Determination of the Predictive Roles and Potentially Pathogenic Antigen Epitopes of α-Enolase Related to the Development of Miscarriage in Females with Autoimmune Thyroiditis.

Autoimmune thyroiditis (AIT) is a common endocrine disease which causes a significantly increased risk of miscarriage. Our recent study has shown that the increased ENO1 autoantibody (ENO1Ab) expression in an experimental AIT mouse model was induced by thyroglobulin (Tg) immunization only. In this study, we explored the potential roles of ENO1Ab in miscarriage occurrence among AIT women, and the specific epitopes of ENO1 targeted by ENO1Ab. A total of 432 euthyroid pregnant participants were selected from the project of Subclinical Hypothyroid during Early Pregnancy, including 48 women with AIT and miscarriage, 96 with miscarriage but no AIT, 96 with AIT but no miscarriage, and 192 without either AIT or miscarriage. The enzyme-linked immunosorbent assay was used to determine the serum levels of total IgG against ENO1 and 18 predicted antigen epitopes of ENO1. The results showed that women with AIT and miscarriage had the highest serum levels of ENO1Ab compared to the other groups. Logistic regression analysis showed that the serum ENO1Ab was an independent risk factor for miscarriage, especially among AIT females. The serum level of total IgG against the predicted epitope peptide 6 (i.e., P6 and aa168-183) of ENO1 was significantly increased in women with AIT and miscarriage when compared with those of both the AIT non-miscarriage group and non-AIT miscarriage group. This pilot study suggests that serum ENO1Ab may have a fair predictive value for AIT-related miscarriage, and the autoantibody specific to P6 epitope may especially be more specifically related to this disorder.

Molecular Optimization on Polymer Acceptor Enables Efficient All-Polymer Solar Cell with High Open-Circuit Voltage of 1.10 V.

Currently, rational design of polymer acceptors is desirable but there is still a challenge to develop high-performance all-polymer solar cells (all-PSCs). In this work, brominated thienyl-fused malononitrile-based monomer is employed to copolymerize with indacenodithiophene (IDT) and benzodithiophene (BDT)-based linking units to develop two polymerized small molecule acceptors (PSMAs) PIDT and PBDT, respectively, for all-PSCs. The two PSMAs show similar absorption edges, while PBDT shows a slightly higher lowest unoccupied molecular orbital (LUMO) energy level than PIDT. Benefitted from the relatively high LUMO levels of the two polymer acceptors, notable open-circuit voltage (Voc ) values over 1.0 V are achieved when using them as acceptor to blend with PTQ10 as polymer donor. Particularly, the all-PSC based on PTQ10:PIDT demonstrates a power conversion efficiency of 10.19%, with an outstanding Voc of 1.10 V benefitted from the higher LUMO energy level of PIDT acceptor. The results demonstrate a feasible strategy to design PSMAs by selecting appropriate linking units for increasing the Voc and improving the efficiency of all-PSCs.

Estrogen receptor ß activation stimulates the development of experimental autoimmune thyroiditis through up-regulation of Th17-type responses.

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 ERß selective agonist followed by thyroglobulin-immunization to induce experimental autoimmune thyroiditis (EAT), and observed the aggravation of EAT after diarylpropionitrile (DPN, ERß 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 ERß 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 ERß 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.

Differential Expression of MicroRNAs and miR-206-Mediated Downregulation of BDNF Expression in the Rat Fetal Brain Following Maternal Hypothyroidism.

To investigate the mechanism responsible for the neurological alterations, miRNA expression profile and brain-derived neurotrophic factor (BDNF) were evaluated in brain tissues of fetal or neonatal rats and from maternal rats with hypothyroidism. Ninety female Wistar rats were divided into a control and a hypothyroid group, which were mated. Brain samples of the offspring were obtained at maternal embryonic day (E) E13 and E17 as well as postnatal day (P) P0 and P7, and the hippocampus and cortex were separated at P7. BDNF mRNA at E13 was tested by real-time PCR and protein expression by Western blot. Luciferase assays were used to confirm that miR-206 targets the 3'-untranslated region (3'-UTR) of BDNF. In the brain tissues of fetal and neonatal rats from maternal rats with hypothyroidism, differentiation miRNAs profile were found at E13, E17, P0, and P7. Compared with the control group, miR-206 levels in the hypothyroidism group were increased by 3.1-fold by micro-array, and were higher as measured by SYBR green real-time qRT-PCR (p<0.01). There was no significant difference in the BDNF mRNA levels at E13 between the hypothyroidism group and the control group (1.767±0.477 vs. 1.798±0.462, respectively; p>0.05), but pro-BDNF and mature BDNF protein levels in the hypothyroid group at E13 were significantly lower than those in the control group (p<0.05). miR-206 targeted 3'-UTR of BDNF. Our data highlight the role of miR-206 as a post-transcriptional inhibitor of BDNF at E13 in pregnant hypothyroid rats.

Gestation-specific changes in maternal thyroglobulin during pregnancy and lactation in an iodine-sufficient region in China: a longitudinal study.

OBJECTIVES: To describe the changes in thyroglobulin (Tg) based upon gestational and postpartum concentrations in healthy pregnant women from an iodine-sufficient region in China, and to evaluate the use of Tg as a biomarker for iodine-sufficient pregnant women. DESIGN: A longitudinal study of Tg change in normal pregnant women from an iodine-sufficient region. PATIENTS AND MEASUREMENTS: Blood and urine samples were obtained from 133 pregnant women. Urinary iodine concentration (UIC) was measured using an ammonium persulfate method. Serum iodine concentration was required by inductively coupled plasma mass spectrometry (ICP-MS). Serum thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), total thyroxine (TT4), total triiodothyronine (TT3), antithyroid peroxidase antibody (TPOAb), antithyroglobulin antibody (TgAb) and Tg were measured using an electrochemiluminescence immunoassay. RESULTS: Thyroglobulin concentrations were higher in early pregnancy (pregnancy at 8 weeks vs nonpregnancy: 11·42 ng/ml vs 8·8 ng/ml, P < 0·01) and maintained a stable level, and then increased greatly at the 36th week. After delivery, Tg decreased to nonpregnant levels. During pregnancy, maternal Tg was not correlated with thyroid function, UIC or urine iodine-creatinine ratio (UI/Cr). Cord blood Tg was much higher compared to maternal Tg levels at the 36w (57·34 vs 14·86 ng/ml, P < 0·001) and correlated positively with cord FT4 (r = 0·256, P < 0·05), cord TT4 (r = 0·263, P < 0·05) and maternal UI/Cr at 36w (r = -0·214, P < 0·05). CONCLUSIONS: Our work demonstrates that Tg is elevated during pregnancy, and the effect of pregnancy should be taken into consideration when Tg is used as a biomarker for the iodine status. Cord blood Tg is much higher than maternal Tg levels at the 36w and is correlated with maternal iodine status.

Association of single nucleotide polymorphism rs3792876 in SLC22A4 gene with autoimmune thyroid disease in a Chinese Han population.

BACKGROUND: The autoimmune thyroid diseases (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are caused by interactions between susceptibility genes and environmental triggers. Single nucleotide polymorphisms (SNPs) of Solute carrier family 22, member 4 (SLC22A4) have been shown to be associated with several autoimmune diseases, including Crohn's disease (CD) and rheumatoid arthritis (RA). The aim of this study is to investigate whether SNP rs3792876 in the SLC22A4 gene is associated with GD, HT and AITD in a Chinese Han population. METHODS: In this study, we collected specimens from 553 Chinese Han individuals of 92 AITD pedigrees in 10 cities in Liaoning province, China (80 GD pedigrees, 478 members; 12 HT pedigrees, 75 members). SNP rs3792876 was genotyped using the TaqMan allelic discrimination assay. Hardy-Weinberg Equilibrium tests were performed among founders of the pedigrees using Haploview software. Family-based association tests performed using FBAT software. RESULTS: No deviation from Hardy-Weinberg equilibrium was observed (p > 0.05). There were not significant association between the SLC22A4 gene polymorphism (rs3792876) and GD, HT and AITD was found. CONCLUSIONS: These results suggest a lack of association between the SLC22A4 gene polymorphism rs3792876 and susceptibility to GD, HT and AITD in a Chinese Han population.

Dynamic changes in the gut microbiota during three consecutive trimesters of pregnancy and their correlation with abnormal glucose and lipid metabolism.

INTRODUCTION: During normal pregnancy, changes in the gut microbiota (GM) in response to physiological alterations in hormonal secretion, immune functions and homeostasis have received extensive attention. However, the dynamic changes in the GM during three consecutive trimesters of pregnancy and their relationship with glucose and lipid metabolism have not been reported. In this study, we aimed to investigate the dynamic changes in the diversity and species of the GM during three consecutive trimesters in women who naturally conceived, and their relationships with abnormal fasting blood glucose (FBG) and serum lipid levels. METHODS: A total of 30 pregnant women without any known chronic or autoimmune inflammatory disease history before pregnancy were enrolled during the first trimester. Serum and stool samples were collected during the first trimester, the second trimester, and the third trimester. Serum samples were tested for FBG and blood lipid levels, and stool specimens were analyzed by 16S rDNA sequencing. RESULTS: The abundance ratio of bacteroidetes/firmicutes showed an increasing tendency in most of the subjects (19/30, 63.3%) from the first to the third trimester. LEfSe analysis showed that the abundance of Bilophila was significantly increased from the first to the third trimester. In addition, at the genus level, the increased relative abundance of Mitsuokella, Clostridium sensu stricto and Weissella were potentially involved in the development of high FBG during pregnancy. The raised relative abundance of Corynebacterium, Rothia and Granulicatella potentially contributed to the occurrence of dyslipidemia during pregnancy. CONCLUSIONS: There are dynamic changes in the GM during the three trimesters, and the alterations in some bacterium abundance may contribute to the development of high FBG and dyslipidemia during pregnancy. Monitoring enterotypes and correcting dysbiosis in the first trimester may become new strategies for predicting and preventing glucolipid metabolism disorders during pregnancy.

Changing Iodine Status and the Incidence of Thyroid Disease in Mainland China: A Prospective 20-Year Follow-Up Study.

Background: We aimed to assess the long-term effects of the transition in iodine status on the incidence of thyroid disorders over 20 years of follow-up. Methods: The original prospective cohort study, started in 1999 (n = 3761), classified three regions in north China based on iodine status (insufficient iodine, more than adequate iodine, and excessive iodine, respectively) for 5 years. Subsequently, participants were followed for up to another 15 years to assess the long-term effects of shifts to adequate iodine on the incidence of thyroid disorders. Panshan transitioned from insufficient to adequate iodine, and Huanghua transitioned from excessive to more than adequate iodine. Both regions were compared with Zhangwu, in which iodine status changed from more than adequate to adequate iodine (from 214 to 167.2 µg/L). A cluster sampling method was used to select participants in the three regions. Participants completed questionnaires and underwent thyroid ultrasonography. Urinary iodine concentrations (UICs), serum thyroid hormone concentration, and thyroid antibodies were measured. Results: When the iodine status changed from insufficient to adequate (with the median UIC increasing from 88 to 141.9 µg/L), the incidence density of subclinical hyperthyroidism, positive thyroperoxidase antibody, positive thyroglobulin antibody (TgAb), and goiter decreased significantly (p < 0.05 for all). Additionally, the cumulative incidence of subclinical hypothyroidism was significantly lower compared with the region where the iodine status changed from being more than adequate to adequate (1.9% vs. 6.0%, p < 0.001). When the iodine status changed from excessive to more than adequate (median UIC from 634 to 266.7 µg/L), a significant decrease in the incidence density of subclinical hyperthyroidism, positive thyroid antibodies, positive TgAb, and goiter (p < 0.05 for all) were also found. However, an increase in thyroid nodule incidence density (17.26 vs. 28.25 per 1000 person-years, p < 0.001) was seen. Conclusions: The incidence of thyroid disorders (except for thyroid nodules) stabilized or decreased among adults in the three communities from year 5 to year 15 of follow-up. Appropriate iodine fortification is safe and effective over the long term. Restoring urinary iodine to appropriate levels reduces population risk for thyroid disorders.

Effect of maternal excessive iodine intake on neurodevelopment and cognitive function in rat offspring.

BACKGROUND: Iodine deficiency and iodine excess are both associated with adverse health consequences. Iodine deficiency during pregnancy leads to insufficient maternal thyroid hormone, subsequently causing irreversible adverse effects on the neurological and cognitive functions of the offspring. The results of our previous epidemiological study suggested that mild iodine excess might increase the prevalence of subclinical hypothyroidism. In the present study, female Wistar rats maintained on low-iodine grain were randomly assigned to three groups based on iodated water concentration: low iodine (LI, 1.2 µg/d), normal iodine (NI, 5-6 µg/d), and 3-fold high iodine (3HI, 15-16 µg/d). The present study investigated whether higher-than-normal iodine intake (3HI) by rats from before pregnancy until breastfeeding affects the postnatal (PN) neurodevelopment (PN7 and PN45) of their offspring during particularly sensitive periods in brain development. RESULTS: After 12 weeks of treatment (before pregnancy), iodine concentrations in urine and thyroid tissue and circulating thyroxine of adult females correlated with iodine intake. Brain-derived neurotrophic factor (BDNF) expression in the hippocampi of pups on PN7 and PN45 was decreased in 3HI group compared to the NI controls (P < 0.05, all) On PN7 and PN45, the BDNF levels of the 3HI pups were 83.5% and 88.8%, respectively, that of the NI pups. In addition, the 3HI group had a higher neuroendocrine-specific protein A (NSP-A) level than the NI controls on PN7 (P < 0.05). NSP-A levels of the 3HI pups were 117.0% that of the NI pups. No significant difference was observed in the expressions of c-Fos or c-Jun in the hippocampal CA1 region of the 3HI group compared to the controls (P > 0.05). Results from the Morris water maze test revealed that pups of the 3HI group had mild learning and spatial memory deficits. CONCLUSIONS: The neurodevelopmental and cognitive deficits of the 3HI pups were mild and temporary, likely related to the changes in hippocampal protein expressions of BDNF and NSP-A.

[Effects of selenium supplementation on antibodies of autoimmune thyroiditis].

OBJECTIVE: To evaluate the effects of selenium (Se) supplementation on concentrations of thyroid peroxidase antibodies (TPOAb) and TPOAb IgG subclasses in autoimmune thyroiditis (AIT) patients with different thyroid functional status. METHODS: A blind and placebo-controlled prospective study was performed for a total of 134 cases with AIT and thyroid peroxidase antibodies above 300 U/ml. Their mean age was 41 years (range: 15-70). All of them were recruited from Department of Endocrinology, First Affiliated Hospital of China Medical University from June 2008 to June 2009 and divided into 2 groups according to thyroid function: euthyroidism or subclinical hypothyroidism (n = 89) and hypothyroidism (n = 45). Then they were randomized into 2 groups: selenium-treated and placebo-treated. And 49 cases in subclinical autoimmune thyroiditis group and 28 cases in hypothyroidism group received 200 µg oral selenium yeast daily for 6 months while others placebo. Serum concentrations of TPOAb, TPOAb IgG subclasses, thyroid-stimulating hormone (TSH), free thyroxine (FT(4)) and Se were measured at baseline and after 3 and 6 months of follow-up. RESULTS: The TPOAb levels showed an overall decrease of 4.3% at 3 months and of 12.6% at 6 months (both P < 0.05) post-supplementation in subclinical autoimmune thyroiditis patients. In overt hypothyroidism patients, the overall decrease of TPOAb concentrations was 21.9% at 3 months and 20.4% at 6 months (both P < 0.05) compared with those at pre-treatment. The predominant TPOAb IgG subclasses in sera from the AIT patients were IgG1, IgG3 and IgG4 and the positive percentages 72%, 41% and 72% respectively. The positive rate and concentrations of IgG3 in the patients with hypothyroidism were significantly higher than those of subclinical autoimmune thyroiditis (P < 0.05). Significant decreases in IgG1 and IgG3 levels were noted in subclinical autoimmune thyroiditis group at 6 months post-supplementation (P < 0.05). IgG1 levels in overt hypothyroidism decreased significantly compared with those at pre-supplementation (P < 0.05). In all patients with supplementation (n = 77), the TPOAb levels decreased in 52 at 6 months while increase or no change occurred in 25. The positive percentage and concentrations of IgG1 in patients whose TPOAb levels decreased at 6 months post-supplementation were markedly higher than those whose TPOAb levels increased (P < 0.05). CONCLUSION: Se is effective in reducing TPOAb concentrations and the predominant decreasing TPOAb IgG subclasses are IgG1 and IgG3. And a high level of IgG1 subclass may explain the difficult decline of TPOAb.

An epidemiological study of the serum thyrotropin reference range and factors that influence serum thyrotropin levels in iodine sufficient areas of China.

The aims of this study performed in 2007 were to verify the selection criteria proposed by the National Academy of Clinical Biochemistry (NACB) guidelines, to investigate factors that influence thyrotropin (TSH) levels, and to determine serum TSH reference range in iodine sufficient areas of China. After excluding 291 subjects, a total of 5,348 inhabitants from three iodine sufficient areas of Liaoning province were asked to fulfill the questionnaire, and take TSH, thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) measurements and a thyroid ultrasound examination. The distribution of TSH was right skewed in normal people. It has been customary to log transform the values to observe the Gaussian distribution. In the subjects 12-19 years of age, the TSH level was significantly higher than in the other age groups (p<0.001), while there were no significant difference in the TSH values of the other age groups. The TSH levels in females(1.68±1.90mIU/L) were significantly higher than in males (1.45±1.92mIU/L) (p<0.001). Therefore, the normal TSH range in males over age 20 was 0.43-4.74mIU/L, and in females the range was 0.48-5.39 mIU/L. A family history of thyroid disease, abnormal thyroid ultrasound, a thyroid antibody-positive status were the factors that influenced the TSH reference range. Non-thyroid disease did not impact the TSH reference range significantly. We recommend use of a TSH reference range 0.46-5.19mIU/L in iodine sufficient areas of China for males and females over 20 years old. We suggest using a normal thyroid ultrasound as a new criterion in addition to the NACB guidelines to determine the TSH reference range.

In Vivo Inhibition of MicroRNA-326 in a NOD.H-2h4 Mouse Model of Autoimmune Thyroiditis.

Background: Previous studies reported that various miRNAs participate in autoimmune diseases, but the potential regulatory mechanism of miRNAs in autoimmune thyroiditis (AIT) needs further exploration. Objective: This study aimed to further verify that miR-326 contributes to AIT by regulating Th17/Treg balance through Ets-1 using lentiviral gene delivery through tail vein and thyroid injection in NOD.H-2h4 mice. Materials and Methods: Five-week-old NOD.H-2h4 mice were divided randomly into tail vein and thyroid injection groups, and each received either mmu-miR-326 sponge (LV-sponge) or lentiviral vector control. Mice were divided for tail vein injection: the therapeutic LV-ctrl, therapeutic LV-sponge, prophylactic LV-ctrl, and prophylactic LV-sponge groups. The control group was fed high-iodine water without vein injection. The thyroid infiltration of lymphocytes and serum TgAb value were investigated by thyroid hematoxylin and eosin (HE) staining and ELISA, respectively. Ets-1 and lymphocyte counts were measured by RT-PCR, western blotting, and flow cytometry. The thyroid CD4+IL-17a+ cells and CD4+Ets-1+ cells were detected by immunofluorescence, and the serum cytokines were tested by ELISA. Results: In the tail vein injection groups, the thyroid inflammatory score and serum TgAb titer were significantly lower in the LV-sponge groups than in the control and LV-ctrl groups while Ets-1 protein expression in mouse spleens was increased in the LV-sponge groups. Moreover, Th17/Treg ratio declined in the LV-sponge group and decreased significantly in the prophylactic LV-sponge group (P = 0.036) tested by flow cytometry. Immunofluorescence showed that, in LV-sponge groups, CD4+IL-17a+ cells were decreased significantly (P = 0.001), while CD4+Ets-1+ cells were increased significantly in the LV-sponge group (P = 0.029). The serum IL-17/IL-10 was decreased significantly in the LV-sponge group (P < 0.05). In the thyroid injection groups, the thyroid inflammatory score and serum TgAb titer in the LV-sponge group decreased significantly compared with those in the LV-ctrl group (P < 0.05). In addition, in LV-sponge groups, CD4+IL-17a+ cells were decreased, while CD4+Ets-1+ cells were increased significantly in the inhibition group evaluated by immunofluorescence. Moreover, tail vein injection of LV-sponge resulted in much lower TgAb levels in thyroiditis compared with thyroid injection. Conclusion: MiR-326 targeted therapy may be a promising approach for AIT. In addition, tail vein injection may achieve a better intervention effect than thyroid injection.

Abnormalities of maternal thyroid function during pregnancy affect neuropsychological development of their children at 25-30 months.

OBJECTIVE: To examine the relationship between specific thyroid abnormalities (subclinical hypothyroidism, hypothyroxinaemia or elevated thyroid peroxidase antibody titres) in women during pregnancy and the subsequent neuropsychological development of their offspring. DESIGN/PATIENTS: Serum was collected from 1268 women at 16-20 weeks of gestation and thyroid stimulating hormone (TSH), total thyroxine (tT(4)), free thyroxine (fT(4)), and Thyroid peroxidase antibodies (TPOAb) levels were measured. Thyroid function reference ranges specific for pregnancy were used to screen for thyroid abnormalities. Patients with isolated subclinical hypothyroidism (18 cases), hypothyroxinaemia (19 cases), and those who were euthyroid patients with elevated titres of TPOAb (34 cases) were identified. One hundred and forty-two euthyroid and TPOAb-negative women matched for gestational age from the same cohort were selected as controls. MEASUREMENTS: Intellectual and motor development score evaluations were performed on the children from the pregnancies at 25-30 months of age. RESULTS: Children of women with subclinical hypothyroidism, hypothyroxinemia and elevated TPOAb titres had mean intelligence scores 8.88, 9.30 and 10.56 points lower than those of the control group (P = 0.008, P = 0.004 and P = 0.001, respectively); mean motor scores were 9.98, 7.57 and 9.03 points lower than those of the controls [P < 0.001, P = 0.007 and P < 0.001, respectively (t-test)]. Unconditional multivariate logistic regression analysis showed that increased maternal serum TSH, decreased maternal serum tT(4), and elevated maternal TPOAb titres were separately associated with lower intelligence scores (ORs 15.63, 12.98, and 6.69, respectively) and poorer motor scores (ORs 9.23, 5.52, and 8.25, respectively). CONCLUSIONS: Intellectual and motor development of children at 25-30 months of age is separately associated with abnormalities of maternal thyroid at 16-20 weeks gestation. Maternal subclinical hypothyroidism, hypothyroxinaemia or euthyroidism with elevated TPOAb titres were all statistically significant predictors of lower motor and intellectual development at 25-30 months.

miRNA expression in a human papillary thyroid carcinoma cell line varies with invasiveness.

The purpose of these studies was to explore the expression pattern of miRNAs associated with invasion and metastasis of human papillary thyroid carcinoma (PTC). A transwell invasion chamber was used to select progressively more invasive cancer cell populations from a clonal cell line of human PTC with cervical lymph node metastasis, IHH-4. Three sublines with progressive invasiveness, designated IHH-4M-1, IHH-4M-2 and IHH-4M-3, were obtained through this in vitro selection process. The sublines manifested an increase in colony-forming ability on soft agar and metastatic potency in nude mice. Then metastasis-related miRNAs differentially expressed between them were analyzed utilizing the miRNA microarray technique. We found that 11 metastasis-related miRNAs were differentially expressed between the invasive subpopulations and their control subpopulations; these miRNAs may account for their significant difference in the invasion capabilities and favor lymphatic metastasis of PTC.

Selenium upregulates CD4(+)CD25(+) regulatory T cells in iodine-induced autoimmune thyroiditis model of NOD.H-2(h4) mice.

Selenium (Se) is required for thyroid hormone synthesis and metabolism. Se treatment reduces serum thyroidspecific antibody titers in patients with autoimmune thyroiditis (AIT), but the exact mechanism is not clear. We investigated the effects of Se treatment on CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) in a iodine-induced autoimmune thyroiditis model. NOD.H-2(h4) mice were randomly divided into control, AIT untreated, and AIT with Se treatment groups. Mice were fed with 0.005% sodium iodine (NaI) water for 8 weeks to induce AIT. Se-treated mice received 0.3 mg/L sodium selenite in drinking water. The AIT mice had fewer Treg cells and reduced Foxp3 mRNA expression in splenocytes compared with the controls (p < 0.01). The percentage of Treg cells and expression of Foxp3 mRNA were increased by Se treatment (as compared with untreated AIT mice, p < 0.05). Mice that received Se supplementation also had lower serum thyroglobulin antibody (TgAb) titers and reduced lymphocytic infiltration in thyroids than untreated AIT mice. These data suggest that CD4(+)CD25(+) T cells play an important role in the development of AIT. Se supplementation may restore normal levels of CD4(+)CD25(+) T cells by up-regulating the expression of Foxp3 mRNA in mice with AIT.

Dynamic Changes in Antithyroperoxidase and Antithyroglobulin Antibodies Suggest an Increased Risk for Abnormal Thyrotropin Levels.

Background: Antithyroperoxidase (TPOAb) and antithyroglobulin (TgAb) antibodies are associated with abnormal thyrotropin (TSH) levels. However, the effect of dynamic changes in TPOAb and TgAb on incident abnormal TSH is unknown. Methods: A total of 2,387 euthyroid participants aged 18 years or older from three rural areas in northern China were enrolled in this cohort study. Questionnaire interviews and laboratory measurements were performed at baseline in 1999 and at follow-up in 2004. Multinomial logistic regression was used to examine the relationship between changes in thyroid antibodies and incident abnormal TSH levels. Results: In this 5 year follow-up study, TPOAb tier gain was significantly associated with an increased risk of subnormal TSH levels (adjusted RR, 1.535; 95% CI: 1.357-1.736) and supranormal TSH levels (adjusted RR, 1.378; 95% CI: 1.196-1.587), and TgAb tier gain was significantly associated with an increased risk of supranormal (adjusted RR, 1.090; 95% CI: 1.007-1.179) TSH levels. Both thyroid antibody-positive seroconversion and persistent positivity were significantly associated with an increased risk of incident abnormal TSH levels. Thyroid antibody positive seroconversion was associated with a higher risk of incident subnormal TSH than incident supranormal TSH, whereas persistent positive thyroid antibody was associated with a higher risk of incident supranormal TSH than incident subnormal TSH. Conclusions: Dynamic thyroid antibody changes may be related to incident abnormal TSH levels. Those with persistent positive thyroid antibody were more likely to have supranormal TSH than subnormal TSH, and those with positive seroconversion were more likely to have subnormal TSH than supranormal TSH. Further studies are needed to confirm this conclusion and to explore this association mediated by TSH receptor antibodies.

Roles of Endogenous IL-10 and IL-10-Competent and CD5+ B Cells in Autoimmune Thyroiditis in NOD.H-2h4 Mice.

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.

Effect of iodine intake on thyroid diseases in China.

BACKGROUND: Iodine is an essential component of thyroid hormones; either low or high intake may lead to thyroid disease. We observed an increase in the prevalence of overt hypothyroidism, subclinical hypothyroidism, and autoimmune thyroiditis with increasing iodine intake in China in cohorts from three regions with different levels of iodine intake: mildly deficient (median urinary iodine excretion, 84 microg per liter), more than adequate (median, 243 microg per liter), and excessive (median, 651 microg per liter). Participants enrolled in a baseline study in 1999, and during the five-year follow-up through 2004, we examined the effect of regional differences in iodine intake on the incidence of thyroid disease. METHODS: Of the 3761 unselected subjects who were enrolled at baseline, 3018 (80.2 percent) participated in this follow-up study. Levels of thyroid hormones and thyroid autoantibodies in serum, and iodine in urine, were measured and B-mode ultrasonography of the thyroid was performed at baseline and follow-up. RESULTS: Among subjects with mildly deficient iodine intake, those with more than adequate intake, and those with excessive intake, the cumulative incidence of overt hypothyroidism was 0.2 percent, 0.5 percent, and 0.3 percent, respectively; that of subclinical hypothyroidism, 0.2 percent, 2.6 percent, and 2.9 percent, respectively; and that of autoimmune thyroiditis, 0.2 percent, 1.0 percent, and 1.3 percent, respectively. Among subjects with euthyroidism and antithyroid antibodies at baseline, the five-year incidence of elevated serum thyrotropin levels was greater among those with more than adequate or excessive iodine intake than among those with mildly deficient iodine intake. A baseline serum thyrotropin level of 1.0 to 1.9 mIU per liter was associated with the lowest subsequent incidence of abnormal thyroid function. CONCLUSIONS: More than adequate or excessive iodine intake may lead to hypothyroidism and autoimmune thyroiditis.

Experimental study on the effects of chronic iodine excess on thyroid function, structure, and autoimmunity in autoimmune-prone NOD.H-2h4 mice.

Iodine is an essential component of thyroid hormones; high intake may lead to thyroid disease. Epidemiologic researches have shown that exposure to iodine may be involved in the onset and development of autoimmune thyroiditis. Iodine may induce hypothyroidism in patients with autoimmune thyroiditis in a dose-dependent manner. The aim of the present study was to investigate the effects of dosages of iodine on thyroid autoimmunity, morphology, structure, and function in autoimmune-prone animals. NOD.H-2h4 mice were randomly divided into normal iodine, 5-fold, 10-fold, 100-fold, 1,000-fold iodine excess group, anesthetized by diethyl ether and bleed from eye socket vein at 4, 8, 16, and 24 weeks after the commencement of experiment. Iodine and thyroid hormone levels in the thyroid tissue and sera, serum thyroglobulin antibody levels, as well as thyroid gland histological appearance were measured. Excessive iodine caused thyroid goiter, and there was a positive correlation between the thyroid weight and the dosage of iodine (r = 0.64-0.92, P < 0.01). Iodine overdose ultrastructurally damaged thyroid epithelial cells in a dose-dependent manner. The incidence of thyroiditis, as well as the degree of lymphocytic infiltration in the thyroid gradually increased as the dosage increased (r = 0.87-0.98, P

[The changes of thyrotropin level in euthyroid population: a 5-year follow-up study in communities with different iodine intakes].

OBJECTIVE: To determine the factors that influence the development of abnormal thyrotropin (TSH) level in an euthyroid population. METHODS: We conducted a follow-up study in 3 communities with different iodine status. Of the 3403 euthyroid subjects at baseline screened in 1999, 80.1% (n = 2727) was visited and sampled in 2004 for measuring TSH, thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb). RESULTS: Iodine status in the 3 communities were stable. Decreased TSH level (< 0.3 mU/L) developed in 2.5% (n = 68) of sampled subjects, while raised TSH level (> 4.8 mU/L) in 2.4% (n = 64). A logistic analysis showed that risk factors for developing decreased TSH level included positive conversion of TPOAb (OR = 5.5), positive TPOAb both in 1999 and in 2004 (OR = 4.0), positive TgAb in 2004 (OR = 3.7) and TSH < 1.0 mU/L in 1999 (OR = 2.6). Risk factors involved in developing raised TSH level included iodine status of Zhangwu community (OR = 4.1), iodine status of Huanghua community (OR = 3.9), positive TgAb in 2004 (OR = 3.7), positive TPOAb both in 1999 and 2004 (OR = 3.6), positive conversion of TPOAb (OR = 2.7) and TSH > 1.9 mU/L in 1999 (OR = 2.6). CONCLUSIONS: Exposure to long-term iodine excess imposes danger of developing hypothyroidism. The risk will be even higher when exposing to iodine adequacy after correction of iodine deficiency. An interval between 1.0 and 1.9 mU/L of TSH level was optimal with the least probability of developing abnormal TSH level.