Search

Background: Autoimmune thyroiditis (AITD) is an organ-specific autoimmune disease. Substantial evidence suggests that Vitamin D (VitD) deficiency is closely associated with an increased risk of AITD. However, the effects of VitD3 on immune cells, especially Th17/Treg cell subsets, and the underlying molecular mechanism in AITD have not yet been investigated., Methods: An experimental autoimmune thyroiditis (EAT) mouse model was established with a high-iodine diet. After 8 weeks, thyroid injury was assessed using hematoxylin and eosin (H&E) staining. ELISA was employed to measure serum levels of thyroxine (T3 and T4), thyroid autoimmune antibodies (Tg-Ab and TPO-Ab), and inflammatory cytokines. Flow cytometry and multiplex fluorescence immunohistochemical (mIHC) assays were used to analyze Th17/Treg cell subsets. The CCK-8 and flow cytometry assays were used to determine cell viability and apoptosis., Results: Administration of VitD3 reduced thyroid follicle destruction, decreased lymphocyte infiltration, and lowered T3, T4, Tg-Ab, and TPO-Ab serum levels in EAT mice. VitD3 treatment also reduced the frequency of Th17 cells while promoting the Treg cell subset both in the thyroid tissue and in the splenocytes cultured in vitro. Furthermore, VitD3 administration suppressed the production of inflammatory cytokines in EAT mice. VitD3 was also found to regulate Treg cells' differentiation, viability, and apoptosis. Mechanistically, we discovered that VitD3 treatment upregulated YAP expression and activated the JAK/STAT pathway. Rescue assays confirmed that depletion of YAP counteracted the effects of VitD3 on Treg cell differentiation and function., Conclusion: Vitamin D3 attenuates AITD by modulating Th17/Treg cell balance via regulating the YAP/JAK1/STAT1 axis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Autoimmune Thyroiditis (AIT) is the most common thyroid disease; however, there were no measures to prevent the progression of the disease. The present study attempts to identify that Notch signaling regulates the differentiation of T helper 17 (Th17) cells by activating downstream Phosphatidylinositol-3 kinase/protein kinase/mechanistic target of rapamycin complex 1 (PI3K/AKT/mTORC1) pathway participating in the thyroid injury of the experimental autoimmune thyroiditis (EAT)., Methods: In vivo experiments, mice were randomly divided into 4 groups: a control group, an EAT group, and two groups with LY294002 treatment (pTg plus 25 mg/kg or 50 mg/kg LY294002, respectively). The degrees of thyroiditis were evaluated, and the percentage of Th17 cells, expression of interleukin-17A (IL-17A), and the main components of the Notch-PI3K signaling pathway were detected in different groups. In vitro experiments, two different dosages of LY294002 (25 and 50 μM) were used to intervene splenic mononuclear cells (SMCs) from EAT mice to further evaluate the regulatory effect of Notch-PI3K pathway on Th17 cells., Results: Our data demonstrate that the infiltration of Th17 cells and the expressions of IL-17A, Notch, hairy and split 1 (Hes1), p‑AKT (Ser473), p‑AKT (Thr308), p‑mTOR (Ser2448), S6K1, and S6K2 increased remarkably in EAT mice. After PI3K pathway was blocked, the degrees of thyroiditis were significantly alleviated, and the proportion of Th17 cells, the expression of IL-17A, and the above Notch-PI3K pathway-related molecules decreased in a dose-dependent manner. Additionally, the proportion of Th17 cells was positively correlated with the concentration of serum thyroglobulin antibody (TgAb), IL-17A, and Notch-PI3K pathway-related molecules mRNA levels., Conclusions: Notch signal promotes the secretion of IL-17A from Th17 cells by regulating the downstream PI3K/AKT/mTORC1 pathway through Hes-Phosphatase and tensin homolog (PTEN) and participates in thyroid autoimmune damage, and the PI3K pathway inhibitor may play important effects on AIT by affecting Th17 cells differentiation., (© 2024. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Introduction: We aimed to comprehensively investigate the causal relationship between 731 immune cell traits and autoimmune thyroiditis (AIT) and to identify and quantify the role of 1400 metabolic traits as potential mediators in between., Methods: Using summary-level data from genome-wide association studies (GWAS) we performed a two-sample bidirectional Mendelian randomization (MR) analysis of genetically predicted AIT and 731 immune cell traits. Furthermore, we used a two-step MR analysis to quantify the proportion of the total effects (that the immune cells exerted on the risk of AIT) mediated by potential metabolites., Results: We identified 24 immune cell traits (with odds ratio (OR) ranging from 1.3166 6 to 0.6323) and 10 metabolic traits (with OR ranging from 1.7954 to 0.6158) to be causally associated with AIT, respectively. Five immune cell traits (including CD38 on IgD+ CD24-, CD28 on CD28+ CD45RA+ CD8br, HLA DR+ CD4+ AC, TD CD4+ %CD4+, and CD8 on EM CD8br) were found to be associated with the risk of AIT, which were partially mediated by metabolites (including glycolithocholate sulfate, 5alpha-androstan-3alpha,17beta-diol disulfate, arachidonoylcholine, X-15486, and kynurenine). The proportion of genetically predicted AIT mediated by the identified metabolites could range from 5.58% to 17.7%., Discussion: Our study identified causal associations between AIT and immune cells which were partially mediated by metabolites, thus providing guidance for future clinical and basic research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Jiang, Qu, Jiang, Zhang, Wang, Chen, Sun, Su and Luo.)

Background: Experimental autoimmune thyroiditis (EAT) is a widely used animal model to study the pathogenesis and treatment of autoimmune thyroid diseases. Yiqi Jiedu Xiaoying Decoction (YJXD) is a traditional Chinese medicine formula with potential immunomodulatory effects. In this study, we investigated the therapeutic effects of YJXD on EAT in rats and explored its underlying mechanisms., Methods: Female Wistar rats were induced to develop EAT by immunization with thyroglobulin (Tg) and taken sodium iodide water (0.05%) and then treated with YJXD or sodium selenite. HE staining was used to observe the pathological changes of thyroid tissue in EAT rats. Th17 and Treg cell frequencies were analyzed by flow cytometry, and the expression levels of Th17- and Treg-related cytokines and thyroid autoantibody were determined by enzyme-linked immunosorbent assay (ELISA). The expression of Th17- and Treg-related transcriptional factors was detected by real-time polymerase chain reaction (RT-PCR) and Immunohistochemistry (IHC)., Results: Our results demonstrated that treatment with YJXD significantly attenuated the severity of EAT, as evidenced by reduced thyroid gland inflammatory infiltration and decreased serum thyroglobulin autoantibody levels. Importantly, YJXD treatment effectively modulated the Th17/Treg cell balance by suppressing Th17 cell differentiation and promoting Treg cell expansion. Moreover, YJXD was also found to regulate the expression levels of Th17- and Treg-related cytokines and transcriptional factors, further supporting its immunomodulatory effects in EAT., Conclusion: YJXD exerted therapeutic effects on EAT by regulating the Th17/Treg cell balance, modulating the production of Th17- and Treg-related cytokines and the expression of transcriptional factors., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

This study aimed to investigate the therapeutic effect of human umbilical cord mesenchymal stem cells (hUCMSCs) on experimental autoimmune thyroiditis (EAT) and the underlying mechanisms by utilizing a porcine thyroglobulin-induced EAT rat model. The rats received four tail vein injections of vehicle or hUCMSCs at an interval of 7 days and were sacrificed on day 28 after the first injection. Hematoxylin and eosin staining and enzyme-linked immunosorbent assays (ELISAs) were used to assess the therapeutic effects of hUCMSCs on EAT. Splenic lymphocytes were isolated from rats, and the proportions of CD4 + T cell subsets were analyzed by flow cytometry. Splenic CD4 + T cells from EAT rats were cocultured with hUCMSCs. A loss-of-function assay for protein tyrosine phosphatase non-receptor type 2 (PTPN2) was performed to explore the involvement of PTPN2/signal transducer and activator of transcription 3 (STAT3) signaling on the therapeutic benefit of hUCMSCs in EAT. hUCMSC treatment significantly alleviated inflammation, reduced serum thyroid antibody levels, and decreased the ratios of IL-17α + /CD25 + FOXP3 + cells and serum IFN-γ/IL-4 in EAT rats. Furthermore, hUCMSC treatment upregulated PTPN2 protein expression in splenic lymphocytes of EAT rats as well as enhanced the PTPN2 protein level and attenuated phosphorylation of STAT3 in CD4 + T cells in vitro. Importantly, knockdown of Ptpn2 significantly reversed hUCMSC-mediated suppression of cell proliferation and hUCMSC-induced alterations in the expression of inflammatory cytokines in CD4 + T cells. Thus, hUCMSC treatment alleviates thyroid inflammation and the CD4 + T cell imbalance in EAT via PTPN2/STAT3 signaling, serving as a promising therapeutic approach for autoimmune thyroiditis.

Background: This is the first study, that aimed: a) to compare immune response, namely the kinetics of neutralizing antibodies (Nabs), after vaccination with BNT162b2 mRNA vaccine (Comirnaty, Pfizer/BioNTech) between patients with autoimmune thyroiditis and controls, and b) to investigate changes in thyroid function in healthy subjects with no history of thyroid dysfunction before and after vaccination with BNT162b2 mRNA vaccine (Comirnaty, Pfizer/BioNTech)., Methods: The entire study consisted of two sub-studies. In the first sub-study, NAbs levels after BNT162b2 mRNA vaccination were compared between 56 patients with autoimmune thyroiditis and 56 age and gender-matched healthy controls from the day of the first dose until a period of up to three months after the second dose. In the second sub-study, thyroid hormones (T3, T4, TSH) and thyroid auto-antibodies levels (anti-TG, anti-TPO) of 72 healthy subjects with no history of thyroid disease were examined before (D1) and one month after completion of the second dose (D50)., Results: Among patients with autoimmune thyroiditis, the median neutralizing inhibition on D22, immediately before second dose, was 62.5%. One month later (D50), values increased to 96.7%, while three months after the second dose NAbs titers remained almost the same (94.5%). In the healthy group, median NAbs levels at D22 were 53.6%. On D50 the median inhibition values increased to 95.1%, while after three months they were 89.2%. The statistical analysis did not show significant differences between two groups (p-values 0.164, 0.390, 0.105 for D22, D50 and three months). Regarding changes in thyroid function, the mean value for T4 before vaccination was 89.797 nmol/L and one month after the second dose was 89.11 nmol/L (p-value=0.649). On D1 the mean T3 value was 1.464 nmol/L, which dropped to 1.389 nmol/L on D50 (p-value = 0.004). For TSH, mean levels were 2.064 mIU/ml on D1 and fell to 1.840 mIU/ml one month after the second dose (p-value=0.037). Despite decrease, all thyroid hormone levels remained within the normal range. No changes were found for anti-TPO or anti-TG., Conclusions: This study provided evidence that patients with autoimmune thyroiditis present similar immunological response to COVID-19 BNT162b2 mRNA vaccine (Comirnaty, Pfizer/BioNTech) with healthy subjects, while vaccination may affect thyroid function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Paschou, Karalis, Psaltopoulou, Vasileiou, Charitaki, Bagratuni, Ktena, Papandroulaki, Gumeni, Kassi, Trougakos, Terpos and Dimopoulos.)

Autoimmune thyroiditis (AIT) is the most prevalent autoimmune endocrine disease, with a higher incidence in women than in men. Immunological abnormalities may lead to the impairment of ovarian folliculogenesis; however, whether the presence of AIT affects immunological microenvironment in follicles remains controversial. We performed a cross-sectional study including 122 patients, aged 20-40 years, who underwent IVF/ICSI treatment owing to isolated male or tube factor infertility. Patients were divided into AIT and control groups according to clinical presentation, thyroid function, and thyroid autoantibody measurements. Follicular fluid was collected and the distribution of cytokines/chemokines in follicular fluid was measured by flow cytometry using multiplex bead assays between the two groups. Based on differences in levels of intrafollicular chemokines and cytokines between the AIT and control groups, the relevant inflammatory cascade was further demonstrated. Among the 12 chemokines analyzed, three (CXCL9, CXCL10, and CXCL11) showed significantly elevated levels in the follicular fluid of patients with AIT. Among the 11 cytokines detected, compared with those in the control group, significantly higher levels of IFNγ were observed in patients with AIT. IFNγ dose-dependently stimulated the expression and secretion of CXCL9/10/11 in cultured primary granulosa cells. The percentage of CXCR3 + T lymphocytes was significantly elevated in the follicular microenvironment of patients with AIT. We concluded that the IFNγ-CXCL9/10/11-CXCR3 + T lymphocyte inflammatory cascade is activated in the follicular microenvironment of patients with AIT. These findings indicate that a considerable immune imbalance occurred in the follicular microenvironment of patients with AIT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Huang, Liu, Lian, Chi and Qiao.)

To evaluate the association between thyroid echogenicity and heterogeneity seen on ultrasonography (US) and thyroid function in pediatric and adolescent populations with autoimmune diffuse thyroid diseases (AITD). From 2000 to 2020, we reviewed thyroid ultrasound (US) images and thyroid function statuses in 133 children and adolescent AITD patients. Our review of the images focused on decreased echogenicity and heterogeneity, which were classified into four grades. Among patients with overt hypothyroidism or overt hyperthyroidism, 94.2% (65/69) showed a US grade of 3 or 4. In patients with subclinical hyper/hypothyroidism or euthyroidism, 45.3% (29/64) showed grades 1 or 2. There were no overt hyper/hypothyroidism patients with US grade 1. When we compared US grades according to thyroid status, more severe thyroid dysfunction was significantly associated with higher US grade (p = 0.047). Thyroid stimulating hormone (TSH) level differed significantly according to US grades when we evaluated hyperthyroid (p = 0.035) and hypothyroid (p = 0.027) states independently. 11 patients showed both US grade and thyroid function status changes on follow-up US. In children and adolescent AITD patients, there was an association between decreased echogenicity and heterogeneity on US and thyroid dysfunction., (© 2021. The Author(s).)

The present study was designed to evaluate the effects of boldenone undecylenate (BL) abuse alone and in combination with vitamin C (VC) on the immune responses and thyroid structure and function in rats. Thirty adult male Wistar rats were randomly divided into five equal groups and were subjected to various treatment regimens for eight weeks as follows: control group, vehicle control group, VC group orally received VC (120 mg/Kg BW/day), BL-treated group intramuscularly injected with BL (5 mg/kg BW, once/week), and BL+VC group received BL and VC. At the end of this experiment, blood and tissue samples (thyroid, thymus, and spleen) were subjected to hematological evaluation, biochemical analysis, histopathological, and immunohistochemical examinations. In comparison to controls, BL significantly increased the levels of serum proinflammatory interleukins (IL-1 β and IL-6), immunoglobulins (IgG and IgM), and complement 3 but reduced anti-inflammatory interleukin-10, lysosome, and nitric oxide. Besides, altered platelet count and leukogram were evident in BL-injected rats. BL notably disturbed thyroid profile as revealed by a significant increase of thyroid-stimulating hormone and thyroid peroxidase antibody. In contrast, both total and free forms of thyroid hormones (tri-iodothyronine and thyroxine), thyroglobulin, and thyroid peroxidase, were significantly decreased. Moreover, BL caused histopathological changes in the thyroid, thymus, and spleen tissues.CD4 + immuno-expression was reduced, but CD8 + immunolabelling was increased in both spleen and thymus. The daily dosing of VC to BL-exposed rats significantly corrected most of the deviations in immune parameters. It restored most of the thyroid architecture and function, revealing a significant protective effect of this vitamin. This experimental study demonstrates that BL abusing disrupts the immune system by different mechanisms and addresses BL, for the first time, as an autoimmune clinical hypothyroidism inducer drug. Additionally, VC is helpful in the management of BL abuse., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Papillary thyroid cancer (PTC) often co-occurs with Hashimoto's thyroiditis, an association that has long been reported in clinical studies yet remains controversial. Some studies, in fact, have suggested a protective effect of thyroiditis while others have not. We generated a mouse model where PTC and thyroiditis develop in a predictable manner, combining the oncogenic drive of the BRAFv600E mutation (inducible by tamoxifen) to the thyroiditis susceptibility of the NOD.H2h4 strain (inducible by iodine). A total of 113 NOD.H2h4&#95;TPO-CRE-ER&#95;BRAFV600E mice (50 followed throughout lifetime and 63 sacrificed at 16 weeks post tamoxifen) were used to determine whether the PTC phenotype differs when thyroiditis precedes or coincides with the onset of PTC. Mice with pre-existing thyroiditis lived longer (median survival of 28.2 weeks post tamoxifen) than those with concomitant (25.6 weeks) or no (24.5 weeks) thyroiditis (P < 0.01 by Laplace regression). PTC developed less frequently (33%) in the pre-existing thyroiditis group than the concomitant (100%) or no (100%) thyroiditis groups (P < 0.001 by chi-squared) and showed less aggressive histopathological features. The intratumoral mononuclear cell infiltration was more prominent in mice with pre-existing thyroiditis (P = 0.002 vs the other groups) and sustained by a significant expansion of effector memory CD8 + T cells and CD19 + B cells. These findings shed light on the controversial PTC-thyroiditis association and emphasize the contribution of intratumoral T and B lymphocytes to the evolution of PTC., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Both polycystic ovary syndrome (PCOS) and autoimmune thyroiditis (AT) are considered to be among the most common endocrinopathies in young women, and they are classified as diseases that affect many processes in the human body. Their role in the development of metabolic disorders and diseases of the cardiovascular system in adult women is also emphasized. However, there are no data available to assess such risk in the teenage girl population. The aim of the study was to assess the hormonal and metabolic profile of adolescent girls with PCOS, additionally diagnosed with AT, as well as to identify possible risk factors for the coexistence of AT and PCOS., Material and Methods: 80 euthyroidic PCOS patients were qualified for the study (chronological age 16.54 ± 1.00 years, BMI 24.60 ± 4.16 kg/m 2 ). Eighteen girls diagnosed with AT were included in the study group and 62 girls without AT-in the control group. Each patient had biochemical and hormonal tests performed. Additionally, to diagnose AT, the level of antibodies against thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-TG), as well as the image of the thyroid gland on ultrasound examination, were taken into account., Results: Estradiol concentration was significantly higher in the study than in the control group (203.00 ± 217.00 vs. 152.00 ± 78.50 pmol/L, p=0.02). Higher DHEAS concentrations were also observed in the AT group compared with the group without AT (391.28 ± 176.40 vs. 317.93 ± 114.27 µg/dl, p=0.04). Moreover, there was a positive correlation between AT and estradiol concentration (r y =0.27; p=0.04). It was also shown that there is a tendency toward statistical significance for the positive correlation between the positive anti-TPO titer and the glucose concentration at 120 min OGTT (r ƴ =0.26; p=0.07) and girls with PCOS and AT had higher glucose levels in 120 min OGTT (115.29±41.70 vs. 98.56±28.02 mg/dl, p=0.08)., Conclusion: The study results showed no difference in the metabolic profile between the groups. The high concentration of estradiol found in girls with PCOS and AT may indicate the role of this hormone in the development of the autoimmune process. However, the numbers are small, and more research is needed to confirm our findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Skrzyńska, Zachurzok and Gawlik.)

Purpose: To evaluate factors influencing the insulin and levothyroxine requirement in patients with autoimmune polyglandular syndrome type 3 (APS-3) vs. patients with type 1 diabetes mellitus (T1DM) and autoimmune hypothyroidism (AH) alone, respectively., Methods: Fifty patients with APS-3, 60 patients with T1DM and 40 patients with AH were included. Anthropometric, clinical and biochemical parameters were evaluated in all patients. Insulin requirement was calculated in patients with APS-3 and T1DM, while levothyroxine requirement was calculated in APS-3 and AH., Results: Patients with APS-3 showed higher age (p = 0.001), age of onset of diabetes (p = 0.006) and TSH (p = 0.004) and lower total insulin as U/day (p < 0.001) and U/Kg (p = 0.001), long-acting insulin as U/day (p = 0.030) and U/kg (p = 0.038) and irisin (p = 0.002) compared to T1DM. Patients with APS-3 had higher waist circumference (p = 0.008), duration of thyroid disease (p = 0.020), levothyroxine total daily dose (p = 0.025) and mcg/kg (p = 0.006), triglycerides (p = 0.007) and VAI (p = 0.010) and lower age of onset of thyroid disease (p = 0.007) than AH. At multivariate analysis, levothyroxine treatment and VAI were associated with insulin and levothyroxine requirement in APS-3, respectively. VAI was independently associated with insulin requirement in T1DM. Circulating irisin levels were independently associated with levothyroxine requirement in AH., Conclusion: Patients with APS-3 show lower insulin requirement and higher levothyroxine requirement than T1DM and AH alone, respectively. Levothyroxine treatment and VAI affect insulin and levothyroxine requirement, respectively, in APS-3. In T1DM, adipose tissue dysfunction, indirectly expressed by high VAI, is associated with an increased insulin requirement, while circulating irisin levels influence the levothyroxine requirement in AH.

Background: Auto-oxidized oxysterols are implicated in the pathogenesis of various chronic diseases. Their concentrations are indicators of oxidative stress in vivo and associated with atherosclerosis. Subclinical hypothyroidism is related with cardiac diseases and oxidative stress, but the exact mechanisms underlying these associations are not clear yet., Objective: To investigate the auto-oxidized oxysterols, 7-ketocholesterol (7-KC) and cholestane-3β,5α,6β-triol (chol-triol), in patients with subclinical hypothyroidism, as well as to evaluate the impact of restoring euthyroidism on oxysterol concentrations., Methods: In this prospective observational study, 64 patients with newly diagnosed autoimmune thyroiditis (41 with subclinical hypothyroidism and 23 euthyroidism), and 45 healthy controls were enrolled. Age, gender, and body mass index were matched among patient groups and healthy controls. Anthropometric measurements were obtained and fasting plasma 7-ketocholesterol and cholestane-3β,5α,6β-triol concentrations were measured by using liquid chromatography coupled with tandem mass spectrometry. Levothyroxine was then administered to all patients with subclinical-hypothyroidism. After three months, measurements of the oxysterols and serum cholesterols from the patients who have become euthyroid were repeated., Results: Concentrations of 7-ketocholesterol and cholestane-3β,5α,6β-triol were significantly higher in patients with subclinical-hypothyroidism when compared to both euthyroid patients and healthy controls (p < 0.001 for both oxysterols). After restoration of euthyroidism, concentrations of 7-ketocholesterol and cholestane-3β,5α,6β-triol decreased significantly and reached similar concentrations observed in healthy controls (p < 0.001 for both oxysterols)., Conclusions: Auto-oxidized oxysterol species are higher in patients with mild thyroid dysfunction, and supported the rationale for treating subclinical-hypothyroidism., (Copyright © 2021 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Thyroid cancer (TC) is one of the most common malignant tumors, with high morbidity and mortality rates worldwide. The incidence of TC, especially that of papillary thyroid carcinoma (PTC); has increased rapidly in recent decades. Autoimmune thyroid disease (AITD) is closely related to TC and has an estimated prevalence of 5%. Thus, it is becoming increasingly important to identify potential diagnostic biomarkers and therapeutic targets for TC and AITD. Circular RNAs (circRNAs) are a class of non-coding RNAs with covalently bonded circular structures that lack 5'-3' polarity and polyadenylated tails. Several circRNAs play crucial roles in the development of various diseases, including TC and AITD, and could be important new biomarkers and/or targets for the diagnosis and therapy of such disorders. Although there are four subtypes of TC, research on circRNA has largely focused on its connection to PTC. Therefore, this review mainly summarizes the relationships between circRNAs and PTC and AITD, including the molecular mechanisms underlying these relationships. In particular, the functions of "miRNA sponges" and their interactions with proteins and RNA are discussed. The possible targeting of circRNAs for the prevention, diagnosis, and treatment of TC and AITD is also described. CircRNAs could be potential biomarkers of TC and AITD, although validation will be required before they can be implemented in clinical practice., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

We have reviewed the available literature on thyroid diseases and coronavirus disease 2019 (COVID-19), and data from the previous coronavirus pandemic, the severe acute respiratory syndrome (SARS) epidemic. We learned that both SARS and COVID-19 patients had thyroid abnormalities. In the limited number of SARS cases, where it was examined, decreased serum T3, T4 and TSH levels were detected. In a study of survivors of SARS approximately 7% of the patients had hypothyroidism. In the previous evaluation evidence was found that pituitary function was also affected in SARS. Others suggested a hypothalamic-pituitary-adrenal axis dysfunction. One result published recently indicates that a primary injury to the thyroid gland itself may play a key role in the pathogenesis of thyroid disorders in COVID-19 patients, too. Subacute thyroiditis, autoimmune thyroiditis and an atypical form of thyroiditis are complications of COVID-19. Thyroid hormone dysfunction affects the outcome by increasing mortality in critical illnesses like acute respiratory distress syndrome, which is a leading complication in COVID-19. Angiotensin-converting enzyme 2 is a membrane-bound enzyme, which is also expressed in the thyroid gland and the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) uses it for docking, entering as well as replication. Based on the available results obtained in the SARS-CoV-2 pandemic, beside others, we suggest that it is necessary to monitor thyroid hormones in COVID-19.

Vitamin D is one of the most important nutrients required by the human body. It is a steroid hormone that plays an important role in regulating calcium and phosphorus metabolism, and bone health. Epidemiological studies have revealed a close correlation between vitamin D and many common chronic diseases. Additionally, vitamin D has recently been shown to act as an immunomodulatory hormone, and, accordingly, vitamin D deficiency was uncovered as a risk factor for autoimmune thyroid diseases, although the underlying mechanisms are still unknown. It is therefore necessary to disclose the role and mechanism of action of vitamin D in the occurrence and development of autoimmune thyroid diseases. This knowledge will help design intervention and early treatment strategies for patients with autoimmune thyroid diseases who present with low levels of vitamin D., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhao, Zhang, Ma, Zhao, Xiong, Wang, Chen and Zheng.)

Objective: Mercury and other toxic metals have been suggested to be involved in thyroid disorders, but the distribution and prevalence of mercury in the human thyroid gland is not known. We therefore used two elemental bio-imaging techniques to look at the distribution of mercury and other toxic metals in the thyroid glands of people over a wide range of ages., Materials and Methods: Formalin-fixed paraffin-embedded thyroid tissue blocks were obtained from 115 people aged 1-104 years old, with varied clinicopathological conditions, who had thyroid samples removed during forensic/coronial autopsies. Seven-micron sections from these tissue blocks were used to detect intracellular inorganic mercury using autometallography. The presence of mercury was confirmed using laser ablation-inductively coupled plasma-mass spectrometry which can detect multiple elements., Results: Mercury was found on autometallography in the thyroid follicular cells of 4% of people aged 1-29 years, 9% aged 30-59 years, and 38% aged 60-104 years. Laser ablation-inductively coupled plasma-mass spectrometry confirmed the presence of mercury in samples staining with autometallography, and detected cadmium, lead, iron, nickel and silver in selected samples., Conclusions: The proportion of people with mercury in their thyroid follicular cells increases with age, until it is present in over one-third of people aged 60 years and over. Other toxic metals in thyroid cells could enhance mercury toxicity. Mercury can trigger genotoxicity, autoimmune reactions, and oxidative damage, which raises the possibility that mercury could play a role in the pathogenesis of thyroid cancers, autoimmune thyroiditis, and hypothyroidism., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Oxidative stress has been proposed as one of the factors concurring in the pathophysiology of autoimmune thyroid diseases. Reactive oxygen species are the main expression of oxidative stress in biological systems, and their production can overcome antioxidant defenses ultimately leading to cell damage, apoptosis, and death. The present review was aimed at describing the state of the art of the relationships between oxidative stress and autoimmune thyroiditis. The most used biomarkers of oxidative stress and their correlation with thyroid function are reported., Evidence Acquisition: We conducted a search of the literature in the English language starting from 2000, using the following search terms: "Hashimoto thyroiditis," "autoimmune thyroiditis," "hypothyroidism," "hyperthyroidism," "oxidative stress," "oxidants," "antioxidant," "advanced glycation end products." Both clinical studies and animal models were evaluated., Evidence Synthesis: Data form clinical studies clearly indicate that the balance between oxidants and antioxidants is shifted towards the oxidative side in patients with autoimmune thyroiditis, suggesting that oxidative stress may be a key event in the pathophysiology of the disease, irrespective of thyroid function. Studies in animal models, such as the NOD.H2h4 mouse, confirm that thyroidal accumulation of ROS plays a role in the initiation and progression of autoimmune thyroiditis., Conclusions: Oxidant/antioxidant imbalance represent a key feature of thyroid autoimmunity. Oxidative stress parameters could be used as biochemical markers of chronic inflammation, to better predict the disease evolution along its natural history. Dietary habits and antioxidant supplements may provide protection from autoimmunity, opening new perspectives in the development of more tailored therapies.

Because of contradictory results, clinical significance of elevated levels of macroprolactin (macroprolactinemia) remains unclear. The aim of this study was to investigate whether macroprolactinemia determines levothyroxine action on hypothalamic-pituitary-thyroid axis activity and thyroid antibody titers in women with autoimmune hypothyroidism. The study population included 2 age-, body mass index-, hormone-, and thyroid antibody-matched groups of premenopausal women with untreated autoimmune subclinical hypothyroidism: 15 subjects with coexisting macroprolactinemia and 29 individuals with prolactin levels within the reference range. All included patients were then treated with levothyroxine for 6 months. Serum levels of thyrotropin, free thyroid hormones, prolactin and 25-hydroxyvitamin D, titers of thyroid peroxidase and thyroglobulin antibodies, as well as macroprolactin content were assessed at the beginning and at the end of the study. Except for 25-hydroxyvitamin D levels and macroprolactin content, there were no significant differences between both study arms in the investigated markers. All participants completed the study. In both treatment arms, levothyroxine treatment decreased thyrotropin levels, increased free thyroxine and free triiodothyronine levels, as well as reduced thyroid peroxidase titers, but this effect was less pronounced in women with macroprolactinemia. In women with normal prolactin levels, levothyroxine reduced also thyroglobulin antibody titers and increased 25-hydroxyvitamin D levels. In this group of patients, treatment-induced changes in hormone levels and thyroid antibody titers correlated with treatment-induced changes in 25-hydroxyvitamin D levels. The obtained results suggest that macroprolactin excess attenuates the impact of levothyroxine on hypothalamic-pituitary-thyroid axis activity and thyroid autoimmunity., (© 2020, The American College of Clinical Pharmacology.)

Background: Despite advances in targeted kinase inhibitor development for patients with medullary thyroid cancer (MTC), most patients develop resistance and would benefit from alternative approaches. Immune-based therapies are now considered for patients with progressive MTC. This study is the first comprehensive assessment of the immune milieu, immune-suppressive molecules, and potential tumor antigens in patients with MTC. Methods: Primary and/or regionally metastatic tumor tissues from 46 patients with MTC were screened for immune infiltrates by using standard immunohistochemistry (IHC) and further analyzed by multispectral imaging for T cell and myeloid markers. RNASeq expression profiling was performed in parallel. RNASeq, targeted sequencing, and IHC techniques identified cancer-associated mutations and MTC-enriched proteins. Results: Organized immune infiltration was observed in 49% and 90% of primary and metastatic tumors, respectively. CD8 + cells were the dominant T cell subtype in most samples, while CD163 + macrophages were most frequent among myeloid infiltrates. PD-1 + T cells were evident in 24% of patients. Myeloid subsets were largely major histocompatibility complex II (MHCII - ), suggesting a dysfunctional phenotype. Expression profiling confirmed enrichment in T cell, macrophage, and inflammatory profiles in a subset of samples. PD-L1 was expressed at low levels in a small subset of patients, while the immune regulatory molecules CD155 and CD47 were broadly expressed. Calcitonin, GRP, HIST1H4E, NOMO3, and NPIPA2 were highly and specifically expressed in MTC. Mutations in tumor suppressors, PTEN and p53, and mismatch repair genes, MSH2 and MSH6 , may be relevant to disease progression and antigenicity. Conclusions: This study suggests that MTC is a more immunologically active tumor that has been previously reported. Patients with advanced MTC should be screened for targetable antigens and immune checkpoints to determine their eligibility for current clinical trials. Additional studies are necessary to fully characterize the antigenic potential of MTC and may encourage the development of adoptive T cells therapies for this rare tumor.

The essential biological action of vitamin D is regulation of calcium and phosphorus metabolism and preserving bone health. In recent years there have been reports about the extraskeletal actions of vitamin D and its role in the regulation of immune system. Vitamin D supplementation appears to reduce the incidence of cardiovascular diseases, cancer, and infections and be able to reduce all-cause mortality. Deficiency of vitamin D has been found to correlate with the increased incidence of autoimmune diseases, including type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis. Autoimmune thyroid diseases (AITD), including Graves' disease, Hashimoto's thyroiditis are relatively common autoimmune disorders affecting more than 5% of general population. It has been shown that vitamin D receptors (VDR) and 1-alpha hydroxylase are expressed in papillary thyroid cancer and normal thyroid tissue, suggesting local synthesis of 1,25(OH)2D in the thyroid. While VDR gene polymorphism has been found in much research to be associated with AITDs, very few studies have examined the impact of vitamin D deficiency on the incidence of AITDs in humans with conflicting results. This review focuses on the association between vitamin D and autoimmune thyroid diseases and summarizes the results of vitamin D supplementation studies in patients with AITD., (This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Interleukin (IL)-10 is a highly important anti-inflammatory cytokine in the immune system. CD1dhi and CD5+ B cells are both traditionally defined IL-10-secreting B cells. In recent years, a B cell group with combined markers of CD1dhi and CD5+ has been widely studied as it has been reported to suppress autoimmunity in mouse models of autoimmune diseases through IL-10 mechanisms. From the perspective of origination, CD1dhi and CD5+ B cells are developed from different B cell lineages. Whether the regulatory capacity of these 2 B cell groups is consistent with their ability to secrete IL-10 has not been determined. In this study, we generated IL-10 knockout NOD.H-2h4 mice to investigate the function of endogenous IL-10 in autoimmune thyroiditis and conducted adoptive transfer experiments to explore the respective roles of CD5+ and CD1dhi B cells. In our results, the IL-10-/- NOD.H-2h4 mice developed thyroiditis, similar to wild-type NOD.H-2h4 mice. The CD5+ B cells were more capable of secreting IL-10 than CD1dhi B cells in flow cytometric analysis, but the CD1dhi B cells showed more suppressive effects on thyroiditis development and autoantibody production, as well as Th17 cell response. In conclusion, endogenous IL-10 does not play an important role in autoimmune thyroiditis. CD1dhi B cells may play regulatory roles through mechanisms other than secreting IL-10., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The impact of concurrent autoimmune thyroid disease on the tumour microenvironment and disease progression in papillary thyroid cancer (PTC) is not well understood. Studies evaluating the programmed cell death ligand 1 (PD-L1) tumour expression in PTC have shown variable results, and the effect of lymphocytic thyroiditis (LT) on tumour PD-L1 expression has not been adequately assessed. The main aim of this study was to determine expression of PD-L1 in PTC with and without LT. We examined 81 PTC cases; 28.5% of all reviewed PTC had presence of LT. In PTC specimens without LT, tumour PD-L1 expression was significantly lower compared to PD-L1 expression in PTC with LT, 6.9% vs 39.1%, respectively. Expression of PD-L1 did not differ with PTC stage, even when sub-categorised according to the presence and absence of LT. Utility of PD- L1 expression as a prognostic marker in thyroid cancer needs to be interpreted with caution., (Crown Copyright © 2020. Published by Elsevier B.V. All rights reserved.)

In the 1990s, selenium was identified as a component of an enzyme that activates thyroid hormone; since this discovery, the relevance of selenium to thyroid health has been widely studied. Selenium, known primarily for the antioxidant properties of selenoenzymes, is obtained mainly from meat, seafood and grains. Intake levels vary across the world owing largely to differences in soil content and factors affecting its bioavailability to plants. Adverse health effects have been observed at both extremes of intake, with a narrow optimum range. Epidemiological studies have linked an increased risk of autoimmune thyroiditis, Graves disease and goitre to low selenium status. Trials of selenium supplementation in patients with chronic autoimmune thyroiditis have generally resulted in reduced thyroid autoantibody titre without apparent improvements in the clinical course of the disease. In Graves disease, selenium supplementation might lead to faster remission of hyperthyroidism and improved quality of life and eye involvement in patients with mild thyroid eye disease. Despite recommendations only extending to patients with Graves ophthalmopathy, selenium supplementation is widely used by clinicians for other thyroid phenotypes. Ongoing and future trials might help identify individuals who can benefit from selenium supplementation, based, for instance, on individual selenium status or genetic profile.

Background: Defined by thyroid-pituitary feedback control, clinical diagnosis of hypothyroidism and hyperthyroidism has become synonymous with TSH measurement. We combined in silico analysis and in vivo data to explore the central influences on thyroidal T3 production., Materials & Methods: A system of five coupled first-order nonlinear parameterised ordinary differential equations (ODEs) is used to model the feedback control of TSH and TRH by thyroid hormones together with the feedforward control of thyroidal T3 secretion and enzymatic T4-T3 conversion. Dependencies of the stable equilibrium solutions of this ODE system, that is the homeostasis of the underlying physiological process, on the system parameters were investigated whether they accounted for clinical observations., Results: During the modelled transition to hypothyroidism, central control imposed an increasing influence in maintaining serum FT3 levels, compared to peripheral conversion efficiency. Numerical continuation analysis revealed dependencies of T3 production on different elements of TSH feedforward control. While T4-T3 conversion provided the main T3 source in euthyroidism, this was overtaken by increasing glandular T3 secretion when thyroid reserve declined. The computational results were in good agreement with data from untreated patients with autoimmune thyroiditis., Conclusions: Dependencies revealed in the expression of control differ in thyroid health and disease, using a physiologically based mathematical model of combined feedback-feedforward control of the hypothalamic-pituitary-thyroid regulation. Strong T3-protective mechanisms of the control system emerge with declining thyroid function, when glandular T3 secretion becomes increasingly influential over conversion efficiency. This has wide-ranging implications for the utility of TSH in clinical decision-making., (© 2020 Stichting European Society for Clinical Investigation Journal Foundation.)

Introduction: As it is generally known, regulatory B cells (Bregs) control inflammation and autoimmunity. The significance of Bregs in the population of children with autoimmune thyroid diseases (AITD) still offers plenty of potential to explore. The aim of this study was to estimate the expression of Bregs (phenotype CD19 + CD24 + CD27 + IL-10 + , CD19 + IL-10 + , CD1d + CD5 + CD19 + IL-10 + and CD1d + CD5 + CD19 + CD24 + CD27 + ) in a paediatric cohort with AITD and in health controls. Materials and methods: A total of 100 blood samples were obtained from 53 paediatric patients with Graves' disease (GD) ( N  = 12 newly diagnosed, mean age 12.5 ± 3.5 and N  = 17 during methimazole therapy, mean age 12.7 ± 4.4), Hashimoto's thyroiditis (HT) ( N  = 10 newly diagnosed, mean age 13.3 ± 2.9 and N  = 10 during L-thyroxine therapy, mean age 13.7 ± 3.4) and compared with healthy controls (C) ( N  = 15, mean age 13.1 ± 3.1). The expressions of the immune cell populations were analysed by four-color flow cytometry using a FASC Canto II cytometer (BD Biosciences). Results: There was a decreasing tendency in the number of lymphocytes B producing IL-10 (B10) cells among all B lymphocytes and more widely, also among all lymphocytes, in each study group, as compared to C. We reported a reduction in IL-10 production in Bregs with the expression of CD19 + CD24 + CD27 + IL-10 and CD1d + CD5 + CD19 + IL-10 + in both untreated and treated AITD. Conclusions: Our data demonstrate that the reduction in the number of Bregs with CD19 + CD24 + CD27 + IL-10 + and CD19 + IL-10 + expression could be responsible for breaking immune tolerance and for AITD development in children.

Background: Autoimmune thyroiditis (AIT) with euthyroid is associated with miscarriage. But the exact mechanism remains unclear. Studies have shown that the programmed cell death-1 (PD-1)/programmed cell death -ligand 1 (PD-L1) pathway is essential for normal pregnancy. However, the expression of PD-L1 in gestational trophoblasts in mice with autoimmune thyroiditis and the mechanisms leading to miscarriage have not been fully investigated., Methods: Immunofluorescence and Western blot were used to detect the expression of PD-L1, p-ERK, MMP-2 and MMP-9 in embryonic trophoblast cells of pregnant mice with AIT. The expression of PD-L1 in HTR-8/SVneo cells were silenced, and the expression of PD-L1, MMP-2, MMP-9, ERK and p-ERK1/2 was detected by Western blot analyses and immunofluorescence assays. Invasive assays were performed in PD-L1 silenced HTR-8/SVneo cells using a Transwell chamber., Results: Compared with normal pregnancy, the expression of PD-L1, ERK, p-ERK, MMP-2 and MMP-9 in embryonic trophoblast cells was significantly lower in pregnant mice with AIT. Compared with the negative control (NC) group (cells transfected with negative control siRNA), phosphorylation of MMP-2, MMP-9 and P-ERK1/2 proteins was significantly reduced in HTR-8/SVneo cells transfected with PD-L1 siRNA, and the number of cells penetrating the membrane was reduced., Conclusion: AIT inhibits ERK/MMP-2 and MMP-9 pathways through PD-L1 reduction, attenuates embryonic trophoblast invasion and ultimalely induces miscarriage ultimately.

Growing data supported that epigenetic modifications, including altered DNA methylation have a potential role in the pathogenesis of autoimmune thyroid diseases (AITD). In the present study we aimed to investigate the methylation status of ICAM-1 gene promoter in patients with AITD. Forty patients with Graves' disease (GD), 40 patients with Hashimoto thyroiditis (HT) and 40 normal controls were included. DNA extraction from blood samples was done to analyze the ICAM-1 methylation status using methylation-specific PCR method. RNA was also extracted to determine the ICAM-1 expression values by real time PCR. We found that the differences in the frequency of ICAM-1 methylation status between GD or HT and healthy individuals were statistically significant (p = 0.04, 0.018 respectively) whereas there was no significant difference between GD and HT patients (p > 0.05). There was a correlation between decreased ICAM-1 methylation and exophthalmos (p = 0.01) and the high TSI level (p < 0.002) in GD patients. However, there was no correlation between ICAM-1 methylation and other clinicopathological features or other laboratory parameters in GD or HT. Furthermore, ICAM-1 mRNA expression showed significant up-regulation in ICAM-1 un-methylated samples compared to methylated samples in both GD and HT patients (p < 0.001 for each). Results provided the evidence of association of the hypo-methylation status of ICAM-1 gene promoter with GD and HT patients. In addition, DNA methylation may have a critical role in the ICAM-1 expression regulation of AITD patients.

This study aims to investigate the level of DNA damage in high iodine (HI)-induced autoimmune thyroiditis (AIT), and to explore the role of DNA repair protein MutT homolog-1 (MTH1) in this process. The levels of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-8 were measured using qRT-PCR and ELISA. The apoptosis was evaluated using TUNEL staining. The pathological changes of thyroid tissues were evaluated using hematoxylin and eosin (HE) staining. The DNA damage was assessed by determining the expression of 8-hydroxy-2'deoxyguanosine (8-OHdG; an indicator of oxidative DNA damage) and performing the Comet assay. Our results showed that both the HI-treated NOD.H-2 h4 mice (experimental AIT mice) and the HI-treated mouse thyroid follicular epithelial cells showed enhanced inflammation, apoptosis, and DNA damage level, accompanied by decreased MTH1 expression. Importantly, overexpression of MTH1 effectively abrogated the HI-induced enhancement of inflammation, apoptosis, and DNA damage in mouse thyroid follicular epithelial cells. In conclusion, HI treatment induces DNA damage in AIT, at least in part, by inhibiting the DNA repair protein MTH1., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To study the effect of Bcl-2 family members on experimental autoimmune thyroiditis(EAT) and explore the pathogenesis of autoimmune thyroiditis., Methods: Twenty-four female 4-5 week old NOD-SCID mice were randomly divided into four groups(six mice in each group): control group, high iodine group, poly(I:C) group and high iodine combined with poly(I:C) group. Control group and poly(I:C) group were fed with distilled water, while the high iodine group and high iodine combined with poly(I:C) group were supplied with 0. 05% NaI in their drinking water for 16 weeks. Poly(I:C) group and high iodine combined with poly(I:C) group received intraperitoneal injection of 100 μL poly(I:C)(1 μg/μL) at monday, wednesday and friday of the 11 th and 15 th week. Serum and thyroid were obtained at the last day of the 16 th week. The EAT model was confirmed by ELISA method and pathological HE staining, the apoptosis of thyroid cell were detected by TUNEL method and Cyt-C immunocytochemistry assay, and the mRNA levels of Bcl-2 family members in thyroid were determined by real-time qPCR method., Results: EAT model was established using NOD-SCID mice through high-iodine feeding combined with poly(I:C) intraperitoneal injection. The degree of cell apoptosis and the Cyt-C expression levels were positively correlated with inflammation in thyroid follicular epithelial cells. The mRNA levels of Noxa, PUMA and Bid of high iodine group and high iodine combined with poly(I:C) group were higher than those in control and poly(I:C) groups(P<0. 05)., Conclusion: Mitochondrial apoptosis pathway is involved in the thyroid cell apoptosis of EAT induced by high iodine, and the apoptosis may be regulated by the up-regulation of Noxa, PUMA and Bid, which belong to the pro-apoptotic members of Bcl-2 family.

Di-isononyl phthalate (DINP) is used as a substitute for traditional phthalates, in a wide range of applications. However, there is growing concern regarding its toxicity. Studies have indicated that DINP is related to thyroid hormone disorder and that phthalates can affect thyroid normal function. In this study, we aim to determine any effects of DINP exposure on autoimmune thyroid disease (AITD), the most common autoimmune disease, and to understand the underlying causal mechanism. AITD model Wistar rats were exposed to 0.15 mg/kg, 1.5 mg/kg or 15 mg/kg DINP. We assessed the thyroid globulin antibody levels, Th1/Th2 balance, histopathological changes and caspase-3 levels in the thyroid. The data show that exposure to DINP does indeed aggravate AITD. To explore the underlying mechanisms, we examined the levels of microtubule-associated protein 1 light chain 3 B (LC3B), Sequestosome 1 (SQSTM1) and the appearance of autophagosomes or autolysosomes to assess autophagy in the thyroid. The results show that DINP can suppress normal autophagy. We found that DINP induced an exacerbation of oxidative stress and the activation of the Akt/mTOR pathway, indicating that oxidative stress and activation of mTOR may play a key role in these processes. Moreover, the activation of mTOR also promoted the expression of IL-17. Importantly, blocking oxidative stress with VE or blocking Akt/mTOR with rapamycin mitigated the exacerbation of AITD and the suppression of normal autophagy. All these results indicate that exposure to DINP, especially high doses of DINP, can aggravate oxidative stress and activate the Akt/mTOR pathway. This exposure then leads to a suppression of normal autophagy and expression of IL-17 in the thyroid, resulting in an eventual exacerbation of AITD., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Myo-inositol (Myo-Ins) plays an important role in thyroid function and autoimmunity. Myo-Ins is the precursor for the synthesis of phosphoinositides, which takes part in the phosphatidylinositol (PtdIns) signal transduction pathway, and plays a decisive role in several cellular processes. In the thyroid cells, PtdIns is involved in the intracellular thyroid-stimulating hormone (TSH) signaling, via Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) (PIP-3). Moreover, the phosphatidyl inositol 3 kinases (PI3K) family of lipid kinases regulates diverse aspects of T, B, and Tregs lymphocyte behaviour. Different mouse models deficient for the molecules involved in the PIP3 pathway suggest that impairment of PIP3 signaling leads to dysregulation of immune responses and, sometimes, autoimmunity. Studies have shown that cytokines modulate Myo-Ins in thyroid cells. Moreover, clinical studies have shown that after treatment with Myo-inositol plus seleniomethionine (Myo-Ins + Se), TSH levels significantly declined in patients with subclinical hypothyroidism due to autoimmune thyroiditis. The treatment was accompanied by a decline of antithyroid autoantibodies. After treatment serum CXCL10 levels declined, confirming the immune-modulatory effect of Myo-Ins. Additional research is necessary in larger population to evaluate the effect on the quality of life, and to study the mechanism of the effect on chemokines.

Chronic lymphocytic thyroiditis (CLT), also known as Hashimoto's thyroiditis, is an autoimmune disease in which the thyroid gland is gradually destroyed. To date, only a limited number of agents can effectively suppress thyroiditis development in CLT patients. The aim of the current study was to investigate the protective effect of emodin on experimental autoimmune thyroiditis (EAT) in mice, which is considered an excellent model for CLT. NaI was used to induce the EAT model in non‑obese diabetic (NOD) mice. An ELISA method was employed to detect the TgAb level (thyroid inflammation) in the serum of the EAT mice. The T cell subsets in peripheral blood and spleen were detected by flow cytometry. The histopathological study revealed that the thyroid inflammatory cell infiltration was significantly reduced by emodin compared with the model group. In addition, ELISA assays indicated that the NaI‑induced serum TgAb upregulation was dramatically revered by emodin. Moreover, the level of serum IFN‑γ and the cell populations of CD3+CD4+IL‑4+, CD3+CD4+ IFN‑γ+, CD3+CD8+IL‑4+, CD3+CD8+ IFN‑γ+ T cells in peripheral blood monocytes and splenic lymphocytes were significantly increased by NaI in the model group compared with in the normal group. Nevertheless, this type of increase was markedly attenuated by emodin. To conclude, the EAT model was successfully established by treating NOD mice with NaI. Emodin indicated an inhibitory effect on the autoimmune response that was significantly different in EAT compared with control mice. Furthermore, the anti‑inflammatory action of emodin on EAT mice may be mediated via the inhibition of the secretion of IFN‑γ and the cell numbers of CD3+CD4+IL‑4+, CD3+CD4+ IFN‑γ+, CD3+CD8+IL‑4+ and CD3+CD8+ IFN‑γ+ T cells in the peripheral blood monocytes and splenic lymphocytes. Therefore, the data may offer valuable insight on the efficacy of treatment of CLT with emodin.

Purpose of Review: To review the latest developments concerning the role of iodine in the pathophysiology of autoimmune thyroiditis., Recent Findings: Recent studies have provided evidence that in areas with excess iodine intake, increased incidence of autoimmune thyroiditis marked by high titers of thyroid peroxidase and thyroglobulin antibodies has occurred. Investigations in the NOD.H2h4 mouse, a strain prone to AIT, showed that they are better adapted to the Wolff-Chaikoff effect., Summary: To provide an overview of the studies conducted during the last few years implicating iodine in the development and manifestation of autoimmune thyroiditis.

Apoptosis occurs in many autoimmune diseases. Excess iodine induces thyrocyte apoptosis and increases the incidence and prevalence of autoimmune thyroiditis (AIT). However, the sequence of events between the appearance of thyrocyte apoptosis and the occurrence of thyroiditis remains uncharacterized. Furthermore, few studies have investigated the role of macrophage phagocytosis in the development of AIT. Therefore, we evaluated the relationship between apoptosis and inflammatory infiltration in NOD.H-2 h4 mouse thyroids by comparing the sequence of events in tissue samples. We also investigated the role of macrophages by comparing macrophage phagocytosis function in BALB/c, C57BL/6, and NOD.H-2 h4 mice treated with different levels of iodine. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays and thyroid inflammatory scores revealed that apoptosis (2 weeks) occurred before inflammatory infiltration (4 weeks). Phosphatidylserine (PS) expression on the extracellular surface of the cell membrane and double-stranded DNA fragments associated with apoptosis appeared at 2 and 8 weeks, respectively. Additionally, although apoptosis was enhanced in the thyroids of mice supplemented with excess iodine (0.05 ± 0.12 vs 1.63 ± 0.82% for BALB/c, 0.09 ± 0.14 vs 1.51 ± 0.34% for C57BL/6, and 0.07 ± 1.11 vs 4.72 ± 0.62% for NOD.H-2 h4 mice), only NOD.H-2 h4 mouse thyroids presented with inflammation. Furthermore, macrophages from NOD.H-2 h4 mice (44.46 ± 1.79%) exhibited decreased phagocytotic activity relative to that in BALB/c (54.21 ± 4.58%) and C57BL/6 (58.96 ± 4.04%) mice. There were no differences in phagocytosis function between NOD.H-2 h4 mice supplemented with excess iodine or left untreated (24.50 ± 2.66 vs 21.71 ± 1.79%, p = 0.06). In conclusion, deficiencies in the apoptosis clearance of macrophages in NOD.H-2 h4 mice may constitute an early pathogenic mechanism in AIT that is not influenced by iodine intake.

Background: Inflammasomes, which mediate maturation of interleukin-1β (IL-β) and interleukin-18 (IL-18) and lead to pyroptosis, have been linked to various autoimmune disorders. This study investigated whether they are involved in the pathogenesis of autoimmune thyroiditis (AIT)., Methods: We collected thyroid tissues from 50 patients with AIT and 50 sex- and age-matched controls. Serum levels of free T3, free T4, thyrotropin, thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) were measured by electrochemiluminescent immunoassays. Expression of several inflammasome components, the NOD-like receptor (NLR) family pyrin domain containing 1 (NLRP1), NLRP3, CARD-domain containing 4 (NLRC4), absent in melanoma 2 (AIM2), the apoptosis-associated speck-like protein that contains a caspase recruitment domain (ASC), caspase-1, IL-1β, and IL-18 was determined by real-time PCR and western blot. Immunohistochemistry was used to localize the expression of NLRP1, NLRP3, NLRC4, and AIM2. The Nthy-ori 3-1 thyroid cell line was stimulated with tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-17A, interleukin-6, and poly(dA:dT). The levels of IL-18 and IL-1β in the cell supernatant were measured by enzyme-linked immunosorbent assay, and lactate dehydrogenase was quantified by absorptiometry. ASC specks were examined by confocal immunofluorescence microscopic analysis. Cell death was examined by flow cytometry, and the N-terminal domain of gasdermin D was detected by western blot analysis., Results: Expression of NLRP1, NLRP3, NLRC4, AIM2, ASC, caspase-1, pro IL-1β, pro IL-18, mRNA, and protein was significantly increased in thyroid tissues from patients with AIT, and enhanced posttranslational maturation of caspase-1, IL-18 and IL-1β was also observed. Expression of NLRP1, NLRP3, NLRC4, and AIM2 was localized mainly in thyroid follicular cells adjacent to areas of lymphatic infiltration. The thyroid mRNA level of NLRP1 and ASC was correlated to the serum TPOAb and TgAb levels in the AIT group. TNF-α and IFN-γ had a priming effect on the expression of multiple inflammasome components in thyroid cells. IFN-γ was found to strengthen poly(dA:dT)-induced cell pyroptosis and bioactive IL-18 release., Conclusion: Our work has demonstrated for the first time that multiple inflammasomes are associated with AIT pathogenesis. The identified NLRP3, NLRP1, NLRC4, AIM2 inflammasomes and their downstream cytokines may represent potential therapeutic targets and biomarkers of AIT.

Estrogens play important roles in autoimmune thyroiditis, but it remains unknown which estrogen receptor (ER) subtype mediates the stimulatory effects. Herein we treated ovariectomized mice with ERα or ERβ selective agonist followed by thyroglobulin-immunization to induce experimental autoimmune thyroiditis (EAT), and observed the aggravation of EAT after diarylpropionitrile (DPN, ERβ selective agonist) administration. The mRNA levels of interleukin(IL)-17A, IL-21 and RORγt and percentages of T helper (Th) 17 cells were up-regulated in the splenocytes of DPN-treated mice. Activated ERβ was found directly binding to IL-17A and IL-21 gene promoters, and also indirectly promoting IL-21 and RORγt gene transcription through interaction with NF-κB. The expressions of co-stimulatory molecules were increased on antigen-presenting cells (APCs) after DPN administration. It suggests that ERβ is the predominant ER subtype responsible for EAT development, and its activation may enhance Th17-type responses through genomic pathways and alteration of APCs' activities., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Autoimmune thyroiditis (AIT) has been found to be associated with polycystic ovary syndrome (PCOS). The aim of this retrospective cohort study using data from a fertility clinic, with patients recruited from 2009 to 2010, was to confirm the higher prevalence of AIT in PCOS and to evaluate the impact of AIT on reproductive and metabolic parameters of PCOS patients., Methods: Patients comprised 827 PCOS subjects seen for reproductive or metabolic complaints. Patients presenting primarily for thyroid problems were excluded. All patients were tested for the presence of AIT by laboratory testing and thyroid ultrasound. The impact of AIT on PCOS was evaluated by determination of reproductive and metabolic parameters., Results: Patients with PCOS and AIT as compared to those only with PCOS, had a lower prevalence of elevated testosterone (45 vs. 61%; p=0,0001), free androgen index (5,96±5,41 vs. 7,02±7,6; p<0,001) and hyperandrogenemia (66 vs. 78%; p<0,001). Also testosterone levels were lower in PCOS patients with AIT (0,50±0,30 vs. 0,63±0,71; p=0,0006). Consequently, in these patients, hirsutism was less frequent (51 vs. 66%; p=0,0021). There was no difference in the prevalence of acne, alopecia, a-/ or oligomenorrhea or PCO-morphology in the two patient groups. Patients with PCOS and AIT were more obese by 2 kg/m² BMI on average. A higher BMI correlated with a higher TSH value, although all patients were euthyroid., Conclusions: AIT is more prevalent in PCOS than in controls. PCOS patients with AIT have less severe hyperandrogenemia and hyperandrogenism but are likely to suffer from an elevated metabolic risk., Competing Interests: All authors declare that no competing financial interests exist. This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector., (© Georg Thieme Verlag KG Stuttgart · New York.)

Previous studies have reported a preponderance of autoimmune thyroiditis (AIT) in females, but the detailed mechanisms have not been elucidated. In this study, we explored the effects of oestrogen on experimental AIT (EAT) and its potential mechanisms in an ovariectomised mouse model through the supplementation of high (equivalent to the level during pregnancy) or low (equivalent to the level at the oestrus stage) doses of oestradiol (E2). We found that EAT incidence, the intrathyroidal inflammatory score, serum anti-thyroglobulin IgG2b levels, splenic mRNA expression of Th1- and Th17-specific transcription factors and typical cytokines and the proportion of IL-12-producing dendritic cells were significantly increased in EAT mice treated with low-dose E2 compared with those in the control group. However, they were not changed when administered with high-dose E2. These findings indicate that low physiological levels of E2 can stimulate the occurrence and development of EAT through the up-regulation of Th1/Th17 responses., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Dysregulated DNA methylation in lymphocytes has been linked to autoimmune disorders. The aims of this study were to identify global DNA methylation patterns in patients with autoimmune thyroid diseases and to observe methylation changes after treatment for these conditions., Methods: A cross-sectional study was conducted, including the following patients: 51 with newly diagnosed Graves' disease (GD), 28 with autoimmune hypothyroidism (AIT), 29 with positive thyroid autoantibodies, and 39 matched healthy volunteers. Forty GD patients treated with radioiodine or antithyroid drugs and 28 AIT patients treated with L-thyroxine were followed for three months. Serum free triiodothyronine, free thyroxine, thyrotropin, thyroid peroxidase antibodies, thyroglobulin antibodies, and thyrotropin receptor antibodies were assayed using electrochemiluminescent immunoassays. CD3 + T and CD19 + B cells were separated by flow cytometry for total DNA and RNA extraction. Global DNA methylation levels were determined by absorptiometry using a methylation quantification kit. DNA methyltransferase (DNMT) expression levels were detected by real-time polymerase chain reaction., Results: Hypomethylation and down-regulated DNMT1 expression in T and B lymphocytes were observed in the newly diagnosed GD patients. Neither the AIT patients nor the positive thyroid autoantibodies patients exhibited differences in their global DNA methylation status or DNMT mRNA levels compared with healthy controls. Antithyroid drugs restored global methylation and DNMT1 expression in both T and B lymphocytes, whereas radioiodine therapy affected only T cells. L-thyroxine replacement did not alter the methylation or DNMT expression levels in lymphocytes. The global methylation levels of B cells were negatively correlated with the serum thyroid peroxidase antibodies in patients with autoimmune thyroid diseases., Conclusions: Hyperthyroid patients with newly diagnosed GD had global hypomethylation and lower DNMT1 expression in T and B lymphocytes. The results provide the first demonstration that antithyroid drugs or radioiodine treatment restore global DNA methylation and DNMT1 expression with concurrent relief of hyperthyroidism.

Purpose: MicroRNA-326 (miR-326), as a member of the microRNA (miRNA) family, which includes endogenous single-stranded, conserved, noncoding small RNAs, has been reported to play important roles in autoimmune diseases such as multiple sclerosis and systemic lupus erythematosus. However, few studies of the role of miR-326 in autoimmune thyroiditis (AIT) have been published. Here, we explored the roles of miR-326 and the involved pathway in iodine-induced AIT., Methods: NOD.H-2 h4 mice, which are a model of human AIT, were randomly divided into a normal water control group and a high-iodine group. Mice in the high-iodine group were administered 0.05% NaI (~1000 times the normal daily iodine intake), and mice in the control group received sterile water. Furthermore, we evaluated small interfering RNA (siRNA) interference in spleen mononuclear cell experiments in vitro., Results: In this study, we found that Th17 cells were significantly increased with a high expression of miR-326 in an iodine-induced thyroiditis NOD.H-2 h4 mouse model. In addition, the expression of Ets-1 protein, a negative regulator of Th17 differentiation, was significantly decreased. Intriguingly, our analysis showed that Ets-1 protein expression was negatively correlated with miR-326 levels in AIT mice (r = -0.814, p < 0.01). Our study indicated that miR-326 inhibited Ets-1 protein expression and promoted the differentiation of Th17 cells during the onset and development of AIT. The addition of a miR-326 inhibitor reversed Th17 cell production and Ets-1 protein expression, supporting this hypothesis., Conclusions: The results of our study suggest that miR-326 may target the Ets-1 protein to contribute to iodide-induced thyroiditis, providing a new theoretical basis for the use of miRNA targeting therapy for the treatment of autoimmune diseases.

Background: High mobility group box-1 (HMGB1), a non-histone protein, plays an important role in autoimmune diseases. However, the significance of HMGB1 in the pathogenesis of autoimmune thyroiditis has not been reported. The purpose of this study was to explore whether HMGB1 participates in the pathogenesis of autoimmune thyroiditis, and whether glycyrrhizin (GL), a direct inhibitor of HMGB1, attenuates the severity of thyroid inflammatory infiltration in a murine model of autoimmune thyroiditis., Methods: A total of 80 male NOD.H-2 h4 mice were randomly divided into a control or iodine supplement (NaI) group at four weeks of age, and the control group was fed with regular water, whereas the NaI group was supplied with 0.005% sodium iodine water. Another 24 male NOD.H-2 h4 mice were also randomized into three groups (eight mice per group) as follows: control, NaI, and GL treatment after iodine supplementation (NaI + GL). The NOD.H-2 h4 mice were fed with 0.005% sodium iodide water for eight weeks to enhance autoimmune thyroiditis. After iodine treatment, the mice received intraperitoneal injections of GL for four weeks. The severity of lymphocytic infiltration in the thyroid gland was measured by histopathological studies. The serum levels of HMGB1, tumor necrosis factor alpha, interleukin (IL)-6, IL-1β, and thyroglobulin antibody titers were measured using an enzyme-linked immunosorbent assay. HMGB1 expression was measured by immunohistochemical staining and real-time polymerase chain reaction. TLR2, HMGB1, MyD88, and nuclear transcription factor κB were measured by Western blot., Results: The mRNA expression of HMGB1 was significantly higher at 8 and 16 weeks in the NaI group than it was in the control group. Serum levels of thyroglobulin antibodies, HMGB1, tumor necrosis factor alpha, IL-6, and IL-1β were significantly increased in the NaI group, but they were dramatically attenuated with GL injection. The prevalence of thyroiditis and the infiltration of lymphocytes were significantly decreased in the NaI + GL group. GL administration also significantly reduced the protein expression of TLR2, MyD88, HMGB1 and nuclear transcription factor κB in the thyroid gland and attenuated the severity of thyroiditis., Conclusion: HMGB1 may play a crucial role in autoimmune thyroiditis by causing inflammatory infiltration, thus increasing the severity of autoimmune thyroiditis. GL effectively attenuated thyroiditis in the iodine-induced NOD.H-2 h4 mice via a molecular mechanism related to the inhibition of TLR2-HMGB1 signaling.

Aim: The aim of the study was to assess the relationship between CCR5-Δ32 polymorphism and the coincidence of celiac and autoimmune thyroid diseases with type 1 diabetes mellitus (T1D) in children., Methods: 420 children with T1D aged 15.5±3.0years and 350 healthy controls were studied. Characterization of CCR5-Δ32 genotypes (rs333) was analyzed by polymerase chain reaction (PCR)., Results: The allele frequency was significantly different in diabetic children as compared to the healthy controls (p<0.0001). We found negative association between T1D and Δ32 allele (OR=0.383; 95% CI=0.268-0.549). Besides, we observed alterations in the frequencies of CCR5-Δ32 genotypes due to celiac and autoimmune thyroid diseases. The risk of celiac disease for patient carriers of the 32-bp deletion was more than threefold higher than for noncarriers (OR=3.490; 95% CI=1.357-8.859; p=0.009). Similar results were obtained in the case of autoimmune thyroiditis. The risk of autoimmune thyroiditis for patient carriers of the 32-bp deletion was also more than threefold higher than for noncarriers (OR=3.466; 95% CI=1.754-6.849; p=0.0004)., Conclusions: The findings of our studies suggest that the CCR5-Δ32 polymorphism is associated with type 1 diabetes mellitus and the Δ32 allele increases the risk of celiac disease and autoimmune thyroid disorders in patients with T1D., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Vitiligo is an acquired hypopigmentary disorder. The prevalence of vitiligo is 0.1-2% worldwide. Numerous autoimmune diseases are associated with vitiligo, including autoimmune thyroid diseases. The prevalence of thyroid abnormalities is up to 34% in vitiligo patients depending on ethnicities., Objective: This study aims to investigate thyroid abnormalities in Thai patients with vitiligo., Methods: Medical records of vitiligo patients attending outpatient dermatology clinic at a university-based hospital from 2012 to 2016 were retrospectively reviewed. Data regarding vitiligo, clinical features, and autoimmune thyroid laboratory results were retrieved and analyzed., Results: Among 325 vitiligo patients identified, anti-thyroid peroxidase and anti-thyroglobulin were positive in 90 (27.7%) and 63 patients (19.4%), respectively. Positive thyroid antibody was associated with female gender ( p < 0.001) and vitiliginous hand lesions ( p < 0.02). Out of 197 patients with complete thyroid function test, the prevalence of autoimmune thyroid diseases (AITD) is 12.7%. Female, nonsegmental type, higher affected area, and the presence of leukotrichia are significantly associated with AITD in vitiligo patients., Conclusions: Prevalence of positive thyroid antibodies and AITD in Thai patients with vitiligo is compatible with previous studies around the world. Screening for AITD with thyroid antibodies and serum TSH is essential for vitiligo patients.

Since the mid 1900s, a significant increase of infectious, hematological, and autoimmune diseases has been reported in patients with Down's syndrome (DS), independent of sex, age, family history, and exposure to other risk factors, suggesting an intrinsic alteration of the immune system. Several in vitro and in vivo studies have demonstrated alterations of both cellular and humoral immunological response mainly, although not exclusively, secondary to alterations of the expression of autoimmune regulator gene (located on chromosome 21), leading to thymic structural and functional impairments. Autoimmune thyroid disorders (i.e. Hashimoto's thyroiditis and Graves' disease) and type 1 diabetes mellitus are the most common autoimmune endocrine disorders associated with DS, and present with some peculiar features. The underlying etiopathogenic mechanisms and clinical significance of some mild laboratory alterations are still poorly understood. For these aspects, together with the associated multiple comorbidities and intellectual impairment - that make DS patients dependent on care givers - and in the absence of definite guidelines, disease management is very challenging and should be patient-tailored., (© 2017 S. Karger AG, Basel.)

Autoimmune polyglandular syndrome 3 variant (APS3v) refers to the co-occurrence of autoimmune thyroiditis (AITD) and type 1 diabetes (T1D) within the same individual. HLA class II confers the strongest susceptibility to APS3v. We previously identified a unique amino acid signature of the HLA-DR pocket (designated APS3v HLA-DR pocket) that predisposes to APS3v. We hypothesized that both thyroid and islet peptides can be presented by the unique APS3v HLA-DR pocket, triggering AITD + T1D together. To test this hypothesis we screened islet and thyroid peptides for their ability to bind to the APS3v HLA-DR pocket. Virtual screen of all possible thyroglobulin (Tg), thyroid-stimulating hormone receptor (TSHR), thyroid peroxidase (TPO), insulin (Ins), and glutamic acid decarboxylase 65 (GAD65) peptides identified 36 peptides that bound to this unique pocket. In vitro binding assays using baculovirus-produced recombinant APS3v HLA-DR identified 11 thyroid/islet peptides (of the 36 predicted binders) that bound with high affinity. By immunizing humanized HLA-DR3 mice carrying the APS3v HLA-DR pocket we identified 4 peptides (Tg.1571, GAD.492, TPO.758, TPO.338) that were presented by antigen presenting cells and elicited T-cell response. We conclude that both thyroid and islet peptides can bind to this flexible APS3v HLA-DR pocket and induce thyroid and islet specific T-cell responses. These findings set the stage to developing specific inhibitors of the APS3v HLA-DR pocket as a precision medicine approach to treating or preventing APS3v in patients that carry this genetic HLA-DR pocket variant., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Oxidative status in autoimmune thyroiditis (AIT) has not been investigated previously in children and adolescents. We investigated oxidant and antioxidant systems in a cohort of Egyptian children and adolescents with AIT to explore these as biomarkers of autoimmunity and thyroid function. Our case control study included 32 children with AIT and 32 healthy subjects with matching age and sex as a control group. After a thorough history and physical examination, a thyroid ultrasound, measurements of thyroid-stimulating hormone (TSH), free thyroxin (FT4), antithyroid peroxidase antibodies (TPOAb), and antithyroglobulin antibody were done with assessment of malondialdehyde (MDA) and total antioxidant capacity (TAC) levels as oxidative stress markers. Overt hypothyroidism was detected in 23/32, while subclinical hypothyroidism was detected in nine of the 32 studied patients. MDA levels were significantly elevated, while TAC levels were significantly decreased in AIT patients compared with healthy controls. The difference was more evident in patients with overt hypothyroidism than those with subclinical hypothyroidism. We also observed significant positive correlations of TPOAb levels with age, TSH, MDA, and thyroid volume, finding a negative correlation with TAC and FT4. In conclusion, the high serum MDA and lower TAC levels in patients with AIT and the correlation of thyroid antibodies with biomarkers of oxidative stress may reflect the role of autoimmunity in the development of oxidative stress. Future studies are needed for evaluation of antioxidant therapy for AIT patients. ClinicalTrials.gov Identifier NCT02318160. https://clinicaltrials.gov/ct2/show/NCT02318160 .

The thyroid is one of the metabolism regulating glands. Its function is to determine the amount of calories that the body has to burn to maintain normal weight. Thyroiditides are inflammatory processes that mainly result in autoimmune diseases. We have conducted the present study in order to have a clear picture of both autoimmune status and the control of body weight. We have evaluated the amount of either thyroid hormones, or antithyroid, or anti-microsomal, or anti-peroxidase antibodies (Abs) in patients with high amounts of Abs. In a diet devoid of carbohydrates (bread, pasta, fruit, and rice), free from goitrogenic food, and based on body mass index, the distribution of body mass and intracellular and extracellular water conducted for 3 weeks gives the following results: patients treated as above showed a significant reduction of antithyroid (-40%, P <0.013), anti-microsomal (-57%, P <0.003), and anti-peroxidase (-44%, P <0,029) Abs. Untreated patients had a significant increase in antithyroid (+9%, P <0.017) and anti-microsomal (+30%, P <0.028) Abs. Even the level of anti-peroxidase Abs increased without reaching statistical significance (+16%, P >0064). With regard to the body parameters measured in patients who followed this diet, reduction in body weight (-5%, P <0.000) and body mass index (-4%, P <0.000) were observed. Since 83% of patients with high levels of autoantibodies are breath test positive to lactase with a lactase deficit higher than 50%, this fact led us to hypothesize a correlation with carbohydrate-responsive element-binding protein and therefore a possible role of carbohydrate metabolism in the development and maintenance of autoimmune thyroiditis associated with body weight increase and slower basic metabolism.

From the recent literature data it may be concluded that vitamin D deficiency is associated with increased risk of thyroid autoimmunity development and thus should be considered as an additional important risk factor for both chronic autoimmune thyroiditis (postpartum thyroiditis including) and Graves´ disease. A higher risk of Graves´ disease development is also associated with several polymorphisms in the gene encoding for vitamin D binding protein and for the specific receptor of active form of vitamin D - 1,25-(OH)2D3 in the respective target cells. Whether careful supplementation with vitamin D aimed to normalize low 25(OH)D levels brings preventive or therapeutic effect is subject to further research.Key words: autoimmune thyroiditis - D vitamin deficiency - D vitamin supplementation - Graves´disease.

Thyroid lymphoepithelial complexes (LECos) are rare, being reported in lymphoma, Graves-Basedow disease, Hashimoto thyroiditis, pericarcinomatous thyroid or in the context of branchial cleft-like cysts. Here we report immunohistochemical expression of cytokeratin 5/6, P63 and TTF1 in 6 cases of thyroid LECos. Two cases had carbimazole treatment for hyperthyroidia and Graves disease. Anti-thyroglobulin, -thyroperoxidase or -TSH antibodies were detected in 4 cases. NSAID or poviodone iodine allergy were present in 2 cases. The treatment consisted in total thyroidectomy or lobectomy. Microscopy showed nodular goiter and focal lymphocytic thyroiditis. Basaloid LECos were seen in all thyroids while squamoid LECos in 2. Associated lesions were papillary thyroid microcarcinoma (2 cases), solid cell nest, thyroglosal duct remnant, lymphoepithelial cyst and thymus-parathyroid unit (one case each). Cytokeratin 5/6 was expressed in both squamoid and basaloid LECos along with P63. TTF1 expression was faint or absent. In conclusion LECos may occur in the context of autoimmune thyroiditis or of a specific immune susceptibility background. The expression of CK5/6 and of P63 suggests a squamous differentiation including in the basaloid LECos. The etiologic relevance of these immunostainings remains limited although rather suggestive of a metaplastic process than of migration-abnormalities., (Copyright © 2016 Elsevier Inc. All rights reserved.)