoantibodies against native myelin basic protein in a patient with MS. Neurol Neuroimmunol Neuroinflamm. 2019;6(4):e569. doi: 10.1212/NXI.0000000000000569 [DOI] [PMC free article] [PubMed] [Google Scholar]
14.Prüss H, Höltje M, Maier N, et al. IgA NMDA receptor antibodies are markers of synaptic immunity in slow cognitive impairment. Neurology. 2012;78(22):1743-1753. doi: 10.1212/WNL.0b013e318258300d [DOI] [PMC free article] [PubMed] [Google Scholar]
15.Wilhelm I, Nyúl-Tóth Á, Suciu M, Hermenean A, Krizbai IA. Heterogeneity of the blood-brain barrier. Tissue Barriers. 2016;4(1):e1143544. doi: 10.1080/21688370.2016.1143544 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eMethods

eFigure 1. Serum and CSF (cerebrospinal fluid) myelin oligodendrocyte glycoprotein (MOG) immunoglobulin (Ig) levels

eFigure 2. Disease manifestations in MOG-Ig isotype subgroups

eFigure 3. Optical coherence tomography (OCT) stratified by optic neuritis (ON)

eFigure 4. Brain and spinal magnetic resonance imaging (MRI)

eFigure 5. Longitudinal MOG-Ig serolevels

eTable 1. Non-available data for clinical parameters

eTable 2. Demographic and clinical features of MOG-IgA and -IgG seropositive patients of the discovery, confirmation, and combined cohorts

eTable 3. Clinical characteristics of MOG-IgA seropositive patients

eReferences

Click here for additional data file.^{(1.5MB, pdf)}

Supplement 2.

Data sharing statement

Click here for additional data file.^{(14.6KB, pdf)}

[nbr230003r1] 1.Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364(9451):2106-2112. doi: 10.1016/S0140-6736(04)17551-X [DOI] [PubMed] [Google Scholar]

[nbr230003r2] 2.O’Connor KC, McLaughlin KA, De Jager PL, et al. Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. Nat Med. 2007;13(2):211-217. doi: 10.1038/nm1488 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nbr230003r3] 3.Pröbstel AK, Dornmair K, Bittner R, et al. Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis. Neurology. 2011;77(6):580-588. doi: 10.1212/WNL.0b013e318228c0b1 [DOI] [PubMed] [Google Scholar]

[nbr230003r4] 4.Marignier R, Hacohen Y, Cobo-Calvo A, et al. Myelin-oligodendrocyte glycoprotein antibody-associated disease. Lancet Neurol. 2021;20(9):762-772. doi: 10.1016/S1474-4422(21)00218-0 [DOI] [PubMed] [Google Scholar]

[nbr230003r5] 5.Pröbstel AK, Rudolf G, Dornmair K, et al. Anti-MOG antibodies are present in a subgroup of patients with a neuromyelitis optica phenotype. J Neuroinflammation. 2015;12(46):46. doi: 10.1186/s12974-015-0256-1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nbr230003r6] 6.Sabatino JJ Jr, Pröbstel AK, Zamvil SS. B cells in autoimmune and neurodegenerative central nervous system diseases. Nat Rev Neurosci. 2019;20(12):728-745. doi: 10.1038/s41583-019-0233-2 [DOI] [PubMed] [Google Scholar]

[nbr230003r7] 7.Wingerchuk DM, Banwell B, Bennett JL, et al. ; International Panel for NMO Diagnosis . International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177-189. doi: 10.1212/WNL.0000000000001729 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nbr230003r8] 8.Banwell B, Bennett JL, Marignier R, et al. Diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease: International MOGAD Panel proposed criteria. Lancet Neurol. 2023;22(3):268-282. doi: 10.1016/S1474-4422(22)00431-8 [DOI] [PubMed] [Google Scholar]

[nbr230003r9] 9.Breedveld A, van Egmond M. IgA and FcαRI: pathological roles and therapeutic opportunities. Front Immunol. 2019;10:553. doi: 10.3389/fimmu.2019.00553 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nbr230003r10] 10.Pröbstel AK, Zhou X, Baumann R, et al. Gut microbiota-specific IgA⁺ B cells traffic to the CNS in active multiple sclerosis. Sci Immunol. 2020;5(53):eabc7191. doi: 10.1126/sciimmunol.abc7191 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nbr230003r11] 11.Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-173. doi: 10.1016/S1474-4422(17)30470-2 [DOI] [PubMed] [Google Scholar]

[nbr230003r12] 12.Pedreño M, Sepúlveda M, Armangué T, et al. Frequency and relevance of IgM, and IgA antibodies against MOG in MOG-IgG-associated disease. Mult Scler Relat Disord. 2019;28:230-234. doi: 10.1016/j.msard.2019.01.007 [DOI] [PubMed] [Google Scholar]

[nbr230003r13] 13.Schumacher H, Wenke NK, Kreye J, et al. IgA autoantibodies against native myelin basic protein in a patient with MS. Neurol Neuroimmunol Neuroinflamm. 2019;6(4):e569. doi: 10.1212/NXI.0000000000000569 [DOI] [PMC free article] [PubMed] [Google Scholar]

[nbr230003r14] 14.Prüss H, Höltje M, Maier N, et al. IgA NMDA receptor antibodies are markers of synaptic immunity in slow cognitive impairment. Neurology. 2012;78(22):1743-1753. doi: 10.1212/WNL.0b013e318258300d [DOI] [PMC free article] [PubMed] [Google Scholar]

[nbr230003r15] 15.Wilhelm I, Nyúl-Tóth Á, Suciu M, Hermenean A, Krizbai IA. Heterogeneity of the blood-brain barrier. Tissue Barriers. 2016;4(1):e1143544. doi: 10.1080/21688370.2016.1143544 [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Immunoglobulin A Antibodies Against Myelin Oligodendrocyte Glycoprotein in a Subgroup of Patients With Central Nervous System Demyelination

Ana Beatriz Ayroza Galvão Ribeiro Gomes, MD

Laila Kulsvehagen, MSc

Patrick Lipps, MD

Alessandro Cagol, MD

Nuria Cerdá-Fuertes, MD

Tradite Neziraj, MD

Julia Flammer, MD

Jasmine Lerner

Anne-Catherine Lecourt, MSc

Nina de Oliveira S Siebenborn, MD

Rosa Cortese, MD, PhD

Sabine Schaedelin, PhD

Vinicius Andreoli Schoeps, MD, MPH

Aline de Moura Brasil Matos, MD

Natalia Trombini Mendes, MD

Clarissa dos Reis Pereira, MD

Mario Luiz Ribeiro Monteiro, MD, PhD

Samira Luisa dos Apóstolos-Pereira, MD, PhD

Patrick Schindler, MD

Claudia Chien, PhD

Carolin Schwake, MD

Ruth Schneider, MD

Thivya Pakeerathan, MD

Orhan Aktas, MD

Urs Fischer, MD

Matthias Mehling, MD

Tobias Derfuss, MD

Ludwig Kappos, MD

Ilya Ayzenberg, MD

Marius Ringelstein, MD

Friedemann Paul, MD

Dagoberto Callegaro, MD, PhD

Jens Kuhle, MD, PhD

Athina Papadopoulou, MD

Cristina Granziera, MD, PhD

Anne-Katrin Pröbstel, MD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Main Outcomes and Measures

Results

Conclusion and Relevance

Introduction

Methods

Study Participants

Clinical and Imaging Data

Live Cell-Based MOG Assay

Statistical Analysis

Results

Figure 1. Study Design and Frequency of Isolated Myelin Oligodendrocyte Glycoprotein (MOG) Immunoglobulin (Ig) A in Central Nervous System Demyelination.

Table. Demographic and Clinical Features of Patients Who Were Seropositive for MOG-IgA and MOG-IgG.

Figure 2. Clinical Characterization of Patients Seropositive for Myelin Oligodendrocyte Glycoprotein (MOG) Immunoglobulin (Ig) A.

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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