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

Abstract

ImportanceDifferential 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.ObjectiveTo investigate the frequency of MOG-IgA and associated clinical features in patients with demyelinating CNS disease and healthy controls.Design, Setting, and ParticipantsThis 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 MeasuresFrequency and clinical features of patients who were seropositive for MOG-IgA and double-seronegative for aquaporin 4 (AQP4) IgG and MOG-IgG.ResultsAfter 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 RelevanceIn 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.

MOG-IgA as a Potential Marker of Germinal Center Activity—Reply

“…In that regard, MOG-IgA as a potential marker for ongoing GC-based immunoglobulin class-switching is an interesting hypothesis raised by Handel and colleagues, especially in patients with coexisting MOG-IgG or MOG-IgM antibodies. Although ongoing GC-based immunoglobulin class-switching has previously been suggested for coexisting N -methyl-D-aspartate receptor (NMDAR) IgA in patients with NMDAR-IgG or NMDAR-IgM in the context of intratumoral tertiary lymphoid structures in teratomas and in cervical lymph nodes, the reported frequency of teratomas in patients positive for MOG immunoglobulin, including our cohort, is low . Further, the relevance of GC activity in patients with isolated IgA autoantibodies remains unclear.…”

“…Regarding future studies, the longitudinal assessment of MOG immunoglobulin serostatus as proposed by Handel and colleagues, especially in the MOG-IgG and MOG-IgA double-seropositive group, will shed light on sites and mechanisms of the divergent immunoglobulin responses. In our study, the sample size was not sufficient to look at treatment response to anti-CD20 . Hence, clinical studies assessing responsiveness to B-cell targeting therapies and immunophenotypic studies of cervical lymph nodes in patients positive for MOG immunoglobulins are needed to guide treatment strategies.…”

“…Upon the identification of isolated and coexisting MOG-IgA in patients with demyelinating central nervous system disease, we suggested that differences in the inflammatory milieu in the context of the type and site of preceding infections or vaccinations may account for the diverse immunoglobulin responses . Indeed, most patients belonging to the isolated MOG-IgA group presented clinical attacks after recent infection or vaccination.…”

Error in Figure 2B

“…In the Original Investigation titled “Immunoglobulin A Antibodies Against Myelin Oligodendrocyte Glycoprotein in a Subgroup of Patients With Central Nervous System Demyelination,” which was published September 1, 2023, the second pair of bars in Figure 2B was inverted. The article was corrected online.…”

MOG-IgA as a Potential Marker of Germinal Center Activity

“…To the Editor Ayroza Galvão Ribeiro Gomes and colleagues recently identified the presence of myelin oligodendrocyte glycoprotein (MOG)–reactive immunoglobulin A (IgA) in a small subset of patients with a range of demyelinating central nervous system syndromes, particularly in those with seronegative central nervous system demyelination in whom clinical attacks occurred after vaccination or infection. In addition to a potential direct immunopathogenic role, we propose that MOG-IgA may represent a valuable marker of germinal center-based immunoglobulin class-switching, with potential clinical implications.…”