Hashimoto and the interplay between immunity and thyroid function

Hashimoto's thyroiditis is one of the most emblematic autoimmune diseases, where the immune system, for reasons not yet fully understood, stops recognizing thyroid cells as its own and begins to progressively destroy them. Dominating this complex scenario are T lymphocytes, immune system cells that, under normal conditions, regulate and coordinate the body's defenses. When this balance is altered, the very cells meant for protection become the cause of damage.

In Hashimoto's thyroiditis, the protagonists of this imbalance are primarily two subtypes of T lymphocytes: Th17 and Treg cells. Th17 cells can be imagined as “impulsive soldiers,” specialized in promoting inflammation through the secretion of interleukin-17 (IL-17). Treg cells, on the other hand, represent the “diplomatic corps” of the immune system: they maintain tolerance toward the body's own tissues and limit excessive responses. When Th17 cells take over and Treg cells lose their ability to control them, a fertile ground is created for thyroid autoimmunity, a sort of cellular civil war that leads to the destruction of thyrocytes (thyroid cells that produce thyroid hormones).

Several studies have consistently described this dynamic: some researchers have shown that in patients with Hashimoto's thyroiditis, Treg cells are significantly reduced, while Th17 cells increase in proportion to the severity of the disease (Xue et al., 2015) [1]. This imbalance is closely correlated with the levels of anti-TPO and anti-Tg autoantibodies, which are markers of autoimmune activity. In other words, the more the immune “peacekeepers” decrease, the more inflammation and damage increase.

The molecular mechanism of this imbalance is complex. Some studies have highlighted how, in patients with Hashimoto's, the expression of transcription factors that control T lymphocyte differentiation is altered. FOXP3, a key regulator of Treg cells, is reduced, while genes associated with effector cells are overexpressed. This shift in the genetic center of gravity confirms the loss of tolerance and the expansion of inflammatory responses (Safdari et al., 2017) [2].

The Th17/Treg ratio, therefore, can be considered an indicator of the immunological state of the thyroid. According to some studies, it has been observed that in subjects with Hashimoto's, this ratio is strongly altered even in peripheral blood, accompanied by an alteration of the immune checkpoint system (a natural “brake” that controls the activation of the immune system), which is normally tasked with curbing the activity of T lymphocytes (Fang et al., 2022) [3].

The most interesting aspect that has emerged in recent years is the plasticity of these cells: Th17 cells, in the presence of appropriate environmental signals (cytokines such as TGF-β or IL-10), can “reprogram” themselves and acquire regulatory traits, demonstrating how the line between inflammation and tolerance is thin and dynamic (González-Amaro and Marazuela, 2016) [4].

Alongside these biological mechanisms, some experimental studies have highlighted the possibility of modulating the Th17/Treg imbalance through external interventions. In animal models, selenium supplementation has shown the ability to reduce the production of inflammatory cytokines and promote the differentiation of Treg cells, improving thyroid structure and function (Wang et al., 2023) [5].

Similarly, in an animal model of autoimmune thyroiditis, treatment with Jiayan Kangtai granules (JYKT, a traditional Chinese medicine formulation composed of a combination of nine medicinal herbs) reduced thyroid damage and lymphocyte infiltration. The treatment also resulted in a decrease in Th17 cells and an increase in regulatory T (Treg) cells, leading to a reduction in the Th17/Treg ratio. At higher doses, thyroid autoantibodies also decreased significantly. The results indicate that the protective effect of JYKT is associated with the restoration of the immunological balance between pro-inflammatory Th17 cells and regulatory Treg cells (Hou et al., 2018) [6].

Even on a genetic basis, Treg cells are confirmed as protective elements. A recent Mendelian randomization analysis (a genetic method used to obtain indications on the possible cause-effect relationship between a factor and a disease) has shown that specific genetic signatures associated with Treg cells significantly reduce the risk of developing Hashimoto's thyroiditis, confirming their causal role in the prevention of autoimmunity (Guo et al., 2024) [7].

In summary, Hashimoto's thyroiditis can be interpreted as a breakdown of the immunological harmony between pro-inflammatory and regulatory forces: Th17 cells light the fuse of inflammation, Treg cells attempt to extinguish it, but when the latter fail, due to environmental or metabolic reasons, the immune system ends up turning its weapons against itself. Restoring this balance, through genetic, nutritional, or pharmacological modulation, represents one of the most promising frontiers today for understanding and treating Hashimoto's thyroiditis.

The relationship between Hashimoto's thyroiditis and insulin resistance represents a complex interplay where metabolism and immunity influence each other, resulting in a state of chronic systemic inflammation that fuels both thyroid and metabolic dysfunction.

Several studies have highlighted that insulin resistance (IR) can be present even in euthyroid subjects—those with normal thyroid function—who carry thyroid autoimmunity. In such cases, reduced insulin sensitivity appears to be associated with higher levels of anti-TPO and anti-Tg antibodies, suggesting that IR may contribute to the very genesis of the autoimmune response. Specifically, for every increase in the HOMA-IR index (an index used to estimate insulin resistance and pancreatic β-cell function), an average 18% increase in antibodies directed against a thyroid enzyme is observed, confirming a direct correlation between metabolic dysfunction and autoantibody activation (Blaslov et al., 2020) [8].

When the disease is already manifest, the presence of insulin resistance worsens the clinical course and reduces the response to conventional treatments. Some researchers have shown that in women with autoimmune subclinical hypothyroidism, levothyroxine (a medication used to compensate for or replace thyroid hormone deficiency) is less effective at reducing antibody titers if IR is present, whereas the combination with metformin, by improving insulin sensitivity, enhances the immunomodulatory effect of the thyroid hormone (Krysiak et al., 2021) [9]. In other words, glucose metabolism acts as an “amplifier or attenuator” of therapeutic efficacy, suggesting that managing IR is an integral part of treating thyroid autoimmunity.

On a pathophysiological level, endoplasmic reticulum stress (an internal network of cellular membranes) emerges as a key mechanism linking inflammation and insulin resistance: in animal models of Hashimoto's thyroiditis, chronic activation of the pathways responsible for the cellular stress response leads to impaired insulin signaling and an increase in pro-inflammatory cytokines such as TNF-α and IL-6. Pharmacological inhibition of reticulum stress with 4-phenylbutyrate, a molecule that helps cells manage internal stress, has been shown to restore insulin sensitivity and reduce thyroid damage, indicating a possible therapeutic pathway to modulate the metabolic-inflammatory component of the disease (Zhou et al., 2025) [10].

Even in hypothyroid patients treated with levothyroxine (a synthetic version of the T4 thyroid hormone), the presence of thyroid autoimmunity can be associated with an altered insulin response. Previous studies had already observed that subjects with autoimmune thyroiditis exhibited higher basal insulin levels compared to healthy controls, suggesting a subclinical defect in insulin sensitivity, even under conditions of thyroid hormonal balance (Lethagen et al., 2002) [11]. Furthermore, the presence of autoantibodies typical of autoimmune diabetes appears to reduce the secretory capacity of pancreatic β-cells, highlighting an immunological bridge between the thyroid and the pancreas.

The role of central obesity as an aggravating factor in this relationship was well illustrated in a recent study: in patients with type 2 diabetes, the triglyceride-glucose (TyG) index and its derivatives, which indirectly estimate insulin resistance, are strongly correlated with the presence of Hashimoto's thyroiditis. In particular, the TyG-BMI parameter (an index that combines glycemia, triglycerides, and BMI to indirectly estimate insulin resistance) mediates up to 74% of the effect between visceral obesity and thyroid autoimmunity, demonstrating that insulin resistance is not just a consequence, but a true mediator of autoimmune risk (Zhai et al., 2024) [12].

Another significant clinical scenario is polycystic ovary syndrome (PCOS), in which Hashimoto's thyroiditis occurs more frequently than in the general population. In these patients, the association between the two conditions amplifies insulin resistance and worsens metabolic alterations, creating a vicious cycle of inflammation, endocrine dysfunction, and hyperinsulinemia. Some studies have highlighted that women with PCOS and Hashimoto's thyroiditis show higher HOMA-IR values and reduced thyroid sensitivity, suggesting a bidirectional interaction between the thyroid system and glucose metabolism (Zhao et al., 2021) [13].

Taken together, these findings paint a unified picture: Hashimoto's thyroiditis and insulin resistance share common molecular pathways, where chronic inflammation, oxidative stress, and mitochondrial dysfunction act as connective factors. Insulin, beyond being a simple metabolic regulator, takes on the role of an “immune modulator,” influencing cytokine production and lymphocyte tolerance. Thus, Hashimoto's thyroiditis is not just an autoimmune disease, but a systemic manifestation of a broader immuno-metabolic disorder, in which the management of IR and lifestyle represents a component as essential as hormone replacement therapy.

In the story of Hashimoto's, mTOR is the metabolic-immune "switchboard" that, when stuck on the attack signal, turns defense into damage. Certain environmental factors can turn up the volume on this switchboard: in an animal model, exposure to the plasticizer DINP (a chemical added to some plastics to increase their flexibility) aggravated autoimmune thyroiditis by activating the AKT/mTOR axis, suppressing cellular "scavenger" autophagy, and amplifying oxidative stress; restarting autophagy with rapamycin (a drug that primarily reduces mTOR activity) or buffering radicals with vitamin E attenuated thyroid lesions, proving the key role of this circuit (Duan et al., 2019) [14].

In the same vein, in thyroid follicular cells, excess IL-23 acts like a foot stuck on the accelerator: it activates the AKT/mTOR pathway, brakes autophagy, and promotes the accumulation of reactive oxygen species, fueling an inflammatory vicious cycle; blocking IL-23 or mTOR reopens the intracellular "cleaning" pathway and reduces oxidative stress (Zheng et al., 2018) [15].

In some experimental models, not only glucose but also oxidized fatty acids activated mTOR, pushing toward Th17 polarization at the expense of Tregs; inhibiting fatty acid oxidation with etomoxir (an experimental inhibitor) in human and murine models reduces pathway activation, improves thyroid histology, and restores regulatory balance, suggesting a concrete metabolic therapeutic target (Zhang et al., 2025) [16].

When endogenous "safety brakes" are missing, mTOR runs even faster: reduced serum levels of the protein sestrin-2, a modulator that normally keeps mTOR in check and supports autophagy, have been observed in patients with Hashimoto's, suggesting a lower intrinsic capacity to clear oxidative stress and contain inflammation (Ates et al., 2025) [17].

Finally, the metabolism of tryptophan (an essential amino acid) adds an additional layer of control: its systemic deficiency and the modulation of the PI3K-AKT pathway influence the balance between effector and regulatory T cells; in animal models, supplementing tryptophan reduces lesions and inflammatory mediators, while inhibiting its metabolism worsens the disease, signaling a dialogue between different metabolic pathways and organs with the upstream nodes of mTOR (Zhang et al., 2025) [18].

Overall, these findings converge on a central point: in Hashimoto's thyroiditis, mTOR can represent a connecting node between metabolic alterations, oxidative stress, autophagy, and immune dysregulation. Its excessive activation can, in fact, reduce cellular "cleaning" mechanisms, promote inflammation, and contribute to the imbalance between Th17 and Treg cells, creating conditions favorable to the persistence of thyroid damage. Conversely, containing its activity emerges, in experimental models, as a possible strategy to interrupt this circuit. These very observations raise a fundamental question: what happens when mTOR is inhibited directly? Studies conducted with specific mTOR inhibitors allow us to understand more clearly what effects the pharmacological control of this node can produce in autoimmune thyroiditis.

In Hashimoto's thyroiditis, the overactivation of mTOR may contribute to maintaining autoimmunity by altering the behavior of both immune cells and thyroid follicular cells. mTOR activity promotes anabolic and glycolytic programs compatible with the expansion of Th17 and Th1 cells, while simultaneously limiting autophagy, an important mechanism for cell protection and renewal. Consequently, the direct or indirect inhibition of this pathway can address various aspects of the disease: lymphocyte metabolism, IL-17 production, oxidative stress, autophagy, and inflammatory infiltration of the thyroid.

Particularly direct evidence was provided in 2018: in thyroid follicular cells from patients with Hashimoto's, the study authors observed an increase in IL-23 associated with the activation of the AKT–mTOR pathway, the suppression of autophagy, and the accumulation of reactive oxygen species. The use of rapamycin, a direct mTOR inhibitor, significantly restored autophagy and reduced ROS accumulation. This result demonstrates that mTOR inhibition can act directly on thyroid cells, interrupting a circuit that links inflammation, impaired cellular degradation, and oxidative stress in Hashimoto's (Zheng et al., 2018) [15].

In a 2021 study on CD4⁺ lymphocytes from patients with Hashimoto's, glycolysis, GLUT1 (a transporter that allows glucose to enter cells), HK2, PKM2, and LDHA (enzymes involved in glucose metabolism) were found to be increased, while the mTOR–HIF-1α–glycolysis axis was activated in the mouse model used in the same study. Treatment with metformin and 2-deoxyglucose (a glucose-like molecule that enters cells but hinders their normal energy metabolism) reduced the activity of this metabolic pathway and decreased Th1 and Th17 populations. Metformin is not a direct mTOR inhibitor, but it can limit its activity through cellular energy regulation, showing how the functional reduction of the mTOR–HIF-1α axis can rebalance the immune response in autoimmune thyroiditis (Zhao et al., 2021) [19].

Further confirmation arrived in 2023, when researchers studied dioscin (a natural compound belonging to steroidal saponins) in an autoimmune thyroiditis model. In diseased rats, mTOR, TLR4, and NF-κB (two important components of the immune and inflammatory response) were increased in thyroid tissue. Treatment with dioscin significantly reduced mTOR expression at both the mRNA and protein levels, decreased TgAb, TPOAb, and TRAb (antibodies directed against specific thyroid structures), and reduced lymphocyte infiltration and follicular destruction. The authors therefore proposed that part of the protective effect of dioscin depends on the suppression of the mTOR pathway, with a consequent attenuation of the thyroid inflammatory response (Zhang et al., 2023) [20].

Finally, a recent 2024 study analyzed blocking the cascade located immediately upstream of mTOR using LY294002, a PI3K inhibitor. In mice with experimental autoimmune thyroiditis, p-AKT, p-mTOR, S6K1, S6K2, Th17 cells, and IL-17A were increased. Treatment with LY294002 dose-dependently reduced AKT/mTORC1 activation, the number of Th17 cells, IL-17A production, and the histological severity of the thyroiditis. The study therefore shows that interrupting the PI3K–AKT–mTORC1 signal can directly reduce the Th17 program responsible for part of the autoimmune thyroid damage (He et al., 2024) [21].

Overall, this evidence indicates that mTOR inhibition can intervene in Hashimoto's thyroiditis through at least two major complementary mechanisms. In thyroid follicular cells, blocking mTOR can promote autophagy; in immune cells, it can limit the metabolic reprogramming that supports Th1 and especially Th17, reducing IL-17 and the immune system's ability to maintain the attack against thyroid tissue. The sequence can therefore be outlined as: PI3K/AKT/mTOR inhibition → glycolysis → reduction of Th17/IL-17 plus recovery of autophagy → decrease in oxidative stress and thyroid inflammation. These results are promising, but they derive primarily from cellular and animal models and do not yet constitute a demonstration of the clinical efficacy of mTOR inhibitors as a standard therapy for Hashimoto's thyroiditis.

In recent years, vitamin D has progressively taken on a central role in the understanding of Hashimoto's thyroiditis, shifting from a simple regulator of bone metabolism to a true immune modulator. Numerous clinical and experimental findings have clarified its impact on the balance between inflammation and tolerance, demonstrating that its deficiency is an active factor in promoting thyroid autoimmunity.

Several clinical studies have documented that vitamin D deficiency is extremely common in patients with Hashimoto's, often exceeding 80% of cases, and is accompanied by elevated levels of anti-TPO antibodies, a direct sign of autoimmune activity. In a study conducted on the island of Crete, researchers observed that after just four months of supplementation with cholecalciferol (1,200–4,000 IU/day), there was an average 20% reduction in anti-TPO titers, with an overall improvement in immune status (Mazokopakis et al., 2015) [22].

These results were subsequently confirmed and expanded by a large intervention program involving over 11,000 subjects, which showed that achieving serum 25(OH)D levels ≥ 50 ng/mL was associated with a 30% decrease in the risk of hypothyroidism and a significant reduction in thyroid autoantibodies. Adequate supplementation, therefore, not only supports endocrine function but also exerts a protective effect on the progression of the disease (Mirhosseini et al., 2017) [23].

The mechanism through which vitamin D exerts this effect appears to be twofold: on one hand, it directly modulates lymphocyte activity, promoting the differentiation of regulatory T cells (Treg) and reducing the pro-inflammatory Th17 fraction; on the other, it acts on dendritic cells (cells that recognize antigens and present them to T lymphocytes), reducing the expression of a specific class of molecules and attenuating antigen presentation. In this way, vitamin D helps to restore the immune system to a state of tolerance (Lebiedziński and Lisowska, 2023) [24].

Clinically, controlled studies on one hundred patients with autoimmune thyroid diseases have shown that vitamin D supplementation can significantly reduce thyroid autoimmunity. After treatment, patients receiving supplementation showed a 46.73% reduction in anti-thyroperoxidase (TPO-Ab) antibodies, compared to 16.6% in the control group. Furthermore, 68% of treated subjects responded to therapy compared to 44% of controls. The results therefore indicate a potential immunomodulatory effect of vitamin D in autoimmune thyroid diseases (Chaudhary et al., 2016) [25].

In 2019, other researchers highlighted that vitamin D supplementation can rebalance CD4+ T-cell subpopulations, reducing the Th17/Tr1 ratio and increasing the expression of the anti-inflammatory cytokine IL-10, elements consistent with an immunoregulation effect sustained over time (Nodehi et al., 2019) [26].

Meta-analyses published in subsequent years have consolidated these data: some researchers analyzed a total of more than 1,500 patients, highlighting a significant reduction in anti-TPO and anti-Tg titers after vitamin D supplementation, accompanied by a slight improvement in thyroid function (increase in FT3 and FT4 hormones, reduction in TSH). The effects are more marked in protocols lasting longer than 12 weeks and with adequate dosages of vitamin D3 or calcitriol (Tang et al., 2023) [27]; (Zhang et al., 2021) [28].

Taken together, these findings paint vitamin D as a silent but powerful modulator of thyroid immunity; in fact, as we saw in Chapter 6 dedicated to the immune system, through the modulation of mTOR, it corrects the imbalance between effector and regulatory cells, dampens systemic inflammation, and improves the sensitivity of thyroid cells to endogenous hormones, which are central mechanisms in the genesis of the disease. Metaphorically, it is as if vitamin D acts as a "conductor" that restores rhythm to a dissonant immune system.

In summary, research converges on a clear concept: vitamin D is not a simple adjuvant, but a key element in the prevention and control of Hashimoto's thyroiditis, especially in deficient individuals. Adequate supplementation, calibrated on an individual basis and continued over time, can help reduce autoimmune activity, stabilize thyroid function, and improve the response to conventional therapies.