| Objective: Autoimmune thyroiditis(AIT)is one of the most frequent autoimmune diseases,which accounts for most cases of hypothyroidism and relates to several other diseases.Yet there is no therapeutic measures target the pathogenesis of AIT.Selenium is an essential micronutrient that is important for human health.The effect of selenium on thyroid is no less than that of iodine.Selenium not only plays a role in thyroid hormone synthesis and metabolism,but also associates with a lot of thyroid diseases.Randomized,blinded,placebo-controlled and prospective clinical trials have revealed that selenium(200μg/d)substitution help to decrease the anti-thyroid peroxidase autoantibody(TPOAb)tilter and alleviate the thyroid inflammation.On the other side,excess selenium intake may also lead to health problem.Several human studies have provided evidence of a U-shape relationship between intake or status of selenium and its protection from cancer.Selenium intake varies considerably between countries and regions of countries and nowadays the investigations on protective effect of selenium on thyroid were mainly conducted in countries in Europe,where the selenium status were marginally adequate.As for Tianjin,a coastal region in China,the selenium status of adult is not available and therefore it might not be appropriate to treat AIT with selenium supplementation.Hence we conduct a cross-sectional study on serum selenium concentration in adults in Tianjin,and analyze the relationship between serum selenium level and prevalence of thyroid diseases.The mechanism through which selenium substitution alleviates the thyroid inflammation remains unclear.Selenoproteins are not only involved in activation,proliferation,and differentiation of immune cells,initiating immunity,but also involved in regulating excessive immune response.Dendritic cells(DCs)are professional antigen presenting cells,which not only initiate immune response,but also play a vital role in immunologic tolerance.Investigations have disclosed metabolic switches in DCs induce tolerogenic DCs phenotype and function.This study aims to investigate whether selenium induce tolerogenic DCs by reprogramming cell metabolism,thereby preventing and alleviating AIT.Methods:Part Ⅰ: TIDE(Thyroid Disorders,Iodine Status and Diabetes: a National Epidemiological Survey-2014)granted by the Research Fund for Public Welfare,National Health and Family Planning Commission of China(Grant No.201402005),was a cross-sectional epidemiological survey on iodine status and thyroid disorders prevalence in adults in thirty-one provinces,cities and autonomous regions in China.This study was based on TIDE in Tianjin.The basic clinical data were collected through a previously well-designed questionnaire,and serum thyroid-stimulating hormone(TSH),TPOAb,and thyroid globulin antibody(TGAb),free thyroxine(FT4),free triiodothyronine(FT3),selelnium concentration,iodine concentration,and urinary iodine concentration(UIC)were all tested.Thyroid ultrasonography was performed to determine thyroid echogenicity.The basic characteristics of participants were compared between different serum selenium level groups,prevalence of hypothyroidism,subclinical hypothyroidism,ultrasound pattern of Hashimoto thyroiditis(HT),TPOAb and TGAb positivity were compared between different serum selenium level groups,and Logistic regression analysis was performed to determine the effect of serum selenium level on prevalence of hypothyroidism,subclinical hypothyroidism,ultrasound pattern of HT,TPOAb and TGAb positivity.Part Ⅱ: Fourty SD rats aged 5-6 weeks were randomized divided into control group(C group),experimental autoimmune thyroiditis group(EAT group),selenium intervention group 1(Se1 group)and selenium intervention group 2(Se2 group).EAT was induced in EAT group,Se1 group and Se2 group rats upon challenge with porcine Tg in Freud’s adjuvant.Se1 group and Se2 group rats were intragastric administrated with sodium selenite with dose of 0.08mg/kg and 0.16mg/kg respectively.The severity of lymphocytic infiltration in thyroid histological sections,concentration of anti-thyroid autoantibodies and thyroid function were compared between the rats in four groups.Surface expression of CD80,CD86 and MHCⅡ were analyzed by flow cytometry in CD11c+ splenocyte.Gene expression in splenocyte related to glycolysis and oxidative phosphorylation were compared between the rats in four groups.Gene expression of selenoprotein K and glutathione peroxidase4 in splenocyte were also compared between the rats in four groups.Results:Part Ⅰ:(1)A total of 1257 subjects aged 42.5±15.2 yrs were enrolled in the study and the median serum selenium concentration was 131.8(103.4-172.1)μg/L.49.2 percent of the participants were male.The distribution by age 18-40 yrs,40-65 yrs,and ≥65yrs were 48.0%,42.5%,and 9.5% respectively.(2)The median UIC was 148.0 μg/L,meeting the iodine sufficiency standard.(3)Both serum selenium level <100 μg/L(OR=1.574,95%CI:1.007-2.461,p=0.046)and ≥200 μg/L(OR=2.853,95%CI:1.643-4.953,p=0.000 for serum selenium level 200-249.99 μg/L and OR=2.450,95%CI:1.462-4.106,p=0.001 for serum selenium level ≥250 μg/L respectively)were independent risk factors for TPOAb positivity.(4)Serum selenium level ≥200 μg/L(OR=2.152,95%CI:1.199-3.860,p=0.010 for serum selenium level 200-249.99 μg/L and OR=2.111,95%CI:1.230-3.623,p=0.007 for serum selenium level ≥250 μg/L respectively)was independent risk factor for TGAb positivity.(5)Serum selenium level ≥200 μg/L(OR=2.236,95%CI:1.182-4.230,p=0.013 for serum selenium level 200-249.99 μg/L and OR=2.091,95%CI:1.176-3.718,p=0.012 for serum selenium level ≥250 μg/L respectively)was independent risk factor for HT diagnosed through B ultrasound pattern.(6)Serum selenium level was not independent risk factor for hypothyroidism and subclinical hypothyroidism.Part Ⅱ:(1)The thyroid inflammation score in Se1 group and Se2 group were significantly lower than that in EAT group.(2)TGAb and TPOAb concentration were significantly higher in EAT group,Se1 group and Se2 group than that in C group(p<0.05).TGAb and TPOAb concentration in Se1 group and Se2 group were significantly lower than that in EAT group(p<0.05).(3)No statistical difference was found in thyroid function between the four groups.(4)Rats in EAT group,Se1 group and Se2 group had an increased proportion of CD11c+ splenocyte than those in C group(p<0.05).Rats in Se1 group and Se2 group had an decreased surface expression of CD80,CD86 and MHCⅡ(Rt1B)than those in EAT group(p<0.05).(5)Gene expression of Glut1 related to glycolysis was downregulated while Gene expression of PDHA1,NDUFA5 and COX5 A related to tricarboxylic acid cycle and oxidative phosphorylation were upregulated in splenocytes in Se1 and Se2 group.(6)SELK and GPX4 gene expression were upregulated in Se1 and Se2 group.Conclusions:(1)Tianjin was iodine sufficient and selenium adequate-high region based on this sample.The prevalence of AIT was the lowest when serum selenium level was 100-200 μg/L and both serum selenium level <100 μg/L and ≥200 μg/L were independent risk factors for AIT.The selenium status should be considered when taking selenium supplementation therapy for AIT,as for selenium deficient or marginally deficient patients,selenium supplementation might reduce TPOAb concentration and alleviate inflammation,however,for patients with high selenium level,selenium supplementation might be counterproductive.(2)EAT rats were successfully prepared upon challenge with porcine Tg in Freud’s adjuvant.Selenium supplementation may induce tolerogenic DCs by reprogramming intracellular metabolism pathways,thereby preventing and alleviating AIT.Selenium supplementation may modulate immune response by upregulating gene expression of SELK and Gpx4. |
