Several studies indicated that vitamin D plays a significant role in the modulation of the immune system [
18,
19]. Immune cells express both VDR and the 1-a-hydroxylase which is responsible for 25-hydroxyvitamin D activation. Indeed, vitamin D has important effects on both monocytes and dendritic cells (DC) including inhibition of inflammatory cytokines (interleukin (IL)-1, IL-6, IL-8, IL-12 and tumor necrosis factor (TNF)-α) in monocyte and reduction of Major Histocompatibility Complex (MHC) class II molecules expression. Moreover, vitamin D also determines suppression of T cell proliferation [
20], whose final effect is a reduction in the number of antigen-presenting cells. Globally, vitamin D may enhance the innate immune system and regulate the adaptive immune system, promoting immune tolerance and acting to decrease the likelihood of developing autoimmune disease [
18].
Autoimmune thyroid diseases (AITD) are the most frequent autoimmune disorders, and the most common pathological conditions of the thyroid gland occurring in approximately 5% of the population [
21,
22]. The AITD comprise two main clinical presentations: Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). Both forms are characterized by lymphocytic infiltration of the thyroid parenchyma, but while GD is clinically characterized by hyperthyroidism, ophthalmopathy and pretibial myxedema [
23], the clinical hallmarks of HT is the hypothyroidism, determined by lymphocytic destruction of the thyroid gland [
24].
As the majority of autoimmune disorders, AITDs is the consequence of a complex interaction between genetic susceptibility factors (i.e. thyroid-specific and immunoregulatory genes), existential factors (sex, parity, etc.), and various environmental triggers (i.e. cigarette smoking, stress, iodine, selenium, etc.) [
25].
The role of both vitamin D and VDR in the pathogenesis of AITD have largely been investigated in the last years. Vitamin D receptor is expressed in lymphocytes, macrophages as well as in antigen presenting cells [
26]. The innate immune system is activated in presence of Vitamin D, while the acquired immune response is inhibited. Moreover, associations between autoimmune disease and reduction of Vitamin D circulating levels have recently been reviewed [
20]. With a specific focus on autoimmune thyroid disorders, several observations have been published in both animal models and in human studies.
3.1 Animal models
Mice previously sensitized with porcine thyroglobulin have been intraperitoneal injected with or without calcitriol (0.1–0.2 micrograms per kg body weight daily) by Fournier and coworkers. Animals receiving these suboptimal doses of vitamin D presented a reduction in the severity thyroid inflammation compared to placebo treated mice [
27]. The effects were even higher when mice were treated with both calcitriol and cyclosporine [
28].
Liu and coworkers pretreated mice with intraperitoneal injection of calcitriol (5 micrograms per kg every 48 h) before performing sensitization with porcine thyroglobulin. Contrary to what observed in the placebo group, the thyroid not showed the typical inflammation signs, suggesting a protective role of vitamin D in prevention of thyroiditis [
29].
Effects of vitamin D in GD animal models have been studied by Misharin et al. [
30]. BALB/c mice have been produced as model of GD by immunization with adenovirus encoding the A-subunit of thyrotropin receptor. Compared with mice fed regular chow, hyperthyroid BALB/mice fed with a vitamin D deprived diet showed fewer splenic B cells, decreased interferon-gamma responses to mitogen and lack of memory T-cell responses to A-subunit protein, but no differences in TSHR antibody levels have been observed. Moreover, vitamin D-deficient BALB/c mice had lower preimmunization T
4 levels and developed persistent hyperthyroidism suggesting that vitamin D directly modulates thyroid function in this animal model [
30].
3.2 Human studies
In the last years, several studies have investigated the circulating vitamin D levels in patients with AITD. A weak connection between low vitamin D levels and AITDs was identified in a study conducted in a population from India [
31], while no correlation between vitamin D and Ab-Tg antibodies was demonstrated in Thai subjects [
12].
By contrast, Kivity et al. observed that anti-thyroid antibodies were more frequently elevated in patients with vitamin D deficiency [
32]. The same study, however, indicates that the prevalence of vitamin D deficiency was similar between hypothyroid patients with AITDs or without AITD (72% vs 52%,
p = 0.08), not allowing to exclude that vitamin D deficiency is determined by hypothyroidism and not a primary phenomenon involved in AITD pathogenesis.
Tamer et al. demonstrated that patients with HT had lower vitamin D levels when compared to age- and sex-matched controls. Moreover, vitamin D insufficiency (<30 ng/mL) occurred more frequently in patients with HT rather than in a healthy population [
33]. Nevertheless, the authors were not able to demonstrate a significant difference among the degree of vitamin D insufficiency between hypothyroid, euthyroid or hyperthyroid patients with HT, suggesting that vitamin D levels do not correlate with the progress of damage to thyrocyte. In contrast, a potential role of vitamin D in the development or progression of HT has been suggested by Bozkurt et al., demonstrating a correlation between severity of vitamin D deficiency and duration of HT, antibody levels and thyroid volume [
34].
The association between AITD and calcidiol was also investigated by Choi and coworkers in a large cross-sectional study, involving about 6700 participants. The authors demonstrated that the levels of serum vitamin D were significantly lower in pre-menopausal, but not in post-menopausal women with AITD [
35].
Shin et al. reported that patients with elevated anti-thyroid antibodies had significantly lower levels of serum 25(OH)D3 when compared to normal subjects. Moreover, after adjusting for age, sex, and body mass index, a negative correlation (
r = −0.252,
p < 0.001) was recognized between 25(OH)D3 and TPOAb levels in the AITDs patients [
36].
By comparing newly diagnosed AITD patients with healthy age-matched controls, Unal et al. demonstrated that both HT and GD patients had lower circulating 25-OH-D3 compared to controls [
37].
The relationships between vitamin D levels and HT in children have been investigated by Camurdan et al. The authors observed lower vitamin D levels and higher prevalence of vitamin D deficiency in children with new diagnosis of HT compared to sex- and age-matched controls [
38]. Relation between vitamin D and AITD in young was recently studied also in a cohort of 56 Egyptian children with AITD and 56 healthy controls [
39]. Also this report indicates that vitamin D deficiency is more frequent in the AITD group compared to the control subjects, and a significant negative correlations can be demonstrated between serum 25-OH vitamin D and age, duration of the disease, BMI, anti-TPO and anti-Tg antibodies and TSH. On the basis of these observations, the authors supposed that the vitamin D level is not an independent risk for the progression of AITD to overt hypothyroidism [
39]. Sönmezgöz et al. confirmed these results in a group of 136 Turkish children. The prevalence of vitamin D deficiency was higher (76%) in HT patients than in the control group (35%). All hypothyroid HT patients also had a vitamin D deficiency [
40]. Similar results have also been reported by Evliyaoğlu, who measured serum 25-OH vitamin D3 levels in 169 subjects, demonstrating that levels lower than 20 ng/mL were associated to HT in children and adolescents [
41].
The relationships between vitamin D and GD have been less investigated. Kivity et al. reported significantly higher prevalence of vitamin D deficiency in GD patients than in healthy individuals matched by age (64% vs 30% respectively,
p < 0.01) [
32]. Newly identified GD female patients were studied for vitamin D levels by Yasuda et al. in 2012. The authors reported a decrease in the circulating vitamin D levels in GD patients and demonstrated a significant association of vitamin D deficiency with thyroid volume, but not with TRAb levels or thyroid function [
42]. The same authors also found lower vitamin D levels in female GD patients without remission than in those with remission [
42].
All the data on the associations between vitamin D and GD have been reviewed in a recent meta-analysis by Xu and coworkers. In this report, the authors conclude that low vitamin D status may increase the risk of Graves’ disease, however pathogenetic mechanisms related to this association still remains unclear, and it has not yet been clarified if supplement of vitamin D may have beneficial effect in GD [
43].
To date, several authors have studied the association between functional polymorphism in the VDR gene and AITD risk. The VDR is the specific vitamin D receptor and its activity can be compromised by certain polymorphisms. The first meta-analysis performed to assess the association between the alleles of vitamin D receptor gene polymorphisms and Graves’ disease was performed by Zhou and coworkers in 2008. The authors concluded that ApaI, BsmI and FokI polymorphisms of the VDR gene were associated with susceptibility to GD in Asian populations, while ApaI, BsmI, TaqI and FokI polymorphisms were not associated with GD in Caucasian populations [
44]. In 2013, Feng and coworkers performed a meta-analysis demonstrating a relevant link between VDR polymorphism and autoimmune thyroiditis [
45]. The results indicated that the BsmI (rs1544410) or TaqI (rs731236) polymorphisms were significantly associated with AITD risk, while ApaI (rs7975232) or FokI (rs2228570) polymorphisms were not. Later, it has been demonstrated that the frequency of allele TT for the TaqI was higher in GD patients rather than in HT patients, while the frequency of the C allele for the ApaI was higher in GD patients than in normal controls [
46]. Meng et al. [
47] also demonstrated a higher frequency of allele A in ApaI in GD patients compared to controls, but no significant difference were found in BsmI, FokI and TaqI polymorphisms.
In conclusion, despite the number of papers studying the associations between vitamin D and AITD is constantly increasing, data are still not conclusive. There are suggestions indicating that vitamin D deficiency may be a condition associated with a higher risk of developing AITD, but it is still unclear whether this has a specific role in the pathogenesis of the diseases or is a consequence of the disease. Moreover, it has not been defined if vitamin D supplementation may modulate the evolution or the treatments of AITD.