Neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) are autoimmune inflammatory disorders of the central nervous system (CNS) (1). NMOSD and MOGAD have a relapsing course, with heterogeneous recovery between episodes (1). NMOSD typically involves several relapses, whereas MOGAD may occur either as a single episode or with recurring episodes, and generally, MOGAD has a more favorable outcome (1).

NMOSD and MOGAD exhibit distinct immunopathological processes (2). NMOSD is primarily driven by autoantibodies against aquaporin-4 (AQP4), leading to astrocyte damage and secondary demyelination, characterized by complement-mediated cytotoxicity and severe inflammation (3). In contrast, MOGAD involves an autoimmune response against the MOG protein expressed on oligodendrocytes, characterized by inflammatory demyelination, perivenous demyelination, and predominance of CD4+ T-cell infiltration (1).

Adequate and early treatment of relapses in NMOSD and MOGAD is crucial, considering the high probability of accumulating residual impairment from relapse, resulting in significant motor and visual disability especially in NMOSD patients (2). While most individuals with MOGAD show good response to acute treatments, some patients with NMOSD may not respond as effectively (2).

Rituximab, mycophenolate mofetil (MMF), methotrexate, and azathioprine (AZA) are traditional medications used to prevent relapses in NMOSD patients (4). In addition, three disease-modifying therapies have been approved by the FDA specifically for NMOSD treatment: eculizumab, inebilizumab, and satralizumab. These drugs have shown high effectiveness in reducing the frequency of relapses in NMOSD (5, 6). In the PREVENT trial, eculizumab reduced relapse risk by 94%, with 88% of patients remaining relapse-free over 3.7 years (7). Inebilizumab reduced relapse risk by 73% in the N-MOmentum trial, with 77% relapse-free at four years (8). Satralizumab, evaluated in the SAkuraSky and SAkuraStar trials, reduced relapse risk by 79% in AQP4-IgG–positive patients, with 89% relapse-free at 48 weeks (9, 10).

Currently, no medications have received FDA approval specifically for MOGAD treatment, but clinical trials are underway for several drugs, including satralizumab and rozanolixizumab. Since relapsing MOGAD patients require long-term treatment, physicians often prescribe FDA-approved medications for other conditions, such as intravenous immunoglobulin (IVIG), AZA, MMF, rituximab, and tocilizumab (11).

Research on new therapeutic strategies for NMOSD is currently centered on restoring immune tolerance (12). The development and implementation of therapies based on immune tolerance in NMOSD is likely to represent crucial progress toward improving treatment outcomes for the disease. Immune tolerance involves the prolonged or permanent modulation of aberrant immune responses toward a homeostatic state, critical for maintaining immune system balance (13). This process occurs through both central and peripheral immune mechanisms (14, 15), and is known to play a pivotal role in various autoimmune diseases including CNS demyelinating diseases (16). For example thymic B cells contribute to tolerance against a group of germinal center-associated antigens, such as AQP-4 (17). Notably, defects in B cell tolerance are linked with the onset and progression of NMOSD (18). These defects typically lead to increased prevalence of systemic autoantibodies and heightened B cell activation (18).

The CD83 molecule plays a crucial role in the development and maintenance of immune tolerance (19, 20). It is expressed on various activated immune cells, including B and T lymphocytes, monocytes, dendritic cells (DCs), microglia, and neutrophils (19). CD83 is essential for modulating and resolving immune responses and has been shown to regulate cellular activation, contributing to the resolution of neuroinflammation in microglial cells (20).

CD83 has two forms: a membrane-bound (mCD83) and a soluble form (sCD83) (21). mCD83 is expressed on activated B and T lymphocytes and DCs and is widely considered a marker of cellular activation in antigen presenting cells (19). It plays a crucial role in immune regulation by promoting maturation, activation, and maintenance of immune homeostasis (19). Conversely, sCD83 exhibits immunomodulatory capabilities, notably inducing responses from tolerogenic DCs and regulatory T (Treg) cells (22, 23). sCD83 interacts with the TLR4/MD-2 receptor complex, leading to inhibition of T cell proliferation and the induction of anti-inflammatory mediators by activating the TGFB/indoleamine-2,3-dioxygenase axis (24). sCD83 secreted by CD83+ B cells reduced, interleukin (IL)-1β, IL-18, and interferon (IFN)-γ secretion by DCs (25).

Studies have shown that knockout of CD83 in Tregs results in a more highly activated, pro-inflammatory phenotype (26) and that CD83 knockout in the autoimmune animal models, EAE and colitis, consistently demonstrated a more severe disease course (27, 28). Additionally, CD83 knockout in microglia leads to an over-activated state during neuroinflammation, emphasizing its role as a regulator of the CNS immune response (20).

Given its tolerogenic properties, sCD83 is emerging as a promising therapeutic candidate for demyelinating diseases. sCD83 has demonstrated a potent therapeutic effect in EAE, uveitis and allergic rhinitis models (29–31). In EAE, sCD83 effectively reduces disease severity by inhibiting DC maturation, altering DC-T cell interactions, and promoting Treg activity (29). This leads to reduced T cell proliferation and inflammatory cytokine production, resulting in significant attenuation of paralysis and enhanced recovery (29). Similarly, in the uveitis model, sCD83 alleviates inflammation by modulating filamentous actin-dependent calcium signaling in DCs, thereby reducing T cell activation and inflammatory cytokine expression (31).

The counterparts of macrophages and DCs as antigen-presenting cells in the CNS are microglia (32). CD83+ microglia have recently been shown to be vital in maintaining CNS homeostasis and modulating neuroinflammation. Dysregulation of these cells has been linked to the progression of neurodegenerative diseases. In EAE, CD83 expression in microglia promotes the resolution of inflammation by limiting the influx of pathogenic immune cells to the CNS (20). In Alzheimer’s disease (AD), a specific CD83+ microglial subtype has been identified in 47% of patients, and is associated with protective immune responses, including antigen presentation and amyloid clearance (33, 34). However, these cells are reduced in AD, contributing to disease progression (33, 34). Similarly, in Parkinson’s disease, the loss of CD83+ microglia in affected brain regions is linked to increased neuroinflammation and neuronal vulnerability (35). Additionally, sCD83 induces an anti-inflammatory macrophage phenotype by upregulating inhibitory markers like ILT-2 and CD163 and downregulating activation markers such as MHC-II (36). Beyond its role in resolving immune responses, sCD83 is vital in the differentiation of T and B lymphocytes and in sustaining immunological tolerance (22, 37).

Studies on sCD83 in NMOSD and MOGAD have not yet been conducted. However, the promising results of sCD83 treatment in EAE and the severe disease course of EAE animals lacking CD83, combined with the lack of data on CD83 in NMOSD and MOGAD, highlights the need for further investigation of CD83 in CNS demyelinating diseases. The current study aims to examine CD83 expression in these conditions and correlate the findings with disease activity.

Our study reveals significant differences in sCD83 expression among NMOSD, MS, and MOGAD patients, with notably lower levels in NMOSD patients. Moreover, in patients with MOGAD, sCD83 levels were significantly reduced in relapsing compared to monophasic patients and were significantly correlated with higher brain volume. Furthermore, sCD83 levels increase in the sera of patients following treatment with either IVIG or AZA, both effective in preventing relapses, particularly in MOGAD. In culture, the immunosuppressive medications MMF and AZA significantly enhance sCD83 secretion by PBMCs, indicating their potential role in achieving tolerance in these diseases.

Beyond their distinct pathogenic mechanisms, the major demyelinating diseases of the CNS also differ significantly in terms of severity, patterns of disability progression, and clinical outcomes. Most MS patients begin with a relapsing disease course that often transitions to progressive disability over time (46). In contrast, NMOSD and MOGAD are predominantly relapsing diseases, where neurological disability is directly linked to relapses (47). MOGAD generally exhibits a favorable response to immunotherapy, has a better functional prognosis and MRI T2-lesions resolve more often compared to NMOSD patients (48).

We show that sCD83 levels are consistently lower in more severe forms of demyelinating diseases, particularly in NMOSD. NMOSD patients in our cohort exhibit significantly lower sCD83 levels in the serum compared to MS patients and significantly lower serum and CSF levels compared to MOGAD patients. Within the MOGAD group, relapsing patients had significantly lower sCD83 levels than those with a milder, monophasic disease course. These findings suggest that reduced sCD83 levels may be associated with a more severe disease course specifically in antibody-mediated CNS demyelinating disorders. Karampoor et al. observed an increase in sCD83 levels in MS patients, which correlated negatively with disease severity (49). Our data demonstrate that MS patients exhibited lower sCD83 levels compared to HCs, although this reduction was less pronounced than was observed in NMOSD and relapsing MOGAD patients. A possible explanation for this difference is that the MS cohort in their study consisted of treated patients, which could influence sCD83 levels. As in the Karampoor et al. observation, we also find a negative correlation between sCD83 levels and disease severity, a correlation that was more significant in the NMOSD and MOGAD patients. Together, these findings support the hypothesis that sCD83 may play a more significant role in the severity of antibody-mediated demyelinating diseases of the CNS than in MS.

Monitoring sCD83 levels may be particularly valuable in patients initiating a new treatment or those experiencing an early relapse following MOGAD onset, as well as in NMOSD patients. In these individuals, a fast-responding biomarker could be critical, as relapses may lead to irreversible neurological damage (50). Early identification of treatment failure or the timely initiation of therapy in untreated patients could significantly improve clinical outcomes. Accurate identification of treatment failure necessitates careful consideration of the timing of blood collection, as sCD83 levels are influenced by ongoing immunosuppressive therapies. Elevated levels in patients already receiving immunosuppressive therapy may confound interpretation, as a lack of further increase in sCD83 levels in subsequent sample may not reliably indicate relapse risk and could lead to a false negative-response assessment.

We observed a negative correlation between sCD83 serum concentrations and disease severity in both MOGAD and NMOSD conditions. Specifically, within the MOGAD group, sCD83 levels were significantly reduced in relapsing compared to monophasic patients, and there was a positive correlation between sCD83 levels and normalized brain volume, indicating that higher sCD83 may contribute to less severe disease manifestations. Although no correlation was seen between total brain volume and sCD83 levels b NMOSD, there was an inverse correlation between sCD83 levels and VEP scores. These findings collectively indicate that higher levels of sCD83 may exert a protective effect and can serve as a biomarker of disease severity in both disorders.

The underlying reasons why certain MOGAD patients exhibit a monophasic course or experience extended intervals between relapses, as opposed to others who suffer from recurrent disease episodes, remain poorly understood (38). Currently, despite ongoing research, it is not feasible to predict the course of MOGAD, including whether it will be monophasic or relapsing, the timing of potential relapses, and the long-term outcomes (38)

Our findings indicate that at disease onset, higher serum levels of sCD83 in MOGAD patients may provide protection against further relapses. In our data, a serum sCD83 concentration of 706.85 pg/mL could predict a relapsing disease course with high specificity (95.24%), although the sensitivity is relatively low (55.56%). Additional validation studies are necessary to determine the use of sCD83 as a prognostic biomarker and to find the optimal threshold for distinguishing between monophasic and relapsing forms of MOGAD.

In our cohort, we observed a slight, non-significant, increase in serum sCD83 levels during relapses compared to remission in MOGAD, NMOSD, and MS patients. A plausible explanation for this trend lies in the transient nature of CD83 upregulation following exposure to pro-inflammatory stimuli (51). Previous studies have shown that LPS and zymosan rapidly induce CD83 surface expression within the first few hours, followed by a return to baseline levels (51). Similarly, cytokines like TNF-α and IFN-γ trigger a short-term increase in CD83 expression, peaking within a few hours (51). Given the known elevation of these cytokines during relapses (52, 53), it is conceivable that CD83 expression and subsequent shedding into the circulation are occurring temporarily in vivo. However, the transient kinetics observed in vitro may explain why we detected only modest differences in sCD83 levels, particularly if serum samples were collected at variable time points relative to the onset of relapse. To fully elucidate the temporal dynamics and clinical relevance of CD83 regulation during disease activity, larger longitudinal studies with standardized sampling protocols are needed.

In patients with NMOSD, we found a significant elevation in the expression ratio of mCD83 to sCD83, indicating predominant expression of mCD83 over its soluble counterpart. This imbalance suggests a dysregulation in the alternative splicing mechanisms responsible for CD83 expression, which may contribute to the inflammatory processes at the core of NMOSD pathogenesis. The skewed mCD83/sCD83 ratio could exacerbate pro-inflammatory responses, potentially aggravating the disease state.

While FDA-approved treatments for NMOSD have significantly improved outcomes, a subset of patients may continue to experience relapses or ongoing symptoms (6, 8, 10). Our study found that the current monoclonal antibody treatments used for NMOSD do not lead to an increase in sCD83 levels. In contrast to monoclonal antibody therapies, broader immunosuppressive treatments such as IVIG, AZA, and MMF significantly upregulate sCD83 levels. These agents are known to broadly impact the Treg–DC axis (54, 55). AZA has been shown to impair DC maturation and function, promoting a shift toward a less immunogenic and more tolerogenic phenotype (56). IVIG enhances both the expansion and suppressive function of Tregs and modulates DC activation through downregulation of costimulatory molecules (57, 58). MMF has similarly been reported to inhibit DC maturation and pro-inflammatory cytokine production (59). It is possible that the broad immunomodulatory effects of these treatments on the Treg–DC axis contribute to the observed upregulation of sCD83. Alternatively, sCD83 upregulation itself may be a downstream effector mediating some of the therapeutic benefits of these agents, particularly through its known role in promoting immune tolerance (19, 20). Interestingly, the marked upregulation of sCD83 observed following treatment with immunosuppressive agents may not solely reflect a disease-specific therapeutic mechanism. Instead, it is possible that this increase represents a broader compensatory or rebound response to immune suppression. This interpretation is supported by our in vitro findings showing that PBMCs from HCs exhibited a similar pattern of sCD83 elevation when exposed to these agents. In patients with NMOSD who do not respond to FDA-approved monoclonal antibody treatments, measuring sCD83 levels before and after therapy may help guide the choice of alternative treatment. If sCD83 levels are low, broad-spectrum immunosuppressive therapy— either alone or in combination with monoclonal antibody treatments—may represent an appropriate therapeutic approach

It is known that MS treatments like natalizumab and dimethyl fumarate, are not only ineffective for preventing NMOSD relapses but can exacerbate disease severity (60, 61). Notably, we found that these MS treatments downregulate or do not affect sCD83, which may explain their lack of efficacy in NMOSD. While both MMF and AZA are effective for NMOSD treatment, MMF has shown better tolerability and a lower incidence of adverse events. Additionally, some studies indicate that MMF may be associated with a lower relapse risk compared to AZA (62). Notably, our in vitro experiments revealed that MMF significantly increased sCD83 secretion from PBMCs in both patients and HCs compared to AZA.

Currently, there are no FDA-approved treatments for MOGAD (11). Commonly used therapies to prevent MOGAD relapses include immunosuppressants such as AZA, MMF and IVIG (11). We observed increased sCD83 levels in both patients and culture systems with these treatments. Although the precise mechanisms underlying IVIG’s therapeutic effects are not fully understood, it is believed to modulate the immune system through multiple pathways (63). Our findings may provide valuable insights into how IVIG may benefit patients with autoimmune diseases.

Limitations of this study include the relatively small number of participants, which can be attributed to the rarity of these disorders. Another limitation is that different treatments can affect sCD83 levels in varying ways; therefore, serum samples intended for disease monitoring should be collected prior to the initiation of therapy. Further research with larger cohorts is necessary to validate the use of sCD83 as a biomarker for CNS antibody-mediated demyelinating disease severity and as a potential therapeutic target for these disorders.

In conclusion, our study consistently identified lower sCD83 levels in NMOSD patients compared to those with MOGAD and HCs. In NMOSD, reduced sCD83 levels correlated with worse VEP scores, while in MOGAD, they were associated with a relapsing disease course and decreased brain volumes. Furthermore, we observed that sCD83 levels increase in the sera of patients following treatment with immunosuppressives or IVIG. These findings highlight sCD83 as a promising biomarker for assessing disease severity, treatment response and early signs of disease activation. Given the risk of irreversible neurological damage associated with relapses, a rapidly responsive biomarker like sCD83 could aid timely therapeutic decision-making. Collectively, our results support sCD83 as both a therapeutic target and a biomarker in CNS demyelinating diseases.