Multiple sclerosis and nervous system protection

Multiple sclerosis can be described as a complex disharmony of the immune system, where the cells responsible for maintaining immunological balance and tolerance—regulatory T cells, or Tregs—lose their ability to contain the aggressiveness of effector cells. Under physiological conditions, Tregs act as the "brakes" of immunity: they maintain tolerance toward the body's own tissues and prevent the immune system from turning against itself. In multiple sclerosis, however, this control mechanism appears profoundly compromised.

Studies conducted in recent years have shown that in patients with relapsing-remitting multiple sclerosis, CD4⁺ T cells, which constitute the main population of Tregs, are reduced in both number and ability to suppress pro-inflammatory effector T cells (Viglietta et al., 2004) [1].

This loss of "regulatory power" facilitates the activation of autoreactive lymphocytes directed against myelin proteins (the protective coating of nerves), resulting in inflammation and demyelination (damage to the protective sheath of the nerves) of the central nervous system. In a sense, it is as if the immune system has lost its sense of proportion: the cells that should mediate peace become unable to contain the internal war.

The alterations are not limited to quantity but also involve the quality of Tregs. Some studies have shown that their suppressive function is selectively impaired and that effector cells resist their inhibitory signals; this double defect—a weakening of control and a resistance of inflammatory cells—creates a vicious cycle that amplifies the autoimmune response. This imbalance is particularly evident in pediatric-onset cases, where an expansion of pro-inflammatory T lymphocytes (Th1 and Th17) and a functional deficit of Tregs are observed (Mexhitaj et al., 2019) [2].

In parallel, more recent research has shown that Treg dysfunction may stem from specific alterations in cells derived from the thymus (the organ where T lymphocytes mature and are selected), the so-called t-Tregs. In patients with multiple sclerosis, these cells show a profoundly altered profile and a reduced capacity to suppress immune activity; this anomaly appears to worsen with age and can be modulated by certain immunomodulatory therapies (Lorenzini et al., 2024) [3].

The ratio between follicular helper T cells (Tfh) and follicular regulatory T cells (Tfr) also appears profoundly disturbed. Normally, these populations maintain a balance that regulates antibody production by B cells. In multiple sclerosis, however, an excess of Tfh compared to Tfr is associated with an abnormal production of immunoglobulins in the cerebrospinal fluid (antibodies present in the fluid that protects the brain and spinal cord), one of the hallmarks of the disease (Puthenparampil et al., 2019) [4]; it is as if, within the germinal centers, the orchestra of immune cells has lost its conductor, leading to a chaotic symphony of autoreactive antibodies.

This complex scenario is not without hope. Understanding the mechanisms underlying this regulatory failure has already paved the way for new therapeutic perspectives. Some studies have shown that drugs like sorafenib, originally developed for oncology, can inhibit the differentiation of Th1 and Th17 cells—the primary architects of the autoimmune response—while simultaneously promoting polarization toward a Treg phenotype (Wang et al., 2025) [5].

More generally, Treg dysfunction represents a paradigm common to autoimmune diseases, but in multiple sclerosis, it assumes a particularly evident role: the impairment of these cells, which normally operate as the arbiters of immunity, partly explains why the central nervous system becomes the target of prolonged aggression. Studies on humans and animal models converge in demonstrating that the loss of balance between effector and regulatory T cells is key to understanding the origin and progression of the disease (Buckner, 2010) [7]; (Kleinewietfeld and Hafler, 2014) [8].

Another study from 2019 highlighted that in multiple sclerosis, regulatory T cells (Tregs) can present quantitative and functional alterations, contributing to the loss of control over autoreactive immune responses and the persistence of neuroinflammation. The evidence analyzed shows that Tregs can suppress effector T cells, B cells, and antigen-presenting cells and, in the central nervous system, may also promote remyelination. On these grounds, the authors indicate the adoptive transfer of Tregs as a promising immunotherapeutic strategy for multiple sclerosis (Duffy et al., 2019) [6].

Ultimately, multiple sclerosis can be seen as the result of a communication error in the language of the immune system. The cells that should speak the language of tolerance become mute or misunderstood, while those of inflammation take over. Restoring a voice to regulatory cells therefore means restoring harmony to a system that has lost its natural self-regulation.

Recent scientific evidence shows that multiple sclerosis (MS) can no longer be considered solely an autoimmune disease of the central nervous system: it also involves metabolism, particularly insulin metabolism. Numerous studies indicate that a significant portion of patients with MS exhibit signs of insulin resistance and hyperinsulinemia, conditions that could amplify neuroinflammation and accelerate the progression of disability.

Even in newly diagnosed MS patients who have not yet been treated and have minimal levels of disability, significant alterations in the insulin response are observed: during an oral glucose tolerance test, these subjects show a much higher insulin peak compared to healthy controls, despite maintaining normal glycemia levels (Penesova et al., 2015) [9]. It is as if the endocrine system (the system that produces and uses hormones to regulate the body's functions) were reacting with excessive zeal, releasing more insulin than necessary to manage the same amount of glucose.

This condition is not an isolated event: a systematic review and meta-analysis that included eighteen independent studies confirmed a significant association between insulin resistance and multiple sclerosis; in patients, the HOMA-IR index (an index used to estimate insulin resistance and the functionality of pancreatic β-cells) results in a standardized mean difference (SMD, a statistical measure used in meta-analysis and research to compare the difference between the means of two groups) of 0.78 compared to healthy controls, while insulin levels result in an SMD of 0.72 (Sepidarkish et al., 2024) [10]. These data reinforce the idea that insulin dysfunction is not a late consequence of the disease, but a pathophysiological element that accompanies its evolution.

The link between metabolism and disability also emerges clearly in clinical studies: in a cohort of 110 patients, insulin resistance was observed in 40% of cases, compared to 21% of controls, and it proved to be an independent predictor of greater disability measured via the EDSS (Expanded Disability Status Scale) (Oliveira et al., 2014) [11]. Insulin-resistant subjects presented higher levels of pro-inflammatory interleukins (IL-6, IL-17) and markers of oxidative stress, testifying to a constant interaction between metabolism and inflammation. In essence, this is a vicious cycle: hyperinsulinemia and insulin resistance fuel inflammation, which in turn increases insulin resistance and oxidative damage.

Other works have described a true “metabolic profile” of insulin resistance in MS: insulin-resistant patients show higher plasma concentrations of α-hydroxybutyrate (an early marker of oxidative stress) and lower concentrations of linoleoyl-glycerophosphocholine, a metabolite associated with mitochondrial efficiency (Ruiz-Argüelles et al., 2018) [12]. These biochemical alterations correlate with greater clinical severity and more progressive forms of the disease, suggesting that the impairment of energy metabolism may contribute directly to neurodegeneration.

Consistently, a subsequent study showed that over 60% of patients with MS present insulin resistance documented by glucose tolerance tests (Maric et al., 2020) [13]. Post-load glycemia after an OGTT (a test that measures the body's ability to control glycemia after a glucose load), particularly at 120 minutes, is associated with disability scores and disease severity. These results indicate that measuring glucose tolerance is not just a metabolic test, but can provide an important prognostic assessment tool in the neurological context.

At a systemic level, multiple sclerosis is accompanied by a broader alteration of iron and lipid metabolism, which is intertwined with insulin dysfunction. In patients with MS, elevated ferritin and hyperinsulinemia are observed. However, in depressed subjects, a frequent comorbidity in MS, iron levels tend to decrease, suggesting that iron metabolism may also influence mood and brain function (Oliveira et al., 2017) [14].

Taken together, these findings paint MS as a disease in which immunity, metabolism, and neurodegeneration coexist in a fragile balance. Insulin, traditionally considered a simple glucose regulator, appears here as a key modulator of neuronal vitality and synaptic plasticity. When its action is hindered, neurons become more vulnerable to oxidative stress and inflammatory cytokines.

In this perspective, insulin resistance in multiple sclerosis can be seen as a pathological bridge between the brain and the periphery: a metabolic signal that amplifies neuroinflammation and accelerates disability. Early identification of this condition, through simple tests like the OGTT, can therefore represent not only a diagnostic step but also a new therapeutic opportunity to protect the brain by intervening in metabolism.

When describing the link between multiple sclerosis and mTOR, it is helpful to imagine this kinase as a "traffic controller" that integrates nutritional and inflammatory signals to decide whether cells should grow, activate, or, conversely, slow down by activating autophagy. When this regulator misjudges timing and intensity, the result can be an amplification of neuroinflammation and a reduced capacity of nervous tissue to protect itself from oxidative stress (Vakrakou et al., 2022) [15].

Excessive signaling along the PI3K/AKT/mTOR pathway supports the differentiation of effector T cells, especially Th17 cells, and the production of pro-inflammatory cytokines, while its inhibition shifts the balance toward more stable Treg cells and less immune "noise." This is one of the reasons why rapamycin and metformin, in experimental models, attenuate relapses by rebalancing the Teff/Treg ratio (Mammana et al., 2018) [16]; (Vakrakou et al., 2022) [15].

However, this is not a switch to be left off for long: in oligodendrocytes (cells in the brain and spinal cord that produce myelin), mTOR is required for the initial stages of maturation. If chronically inhibited, it can theoretically interfere with myelination programs—the cellular processes that allow for the formation of the myelin sheath around neurons. Consequently, mTOR function tends to be more useful as a brake on inflammation than as a direct lever for remyelination (Mammana et al., 2018) [16].

In the inflamed brain, mTOR also modulates glial cells (non-neuronal cells that are essential for brain function): in microglia (resident immune cells of the central nervous system), high activity promotes an M1 profile with increased TNF-α and IL-1β, while its inhibition "cools" the response; in astrocytes (star-shaped glial cells present in the central nervous system), it regulates the dynamics of the enzyme responsible for producing large quantities of nitric oxide (a signaling molecule produced by cells); in oligodendrocytes, as mentioned, it supports maturation and must be carefully dosed so as not to penalize myelin processes (Dello Russo et al., 2013) [17].

In practice, the anti-inflammatory benefits of mTOR inhibition coexist with potential costs if the signal is turned off indiscriminately and at the wrong time, which explains why results with analogs in clinical trials have been heterogeneous and why current research is focusing on more selective approaches (Vakrakou et al., 2022) [15].

Overall, this evidence shows that in multiple sclerosis, mTOR represents a regulatory node whose balance appears to be decisive. Excessive activation can promote neuroinflammation, Th17 response, and microglia activation, while its inhibition can promote a more regulatory immunological environment that is favorable to Treg cells. However, excessive or prolonged suppression could interfere with functions necessary for oligodendrocytes and myelination. Therefore, rather than turning off mTOR, the goal seems to be restoring a balanced, selective, and temporally appropriate modulation.

In the context of multiple sclerosis, mTOR inhibitors act as a regulator that “turns down the volume” of inflammatory signals without completely shutting off the nervous system's ability to protect itself. In experimental models, rapamycin and everolimus attenuate the Th1/Th17 drive, improve clinical outcomes, and, especially in progressive phases, activate programs of mitochondriogenesis (the formation of new mitochondria within the cell) that support neuronal bioenergetics, delaying progression and prolonging survival (Buonvicino et al., 2024) [18].

From this “metabolic-immunological” perspective, the benefit does not depend solely on the immunosuppressive effect: rapamycin, for example, switches off mTOR, which fuels Th1/Th17 differentiation and reduces pro-inflammatory cytokines, with a tangible impact on EAE (experimental autoimmune encephalomyelitis, an animal model used to study the mechanisms of multiple sclerosis) clinical scores even when administered after symptoms have already begun (Hou et al., 2017) [19].

At the same time, rapamycin helps to “straighten out” Tregs when they cross a hostile microenvironment such as the endothelium of the blood-brain barrier (a selective filter that protects the brain from potentially harmful substances in the blood): in the presence of signals that destabilize Tregs toward effector phenotypes, targeted inhibition of mTORC1 restores their suppressive function, clarifying why combining regulatory cell therapy and mTORC1 modulation could strengthen tolerance in the central nervous system (Baeten et al., 2024) [20].

Regarding administration, the goal is to deliver the drug “where it is needed, as much as is needed”: a microneedle patch with concentrated everolimus improves skin penetration, allows for controlled release, and, in EAE models, reduces inflammation and demyelination with fewer systemic effects, offering a practical and potentially self-manageable route (Yang et al., 2022) [21].

Even molecules not classified as mTOR inhibitors can intercept the same pathway: fingolimod (a drug that limits the circulation of certain lymphocytes, reducing inflammatory activity in multiple sclerosis), in addition to sequestering lymphocytes in the lymph nodes, directly dampens the AKT-mTOR axis and restores the balance between Th1 and Tregs, providing an additional explanation for its clinical efficacy (Hou et al., 2016) [22].

Finally, upstream of the pathway, selective inhibition of PI3K with new chemical derivatives blocks the entire PI3K/AKT/mTOR insulin pathway in immune cells, reducing the severity of EAE with a selectivity profile that is promising for more targeted and less toxic clinical translations (Yu et al., 2024) [23].

Overall, these data form a unified message for the reader: intervening on mTOR, either directly or upstream, does not just mean curbing autoimmunity, but also supporting the energy mechanisms that allow nervous tissue to resist. The key is moderation: dosing the inhibition according to the timing of the inflammation, while preserving the endogenous capacity for repair and the stability of Tregs in the brain microenvironment.

In multiple sclerosis, the persistent activation of mTOR can contribute to the formation of an immunometabolic environment favorable to the differentiation of Th17 lymphocytes, cells that are particularly important in autoimmune neuroinflammation. One of the main effectors through which mTOR exerts this function is HIF-1α. When mTOR is active, it increases the expression and stabilization of HIF-1α, promoting the cell's shift toward a more glycolytic metabolism; this change does not merely represent a different mode of energy production, but directly modifies the fate of T lymphocytes, favoring pro-inflammatory Th17 cells at the expense of regulatory Treg cells. Indeed, HIF-1α increases the expression of glycolytic genes and the production of IL-17 and, at the same time, can counteract the regulatory program associated with FOXP3. In multiple sclerosis, therefore, the hyperactivation of mTOR can translate through HIF-1α into a metabolic reprogramming capable of sustaining an autoimmune response directed against the central nervous system.

One of the most important demonstrations was provided in 2011: the authors of the research showed that HIF-1α was selectively expressed during the differentiation of Th17 cells and that its induction required mTOR signaling. The loss of HIF-1α reduced glycolysis, decreased the formation of Th17 cells, and instead favored the differentiation of Tregs. The aspect particularly relevant to multiple sclerosis is that mice lacking HIF-1α in T cells were protected from experimental autoimmune neuroinflammation. The study therefore directly identifies the mTOR → HIF-1α → glycolysis → Th17 axis as a determining mechanism of central nervous system autoimmunity (Shi et al., 2011) [24].

A second mechanistic study was formulated the following year, when the effect of oxygen availability on Th17 differentiation was analyzed. Under conditions of reduced oxygen tension, similar to those present in lymphoid tissues, mTORC1 was activated, resulting in the stabilization of HIF-1α in Th17 cells. This activation strongly favored their differentiation. In the absence of HIF-1α, mTORC1 activation could no longer effectively support Th17 expansion. The authors therefore identified a positive mTORC1–HIF-1α circuit capable of supporting the Th17 program (Ikejiri et al., 2012) [25].

Particularly significant confirmation in the multiple sclerosis model was provided by other researchers in 2016 using mice affected by experimental autoimmune encephalomyelitis. Treatment with metformin (a drug that helps reduce glycemia and improve insulin action) reduced the clinical severity of the disease, decreased Th17 cells, and increased Tregs. In parallel, a reduction in the activation of mTOR and its downstream target HIF-1α was observed. The authors interpreted these results as indicative of the fact that the inhibition of the AMPK/mTOR/HIF-1α axis modifies T lymphocyte metabolism and rebalances the Th17/Treg ratio. The study therefore directly links the modulation of mTOR and HIF-1α to the improvement of autoimmune neuroinflammation (Sun et al., 2016) [26].

Finally, in a 2021 study, it was directly demonstrated how important HIF-1α is downstream of this cascade: the authors developed a molecule capable of entering the cell and reducing the activity of HIF-1α in the nucleus; the treatment dose-dependently blocked the differentiation of Th17 cells, reduced the expression of IL-17A, and functionally transformed the cells toward a less inflammatory phenotype. In mice with EAE, the functional inhibition of HIF-1α significantly attenuated the neurological disease. This study therefore demonstrates that HIF-1α represents an essential effector of the Th17 program involved in the pathogenesis of autoimmune neuroinflammation (Shin et al., 2021) [27].

Taken together, these findings allow for the reconstruction of a coherent model. In multiple sclerosis and experimental autoimmune encephalomyelitis, immunological, metabolic, and environmental signals can determine the activation of mTOR. Downstream, mTOR promotes the expression and stabilization of HIF-1α, which then increases glycolysis and supports the transcriptional program characteristic of Th17 cells and the production of IL-17. In parallel, this metabolic state makes the differentiation of Treg cells less favorable: the result is an immune imbalance that facilitates the infiltration of autoreactive cells into the central nervous system, the production of inflammatory cytokines, and the maintenance of demyelination and neuroinflammation. The sequence can therefore be summarized as mTOR activation → increase/stabilization of HIF-1α → increase in glycolysis → Th17 expansion and relative reduction of Tregs → increase in IL-17 → autoimmune neuroinflammation.

In the narrative of multiple sclerosis, vitamin D enters the scene as a silent modulator that shifts the balance of immunity from the inflammatory side to the regulatory one: in preclinical models, supplementation reduces the severity of EAE by limiting the proliferation of CD4⁺ T cells, lowering the Th17 fraction, and remodeling transcriptional and epigenetic circuits (mechanisms that control which genes are activated or deactivated) in an anti-inflammatory direction (Zeitelhofer et al., 2017) [28].

In a study of 184 patients with relapsing-remitting multiple sclerosis, an association was highlighted between low serum levels of vitamin D and greater disease severity. Patients with higher disability had significantly lower winter concentrations of 25(OH)D compared to milder cases and healthy controls. Furthermore, vitamin D levels were significantly lower in patients who experienced relapses, both in winter and summer. The study therefore associates vitamin D deficiency with greater disability and frequency of relapses (Brola et al., 2016) [29].

Regarding progression, the evidence converges: through a systematic review and meta-analysis of 14 studies, a significant negative correlation was highlighted between serum levels of 25(OH) vitamin D and disability in patients with multiple sclerosis. Increasing vitamin D concentrations corresponded to lower disability, with an overall correlation of −0.29, which was more marked in women (−0.35). The results therefore suggest that higher levels of vitamin D are associated with less functional impairment in patients with multiple sclerosis (Moosazadeh et al., 2021) [32].

In observational cohorts, 133 patients with relapsing-remitting multiple sclerosis were followed for 24 months, evaluating vitamin D, clinical progression, and radiological activity. Supplementation was not significantly associated with disability or relapses. However, patients taking vitamin D had a significantly lower number of new T2 brain lesions (areas of altered brain tissue visible on MRI). Similarly, maintaining serum levels above 30 ng/mL during follow-up was associated with fewer new lesions. The results therefore suggest a potential radiological benefit of vitamin D in multiple sclerosis (Galus et al., 2023) [33].

Even before onset, other researchers prospectively examined the association between vitamin D intake and the risk of multiple sclerosis in over 187,000 women, documenting 173 cases during follow-up. Women who took at least 400 IU per day of vitamin D through supplements had a 41% lower risk of developing the disease compared to those who did not use supplements (RR 0.59, relative risk:). No significant association emerged with vitamin D from food. The results support a possible protective effect of vitamin D (Munger et al., 2004) [30].

In a systematic review and meta-analysis of 14 case-control studies including 4,130 patients with multiple sclerosis and 4,604 controls, an association was highlighted between vitamin D deficiency and multiple sclerosis. Deficient subjects had a 54% higher probability of MS compared to those with sufficient levels (OR 1.54). In studies that excluded those taking supplements, the association was even more marked (OR 2.19, a statistical measure that compares how much an event is associated with a specific factor between two groups:). The authors therefore indicate vitamin D sufficiency as a potential modifiable risk factor (Balasooriya et al., 2024) [31].

During the relapse phase, other researchers have shown that vitamin D can increase the efficacy of glucocorticoids in multiple sclerosis through the inhibition of mTORC1 in T cells. In vitro, vitamin D increased the expression of the glucocorticoid receptor and promoted treatment-induced T cell apoptosis. In animal models, the vitamin D-glucocorticoid combination improved the disease more than individual therapies. Furthermore, in patients with multiple sclerosis, vitamin D deficiency was associated with relapses resistant to glucocorticoid treatment (Hoepner et al., 2019) [34].

In practical terms for the non-specialist reader: think of vitamin D as a traffic light that, when sufficient, keeps the green light on longer for regulatory signals and shortens the red light of inflammation. The evidence suggests monitoring vitamin D regularly and correcting deficiencies, both for the potential impact on risk and for disease activity and lesion load; in acute phases, an adequate vitamin status could also make steroid therapy more effective.

In conclusion, therefore, vitamin D plays a fundamental regulatory role in the balance between the immune system and metabolism; in fact, as we saw in chapter 6 dedicated to the immune system, through the modulation of mTOR, it contributes to reducing the synthesis of inflammatory mediators, limits the excessive proliferation of effector T lymphocytes, and promotes the differentiation of regulatory T lymphocytes, which are central mechanisms in the genesis of the disease. Thanks to this modulation action, vitamin D helps keep the immune response under control, preventing it from turning abnormally against the tissues.