Myelin oligodendrocyte glycoprotein (MOG), a glycoprotein that is highly conserved among species and uniquely expressed in oligodendrocytes of the mammalian central nervous system (CNS) (Lebar et al., 1989). Masses of experimental models of inflammatory demyelinating diseases have identified that MOG is an encephalitogentic protein capable of triggering a demyelinating immune response (Iglesias et al., 2001; Peschl et al., 2017). These findings have spurred researchers to investigate the role of MOG-IgG in CNS diseases. With the development of cell-based assays (CBAs), MOG-IgG has frequently been detected in serum samples from patients with anti- aquaporin-4-antibody (AQP4-Ab)-seronegative neuromyelitis optica spectrum disorder (NMOSD). These patients frequently present with the clinical phenotypes, such as acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), myelitis, brainstem encephalitis, cerebellar encephalitis, and cortical encephalitis (CE). These clinical syndromes associated with MOG-IgG are collectively referred to as MOG antibody-associated disease (MOGAD)(Banwell et al., 2023).

MOGAD stands as an inflammatory demyelinating disease of the CNS, marking a distinct clinical entity from NMOSD and multiple sclerosis (MS), with a single or recurrent course (Jarius et al., 2018; López-Chiriboga et al., 2018). Autoimmune thyroid disease (AITD) represents one of the most prevalent organ-specific autoimmune diseases, caused by immune system dysregulation that leads to in an immune attack on the thyroid (Antonelli et al., 2015). Previous studies have confirmed that AITD usually co-exists with NMOSD and MS, and delving into the significance of anti-thyroid antibodies (ATAbs) and thyroid function among these patient groups (Niederwieser et al., 2003; Munteis et al., 2007; Wang et al., 2016). Nonetheless, the exploration of thyroid function and ATAbs in MOGAD patients has been scant.

This study was designed to assess whether there were abnormalities in thyroid function or antibodies in adult patients with MOGAD and to unearth the clinical significance of thyroid dysfunction/ATAbs-seropositive in adult patients with MOGAD.

Our research is the first to underscore the significance of thyroid function and antibodies in adult patients with MOGAD. Notably, thyroid dysfunction, particularly low T3 syndrome, occurred with greater frequency in MOGAD patients compared to healthy controls. Moreover, our findings revealed that EDSS scores differed significantly between MOGAD patients with and without low T3 syndrome. In addition, we observed that ATAbs-positive patients had fewer typical brain damage and para-lateral ventricle damage compared with ATAbs-negative patients, even though the seroprevalence of ATAbs was not statistically different between the MOGAD patients and healthy controls.

Some researchers have shown that low T3 syndrome is often present in various autoimmune diseases, such as systemic lupus erythematosus, MS, and NMOSD (Niederwieser et al., 2003; Antonelli et al., 2010; Kumar et al., 2012; Cho et al., 2016; Carnero Contentti et al., 2023). Cho et al. (2016) reported that 56.9% NMOSD patients had thyroid dysfunction and the most prevalent type is low T3 syndrome, accounting for 22.4%, followed by subclinical hyperthyroidism, subclinical hypothyroidism, and clinical hypothyroidism. Consistent with obvious studies, thyroid dysfunction occurs in about half of adult MOGAD patients (55.6%) in this study, with low T3 syndrome occupying the highest proportion (25%).

It is traceable to a relatively higher incidence of low T3 syndrome in adult patients with MOGAD. Deiodinases (Ds) are dimeric integral membrane proteins involved in the activation and/or inactivation of thyroid hormone (TH), including type 1, type2, and type 3 (Gereben et al., 2008). Type 2 iodothyronine deiodinase (D2) is responsible for facilitating the conversion of T4 to T3. While type-3 iodothyronine deiodinase (D3) is the main physiological inactivator that promotes the conversion of T3 to T2 (Darras et al., 2015). The experimental model of MS, characterized by severe CNS inflammation, oligodendrocyte degeneration, and severe demyelination, showed elevated levels of D3 mRNA in inflammatory expression regions (D'Intino et al., 2011; Dell'Acqua et al., 2012). Similarly, studies in rats also confirmed that D3 expression increased rapidly in distal and proximal segments after nerve injury (Li et al., 2001). More than that, it had been reported that increased inflammatory cytokines and chemokines also contributed to D2 dysregulation and increased D3 activity (Calza et al., 2015). These factors collectively might underpin the susceptibility of MOGAD patients to low T3 syndrome. Although the specific pathogenic mechanism of MOGAD remain somewhat elusive, the brain biopsy results of one MOGAD patient showed that the inflammatory demyelination manifestations, in line with a type II MS pattern, included partial axon retention, reactive astrocyte scarring, T cell, macrophage, or microglia infiltration, and complement deposition (Jarius et al., 2016). These observations suggest that the reduction in serum T3 levels in MOGAD patients could primarily result from D2 inactivation and D3 activation. Another plausible explanation for low T3 syndrome involves the regulatory effect of IL-6 on TH, with IL-6 reported to inhibit TH activation while promoting its inactivation in human cells (Wajner et al., 2011). Despite the uncertain role of IL-6 in MOGAD to date, the disease's features, such as antibody- and complement-mediated CNS damage, increased IL-6 levels in CSF, and the efficacy of IL-6 inhibitors, underscore the involvement of IL-6 in the disease's pathogenesis (Kothur et al., 2016; Kaneko et al., 2018; Ringelstein et al., 2022).

Our study also found that patients with low T3 syndrome had higher mean EDSS scores and a higher proportion of unfavorable condition. Moreover, the correlation analysis showed a significantly negative correlation between TT3 and FT3 levels and EDSS scores in MOGAD patients, suggesting that low T3 syndrome is associated with the severity of MOGAD exacerbation during acute attacks. MOGAD is characterized by inflammatory demyelination (Marignier et al., 2021), and previous studies have highlighted the critical role of T3 in the development, maturation, and regeneration of myelin. For instance, the necessity of T3 for oligodendrogenesis and developmental myelination has been corroborated by the reduced CNS myelination observed in hypothyroid sufferers and rodents (Calza et al., 2015). Experimental work demonstrated that T3 acted on the formation of myelinating oligodendrocytes by stimulating oligodendrocyte progenitor cells to stop proliferating to induce cell cycle exit and terminal differentiation or other distinct molecular pathways both in vivo and in vitro (Calza et al., 2002; Raff, 2006). Furthermore, there are studies have suggested that T3 administration improves remyelination (Franco et al., 2008; Harsan et al., 2008). Based on these findings, we put forward the hypothesis that increased the exacerbation of disease observed in MOGAD patients with low T3 syndrome during the episode, possibly related to the critical function of T3 in the CNS. Therefore, it is necessary for first-line clinicians to timely identify and correct low T3 syndrome, but further clinical research is needed to determine whether this can greatly improve the disability of patients.

The prevalence of positive TPO-Ab and TG-Ab was reported in patients with NMOSD, ranging from 20.9% to 49% and 27.9% to 38.8%, respectively (Sellner et al., 2011; Long et al., 2014). Intriguingly, we found that TPO-Ab and TG-Ab positivity were less frequently observed in MOGAD patients (13.9%, 13.9%). What is noteworthy is that the existing studies have highlighted that a significant difference in the incidence of positive ATAbs between NMOSD patients and healthy subjects and indicated that a potential association between ATAbs status and various clinical outcomes, including disability status, EEG abnormalities, and longitudinally extensive spinal cord lesions (Li et al., 2015; Huo et al., 2022). However, our study did not replicate these findings. Typical brain lesions and paralateral ventricle lesions were significantly rare in patients with positive ATAbs compared to those with negative ATAbs, possibly due to the sparse number of patients with positive ATAbs. Therefore, large-scale studies are urgently required to clarify the clinically meaningful of these results.

There are some limitations to our study. Firstly, this was a single-center with small-sample size study and limited to adult Chinese. Inevitably, this leads to selection bias and limits the generalizability of our findings. Thus, the conclusion drawn needs further confirmation using large sample sizes and multi-center studies. Secondly, Furthermore, although CBAs are considered a relatively accurate method for detecting MOG-IgG at present, false positives can also occur, thereby potentially affecting the accuracy of antibody titers. Finally, our study only focused on thyroid dysfunction in MOGAD patients during acute attack and lacked clinical data on remission. Future studies should include data from the remission phase to determine whether the findings from the acute phase are applicable to the remission phase in MOGAD patients.

Overall, this study confirmed thyroid dysfunction is frequent in adult MOGAD patients, especially low T3 syndrome. Patients with low T3 syndrome had higher EDSS scores and a significantly higher proportion of unfavorable condition. Moreover, the correlation analysis model manifests that FT3 and TT3 levels were negatively correlated with the EDSS scores. These evidences indicate that low T3 syndrome is associated with the severity of MOGAD exacerbation.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

The studies involving humans were approved by the Ethics Committee of the Affiliated Brain Hospital of Nanjing Medical University. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

YW: Conceptualization, Data curation, Formal analysis, Methodology, Writing – original draft, Writing – review & editing. HZ: Data curation, Formal analysis, Writing – review & editing. XC: Visualization, Writing – review & editing. JL: Funding acquisition, Supervision, Writing – review & editing.