Tolerising cellular therapies: what is their promise for autoimmune disease?
Mosanya Chijioke H,Isaacs John D
Annals of the rheumatic diseases
The current management of autoimmunity involves the administration of immunosuppressive drugs coupled to symptomatic and functional interventions such as anti-inflammatory therapies and hormone replacement. Given the chronic nature of autoimmunity, however, the ideal therapeutic strategy would be to reinduce self-tolerance before significant tissue damage has accrued. Defects in, or defective regulation of, key immune cells such as regulatory T cells have been documented in several types of human autoimmunity. Consequently, it has been suggested that the administration of ex vivo generated, tolerogenic immune cell populations could provide a tractable therapeutic strategy. Several potentially tolerogenic cellular therapies have been developed in recent years; concurrent advances in cell manufacturing technologies promise scalable, affordable interventions if safety and efficacy can be demonstrated. These therapies include mesenchymal stromal cells, tolerogenic dendritic cells and regulatory T cells. Each has advantages and disadvantages, particularly in terms of the requirement for a bespoke versus an 'off-the-shelf' treatment but also their suitability in particular clinical scenarios. In this review, we examine the current evidence for these three types of cellular therapy, in the context of a broader discussion around potential development pathway(s) and their likely future role. A brief overview of preclinical data is followed by a comprehensive discussion of human data.
Postpartum thyroid dysfunction in women with autoimmune thyroiditis.
Argatska Antoaneta,Nonchev Boyan,Orbetzova Maria,Pehlivanov Blagovest
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology
INTRODUCTION:Autoimmune thyroiditis (AIT) is a predisposing factor for developing postpartum thyroid dysfunction (PPTD). AIM:To study the characteristics of PPTD in women with AIT. METHODS:Thirty-eight women with pre-existing AIT were included in the study. Thyroid-stimulating hormone, free triiodthyronine, free thyroxine, thyroid peroxidase antibodies, thyroglobulin antibodies were measured and ultrasound evaluation of the thyroid gland was performed in the first trimester of pregnancy and during the first year following delivery. RESULTS:Thyroid dysfunction was recognized in 68.4% of the patients - 28.9% presented with hypothyroidism and 39.5 % with thyrotoxicosis. The immunological and morphological parameters did not differ between euthyroid women and those with thyroid dysfunction. At the end of the postpartum period restoration of euthyroid state (being on the treatment before pregnancy) was observed in 15.4% of patients with PPTD, while 84.6% required increase of the levothyroxine dose. The analysis found a significantly lower volume of the thyroid gland, shorter duration of the disease, a lower dose of levothyroxine before and during gestation in patients with impaired thyroid function at the end of the postpartum period. CONCLUSION:The risk of PPTD in women with AIT predating pregnancy is higher among women with preserved thyroid functional capacity motivating a thorough assessment of thyroid hormone levels and close follow-up of those women during the postpartum period.
Selenium supplementation could restore euthyroidism in subclinical hypothyroid patients with autoimmune thyroiditis.
Pirola Ilenia,Gandossi Elena,Agosti Barbara,Delbarba Andrea,Cappelli Carlo
INTRIDUCTION:The thyroid is an organ with one of the highest selenium concentrations, containing many selenoproteins implicated in thyroid hormone metabolism. Treatment with levothyroxine has been recommended for all subclinical hypothyroid patients with TSH levels > 10 mU/L, whereas for those with TSH< 10 mU/L treatment remains controversial. AIM:A randomised controlled prospective study was performed to investigate the effects of Se treatment on patients with autoimmune thyroiditis and mild sub-clinical hypothyroidism (TSH < 10 mU/L). MATERIAL AND METHODS:A total of 196 patients with autoimmune thyroiditis were recruited in the study. Patients were assigned to receive (case) or not receive (control) an oral selenomethionine treatment. Cases received 83 mcg selenomethionine/day orally for four months. All the patient's charts were submitted to thyroid hormonal profile (TSH, fT4) and TPOAb evaluation upon enrolment and at the end of the study. RESULTS:In total 192 patients completed the study. Cases and controls were superimposable for age, gender, thyroid hormonal profile, and TPOAb levels. At the end of the study, 33/192 (17.2%) participants restored euthyroidism (Responders). Responders were significantly more frequent among Cases than Controls (30/96 [31.3%] vs. 3/96 [3.1%], p < 0.0001). CONCLUSION:Selenium supplementation could restore euthyroidism in one third of subclinical hypothyroidism patients with autoimmune thyroiditis. (Endokrynol Pol 2016; 67 (6): 567-571).
[Biochemical and immunological markers of autoimmune thyroiditis].
Biktagirova E M,Sattarova L I,Vagapova G R,Skibo Y V,Chuhlovina E N,Kravtsova O A,Abramova Z I
Correlations between biochemical and immunological markers of programmed cell death (apoptosis), and the functional state of the thyroid gland (hyperthyroidism, euthyroidism, hypothyroidism) have been investigated in autoimmune thyroiditis (AT) (also known as chronic autoimmune thyroiditis). Annexin V, TRAIL and TNF-a, as well as DNA-hydrolyzing antibodies were used as the main markers. Increased levels of TRAIL were found in the serum of AT patients (hyperthyroidism>hypothyroidism>euthyroidism) compared with healthy individuals. The highest frequency of antibodies to denatured DNA (Abs-dDNA) had the highest frequency in AT patients (97%) compared with healthy controls. Among these patients, 75% had hyperthyroidism, 85% had hypothyroidism, and 84.7% had euthyroidism. Abs hydrolyzing activity demonstrated correlation dependence with symptoms of the thyroid dysfunction.
Vitamin D status in children and adolescents with autoimmune thyroiditis.
Metwalley K A,Farghaly H S,Sherief T,Hussein A
Journal of endocrinological investigation
BACKGROUND:Vitamin D deficiency is a global health problem. Its role as an immune modulator has been recently emphasized. There is increasing evidence for the significant role of vitamin D in reducing the incidence of autoimmune diseases. However, little is known about the status of vitamin D in children and adolescents with autoimmune thyroiditis (AIT). OBJECTIVE:The goal of the present study was to assess vitamin D status in Egyptian children and adolescents with AIT and to explore its relation to biomarkers of autoimmunity and thyroid function. DESIGN:A prevalence case-control study that included 56 children with AIT and 56 healthy, age- and sex-matched subjects that served as the control group. The following was done for all participants: thorough history, physical examination, thyroid ultrasound, measurement of thyroid-stimulating hormone (TSH), free thyroxin (FT4), anti-thyroid peroxidase antibodies (TPOAb), anti-thyroglobulin antibody (TgAb) and assessment of serum 25-hydroxy vitamin D (25OHD) level. RESULTS:Overt hypothyroidism was detected in 42/56 while subclinical hypothyroidism was detected in 14/56 of the studied patients. Vitamin D deficiency rate was significantly higher in the AIT group compared to the control subjects (71.4 vs 21.4 %, P < 0.001). In AIT group, the mean level of 25OHD was significantly lower compared to the control group (16.2 ± 8.2 vs 33.9 ± 12.7 nmol/L, P < 0.001). The difference was more evident in patients with overt hypothyroidism than those with subclinical hypothyroidism (P < 0.01). There were significant negative correlations between serum 25OHD and age, duration of the disease, BMI, anti-TPOAb, anti-TGAb and TSH (P < 0.001 each). On the other hand, serum 25OHD correlated positively with FT4 levels. While 25OHD level was an independent risk factor for AIT, it failed to qualify as an independent risk for the progression of AIT to overt hypothyroidism after adjustment for other potential confounding factors; age, sex and BMI. CONCLUSIONS:Low serum vitamin D is significantly associated with AIT in Egyptian children. However, vitamin D level is not an independent risk for the progression of AIT to overt hypothyroidism. BMI may have an influence on serum 25OHD levels.
Elevated interleukin-1β in peripheral blood mononuclear cells contributes to the pathogenesis of autoimmune thyroid diseases, especially of Hashimoto thyroiditis.
Sun Li,Zhang Xiaoxu,Dai Fang,Shen Jijia,Ren Cuiping,Zuo Chunlin,Zhang Qiu
PURPOSE OF THE STUDY:To explore the relationship between IL-1β expression and two common autoimmune thyroid diseases: Hashimoto thyroiditis (HT) and Graves' disease (GD). MATERIALS AND METHODS:qRT-PCR, Quantiglo ELISA, and flow cytometry were used to evaluate the expression levels of IL-1β in serum, peripheral blood mononuclear cells (PBMCs), and thyroid tissue samples from patients with HT or GD. Local infiltration of monocytes was assessed by immunohistochemical study of patients' thyroid tissue samples. RESULTS:Although no significant differences in IL-1β levels were found between samples of serum from patients with HT or GD and normal controls, we found that IL-1β mRNA and protein levels in PBMCs of HT patients were significantly higher than those of patients with GD, which were in turn higher than the level in normal controls. In addition, IL-1β mRNA was also increased in thyroid gland tissue from patients with HT compared to those with GD, and this was accompanied by increased local infiltration of monocytes into thyroid tissues. Correlation analysis of the clinical samples validated the association of high IL-1β levels with the pathogenesis of HT. CONCLUSION:Our study suggests that IL-1β may be an active etiologic factor in the pathogenesis of HT and thus present a new target for novel diagnostics and treatment.
Regulatory T Cells and Vitamin D Status in Children with Chronic Autoimmune Thyroiditis.
Şıklar Zeynep,Karataş Deniz,Doğu Figen,Hacıhamdioğlu Bülent,İkincioğulları Aydan,Berberoğlu Merih
Journal of clinical research in pediatric endocrinology
OBJECTIVE:It is suggested that vitamin D is one of the factors that can regulate the function of Treg cells. In this study, the relationships between Treg cells and vitamin D levels was investigated in pediatric chronic autoimmune thyroiditis (CAT) patients. METHODS:Thirty-two children with CAT and 24 healthy subjects were studied. FOXP3 expressing CD4+CD25+high Foxp3+T cells were identified as Treg cells. At diagnosis, 25-hydroxycholecalciferol (25OHD3) levels were determined in all patients. FOXP3 expression was measured before and after vitamin D replacement therapy in patients having low levels of 25OHD3. RESULTS:In the CAT patients, Treg cell levels did not differ from the control group, while the frequency of vitamin D deficiency was higher and FOXP3 molecule expression was lower. FOXP3 molecule expression significantly increased in CAT patients having vitamin D deficiency who were given vitamin D replacement. CONCLUSION:FOXP3 expression is decreased in pediatric CAT patients. This reduction seems to be associated with vitamin D levels. Vitamin D can play a role in enhancing natural Treg cell functions.
Insufficient documentation for clinical efficacy of selenium supplementation in chronic autoimmune thyroiditis, based on a systematic review and meta-analysis.
Winther Kristian Hillert,Wichman Johanna Eva Märta,Bonnema Steen Joop,Hegedüs Laszlo
By a systematic review and meta-analysis to investigate clinically relevant effects of selenium supplementation in patients with chronic autoimmune thyroiditis. Controlled trials in adults (≥18 years) with autoimmune thyroiditis, comparing selenium with or without levothyroxine substitution, versus placebo and/or levothyroxine substitution, were eligible for inclusion. Identified outcomes were serum thyrotropin (thyroid stimulating hormone) levels in LT4-untreated patients, thyroid ultrasound and health-related quality of life. Eleven publications, covering nine controlled trials, were included in the systematic review. Random effects model meta-analyses were performed in weighted mean difference for thyroid stimulating hormone, ultrasound and health-related quality of life. Quality of evidence was assessed per outcome, using GRADE. Meta-analyses showed no change in thyroid stimulating hormone, or improvements in health-related quality of life or thyroid echogenicity (ultrasound), between levothyroxine substitution-untreated patients assigned to selenium supplementation or placebo. Three trials found some improvement in wellbeing in patients receiving levothyroxine substitution, but could not be synthesized in a meta-analysis. The quality of evidence ranged from very low to low for thyroid stimulating hormone as well as ultrasound outcomes, and low to moderate for health-related quality of life, and was generally downgraded due to small sample sizes. We found no effect of selenium supplementation on thyroid stimulating hormone, health-related quality of life or thyroid ultrasound, in levothyroxine substitution-untreated individuals, and sporadic evaluation of clinically relevant outcomes in levothyroxine substitution-treated patients. Future well-powered RCTs, evaluating e.g. disease progression or health-related quality of life, are warranted before determining the relevance of selenium supplementation in autoimmune thyroiditis.
l-selenomethionine supplementation in children and adolescents with autoimmune thyroiditis: A randomized double-blind placebo-controlled clinical trial.
Kyrgios Ioannis,Giza Styliani,Kotanidou Eleni P,Kleisarchaki Angeliki,Tsinopoulou Vasiliki Rengina,Papadopoulou Anastasia,Markantonatou Anthi-Marina,Kanellidou Eleni,Giannakou Anastasia,Galli-Tsinopoulou Assimina
Journal of clinical pharmacy and therapeutics
WHAT IS KNOWN AND OBJECTIVE:Although a beneficial effect of selenium (Se) administration has been proposed in adults with autoimmune thyroiditis (AT), there is a paucity of similar data in children and adolescents. The purpose of the study was to investigate whether administration of a high dose of organic Se (200 μg daily as l-selenomethionine) has an effect on antithyroid antibody titres in children and adolescents with AT. METHODS:Seventy-one (71) children and adolescents, with a mean age of 11.3 ± 0.3 years (range 4.5-17.8), diagnosed with AT (antibodies against thyroid peroxidase [anti-TPO] and/or thyroglobulin [anti-Tg] ≥60 IU/mL, euthyroidism or treated hypothyroidism and goitre in thyroid gland ultrasonography) were randomized to receive 200 μg l-selenomethionine or placebo daily for 6 months. Blood samples were drawn for measurement of serum fT4, TSH, anti-TPO and anti-Tg levels, and thyroid gland ultrasonography was performed at the entry to the study and after 6 months of treatment. RESULTS AND DISCUSSION:At the end of the study, a statistically significantly higher reduction in anti-Tg levels was observed in the Se group compared to the placebo group (Δ: -70.9 ± 22.1 vs -6.7 ± 60.6 IU/mL, P = 0.021). Although anti-TPO levels were also decreased in the Se group, this change was not statistically different from that of the control group (Δ: -116.2 ± 68.4 vs +262.8 ± 255.5 IU/mL, P = 0.219). No significant difference in thyroid gland volume was observed between the two study groups (P > 0.05). WHAT IS NEW AND CONCLUSION:In this original study, organic Se supplementation appears to reduce anti-Tg levels in children and adolescents with AT.
[Effects of Bcl-2 family on the thyroid cell apoptosis of experimental autoimmune thyroiditis mice induced by iodine].
Tan Xue,Xu Jing,Ma Wei,Wang Haiyan,Cao Xiaoxiao,He Li
Wei sheng yan jiu = Journal of hygiene research
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.
Effects of selenium and vitamin C on the serum level of antithyroid peroxidase antibody in patients with autoimmune thyroiditis.
Karimi F,Omrani G R
Journal of endocrinological investigation
PURPOSE:Selenium (Se), an essential trace element, has been implicated in pathogenesis of autoimmune thyroiditis (AIT). Most studies attributed the immune modulating effects of Se to its antioxidant properties. However, there is insufficient evidence to support the use of selenium supplementation or other antioxidants in patients with AIT. This clinical trial was designed to investigate the impact of Se and vitamin C supplementation on antithyroid peroxidase antibody (TPO-Ab) level in patients with AIT. METHODS:One hundred and two subjects aged 15-78 years were randomized into three groups. Group one (GI) (n = 38) was treated with 200 μg/day sodium selenite, group two (GII) (n = 36) received 500 mg vitamin C/day, and group three (GIII) (n = 28) received placebo over a 3-month period. Thyroid stimulating hormone (TSH), TPO-Ab, antithyroglobulin antibody (Tg-Ab) and Se concentrations were once measured before treatment and at the end of the study. RESULTS:After 3 months, TPO-Ab concentrations decreased within Se and vitamin C-treated groups, but did not change in the placebo subjects. In this regard, there was no significant difference between the groups. We also did not find any statistically significant difference in TSH and Tg-Ab levels within and between the groups. At the end of the study, Se level was significantly higher in GI compared with GII and GIII. CONCLUSION:Our findings supported the hypothesis of antioxidant beneficial effects of Se in AIT. However, it was not superior to vitamin C, regarding its effects on thyroid-specific antibodies.
To reflect human autoimmune thyroiditis, thyroid peroxidase (not thyroglobulin) antibodies should be measured in female (not sex-independent) NOD.H2 mice.
McLachlan S M,Aliesky H A,Rapoport B
Clinical and experimental immunology
NOD.H2 mice are the most commonly used model for human autoimmune thyroiditis. Because thyroid autoimmunity develops slowly (over months), NOD.H2 mice are usually exposed to excess dietary iodide to accelerate and amplify the process. However, unlike the female bias in human thyroid autoimmunity, autoantibodies to thyroglobulin (TgAb) are reported to be similar in male and female NOD.H2 . We sought evidence for sexual dimorphism in other parameters in this strain maintained on regular or iodized water. Without iodide, TgAb levels are higher in males than in females, the reverse of human disease. In humans, autoantibodies to thyroid peroxidase (TPOAb) are a better marker of disease than TgAb. In NOD.H2 mice TPOAb develop more slowly than TgAb, being detectable at 6 months of age versus 4 months for the latter. Remarkably, unlike TgAb, TPOAb levels are higher in female than male NOD.H2 mice on both regular and iodized water. As previously observed, serum T4 levels are similar in both sexes. However, thyroid-stimulating hormone (TSH) levels are significantly higher in males than females with or without iodide exposure. TSH levels correlate with TgAb levels in male NOD.H2 mice, suggesting a possible role for TSH in TgAb development. However, there is no correlation between TSH and TPOAb levels, the latter more important than TgAb in human disease. In conclusion, if the goal of an animal model is to closely reflect human disease, TPOAb rather than TgAb should be measured in older female NOD.H2 mice, an approach requiring patience and the use of mouse TPO protein.
Sphk1/S1P/S1PR1 Signaling is Involved in the Development of Autoimmune Thyroiditis in Patients and NOD.H-2 Mice.
Han Cheng,He Xue,Xia Xinghai,Guo Jiahui,Liu Aihua,Liu Xin,Wang Xinyi,Li Chengyan,Peng Shiqiao,Zhao Wei,Zhou Mi,Shi Xiaoguang,Li Yushu,Li Yongze,Shan Zhongyan,Teng Weiping
Thyroid : official journal of the American Thyroid Association
There is growing evidence that sphingosine-1-phosphate (S1P), a pleiotropic bioactive sphingolipid metabolite synthesized intracellularly by two closely related sphingosine kinases (SphKs), SphK1 and SphK2, is involved in inflammation. However, the role of SphKs/S1P/S1P receptors (S1PRs) in autoimmune thyroiditis (AIT) has not been studied to date. This study examined whether SphK1/S1P/S1PR1 signaling is aberrantly altered in thyroid tissues and serum of both AIT patients and a spontaneously autoimmune thyroiditis (SAT) mouse model. Murine CD4+T cells were employed to further investigate the downstream signaling of SphK1/S1P/S1PR1. Furthermore, a total of 102 NOD.H-2 mice, randomly divided into different groups, were used to investigate the therapeutic effect of S1PR1 blockade and its potential mechanism. We found that components of the SphK1/S1P/S1PR1 pathway were abnormally expressed in patients with Hashimoto thyroiditis and in a SAT mouse model. In addition, S1P could activate signal transducer and activator of transcription 3 (STAT3) through S1PR1 and its downstream signaling pathways in CD4+T cells of NOD.H-2 mice. Furthermore, an study demonstrated that blocking S1PR1 by FTY720 administration could reduce the incidence and severity of thyroiditis and goiter in SAT mice in a time-dependent manner. The proportions of STAT3-related and inflammation-related cell subtypes, such as T helper 1, T helper 17, and follicular T helper cells, were elevated in the SAT group when compared to the control group, and these cell subtypes decreased after FTY720 administration. Furthermore, the downstream inflammatory cytokines of STAT3 were also downregulated after FTY720 administration. The present study shows that blocking Sphk1/S1P/S1PR1 signaling can ameliorate the severity of AIT, providing evidence of a promising therapeutic target for AIT.
Vitamin D Receptor Gene Polymorphisms and Autoimmune Thyroiditis: Are They Associated with Disease Occurrence and Its Features?
Maciejewski Adam,Kowalczyk Michał J,Herman Waldemar,Czyżyk Adam,Kowalska Marta,Żaba Ryszard,Łącka Katarzyna
BioMed research international
Purpose:Vitamin D, besides its role in calcium-phosphorus metabolism, turned out to play a significant immunomodulating function. Until now four single nucleotide polymorphisms of vitamin D receptor gene (), rs2228570 (I), rs1544410 (I), rs7975232 (I), and rs731236 (I), have been studied in autoimmune thyroid disorders, with conflicting results. Another functional polymorphism of the gene, rs11568820 (Cdx2), has been shown to influence the immune system, although it has not been studied for its association with autoimmune thyroiditis to date. Therefore, the study aimed to evaluate the association of these five gene polymorphisms with susceptibility to autoimmune thyroiditis among Caucasian Polish population. A relationship between the studied polymorphisms and selected clinical features of the disease was additionally assessed. Methods:223 patients with autoimmune thyroiditis and 130 control subjects were enrolled in the study. polymorphisms were studied by PCR-RFLP or TaqMan real-time PCR. Results:Allele and genotype distributions of any of the studied polymorphisms did not differ significantly between patients and controls. Similarly, frequencies of haplotypes derived from rs1544410-rs7975232-rs731236 (I-I-I) polymorphisms were not significantly different in the two studied groups. However, a weak association between rs1544410 (I) or rs7975232 (I) polymorphisms and thyroid volume was found (p = 0.03 and p = 0.04, resp.). Conclusions:Our results suggest that gene is not a major susceptibility factor for autoimmune thyroiditis development, at least in Caucasian Polish population.
The effect of vitamin D on thyroid autoimmunity in euthyroid men with autoimmune thyroiditis and testosterone deficiency.
Krysiak Robert,Kowalcze Karolina,Okopień Bogusław
Pharmacological reports : PR
BACKGROUND:Autoimmune (Hashimoto's thyroiditis) is characterized by a strong female preponderance, which may suggest that sex hormones have an impact on thyroid autoimmunity. The aim of this study was to investigate whether testosterone determines vitamin D action on thyroid antibody titers and thyroid function tests in men with autoimmune thyroiditis and low testosterone levels. METHODS:The study included 36 men with testosterone deficiency, 17 of whom had been treated for at least 26 weeks with oral testosterone undecanoate (120 mg daily). Because of coexistent euthyroid Hashimoto's thyroiditis, all participants were then treated with vitamin D (100 μg daily). Serum titers of thyroid peroxidase and thyroglobulin antibodies, serum levels of thyrotropin, free thyroid hormones, testosterone and 25-hydroxyvitamin D, as well as Jostel's thyrotropin index, SPINA-GT and SPINA-GD were assessed before vitamin D treatment and 26 weeks later. RESULTS:With the exception of testosterone levels, there were no significant differences between both study groups in serum hormone levels, antibody titers and thyroid function tests. All participants completed the study. In addition to increasing 25-hydroxyvitamin D levels, vitamin D increased SPINA-GT and reduced thyroid peroxidase and thyroglobulin antibody titers. In testosterone-treated men, vitamin D increased testosterone levels. Vitamin D did not affect serum levels of thyrotropin, free thyroid hormones, Jostel's thyrotropin index and SPINA-GD. Treatment-induced changes in thyroid antibody titers and SPINA-GT were more pronounced in testosterone-treated than testosterone-naïve men. CONCLUSIONS:The obtained results suggest that the beneficial effect on thyroid autoimmunity and thyroid secretory function is stronger in men receiving testosterone therapy.
The Relationship between High Iodine Consumption and Levels of Autoimmune Thyroiditis-Related Biomarkers in a Chinese Population: a Meta-Analysis.
Wan Siyuan,Jin Baiming,Ren Bingxuan,Qu Mengying,Wu Huaiyong,Liu Lixiang,Boah Michael,Shen Hongmei
Biological trace element research
To comprehensively evaluate the relationship between high iodine concentration and biomarker abnormalities related to autoimmune thyroiditis in a Chinese population. Medline, PubMed, and Embase electronic databases were searched for articles published domestically and internationally on the relationship between high iodine concentrations and thyroid hormone antibodies and thyroid-stimulating hormone in China before March 2019. Articles published in Chinese were searched in the China Biology Medicine (CBM) disc, Wanfang Database, and China National Knowledge Infrastructure (CNKI). A total of 16 cross-sectional articles were included in this study, including 9061 participants. A meta-analysis was conducted in Stata 14.0. The binary categorical and continuous variables used odds ratios (ORs) and standardized mean differences (SMDs) with the corresponding 95% confidence intervals (CIs) as the effect statistics, respectively. The results showed that high iodine concentrations had a minimal association with the abnormal rates of thyroid peroxidase antibody (TPOAb) (OR = 1.274, 95% CI (0.957, 1.695), P > 0.05) and thyroglobulin antibody (TGAb) (OR = 1.217, 95% CI (0.911, 1.626), P > 0.05) in the entire population. The thyroid-stimulating hormone (TSH) level in the high iodine group was greater than that in the adaptive iodine group (SMD = 0.202, 95% CI (0.096, 0.309), P < 0.05). The results of the subgroup analysis showed that the abnormal TPOAb rate in pregnant women (OR = 1.519, 95% CI (1.007, 2.291), P < 0.05) and children (OR = 3.365, 95% CI (1.966, 5.672), P < 0.05) in the high iodine group was greater than that in the adaptive iodine group, and the abnormal TGAb rate of children in the high iodine group was greater than that in the adaptive iodine group. The TSH levels of lactating women (SMD = 0.24, 95% CI (0.053, 0.427), P < 0.05), pregnant women (SMD = 0.301, 95% CI (0.176, 0.426), P < 0.05), and children (SMD = 0.25, 95% CI(0.096, 0.309), P < 0.05) in the high iodine group were higher than those in the adaptive iodine group. Egger's and Begg's tests showed no significant (P > 0.1) publication bias. High iodine can increase the risk of abnormal levels of TPOAb, TGAb, and TSH related to autoimmune thyroiditis in pregnant women, lactating women, and children in China.
Potential role of IL-37 signaling pathway in feedback regulation of autoimmune Hashimoto thyroiditis.
Ren Cui-Ping,Sun Li,Liu Feng-Chun,Zuo Chun-Lin,Liu Miao,Gao Wenda,Shen Ji-Jia
Histochemistry and cell biology
IL-37, the anti-inflammatory cytokine of the IL-1 family, plays several key roles in the regulation of autoimmune diseases. Yet, its role in Hashimoto's thyroiditis (HT) is not clear. In the present study, we found that, in tissues from HT patients, most of the follicular epithelial cells were positive for both IL-37 and single Ig IL-1-related receptor (SIGIRR) by immunohistochemical staining, while the infiltrating lymphocytes and other inflammatory cells hardly expressed any. Meanwhile, mRNA expression levels of IL-37 in peripheral blood mononuclear cells (PBMC) of HT patients were significantly higher than those in normal controls measured by quantitative real-time PCR. Finally, we studied the possible role of IL-37 in IFN-γ-stimulated rat FRTL-5 cells. The results showed that IL-1β, TNF-α, and MCP-1 mRNA levels were significantly decreased, while the expression of IL-4 mRNA was dramatically up-regulated in IFN-γ-stimulated rat thyroid cell line FRTL-5 pre-treated with IL-37. The current study, for the first time, demonstrated that the IL-37 network is involved in Hashimoto's thyroiditis, and IL-37 signaling pathway may ameliorate the excessive autoimmune responses in this chronic lymphocytic thyroiditis.
Vitamin D Status and Thyroid Autoantibodies in Autoimmune Thyroiditis.
Koehler Viktoria F,Filmann Natalie,Mann W Alexander
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
A lack of vitamin D seems to be related to autoimmune diseases including autoimmune thyroiditis (AIT). This study intends to determine the correlation between improvement of 25-hydroxyvitamin D [25(OH)D] levels and AIT in patients from an outpatient endocrine clinic in Frankfurt, Germany. This study included 933 patients with thyroid peroxidase antibodies (anti-TPO-Ab) ≥34 kIU/l, including most patients with clear AIT due to a concurrent sonographic evidence of reduced echogenicity. We performed clinical evaluation and laboratory analysis at five points in time within two years retrospectively. Due to a high dropout rate within the observation period, we excluded the last two time points from analysis. Data from 933 AIT patients revealed 89% having vitamin D deficiency or insufficiency [25(OH)D <75 nmol/l] with a median 25(OH)D level of 39.7 nmol/l. At baseline, a weak inverse correlation between 25(OH)D and anti-TPO-Ab was observed during winter (r=-0.09, p=0.048*), but not during summer time (p>0.2). We discovered 58 patients having initially a 25(OH)D level < 75 nmol/l (median: 40.2 nmol/l), which improved over time to a 25(OH)D level ≥ 75 nmol/l (median: 83.2 nmol/l, p<0.0005***). Simultaneously, the median anti-TPO-Ab level showed a significant decrease of 25% from 245.8 to 181.3 kIU/l (p=0.036*). A significant reduction of the median anti-TPO-Ab level of 9% was also observed in the control group, which consisted of patients having constantly a 25(OH)D level <75 nmol/l. The result may suggest that in particular patients with 25(OH)D levels < 75 nmol/l benefit from an increase of 25(OH)D levels ≥ 75 nmol/l. Further prospective randomized controlled clinical trials are needed to finally evaluate if vitamin D has immunmodulatory effects in AIT.
Cytological, histopathological and immunological aspects of autoimmune thyroiditis: a review.
Buzdugă Cătălin Mihai,Costea Claudia Florida,Dumitrescu Gabriela FlorenŢa,Turliuc Mihaela Dana,Bogdănici Camelia Margareta,Cucu Andrei,Dumitrescu Nicoleta,Indrei Lucia,Şapte Elena,Ciobanu Apostol Delia Gabriela
Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie
Autoimmune thyroiditis (AT) is a disease that may be associated with many other autoimmune endocrine and non-endocrine disorders. This disease is mediated by both humoral and cellular mechanisms and it is the result of combined effects of human leukocyte antigen (HLA) class II genes and non-HLA genes polymorphisms. The clinical course of AT is variable and may be characterized by spontaneous remission and by irreversible thyroid insufficiency as the consequence of atrophic and fibrous transformation of the thyroid gland in other cases. In this paper, the AT's etiology and immunological mechanism along with its cytological and histopathological features are reviewed in order to increase our understanding about the mechanism involved in pathogenesis of this disease and to open new directions of investigations that will be useful in a better clinical practice.
Treatment with Myo-Inositol and Selenium Ensures Euthyroidism in Patients with Autoimmune Thyroiditis.
Nordio Maurizio,Basciani Sabrina
International journal of endocrinology
Clinical evidences have highlighted the efficacy of myo-inositol and selenium in the treatment of autoimmune thyroiditis. Aim of this study was to further analyze the role of myo-inositol plus selenium (Myo-Ins-Se) in restoring a normal thyroid function of Hashimoto's patients with subclinical hypothyroidism. Eighty-six patients with Hashimoto's thyroiditis having thyroid-stimulating hormone (TSH) levels between 3 and 6 mIU/L, elevated serum antithyroid peroxidase (TPOAb) and/or antithyroglobulin (TgAb), and normal free thyroxine (fT) and free triiodothyronine (fT) levels were enrolled in the study: one hyperthyroid subject with TSH about 0.14 U/ml was included in this trial as a single case. Patients were assigned to receive Myo-Ins-Se. TSH, TPOAb, and TgAb levels were significantly decreased in patients treated with combined Myo-Ins-Se after 6 months of treatment. In addition, a significant fT and fT increase, along with an amelioration of their quality of life, was observed. Remarkably, TSH values of the hyperthyroid patient increased from 0.14 U/ml up to 1.02 U/ml, showing a complete restoration of TSH values at a normal range. In conclusion, the administration of Myo-Ins-Se is significantly effective in decreasing TSH, TPOAb, and TgAb levels, as well as enhancing thyroid hormones and personal wellbeing, therefore restoring euthyroidism in patients diagnosed with autoimmune thyroiditis.
Expression and Function of the Costimulatory Receptor SLAMF1 Is Altered in Lymphocytes From Patients With Autoimmune Thyroiditis.
Vitales-Noyola Marlen,Ramos-Levi Ana M,Serrano-Somavilla Ana,Martínez-Hernández Rebeca,Sampedro-Nuñez Miguel,Di Pasquale Carmelina,González-Amaro Roberto,Marazuela Mónica
The Journal of clinical endocrinology and metabolism
Context:Signaling lymphocytic activation molecule family 1 (SLAMF1) is a costimulatory receptor expressed by most immune cells. Its role in autoimmune thyroid disease (AITD) is not well known. Objective:To analyze the expression and function of the costimulatory receptor SLAMF1 in lymphocytes of patients with AITD. Design:Cross-sectional, prospective, single-center study. Setting:Department of Endocrinology, Hospital Universitario de la Princesa, Madrid. Patients:Twenty-eight patients with AITD (17 with Graves disease and 11 with Hashimoto thyroiditis) and 21 controls. Intervention:Multiparametric flow cytometry and immunofluorescence techniques to analyze the expression of SLAMF1 in peripheral blood (n = 28) and thyroid tissue (n = 5) mononuclear cells. Assay of inhibition of cellular proliferation to study the function of SLAMF1 in CD4+CD25+ T regulatory (Treg) cells. Main Outcome Measure:Expression levels and the function of SLAMF1 in lymphocytes in AITD patients and controls. Results:Expression of SLAMF1 was significantly increased in peripheral blood CD4+, T helper 17, and CD19+ B cells from AITD patients. Immunofluorescence microscopy detected the presence of SLAMF1+ lymphocytes in thyroid inflammatory cell infiltrate. Functional studies showed that SLAMF1 engagement in Treg cells increased their suppressive function in healthy controls but not in AITD patients. Conclusions:The altered expression of SLAMF1, as well as its defective function observed in patients with AITD, may have a relevant role in the defective immune-regulatory function observed in this condition.
Glycyrrhizin, a Direct HMGB1 Antagonist, Ameliorates Inflammatory Infiltration in a Model of Autoimmune Thyroiditis via Inhibition of TLR2-HMGB1 Signaling.
Li Chenyan,Peng Shiqiao,Liu Xin,Han Cheng,Wang Xinyi,Jin Ting,Liu Shanshan,Wang Weiwei,Xie Xiaochen,He Xue,Zhang Hanyi,Shan Ling,Fan Chenling,Shan Zhongyan,Teng Weiping
Thyroid : official journal of the American Thyroid Association
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 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 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 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 mice via a molecular mechanism related to the inhibition of TLR2-HMGB1 signaling.
Changes in the DNA Methylation and Hydroxymethylation Status of the Intercellular Adhesion Molecule 1 Gene Promoter in Thyrocytes from Autoimmune Thyroiditis Patients.
Liu Tingting,Sun Jie,Wang Zhaojun,Yang Wenqing,Zhang Hao,Fan Chenling,Shan Zhongyan,Teng Weiping
Thyroid : official journal of the American Thyroid Association
BACKGROUND:The intercellular adhesion molecule 1 (ICAM1) gene is not expressed in normal thyroid tissue but was shown to be expressed in the thyroid tissue of autoimmune thyroiditis (AIT) patients. METHODS:This study aimed to explore whether the DNA methylation and hydroxymethylation status of the ICAM1 promoter are aberrantly altered in the thyroid cells of AIT patients and whether this change is associated with dysfunctional expression of ICAM1. A total of 35 AIT patients and 35 sex- and age-matched controls were studied. After the isolation of thyrocytes via density-gradient centrifugation, ICAM1 mRNA expression was measured using real-time PCR. The DNA methylation and hydroxymethylation status were assessed using quantitative PCR following T4 β-glucosyltransferase treatment and MspI/HpaII cleavage at -937 bp, -701 bp, -226 bp, and -65 bp upstream of the transcription start site (TSS). The DNA methylation level was verified via pyrosequencing. RESULTS:The AIT group showed increased DNA hydroxymethylation at -937 bp and -226 bp and decreased methylation at -937 bp, -701 bp, and -226 bp upstream of the TSS. Pyrosequencing also revealed DNA hypomethylation at -708 bp, -692 bp, -690 bp, and -688 bp upstream of the TSS. The DNA methylation status at -708 bp, -692 bp, and -226 bp upstream of the TSS was negatively associated with ICAM1 mRNA expression. CONCLUSION:In summary, we identified aberrant DNA methylation and hydroxymethylation of the ICAM1 gene promoter in the thyrocytes of AIT patients. This aberrant epigenetic modification is associated with increased expression of the ICAM1 gene.
Autoimmune Thyroiditis and Glomerulopathies.
Santoro Domenico,Vadalà Carmela,Siligato Rossella,Buemi Michele,Benvenga Salvatore
Frontiers in endocrinology
Autoimmune thyroiditis (AIT) is generally associated with hypothyroidism. It affects ~2% of the female population and 0.2% of the male population. The evidence of thyroid function- and thyroid autoantibody-unrelated microproteinuria in almost half of patients with AIT and sometimes heavy proteinuria as in the nephrotic syndrome point to a link of AIT with renal disease. The most common renal diseases observed in AIT are membranous nephropathy, membranoproliferative glomerulonephritis, minimal change disease, IgA nephropathy, focal segmental glomerulosclerosis, antineutrophil cytoplasmic autoantibody (ANCA) vasculitis, and amyloidosis. Different hypotheses have been put forward regarding the relationship between AIT and glomerulopathies, and several potential mechanisms for this association have been considered. Glomerular deposition of immunocomplexes of thyroglobulin and autoantibodies as well as the impaired immune tolerance for megalin (a thyrotropin-regulated glycoprotein expressed on thyroid cells) are the most probable mechanisms. Cross-reactivity between antigens in the setting of genetic predisposition has been considered as a potential mechanism that links the described association between ANCA vasculitis and AIT.
Myo-inositol and selenium reduce the risk of developing overt hypothyroidism in patients with autoimmune thyroiditis.
Ferrari S M,Fallahi P,Di Bari F,Vita R,Benvenga S,Antonelli A
European review for medical and pharmacological sciences
OBJECTIVE:The beneficial effects obtained by myo-inositol in association with seleno-methionine in patients affected by subclinical hypothyroidism have been recently demonstrated. Here, we evaluate the immune-modulating effect of myo-inositol in association with seleno-methionine in patients with euthyroid autoimmune thyroiditis (AT). PATIENTS AND METHODS:Twenty-one consecutive Caucasian patients with newly diagnosed euthyroid chronic AT were evaluated. All subjects were treated with myo-inositol in association with selenium (600 mg/83 mg) tablets, twice per day, for six months. A complete thyroid assessment was done before the treatment, and after six months. RESULTS:After the treatment thyroid-stimulating hormone (TSH) levels significantly declined with respect to basal values, overall in patients with an initial TSH value in the high normal range (2.1<TSH<4.0), suggesting that the combined treatment can reduce the risk of a progression to hypothyroidism in subjects with autoimmune thyroid diseases (AITD). We found that after the treatment antithyroid autoantibodies levels declined. Moreover, the immune-modulatory effect was first confirmed by the fact that after the treatment CXCL10 levels declined, too. CONCLUSIONS:We first show an immune-modulatory effect of myo-inositol in association with seleno-methionine in patients with euthyroid AT. Further studies are needed to extend the observations in a large population, to evaluate the effect on the quality of life, and to study the mechanism of the effect on chemokines.
Papillary Thyroid Cancer and Coexisting Autoimmune Thyroiditis.
Veit Franziska,Graf Dieter,Momberger Saskia,Helmich-Kapp Brigitte,Ruschenburg Ilka,Peters Anja,Kussmann Jochen,Saeger Wolfgang,Schmidt Kurt Werner,Toetsch Martin,Nestler Kai,Mann Klaus
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
Histological findings often display an association between papillary thyroid carcinomas (PTC) and autoimmune thyroiditis (AIT) and so differ significantly from follicular thyroid carcinomas (FTC). The aim of this interdisciplinary, retrospective study was to evaluate the association of AIT in patients with PTC and FTC and a control group of benign nodular goiters. One hundred thyroidectomies with histologically confirmed differentiated thyroid carcinomas, 67 with PTC and 33 with FTC, were submitted for examination. The two control groups consisted of 60 patients with euthyroid nodular goiter, displaying no signs for malignancy (no surgery) and 100 patients (second control group) with surgery of a benign nodular goiter. Controls were collected to obtain data about the incidence of significantly increased TPOAbs in the first group and of lymphocytic infiltrates (LI) in the second group. High TPOAbs were found in 35% (23/67) of patients with PTC. LI were detected by histology in 48% (32/67) of PTC. Ten patients (10/32) of this group showed the clinical and histological manifestation of a classic AIT with diffuse dense LI as well as diffuse hypoechogeneity in ultrasonography. In 7/32 cases, the histological report described focal dense LI (fAIT) and in 15/32 cases scant scattered LI. AIT and fAIT, together 25% of all PTC (17/67), showed germinal centers and can therefore be characterized as chronic autoimmune thyroiditis. In this group, high TPOAb could be detected in 94% (16/17). Scan scattered LI without germinal centers (15/32) do not represent a fAIT, although TPOAb are high in 47% (7/15). The younger age group (<45 years) showed significantly more often high TPOAbs (p<0.023) in comparison with the age-group older than 60 years. In contrast to PTC, only 4/33 (12%) patients with FTC had high TPOAb levels. We conclude that in contrast to benign euthyroid goiters and to FTC, different degrees of LI are often associated with high TPOAb levels and seem to be significantly increased in PTC, particularly prominent in younger age. There is a high coincidence between LI and high TPOAb levels. In the presence of hypoechoic thyroid nodule, signs of thyroid autoimmunity such as the presence of high TPOAbs, lymphocytic infiltration in cytology, and/or characteristic ultrasonic features, are arguments that might favor the decision for surgery if a cytologically indeterminate thyroid nodule is found and focal autonomy is excluded by szintiscan.
BREG cells in Hashimoto's thyroiditis isolated or associated to further organ-specific autoimmune diseases.
Santaguida Maria Giulia,Gatto Ilenia,Mangino Giorgio,Virili Camilla,Stramazzo Ilaria,Fallahi Poupak,Antonelli Alessandro,Segni Maria,Romeo Giovanna,Centanni Marco
Clinical immunology (Orlando, Fla.)
Hashimoto thyroiditis (HT) may occur isolated or associated with other non-endocrine autoimmune disorders (NEAD). No data are available about Breg cells in these disorders and this represented the aim of the study. Th17 and Breg cells subset were characterized on peripheral blood mononuclear cells isolated from 18 healthy donors (HD), 19 patients with isolated HT and 26 patients with HT+NEAD. Th17 were higher in patients with isolated HT than in HD but no further changes were seen in patients with HT+NEAD. CD24CD38 unstimulated Breg cells were similar in HT patients and in HD, but significantly higher in patients with HT+NEAD than in both HT and in HD. CD19CD24CD27 Breg memory phenotype was similar in HD and in HT patients, but decreased in patients with HT+NEAD (23.4%vs38.5%). Upon CpG-stimulation, CD24CD38 IL-10 Breg cells were higher in HT patients than in HD (3.9%vs1.8%) but similar in patients with HT+NEAD (2.4%).
Low 25 Hydroxyvitamin D Levels are Independently Associated with Autoimmune Thyroiditis in a Cohort of Apparently Healthy Overweight and Obese Subjects.
De Pergola Giovanni,Triggiani Vincenzo,Bartolomeo Nicola,Giagulli Vito Angelo,Anelli Michele,Masiello Michele,Candita Vittoria,De Bellis Dario,Silvestris Franco
Endocrine, metabolic & immune disorders drug targets
BACKGROUND:Low vitamin D levels have been associated with autoimmune disorders and, then, with the Hashimoto's autoimmune thyroiditis (AT), the most common autoimmune disease. Obesity is characterized by lower vitamin D levels and higher risk to develop autoimmune diseases. The aim of the study was to examine the possibility of an association between AT and decreased 25(OH) vitamin D (25(OH)D) levels in a cohort of otherwise healthy overweight and obese subjects. MATERIALS AND METHODS:Two hundred sixty one overweight subjects (mean age: 40.9 + 15.6 years, 200 women and 61 men) were enrolled for this study. All of them did not show any clinically evident metabolic or chronic diseases (i.e. hypertension, diabetes mellitus, renal failure, etc.) and did not use any kind of drug. Serum fasting levels of 25(OH)D, anti-thyroid peroxidase (TPO-Ab) and antithyroglobulin (TG-Ab) antibodies, free triiodothyronine (FT3), free thyroxine (FT4), thyroid stimulating hormone (TSH), glucose, uric acid and lipids (triglycerides, total, HDL and LDL cholesterol) were measured. Demographic, anthropometric and clinical parameters (age, body mass index (BMI), waist circumference, blood pressure) were also assessed. RESULTS:Fifty five percent of all subjects (144/261) showed vitamin D deficiency (≤ 20 ng/ml), and 17% of all individuals had AT (45/261). The percentage of subjects having vitamin D deficiency was significantly higher among those with AT (31 of 45, 69%) than in those without AT (113 of 216, 52%) (χ2= 4.1, p = 0.042). TSH levels were significantly higher in subjects with AT as compared to those without AT (M-W = 7715.5, p < 0.0001). The final logistic model of a multivariate analysis, performed with AT as the dependent variable and sex, age, BMI category, 25(OH)D category, and HDLcholesterol and TSH levels as the independent ones, showed that patients with AT were more likely to have deficiency of 25(OH)D (p = 0.031) and higher TSH (p < 0.005) levels. Seventy six percent of patients with vitamin D deficiency (110 of 144) were obese whereas 59% of patients without vitamin D deficiency were obese (69 of 117) (p=0.003). Waist circumference was different between subjects with deficiency or normal 25 (OH) D levels (p=0.016). CONCLUSION:This study clearly shows that vitamin D deficiency is significantly associated to AT in overweight and obese subjects and confirms that obesity is associated to lower vitamin D circulating levels. We suggest that screening for AT should be suggested in all obese subjects with vitamin D deficiency and that vitamin D deficiency should be researched in all obese subjects with AT.
The effect of vitamin D supplementation on thyroid autoantibody levels in the treatment of autoimmune thyroiditis: a systematic review and a meta-analysis.
Wang Su,Wu Yaping,Zuo Zhihua,Zhao Yijing,Wang Kun
PURPOSE:Although observational studies suggested that vitamin D plays a role in autoimmune thyroiditis (AIT), intervention trials yielded inconsistent findings. We therefore conducted a systematic review and a meta-analysis to evaluate the effects of Vitamin D on decreasing autoantibodies in patients with AIT. METHOD:We identified all studies that assessed the changes of TPO-Ab and Tg-Ab in patients with AIT under the treatment of vitamin D from PubMed, Embase, The Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang, and VIP Database. RESULTS:Six randomized controlled trials (RCTs) were included in this systematic review representing a total of 344 patients with AIT. The results showed that Vitamin D supplementation significantly dropped TPO-Ab titers [three studies, random effects standardized mean difference (SMD): -1.11, 95% CI -1.52 to -0.70, P < 0.01] at six months, but not at no more than 3 months [random effects SMD: -0.12, 95% CI: -0.69 to 0.44, P = 0.67]. As compared with control group, participants who received vitamin D supplementation demonstrated significantly lower Tg-Ab [random effects SMD: -0.55, 95% CI: -1.05 to -0.04, P = 0.033]. In addition, no serious adverse effect was reported. CONCLUSIONS:The current evidence suggests that vitamin D supplementation could decrease serum TPO-Ab and Tg-Ab titers of patients with AIT in the short-term (about six months). More high quality studies are needed to further confirm the effects, especially the long-term effects of Vitamin D supplementation on thyroid autoantibodies levels in the treatment of AIT.
Physiological low-dose oestrogen promotes the development of experimental autoimmune thyroiditis through the up-regulation of Th1/Th17 responses.
Xiang Yang,Jin Qian,Li Li,Yang Yali,Zhang Hongmei,Liu Miao,Fan Chenling,Li Jing,Shan Zhongyan,Teng Weiping
Journal of reproductive immunology
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.
Cytokine Secretion and Pyroptosis of Thyroid Follicular Cells Mediated by Enhanced NLRP3, NLRP1, NLRC4, and AIM2 Inflammasomes Are Associated With Autoimmune Thyroiditis.
Guo Qingling,Wu Ying,Hou Yuanyuan,Liu Yongping,Liu Tingting,Zhang Hao,Fan Chenling,Guan Haixia,Li Yushu,Shan Zhongyan,Teng Weiping
Frontiers in immunology
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.
Association of Depression and Anxiety Disorders With Autoimmune Thyroiditis: A Systematic Review and Meta-analysis.
Siegmann Eva-Maria,Müller Helge H O,Luecke Caroline,Philipsen Alexandra,Kornhuber Johannes,Grömer Teja Wolfgang
Importance:With a prevalence of 4% to 13% in the United States, autoimmune thyroiditis (AIT) is a major health problem. Besides somatic complications, patients with AIT can also experience psychiatric disorders. The extent of these organic psychiatric diseases in patients with AIT, however, is so far not commonly known. Objective:To provide meta-analytic data on the association of depression and anxiety with AIT. Data Sources:Google Scholar, the EBSCO Host databases, the Web of Knowledge, and PubMed were searched from inception through December 5, 2017. Articles identified were reviewed and reference lists were searched manually. Study Selection:Case-control studies that reported the association between AIT and either depression or anxiety disorders or both were included. Data Extraction and Synthesis:Data extraction was performed by multiple observers following the PRISMA guidelines. Two univariate random-effects meta-analyses were performed, and moderators were tested with Bonferroni-corrected meta-regression analysis. Heterogeneity was assessed with the I2 statistic. Sensitivity analyses tested the robustness of the results. Small study effects were assessed with funnel plots and the Egger test. Main Outcomes and Measures:The odds ratio of patients with AIT and depression compared with a healthy control group, as well as the odds ratio of patients with AIT and anxiety disorders compared with a healthy control group. Results:Nineteen studies comprising 21 independent samples were included, with a total of 36 174 participants (35 168 for depression and 34 094 for anxiety). Patients with AIT, Hashimoto thyroiditis, or subclinical or overt hypothyroidism had significantly higher scores on standardized depression instruments, with an odds ratio of 3.56 (95% CI, 2.14-5.94; I2 = 92.1%). For anxiety disorders, patients with AIT, Hashimoto thyroiditis, or subclinical or overt hypothyroidism had an odds ratio of 2.32 (95% CI, 1.40-3.85; I2 = 89.8%). Funnel plot asymmetry was detected for studies of depression. Study quality assessed with the Newcastle-Ottawa Scale for case-control studies (mean [SD] score: anxiety, 5.77 [1.17]; depression, 5.65 [1.14]; of a possible maximum score of 9) and proportion of females did not modulate the meta-analytic estimate, whereas mean age did. Conclusions and Relevance:This meta-analysis establishes the association between AIT and depression and anxiety disorders. Patients with AIT exhibit an increased chance of developing symptoms of depression and anxiety or of receiving a diagnosis of depression and anxiety disorders. This finding has important implications for patients and could lead to the choice of early treatment-and not only psychotherapeutic treatment-of the organic disorder.
Autoimmune disease, familial clustering and thyroid carcinoma coexistent with autoimmune thyroiditis in children and adolescence: A cross-sectional study from the Czech Republic.
Pomahacova Renata,Zamboryova Jana,Paterova Petra,Fiklik Karel,Cerna Zdenka,Lad Vaclav,Skalicka Eva,Huml Michal,Sykora Josef
Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia
BACKGROUND:The prevalence of autoimmune thyroiditis (AIT), as the most common autoimmune disease (AD) and papillary thyroid cancer (PTC) is steadily rising in children. The aim of this study was to determine the coexistence of other AD and thyroid carcinoma (TC) in AIT. METHODS:The cross-sectional study conducted at a tertiary center comprised AIT children (< 19 years). Data on age/sex, thyroid function and ultrasound, autoantibodies, associated AD, familial occurence of AD and the occurence of TC for each child were collected. RESULTS:In total, 231 eligible patients (77% females) were included. The most common onset (66%) was during adolescence. At onset, hypothyroidism was detected in 59.3%; hashitoxicosis in 1.3%. The positivity of both autoantibodies was present in 60.6%, the negativity was in 3,5%. We confirmed a high frequency (44.6%) of AD with AIT predominance in parents and/or grandparents of patients and in siblings (7.4%). 15.2% had at least 1 comorbid AD, of which type 1 diabetes mellitus was the most common (8.5%). Over a period of 7 years TC was diagnosed in 16 patients (mean age 13.5 years) with predominance of PTC in 15 (94%) patients. AIT had concurrently 69% patients. 56% of patients had metastases (89% in AIT subjects). An invasive PTC was present in 44% (86% in AIT subjects). CONCLUSIONS:The prevalence rate of AD in AIT and first-degree relatives is high, and several new associations have been reported. Providers should be aware of comorbidities and TC in AIT as this would help in early diagnoses and timely interventions.
Edaravone ameliorates experimental autoimmune thyroiditis in rats through HO-1-dependent STAT3/PI3K/Akt pathway.
Li Hong,Min Jie,Mao Xiaoming,Wang Xueyang,Yang Yucheng,Chen Yuting
American journal of translational research
Autoimmune thyroiditis is among the most prevalent of all the autoimmunities in population. It is characterized as both cellular immune responses with T, B cells infiltrating to the thyroid gland followed by hypothyroidism as a result of destruction of the thyroid follicles and fibrous replacement of the parenchymal tissue, as well as immune response for TPO and Tg-antibody production. Experimental autoimmune thyroiditis (EAT) has been proven to be an ideal model to study autoimmune thyroiditis. In the present study, we induced an EAT model in rats and examined the effect of edaravone, a hydroxyl radical scavenging agent, on EAT severity and explored the mechanism. The results showed that edaravone reduced the severity score of thyroiditis dose-dependently and the levels of serum TPOAb, TgAb, T3 and T4. Edaravone significantly decreased the mRNA level of IL-17, but increased the mRNA level of IL-10, IL-4, TNF-α and IFN-γ. EAT model significantly induced oxidative stress, which was inhibited by the treatment of 10 mg/kg, 20 mg/kg or 40 mg/kg of edaravone. The EAT model significantly increased the Akt and STAT3 phosphorylation, but when rats were treated with 20 mg/kg or 40 mg/kg edaravone, they were significantly inhibited. The HO-1 expression was greatly increased by 20 mg/kg or 40 mg/kg edaravone. The PI3K inhibitor LY294002, Akt inhibitor triciribine or STAT3 inhibitor WP1066 all significantly decreased the severity score of thyroiditis in the EAT model group, while the HO-1 inhibitor ZnPP-IX increased the severity score of thyroiditis. These results confirm the invlovment of ROS and HO-1-dependent STAT3/PI3K/Akt pathway in the process of Hashimoto's thyroiditis and suggest the potential usage of edaravone in the therapy of it.
Patients With Autoimmune Thyroiditis Show Diminished Levels and Defective Suppressive Function of Tr1 Regulatory Lymphocytes.
Vitales-Noyola Marlen,Serrano-Somavilla Ana,Martínez-Hernández Rebeca,Sampedro-Nuñez Miguel,Ramos-Levi Ana M,González-Amaro Roberto,Marazuela Mónica
The Journal of clinical endocrinology and metabolism
Context:T regulatory type 1 (Tr1) cells are a subpopulation of T lymphocytes (CD4+CD49+LAG-3+IL-10+) that exert a considerable immunosuppressive effect. However, their possible role in autoimmune thyroid disease (AITD) has not been explored so far. Purpose:To analyze the levels and function of Tr1 cells in peripheral blood and thyroid tissue of patients with AITD. Design:Cases and controls, observational study. Setting:Department of Endocrinology, Hospital Universitario de la Princesa, Madrid, Spain. Patients:Thirty-eight patients with AITD (23 with Graves disease and 15 with Hashimoto thyroiditis) and 26 controls. Intervention:Multiparametric flow cytometry and immunofluorescence techniques were used to analyze the levels in peripheral blood (n = 38) and thyroid mononuclear cells (n = 5). An in vitro assay of suppression of cellular activation and cytokine release was performed to study the function of Tr1 cells. Main Outcome Measure:Levels and function of Tr1 cells in patients with AITD and controls. Results:Levels of Tr1 cells were significantly diminished in peripheral blood from patients with AITD. Functional studies showed that Tr1 cells from patients with AITD exhibit a diminished suppressive function compared with healthy controls. Tr1 levels were associated with disease severity, including longer duration of the disease and ophthalmopathy activity, and with autoantibody titers. Conclusions:The low levels of Tr1 cells and their diminished function may have a relevant role in the defective immune-regulatory function characteristic of patients with AITD.
The catalytic role of iodine excess in loss of homeostasis in autoimmune thyroiditis.
Duntas Leonidas H
Current opinion in endocrinology, diabetes, and obesity
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.
Safety and Efficacy of Low-Level Laser Therapy in Autoimmune Thyroiditis: Long-Term Follow-Up Study.
Höfling Danilo Bianchini,Chavantes Maria Cristina,Buchpiguel Carlos Alberto,Cerri Giovanni Guido,Marui Suemi,Carneiro Paulo Campos,Chammas Maria Cristina
International journal of endocrinology
Introduction:A randomized clinical trial (RCT) was performed to evaluate the efficacy of low-level laser therapy (LLLT) for hypothyroidism induced by chronic autoimmune thyroiditis (CAT). Objective:The objective was to assess the safety and actions of LLLT 6 years after completion of the RCT. Materials and Methods:Forty-three participants were invited to participate in this study 6 years after completion of the RCT. Twenty-five were subjected to LLLT (group L), and 18 were subjected to placebo (group P). Primary outcome measure: frequency of thyroid nodules, which were subjected to fine-needle aspiration biopsy. Secondary outcome measures: dose of levothyroxine required to treat hypothyroidism, thyroid peroxidase antibodies (anti-TPO), and anti-thyroglobulin antibodies (anti-Tg). Results:In group L, a nodule was observed in three patients, who all had a Bethesda II classification. In group P, a nodule was also observed in three patients, with two classified as Bethesda II and one as Bethesda III. The levothyroxine dose required by group L was significantly lower than that required by group P ( = 0.002). The anti-TPO and anti-Tg levels did not differ between the groups. Conclusion:LLLT, by the methods described, has been shown to be safe for the treatment of hypothyroidism resulting from CAT. This trial is registered with ClinicalTrials.gov Identifier: NCT02240563.
Decreased Thyroid Peroxidase Antibody Titer in Response to Selenium Supplementation in Autoimmune Thyroiditis and the Influence of a Selenoprotein P Gene Polymorphism: A Prospective, Multicenter Study in China.
Wang Weiwei,Mao Jinyuan,Zhao Jiajun,Lu Juming,Yan Li,Du Jianling,Lu Zhaohui,Wang Hai,Xu Mingtong,Bai Xue,Zhu Lin,Fan Chenling,Wang Hong,Zhang Hongmei,Shan Zhongyan,Teng Weiping
Thyroid : official journal of the American Thyroid Association
Recent intervention studies have suggested that selenium (Se) is an effective treatment for autoimmune thyroiditis (AIT). However, the exact effect of Se on AIT is unclear as well as the mechanism of action. The aim of the present study was to explore the effect of Se on thyroid peroxidase antibody (TPOAb) titers in patients with AIT and to analyze the potential impact of the genetic background on the effect of Se supplementation. This was a randomized, placebo-controlled, double-blind trial. Three hundred and sixty-four patients with elevated TPOAb (>300 IU/mL) were recruited and randomized to receive Se yeast 200 μg/day supplementation or placebo. Urinary iodine concentration, serum thyrotropin, free thyroxine, TPOAb, Se, malondialdehyde, and serum glutathione peroxidase activity were measured at baseline and follow-up. Ninety-six patients were genotyped for single nucleotide polymorphism r25191G/A in the selenoprotein P ( gene. The median urinary iodine concentration was 182 μg/L. Serum Se increased significantly ( < 0.001) after Se treatment. TPOAb titer decreased by 10.0% at 3 months and by 10.7% at 6 months after Se supplementation, while there was a moderate increase in TPOAb titers over the follow-up period in patients receiving placebo. Glutathione peroxidase activity significantly increased ( < 0.001), and malondialdehyde significantly decreased ( < 0.001) after 6 months of Se supplementation. TPOAb titers decreased to variable extents in patients with different genotypes of single nucleotide polymorphism r25191G/A after Se supplementation. Serum TPOAb titers in patients with the AA genotype showed a more significant decrease (by 46.2%) than those with the GA and GG genotypes (by 14.5 and 9.8% respectively) at 3 months of Se supplementation ( = 0.070). Se supplementation significantly reduced TPOAb titers in patients with AIT, and there may be an important genetic component influencing interindividual differences in the decrease in TPOAb titers.
Autoimmune thyroid disease during pregnancy.
De Leo Simone,Pearce Elizabeth N
The lancet. Diabetes & endocrinology
Understanding of changes in thyroid function and the consequences of thyroid disease during pregnancy has rapidly grown in the past two decades, and revised American Thyroid Association guidelines on this topic were published in 2017. This Review explores the association between thyroid autoimmunity and complications during and after pregnancy. Thyroid autoimmunity refers to the presence of antibodies to thyroperoxidase or thyroglobulin, or thyroid-stimulating hormone receptor antibodies (TRAbs), or a combination of these, and is present in up to 18% of pregnant women. Thyroid antibodies in pregnant women with normal functioning thyroids (ie, euthyroid) have been associated with several complications, including miscarriage and premature delivery. Treatments to improve pregnancy outcomes are being studied. Whether thyroid antibodies are associated with infertility and assisted reproductive technology outcomes is unclear; although, treatment with low doses of levothyroxine, which is usually used to treat hypothyroidism, can be considered in such situations. Additionally, thyroid antibodies have been associated with other neonatal and maternal complications. All these associations require confirmation in larger prospective studies, and their pathogenic mechanisms need to be better understood. Post-partum thyroiditis is substantially more frequent in women who have thyroid antibodies during pregnancy than in those who do not have thyroid antibodies; however, whether treatment can prevent post-partum thyroiditis in women who are or have been antibody positive is unknown. Finally, TRAbs cross the placenta from the mother to the fetus and can cause fetal or neonatal hyperthyroidism. Therefore, women who are positive for TRAbs during pregnancy should be monitored.
Effect of emodin on T cell subsets in NOD mice with NaI‑induced experimental autoimmune thyroiditis.
Sun Huaqin,Ye Zhipeng,Li Ning,Jin Fa,Yan Jiuliang,Wu Keren
Molecular medicine reports
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.