Myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) antibody-associated disease (MOGAD) is a rare form of acquired demyelinating syndrome (ADS), distinguished by the presence of serum autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG). This disorder is characterized by central nervous system (CNS) demyelination with mild axonal damage, concurrent with inflammatory cell infiltration, primarily composed of CD4+ T cells and granulocytes (1).MOGAD was not initially acknowledged as a distinct disease entity, but instead was viewed as a subtype or variant of multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD) (2, 3).This shift in perception exemplifies the progressively nuanced understanding of autoantibodies and their associated disorders within the realm of neuroimmunology.In 2011, Mader et al. published a seminal study that delineated the clinical characteristics of MOG antibody-positive patients and systematically differentiated them from MS and NMOSD patients (4). Subsequent research in this field progressed rapidly. In 2018, an international expert panel formally proposed MOGAD as a distinct disease entity, established its diagnostic criteria, and emphasized the crucial role of MOG antibody detection in diagnosis (5). The diagnostic differences, clinical aspects, and pathophysiological mechanisms of CNS demyelinating disorders are comprehensively summarized in Table 1 .

MOG protein, the target antigen of MOGAD, is predominantly expressed on the surface of oligodendrocytes in the outermost layer of central nervous system myelin (29). The molecular basis of its pathogenicity primarily stems from the β-sheet conformation of the MOG protein’s extracelluldomain, which forms a unique immunoglobulin-like structure, exposing multiple potential antigen-binding sites (30). The binding of MOG-IgG autoantibodies (predominantly of the IgG1 subtype (31)) produced by B cells to these exposed epitopes triggers a cascade of immune responses. These responses encompass: [1] complement activation leading to the formation of membrane attack complexes (4), [2] antibody-dependent cell-mediated cytotoxicity (32), and [3] T cell-mediated inflammatory responses (33). Furthermore, activated microglia and infiltrating macrophages secrete pro-inflammatory factors, exacerbating local inflammation (34). These complex pathological mechanisms collectively result in demyelination, oligodendrocyte death, and potential axonal damage (12). Crucially, the persistent inflammatory milieu and the presence of autoantibodies may impede the remyelination process, thereby impacting disease recovery (35). But the underlying pathogenic mechanisms, particularly the interplay between humoral and cellular immunity, remain incompletely understood.

MOGAD exhibits distinctive clinical, radiological, and pathological features compared to other types of ASD (36–39). Firstly, MOGAD manifests with a highly heterogeneous clinical presentation, predominantly encompassing phenotypes such as optic neuritis (ON), transverse myelitis, acute disseminated encephalomyelitis (ADEM), and brainstem encephalitis. These phenotypes can occur in isolation or in combination (40). Pediatric patients predominantly present with ADEM and optic neuritis, necessitating early recognition and prompt initiation of steroid therapy. Conversely, adult patients more frequently manifest with relapsing optic neuritis and myelitis, warranting particular vigilance regarding steroid dependence and relapse risk (41, 42). Secondly, MOGAD typically follows a relapsing-remitting disease course, which is potentially associated with fluctuations in antibody titers and dynamic changes in immune regulation (43). Notably, MOGAD patients often demonstrate a greater capacity for repair and more favorable prognosis compared to those with MS and NMOSD, potentially attributable to the distinct pathophysiological mechanisms underlying MOGAD (36).

In the absence of established MOGAD treatment guidelines, a comprehensive understanding of these mechanisms is imperative for guiding acute attack management, personalized symptom control, and long-term relapse prevention strategies. The current standard of care for acute MOGAD exacerbations involves intravenous high-dose methylprednisolone (IVMP), typically administered at 1g/day for 5 consecutive days (44). However, the risk of disease relapse increases significantly during the steroid tapering and discontinuation phase (45). For patients experiencing further clinical deterioration, plasma exchange or intravenous immunoglobulin (IVIG) may be considered as second-line therapeutic interventions (46). MOGAD therapeutic responses exhibit significant age-dependent variations. Regarding glucocorticoid sensitivity, pediatric patients respond favorably to high-dose corticosteroids during acute phases, although rapid tapering frequently precipitates relapses (41). Research indicates that children with ADEM phenotypes demonstrate steroid sensitivity, yet approximately 20% experience relapse following dose reduction (47). In contrast, while adult patients similarly exhibit marked responses to steroids during acute episodes, they face higher relapse risks, which may be independent of steroid tapering velocity (48). Some adult patients require adjunctive plasma exchange (PLEX) or intravenous immunoglobulin (IVIG) to manage severe exacerbations (49). Age-related distinctions also manifest in maintenance therapy selection, with pediatric patients preferentially receiving IVIG as long-term immunomodulatory treatment due to its superior efficacy compared to other immunosuppressants (such as azathioprine and mycophenolate mofetil) and its more manageable side effect profile (48). Adult patients, however, typically opt for rituximab (B-cell depleting agent) or alternative immunosuppressants, though their relapse prevention efficacy is less pronounced than in NMOSD, necessitating recognition that rituximab offers limited relapse control in certain adult patients (50).

The optimal maintenance therapy for MOGAD patients remains a subject of debate in the medical community. Frequently employed pharmacological interventions include oral corticosteroids, azathioprine (AZA), mycophenolate mofetil (MMF), and B cell-targeted biologics such as rituximab (RTX) and tocilizumab (TCZ). Studies have demonstrated that these agents can significantly mitigate the risk of disease recurrence and improve the annualized relapse rate (ARR) (51, 52).

Regarding relapse risk and treatment duration, approximately 20-34% of pediatric patients progress to relapsing disease courses, particularly when MOG antibodies persist. Oral corticosteroids administered for at least three months (≥0.16 mg/kg/day) reduce relapse risk by 88% (53). Adult patients exhibit substantially higher relapse rates (40-80%), especially within six months following initial presentation, thus requiring more aggressive maintenance therapy. However, standardized protocols remain elusive, and some patients may necessitate extended immunosuppression for several years (42).

Complementing pharmacological approaches, non-pharmacological interventions such as long-term functional rehabilitation, regular MOG antibody serological monitoring, and longitudinal MRI surveillance are equally crucial for pediatric MOGAD patients (54).Furthermore, in pediatric patients, MOG antibody titers typically exceed those observed in adults, potentially indicating more robust immune responses and necessitating more cautious tapering strategies (41). From an age-stratified treatment perspective, pediatric patients often benefit from IVIG and gradual steroid tapering to minimize long-term adverse effects (such as growth suppression and metabolic dysregulation) (48, 50). Adult patients require careful balancing of relapse control against medication toxicity, as rituximab may increase infection susceptibility, thus demanding individualized selection (48).

Experimental autoimmune encephalomyelitis (EAE) has long served as a pivotal animal model in neuroimmunological research, providing fundamental insights into the pathogenesis of various demyelinating disorders (55). The evolution of MOG-specific EAE models, particularly those incorporating human MOG-specific T cells and antibodies, has created unprecedented opportunities for investigating MOGAD-specific immunopathological mechanisms (56). Elucidating the parallels between EAE and MOGAD is crucial for unraveling the underlying pathogenic mechanisms and subsequently developing more effective and targeted therapeutic strategies.

This comprehensive review aims to address critical knowledge gaps by synthesizing experimental and clinical evidence across multiple mechanistic and therapeutic domains. Our primary objectives are threefold: First, to provide a detailed analysis of MOGAD pathogenic mechanisms as elucidated through the lens of EAE models, emphasizing novel insights into disease initiation and progression. Second, to critically evaluate current therapeutic strategies in light of experimental evidence, identifying mechanisms of action and potential areas for optimization. Third, to explore emerging therapeutic approaches based on recent mechanistic discoveries, with particular emphasis on targeted interventions that may offer improved efficacy and safety profiles for diverse patient populations.

In the context of rapidly evolving MOGAD research, this narrative review seeks to provide an integrated perspective on disease mechanisms and therapeutic approaches, bridging preclinical insights with clinical applications. We systematically analyze current mainstream therapeutic strategies and comprehensively summarize ongoing clinical trials, thereby offering valuable insights for both evidence-based clinical practice and translational research directions.

In conclusion, MOGAD’s age-dependent characteristics significantly influence treatment strategies: pediatric patients require focus on achieving complete remission of predominantly monophasic disease courses and minimizing steroid tapering risks, while adult patients necessitate reinforcement of long-term management for more frequently relapsing disease. Given the ongoing advancement of MOGAD-related research, this article provides a critical overview of current treatment strategies, anticipating that additional high-quality clinical studies, particularly randomized controlled trials, will furnish stronger evidence-based guidance for disease management.

Research on MOG protein has predominantly focused on its role as an autoantigen in EAE and MS (57, 58). However, MOG protein is now recognized as the principal target antigen in MOGAD (5). MOG protein is a crucial encephalitogenic protein, with expression confined to the outermost layer of CNS myelin and the plasma membrane of oligodendrocytes (59). Its extracellular domain exhibits high CNS specificity and can elicit both cellular and humoral immune responses (60, 61). In humans, MOG antibodies (MOG-Ab) exert pathogenicity by recognizing conformational epitopes of the MOG protein and forming bivalent interactions with its extracellular domain (13). This process can activate the complement system, leading to demyelination through complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cellular cytotoxicity (ADCC) mechanisms (14). Notably, while all MOG-IgG subclasses can induce ADCP, the MOG-IgG1 and MOG-IgG3 subclass autoantibodies are particularly potent in inducing CDC (14). Moreover, MOG protein itself can directly activate the classical pathway of the complement system by binding to complement components C1q and C3d, functioning as adhesion molecules, signaling molecules, or activators of the complement cascade (62). This process further amplifies the demyelinating effect.

The current understanding of MOGAD pathogenesis is largely derived from EAE (63, 64), and Table 2 provides a detailed overview of the pathogenic mechanisms and therapeutic insights gained from these models. Additionally, neuropathological and clinical studies have provided corroborating evidence. The CNS pathology in MOGAD patients exhibits complex histological features. Lesions are primarily characterized by confluent primary demyelination surrounding small and medium-sized veins, accompanied by relative axonal preservation in both white and cortical matter, and reactive gliosis. Furthermore, significant complement deposition, along with infiltration and activation of macrophages and microglia, has been observed (12).The inflammatory infiltrate predominantly comprises CD4+ T lymphocytes and neutrophils, reflecting the immune-mediated nature of MOGAD (15). While MOGAD patients exhibit demyelination, the damage to astrocytes and oligodendrocytes is comparatively mild (15). This characteristic suggests fundamental differences in the pathological mechanisms between MOGAD and NMOSD. Moreover, clinical observations have revealed significant peripheral immune activation in MOGAD patients, contrasted with relatively less chronic inflammation within the CNS (12). This feature stands in stark contrast to multiple sclerosis (MS). These findings provide a theoretical foundation for treating MOGAD with plasma exchange (PLEX) or specific immunosuppressants (75), while also paving the way for novel research into targeted therapeutic strategies against specific inflammatory mediators or immune cell subpopulations.

The EAE model provides a fundamental basis for understanding the immunopathological mechanisms of MOGAD; however, the clinical heterogeneity of MOGAD far exceeds the singular pathological manifestations observed in animal models. EAE is an autoimmune disease animal model induced by immunization with MOG protein, widely used in studying the pathological mechanisms of multiple sclerosis (MS). In comparing EAE with MOGAD, certain similarities exist, such as MOG serving as the target antigen in the EAE model, which aligns with the autoantibody target in MOGAD patients, suggesting that both conditions may share partial immune pathogenic mechanisms (76). Nevertheless, significant differences exist in their pathological mechanisms: MOGAD patients exhibit marked activation of the complement system (e.g., elevated C3 and C4 levels), whereas T cell-mediated inflammation predominates in the EAE model (77). Additionally, MOGAD patients demonstrate a significantly lower positivity rate of oligoclonal bands (OCB) in cerebrospinal fluid compared to MS patients (16.7% versus 94.2%), which differs markedly from the presentation in MS and its EAE model (77). Additionally, MOGAD patients demonstrate a significantly lower positivity rate of oligoclonal bands (OCB) in cerebrospinal fluid compared to MS patients (16.7% versus 94.2%), which differs markedly from the presentation in MS and its EAE model (78, 79). These differences indicate that although the EAE model helps us understand certain pathological aspects of MOGAD, more comprehensive research models are needed to elucidate the disease’s specific immune characteristics and clinical diversity. Future research should further explore the molecular-level similarities and differences between MOGAD and EAE to deepen our understanding of this disease’s heterogeneity.

The 2023 MOGAD expert consensus guidelines emphasize the critical importance of MOG-IgG1 testing in patients presenting with compatible clinical phenotypes (1). MOG-IgG titers exhibit significant correlation with patients’ clinical manifestations and relapse risk. Clinical studies demonstrate that patients with elevated MOG-IgG titers tend to present with more severe clinical symptoms and may exhibit more extensive CNS involvement, including concurrent optic nerve and spinal cord engagement (79). Furthermore, persistently elevated MOG-IgG titers are associated with a less favorable long-term prognosis, characterized by an increased risk of disability and higher frequency of disease relapses (80).

Studies have demonstrated that MOGAD patients exhibit a higher probability of intrathecal MOG-IgG presence compared to other ADS (81). This phenomenon may be attributed to several factors: Firstly, MOGAD patients may exhibit more pronounced blood-brain barrier (BBB) disruption, facilitating antibody penetration into the CNS (17); Secondly, defects in the blood-spinal cord barrier at the central nervous system-peripheral nervous system (CNS-PNS) transition zones may contribute (82); Lastly, intrathecal synthesis (ITS) of MOG-IgG may also be a contributing factor (83). Clinical observations reveal that the degree of disability, cerebrospinal fluid (CSF) leukocyte count, and protein levels in MOGAD patients correlate with CSF MOG-IgG titers, but not significantly with serum MOG-IgG titers (81) Furthermore, studies indicate that patients with MOG-IgG ITS tend to exhibit more severe clinical courses, characterized by more pronounced pyramidal tract involvement and spinal cord lesions, with longitudinally extensive transverse myelitis being particularly prominent (83). The complex immunopathogenesis of MOGAD, leading to oligodendrocyte injury, is schematically depicted in Figure 1 , setting the stage for a detailed examination of the contributions from B cells and plasma cells (Section 2.1), T cells (Section 2.2), and innate immunity (Section 2.3).

Currently, MOGAD treatment approaches are primarily based on clinical experience and extrapolation from other neuroimmunological diseases (particularly MS and AQP4-NMOSD). While large-scale randomized controlled trials (RCTs) specific to this patient population are lacking, observational studies and retrospective analyses have provided relevant evidence for MOGAD treatment.

Translational investigations linking EAE models and MOGAD have significantly progressed our knowledge of disease mechanisms and potential therapeutic goals. In recent years, the pathophysiological mechanisms of MOGAD have been elucidated to a great extend upon lessons learned from EAE models. These experimental results have, in turn, led to lead therapeutic innovations including engineered glucocorticoids and the discovery of novel therapy candidates such as MANF. Systemic evaluation strategies, and borrowing therapeutic approaches from MS and NMOSD have opened up new possibilities for the treatment of MOGAD. The advent of different treatment options, such as monoclonal antibody therapies and cellular-based treatments offers hope for MOGAD patients but needs to be confirmed in future adequately powered clinical trials prior implementing their use widespread.

The integration of EAE models with clinical MOGAD research is of paramount importance for elucidating the pathological mechanisms underlying this disorder. Regarding pathogenesis, EAE models have definitively demonstrated that MOG-specific T cells are essential for disease initiation, while anti-MOG antibodies merely exacerbate demyelination. In contrast, clinical investigations of MOGAD suggest that anti-MOG antibodies may directly participate in the pathogenic process, exemplified by their capacity to disrupt the microtubule cytoskeleton in oligodendrocytes (50, 186). Therefore, when synthesizing findings from both research domains, it is crucial to differentiate between the predominant role of T cells in EAE and the potential direct pathogenic effects of antibodies in MOGAD, while concurrently exploring cooperative mechanisms such as T-B cell interactions in human disease (187, 188). Concerning the controversial role of antibody pathogenicity, although antibodies are not requisite in EAE models, studies have revealed that serum from MOGAD patients can aggravate demyelination in animal models. This observation indicates the necessity for further validation of antibody pathogenicity in human disease through clinical research, such as analyzing correlations between antibody titers and disease activity (50, 189). Notably, transgenic mouse models expressing human MOG have provided valuable platforms for investigating the pathogenicity of human anti-MOG antibodies, further supporting the observation that MOGAD patient serum can exacerbate demyelination in experimental settings (190).

In comparing animal models with clinical phenotypes, EAE models typically manifest as acute monophasic disease courses, whereas approximately 50% of MOGAD patients exhibit relapsing disease trajectories (144). Radiological investigations have revealed that T2 lesions in MOGAD demonstrate greater propensity for complete resolution compared to those in NMOSD and MS, resembling the reversibility of acute inflammation observed in EAE (191). This similarity suggests that EAE models may be valuable for investigating acute-phase mechanisms, though they must be complemented with longitudinal observations that account for the chronic relapsing characteristics of MOGAD. Beyond EAE, toxin-induced demyelination models (such as those utilizing Pseudomonas aeruginosa lipopolysaccharide and lysophosphatidylcholine) have contributed significant insights into myelin repair mechanisms in MOGAD. Particularly, these models demonstrate that remyelination capacity may be more robust in MOGAD compared to MS, which aligns with the clinical observation that MOGAD T2 lesions show greater tendency for complete resolution compared to those in NMOSD and MS (192).Furthermore, MOGAD patients frequently present with multifocal central nervous system involvement, while optic neuritis and myelitis predominate in EAE models (144). This discrepancy indicates the necessity of incorporating multifocal pathology in experimental model design to more accurately recapitulate human disease phenotypes.

Translational research on therapeutic strategies demonstrates that B-cell depletion is ineffective or potentially disease-exacerbating in EAE models, whereas clinical studies of MOGAD indicate that rituximab (anti-CD20) may be efficacious in a subset of patients (144, 193). This discrepancy underscores the necessity for comprehensive analysis of functional differences among B-cell subpopulations (such as plasma cells) in disease pathogenesis, and for exploration of novel B-cell-targeted therapies, including Bruton’s tyrosine kinase inhibitors (194). Regarding antibody-targeted therapeutics, EAE model investigations have demonstrated that anti-FcRn antibodies can reduce IgG circulation, ameliorate neurological dysfunction, and improve visual function, thereby providing a theoretical foundation for clinical MOGAD treatments (such as efgartigimod) (189, 195). However, these findings require further validation through rigorous clinical trials.

In the domain of biomarker development for diagnosis and prognosis, cerebral lesions in MOGAD predominantly involve cortical and subcortical regions, whereas periventricular lesions characterize MS (196, 197). EAE models can be utilized to simulate specific lesion patterns (such as optic neuritis) and, in conjunction with high-resolution MRI, validate human imaging biomarkers (such as “H-type” spinal cord lesions) (144). Concurrently, optimization of anti-MOG antibody detection methodologies (comparing live-cell versus fixed-cell assays) and stratification studies correlating antibody titers with clinical phenotypes (such as monophasic versus relapsing disease) hold significant clinical relevance (144, 189).

Regarding the investigation of cooperative mechanisms and disease model optimization, T-B cell cooperative pathogenesis has been documented in EAE models, and analogous immune interactions may exist in MOGAD patients (188). The establishment of humanized murine models (such as those incorporating transplanted patient T and B lymphocytes) to simulate the human immune microenvironment facilitates comprehensive understanding of these mechanisms (187). Additionally, given that EAE predominantly represents acute disease manifestations while the progression mechanisms of MOGAD remain incompletely elucidated, the development of chronic or relapsing-remitting EAE models, in combination with passive transfer of anti-MOG antibodies, may more accurately recapitulate human disease progression (187, 194).

In conclusion, the integration of EAE and MOGAD research necessitates careful consideration of both similarities and differences between experimental models and clinical manifestations, with particular emphasis on T-B cell interactions, validation of antibody pathogenicity, and translation of therapeutic strategies. Through interdisciplinary collaboration encompassing fundamental immunology, neuroradiology, and clinical trial design, advancements in mechanistic elucidation and precision therapeutics for MOGAD can be substantially accelerated.

There are many challenges on the horizon in MOGAD that need to be addressed, but we anticipate a rapidly changing therapeutic landscape. Given the clinical heterogeneity of MOGAD and limitations in current EAE models to capture all aspects of human disease, continued experimental optimization is required. It is essential that EAE models mimicking MOGAD-specific pathogenic mechanisms be developed, particularly in developing platforms that incorporate human MOG-specific immune responses. Fundamental scientific investigation should push the boundaries of our understanding into molecular processes underlying MOGAD, including production and implications of the MOG IgGs by expansion in B cells as well as functions both regulatory on T-cells and within CNS inflammatory cascades. This knowledge has to be translated into therapeutic targets or biomarkers, and clinical research should combine evaluation of new therapies as well as predictive strategies for differential responsiveness to treatment.

We need to work with researchers, clinicians and patient communities across disciplines. Through enhanced international cooperation and continuous innovation in research methodologies, we anticipate significant improvements in personalized treatment approaches for MOGAD patients. Our ultimate goal extends beyond symptom management to developing comprehensive strategies for preventing disease onset and halting progression. These concerted efforts aim to provide more effective personalized treatment regimens for MOGAD patients, potentially leading to better quality of life and long-term prognosis in the near future.