RESUMO
Introduction: We aimed to comprehensively investigate the causal relationship between 731 immune cell traits and autoimmune thyroiditis (AIT) and to identify and quantify the role of 1400 metabolic traits as potential mediators in between. Methods: Using summary-level data from genome-wide association studies (GWAS) we performed a two-sample bidirectional Mendelian randomization (MR) analysis of genetically predicted AIT and 731 immune cell traits. Furthermore, we used a two-step MR analysis to quantify the proportion of the total effects (that the immune cells exerted on the risk of AIT) mediated by potential metabolites. Results: We identified 24 immune cell traits (with odds ratio (OR) ranging from 1.3166 6 to 0.6323) and 10 metabolic traits (with OR ranging from 1.7954 to 0.6158) to be causally associated with AIT, respectively. Five immune cell traits (including CD38 on IgD+ CD24-, CD28 on CD28+ CD45RA+ CD8br, HLA DR+ CD4+ AC, TD CD4+ %CD4+, and CD8 on EM CD8br) were found to be associated with the risk of AIT, which were partially mediated by metabolites (including glycolithocholate sulfate, 5alpha-androstan-3alpha,17beta-diol disulfate, arachidonoylcholine, X-15486, and kynurenine). The proportion of genetically predicted AIT mediated by the identified metabolites could range from 5.58% to 17.7%. Discussion: Our study identified causal associations between AIT and immune cells which were partially mediated by metabolites, thus providing guidance for future clinical and basic research.
Assuntos
Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Tireoidite Autoimune , Humanos , Tireoidite Autoimune/genética , Tireoidite Autoimune/imunologia , Tireoidite Autoimune/metabolismo , Polimorfismo de Nucleotídeo Único , Predisposição Genética para DoençaRESUMO
PURPOSE: Autoimmune Thyroiditis (AIT) is the most common thyroid disease; however, there were no measures to prevent the progression of the disease. The present study attempts to identify that Notch signaling regulates the differentiation of T helper 17 (Th17) cells by activating downstream Phosphatidylinositol-3 kinase/protein kinase/mechanistic target of rapamycin complex 1 (PI3K/AKT/mTORC1) pathway participating in the thyroid injury of the experimental autoimmune thyroiditis (EAT). METHODS: In vivo experiments, mice were randomly divided into 4 groups: a control group, an EAT group, and two groups with LY294002 treatment (pTg plus 25 mg/kg or 50 mg/kg LY294002, respectively). The degrees of thyroiditis were evaluated, and the percentage of Th17 cells, expression of interleukin-17A (IL-17A), and the main components of the Notch-PI3K signaling pathway were detected in different groups. In vitro experiments, two different dosages of LY294002 (25 and 50 µM) were used to intervene splenic mononuclear cells (SMCs) from EAT mice to further evaluate the regulatory effect of Notch-PI3K pathway on Th17 cells. RESULTS: Our data demonstrate that the infiltration of Th17 cells and the expressions of IL-17A, Notch, hairy and split 1 (Hes1), pAKT (Ser473), pAKT (Thr308), pmTOR (Ser2448), S6K1, and S6K2 increased remarkably in EAT mice. After PI3K pathway was blocked, the degrees of thyroiditis were significantly alleviated, and the proportion of Th17 cells, the expression of IL-17A, and the above Notch-PI3K pathway-related molecules decreased in a dose-dependent manner. Additionally, the proportion of Th17 cells was positively correlated with the concentration of serum thyroglobulin antibody (TgAb), IL-17A, and Notch-PI3K pathway-related molecules mRNA levels. CONCLUSIONS: Notch signal promotes the secretion of IL-17A from Th17 cells by regulating the downstream PI3K/AKT/mTORC1 pathway through Hes-Phosphatase and tensin homolog (PTEN) and participates in thyroid autoimmune damage, and the PI3K pathway inhibitor may play important effects on AIT by affecting Th17 cells differentiation.
Assuntos
Diferenciação Celular , Alvo Mecanístico do Complexo 1 de Rapamicina , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Receptores Notch , Transdução de Sinais , Células Th17 , Tireoidite Autoimune , Animais , Células Th17/metabolismo , Camundongos , Diferenciação Celular/efeitos dos fármacos , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Tireoidite Autoimune/metabolismo , Tireoidite Autoimune/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Interleucina-17/metabolismo , Glândula Tireoide/patologia , Glândula Tireoide/metabolismo , Feminino , Cromonas/farmacologia , Morfolinas/farmacologiaRESUMO
Background: This is the first study, that aimed: a) to compare immune response, namely the kinetics of neutralizing antibodies (Nabs), after vaccination with BNT162b2 mRNA vaccine (Comirnaty, Pfizer/BioNTech) between patients with autoimmune thyroiditis and controls, and b) to investigate changes in thyroid function in healthy subjects with no history of thyroid dysfunction before and after vaccination with BNT162b2 mRNA vaccine (Comirnaty, Pfizer/BioNTech). Methods: The entire study consisted of two sub-studies. In the first sub-study, NAbs levels after BNT162b2 mRNA vaccination were compared between 56 patients with autoimmune thyroiditis and 56 age and gender-matched healthy controls from the day of the first dose until a period of up to three months after the second dose. In the second sub-study, thyroid hormones (T3, T4, TSH) and thyroid auto-antibodies levels (anti-TG, anti-TPO) of 72 healthy subjects with no history of thyroid disease were examined before (D1) and one month after completion of the second dose (D50). Results: Among patients with autoimmune thyroiditis, the median neutralizing inhibition on D22, immediately before second dose, was 62.5%. One month later (D50), values increased to 96.7%, while three months after the second dose NAbs titers remained almost the same (94.5%). In the healthy group, median NAbs levels at D22 were 53.6%. On D50 the median inhibition values increased to 95.1%, while after three months they were 89.2%. The statistical analysis did not show significant differences between two groups (p-values 0.164, 0.390, 0.105 for D22, D50 and three months). Regarding changes in thyroid function, the mean value for T4 before vaccination was 89.797 nmol/L and one month after the second dose was 89.11 nmol/L (p-value=0.649). On D1 the mean T3 value was 1.464 nmol/L, which dropped to 1.389 nmol/L on D50 (p-value = 0.004). For TSH, mean levels were 2.064 mIU/ml on D1 and fell to 1.840 mIU/ml one month after the second dose (p-value=0.037). Despite decrease, all thyroid hormone levels remained within the normal range. No changes were found for anti-TPO or anti-TG. Conclusions: This study provided evidence that patients with autoimmune thyroiditis present similar immunological response to COVID-19 BNT162b2 mRNA vaccine (Comirnaty, Pfizer/BioNTech) with healthy subjects, while vaccination may affect thyroid function.
Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vacina BNT162/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Tireoidite Autoimune/imunologia , Adulto , Autoanticorpos/sangue , Autoanticorpos/imunologia , Vacina BNT162/administração & dosagem , Vacina BNT162/genética , COVID-19/prevenção & controle , COVID-19/virologia , Estudos de Casos e Controles , Feminino , Seguimentos , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/genética , Glândula Tireoide/metabolismo , Hormônios Tireóideos/sangue , Hormônios Tireóideos/metabolismo , Tireoidite Autoimune/metabolismo , VacinaçãoRESUMO
This study aimed to investigate the therapeutic effect of human umbilical cord mesenchymal stem cells (hUCMSCs) on experimental autoimmune thyroiditis (EAT) and the underlying mechanisms by utilizing a porcine thyroglobulin-induced EAT rat model. The rats received four tail vein injections of vehicle or hUCMSCs at an interval of 7 days and were sacrificed on day 28 after the first injection. Hematoxylin and eosin staining and enzyme-linked immunosorbent assays (ELISAs) were used to assess the therapeutic effects of hUCMSCs on EAT. Splenic lymphocytes were isolated from rats, and the proportions of CD4+ T cell subsets were analyzed by flow cytometry. Splenic CD4+ T cells from EAT rats were cocultured with hUCMSCs. A loss-of-function assay for protein tyrosine phosphatase non-receptor type 2 (PTPN2) was performed to explore the involvement of PTPN2/signal transducer and activator of transcription 3 (STAT3) signaling on the therapeutic benefit of hUCMSCs in EAT. hUCMSC treatment significantly alleviated inflammation, reduced serum thyroid antibody levels, and decreased the ratios of IL-17α+/CD25+FOXP3+ cells and serum IFN-γ/IL-4 in EAT rats. Furthermore, hUCMSC treatment upregulated PTPN2 protein expression in splenic lymphocytes of EAT rats as well as enhanced the PTPN2 protein level and attenuated phosphorylation of STAT3 in CD4+ T cells in vitro. Importantly, knockdown of Ptpn2 significantly reversed hUCMSC-mediated suppression of cell proliferation and hUCMSC-induced alterations in the expression of inflammatory cytokines in CD4+ T cells. Thus, hUCMSC treatment alleviates thyroid inflammation and the CD4+ T cell imbalance in EAT via PTPN2/STAT3 signaling, serving as a promising therapeutic approach for autoimmune thyroiditis.
Assuntos
Doença de Hashimoto , Células-Tronco Mesenquimais , Proteína Tirosina Fosfatase não Receptora Tipo 2 , Fator de Transcrição STAT3 , Tireoidite Autoimune , Animais , Linfócitos T CD4-Positivos/metabolismo , Doença de Hashimoto/metabolismo , Humanos , Inflamação/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 2/metabolismo , Ratos , Fator de Transcrição STAT3/metabolismo , Suínos , Linfócitos T/metabolismo , Tireoidite Autoimune/metabolismo , Tireoidite Autoimune/terapia , Cordão Umbilical/metabolismoRESUMO
Autoimmune thyroiditis (AIT) is the most prevalent autoimmune endocrine disease, with a higher incidence in women than in men. Immunological abnormalities may lead to the impairment of ovarian folliculogenesis; however, whether the presence of AIT affects immunological microenvironment in follicles remains controversial. We performed a cross-sectional study including 122 patients, aged 20-40 years, who underwent IVF/ICSI treatment owing to isolated male or tube factor infertility. Patients were divided into AIT and control groups according to clinical presentation, thyroid function, and thyroid autoantibody measurements. Follicular fluid was collected and the distribution of cytokines/chemokines in follicular fluid was measured by flow cytometry using multiplex bead assays between the two groups. Based on differences in levels of intrafollicular chemokines and cytokines between the AIT and control groups, the relevant inflammatory cascade was further demonstrated. Among the 12 chemokines analyzed, three (CXCL9, CXCL10, and CXCL11) showed significantly elevated levels in the follicular fluid of patients with AIT. Among the 11 cytokines detected, compared with those in the control group, significantly higher levels of IFNγ were observed in patients with AIT. IFNγ dose-dependently stimulated the expression and secretion of CXCL9/10/11 in cultured primary granulosa cells. The percentage of CXCR3+ T lymphocytes was significantly elevated in the follicular microenvironment of patients with AIT. We concluded that the IFNγ-CXCL9/10/11-CXCR3+ T lymphocyte inflammatory cascade is activated in the follicular microenvironment of patients with AIT. These findings indicate that a considerable immune imbalance occurred in the follicular microenvironment of patients with AIT.
Assuntos
Microambiente Celular/imunologia , Citocinas/imunologia , Líquido Folicular/imunologia , Tireoidite Autoimune/imunologia , Adulto , Células Cultivadas , Microambiente Celular/genética , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Quimiocina CXCL10/metabolismo , Quimiocina CXCL11/genética , Quimiocina CXCL11/imunologia , Quimiocina CXCL11/metabolismo , Quimiocina CXCL9/genética , Quimiocina CXCL9/imunologia , Quimiocina CXCL9/metabolismo , Citocinas/genética , Citocinas/metabolismo , Feminino , Fertilização in vitro , Citometria de Fluxo , Líquido Folicular/metabolismo , Humanos , Masculino , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Injeções de Esperma Intracitoplásmicas , Tireoidite Autoimune/genética , Tireoidite Autoimune/metabolismoRESUMO
To evaluate the association between thyroid echogenicity and heterogeneity seen on ultrasonography (US) and thyroid function in pediatric and adolescent populations with autoimmune diffuse thyroid diseases (AITD). From 2000 to 2020, we reviewed thyroid ultrasound (US) images and thyroid function statuses in 133 children and adolescent AITD patients. Our review of the images focused on decreased echogenicity and heterogeneity, which were classified into four grades. Among patients with overt hypothyroidism or overt hyperthyroidism, 94.2% (65/69) showed a US grade of 3 or 4. In patients with subclinical hyper/hypothyroidism or euthyroidism, 45.3% (29/64) showed grades 1 or 2. There were no overt hyper/hypothyroidism patients with US grade 1. When we compared US grades according to thyroid status, more severe thyroid dysfunction was significantly associated with higher US grade (p = 0.047). Thyroid stimulating hormone (TSH) level differed significantly according to US grades when we evaluated hyperthyroid (p = 0.035) and hypothyroid (p = 0.027) states independently. 11 patients showed both US grade and thyroid function status changes on follow-up US. In children and adolescent AITD patients, there was an association between decreased echogenicity and heterogeneity on US and thyroid dysfunction.
Assuntos
Biomarcadores , Doenças da Glândula Tireoide/diagnóstico por imagem , Doenças da Glândula Tireoide/metabolismo , Tireoidite Autoimune/diagnóstico por imagem , Tireoidite Autoimune/metabolismo , Ultrassonografia , Adolescente , Adulto , Autoanticorpos/imunologia , Autoimunidade , Criança , Pré-Escolar , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Estudos Retrospectivos , Índice de Gravidade de Doença , Testes de Função Tireóidea , Ultrassonografia/métodos , Adulto JovemRESUMO
Introduction: Both polycystic ovary syndrome (PCOS) and autoimmune thyroiditis (AT) are considered to be among the most common endocrinopathies in young women, and they are classified as diseases that affect many processes in the human body. Their role in the development of metabolic disorders and diseases of the cardiovascular system in adult women is also emphasized. However, there are no data available to assess such risk in the teenage girl population. The aim of the study was to assess the hormonal and metabolic profile of adolescent girls with PCOS, additionally diagnosed with AT, as well as to identify possible risk factors for the coexistence of AT and PCOS. Material and Methods: 80 euthyroidic PCOS patients were qualified for the study (chronological age 16.54 ± 1.00 years, BMI 24.60 ± 4.16 kg/m2). Eighteen girls diagnosed with AT were included in the study group and 62 girls without AT-in the control group. Each patient had biochemical and hormonal tests performed. Additionally, to diagnose AT, the level of antibodies against thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-TG), as well as the image of the thyroid gland on ultrasound examination, were taken into account. Results: Estradiol concentration was significantly higher in the study than in the control group (203.00 ± 217.00 vs. 152.00 ± 78.50 pmol/L, p=0.02). Higher DHEAS concentrations were also observed in the AT group compared with the group without AT (391.28 ± 176.40 vs. 317.93 ± 114.27 µg/dl, p=0.04). Moreover, there was a positive correlation between AT and estradiol concentration (ry=0.27; p=0.04). It was also shown that there is a tendency toward statistical significance for the positive correlation between the positive anti-TPO titer and the glucose concentration at 120 min OGTT (rÆ´=0.26; p=0.07) and girls with PCOS and AT had higher glucose levels in 120 min OGTT (115.29±41.70 vs. 98.56±28.02 mg/dl, p=0.08). Conclusion: The study results showed no difference in the metabolic profile between the groups. The high concentration of estradiol found in girls with PCOS and AT may indicate the role of this hormone in the development of the autoimmune process. However, the numbers are small, and more research is needed to confirm our findings.
Assuntos
Biomarcadores/sangue , Estradiol/metabolismo , Insulina/metabolismo , Síndrome do Ovário Policístico/patologia , Glândula Tireoide/patologia , Hormônios Tireóideos/metabolismo , Tireoidite Autoimune/patologia , Adolescente , Glicemia/análise , Criança , Feminino , Seguimentos , Humanos , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/metabolismo , Prognóstico , Estudos Retrospectivos , Glândula Tireoide/metabolismo , Tireoidite Autoimune/complicações , Tireoidite Autoimune/metabolismoRESUMO
The present study was designed to evaluate the effects of boldenone undecylenate (BL) abuse alone and in combination with vitamin C (VC) on the immune responses and thyroid structure and function in rats. Thirty adult male Wistar rats were randomly divided into five equal groups and were subjected to various treatment regimens for eight weeks as follows: control group, vehicle control group, VC group orally received VC (120 mg/Kg BW/day), BL-treated group intramuscularly injected with BL (5 mg/kg BW, once/week), and BL+VC group received BL and VC. At the end of this experiment, blood and tissue samples (thyroid, thymus, and spleen) were subjected to hematological evaluation, biochemical analysis, histopathological, and immunohistochemical examinations. In comparison to controls, BL significantly increased the levels of serum proinflammatory interleukins (IL-1 ß and IL-6), immunoglobulins (IgG and IgM), and complement 3 but reduced anti-inflammatory interleukin-10, lysosome, and nitric oxide. Besides, altered platelet count and leukogram were evident in BL-injected rats. BL notably disturbed thyroid profile as revealed by a significant increase of thyroid-stimulating hormone and thyroid peroxidase antibody. In contrast, both total and free forms of thyroid hormones (tri-iodothyronine and thyroxine), thyroglobulin, and thyroid peroxidase, were significantly decreased. Moreover, BL caused histopathological changes in the thyroid, thymus, and spleen tissues.CD4+ immuno-expression was reduced, but CD8+ immunolabelling was increased in both spleen and thymus. The daily dosing of VC to BL-exposed rats significantly corrected most of the deviations in immune parameters. It restored most of the thyroid architecture and function, revealing a significant protective effect of this vitamin. This experimental study demonstrates that BL abusing disrupts the immune system by different mechanisms and addresses BL, for the first time, as an autoimmune clinical hypothyroidism inducer drug. Additionally, VC is helpful in the management of BL abuse.
Assuntos
Ácido Ascórbico/metabolismo , Hipotireoidismo/metabolismo , Sistema Imunitário/metabolismo , Testosterona/análogos & derivados , Glândula Tireoide/metabolismo , Animais , Plaquetas/metabolismo , Doença de Hashimoto/metabolismo , Humanos , Imunoglobulinas/metabolismo , Interleucinas/metabolismo , Iodeto Peroxidase/metabolismo , Masculino , Ratos , Ratos Wistar , Transdução de Sinais , Baço , Testosterona/metabolismo , Timo , Tireoglobulina/metabolismo , Hormônios Tireóideos , Tireoidite Autoimune/metabolismoRESUMO
Papillary thyroid cancer (PTC) often co-occurs with Hashimoto's thyroiditis, an association that has long been reported in clinical studies yet remains controversial. Some studies, in fact, have suggested a protective effect of thyroiditis while others have not. We generated a mouse model where PTC and thyroiditis develop in a predictable manner, combining the oncogenic drive of the BRAFv600E mutation (inducible by tamoxifen) to the thyroiditis susceptibility of the NOD.H2h4 strain (inducible by iodine). A total of 113 NOD.H2h4_TPO-CRE-ER_BRAFV600E mice (50 followed throughout lifetime and 63 sacrificed at 16 weeks post tamoxifen) were used to determine whether the PTC phenotype differs when thyroiditis precedes or coincides with the onset of PTC. Mice with pre-existing thyroiditis lived longer (median survival of 28.2 weeks post tamoxifen) than those with concomitant (25.6 weeks) or no (24.5 weeks) thyroiditis (Pâ <â 0.01 by Laplace regression). PTC developed less frequently (33%) in the pre-existing thyroiditis group than the concomitant (100%) or no (100%) thyroiditis groups (Pâ <â 0.001 by chi-squared) and showed less aggressive histopathological features. The intratumoral mononuclear cell infiltration was more prominent in mice with pre-existing thyroiditis (Pâ =â 0.002 vs the other groups) and sustained by a significant expansion of effector memory CD8â +â T cells and CD19â +â B cells. These findings shed light on the controversial PTC-thyroiditis association and emphasize the contribution of intratumoral T and B lymphocytes to the evolution of PTC.
Assuntos
Doença de Hashimoto/complicações , Câncer Papilífero da Tireoide/complicações , Neoplasias da Glândula Tireoide/complicações , Animais , Antígenos CD19/biossíntese , Linfócitos T CD8-Positivos/citologia , Cruzamentos Genéticos , Modelos Animais de Doenças , Feminino , Genótipo , Doença de Hashimoto/metabolismo , Doença de Hashimoto/terapia , Humanos , Sistema Imunitário , Masculino , Camundongos , Camundongos Endogâmicos NOD , Mutação , Fenótipo , Proteínas Proto-Oncogênicas B-raf/genética , Análise de Regressão , Tamoxifeno/farmacologia , Câncer Papilífero da Tireoide/terapia , Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/terapia , Tireoidite Autoimune/metabolismo , Tiroxina/metabolismoRESUMO
Thyroid cancer (TC) is one of the most common malignant tumors, with high morbidity and mortality rates worldwide. The incidence of TC, especially that of papillary thyroid carcinoma (PTC); has increased rapidly in recent decades. Autoimmune thyroid disease (AITD) is closely related to TC and has an estimated prevalence of 5%. Thus, it is becoming increasingly important to identify potential diagnostic biomarkers and therapeutic targets for TC and AITD. Circular RNAs (circRNAs) are a class of non-coding RNAs with covalently bonded circular structures that lack 5'-3' polarity and polyadenylated tails. Several circRNAs play crucial roles in the development of various diseases, including TC and AITD, and could be important new biomarkers and/or targets for the diagnosis and therapy of such disorders. Although there are four subtypes of TC, research on circRNA has largely focused on its connection to PTC. Therefore, this review mainly summarizes the relationships between circRNAs and PTC and AITD, including the molecular mechanisms underlying these relationships. In particular, the functions of "miRNA sponges" and their interactions with proteins and RNA are discussed. The possible targeting of circRNAs for the prevention, diagnosis, and treatment of TC and AITD is also described. CircRNAs could be potential biomarkers of TC and AITD, although validation will be required before they can be implemented in clinical practice.
Assuntos
Regulação Neoplásica da Expressão Gênica , RNA Circular/genética , RNA Neoplásico/genética , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Tireoidite Autoimune/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Humanos , RNA Circular/metabolismo , Câncer Papilífero da Tireoide/metabolismo , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Tireoidite Autoimune/metabolismo , Tireoidite Autoimune/patologiaRESUMO
BACKGROUND: Auto-oxidized oxysterols are implicated in the pathogenesis of various chronic diseases. Their concentrations are indicators of oxidative stress in vivo and associated with atherosclerosis. Subclinical hypothyroidism is related with cardiac diseases and oxidative stress, but the exact mechanisms underlying these associations are not clear yet. OBJECTIVE: To investigate the auto-oxidized oxysterols, 7-ketocholesterol (7-KC) and cholestane-3ß,5α,6ß-triol (chol-triol), in patients with subclinical hypothyroidism, as well as to evaluate the impact of restoring euthyroidism on oxysterol concentrations. METHODS: In this prospective observational study, 64 patients with newly diagnosed autoimmune thyroiditis (41 with subclinical hypothyroidism and 23 euthyroidism), and 45 healthy controls were enrolled. Age, gender, and body mass index were matched among patient groups and healthy controls. Anthropometric measurements were obtained and fasting plasma 7-ketocholesterol and cholestane-3ß,5α,6ß-triol concentrations were measured by using liquid chromatography coupled with tandem mass spectrometry. Levothyroxine was then administered to all patients with subclinical-hypothyroidism. After three months, measurements of the oxysterols and serum cholesterols from the patients who have become euthyroid were repeated. RESULTS: Concentrations of 7-ketocholesterol and cholestane-3ß,5α,6ß-triol were significantly higher in patients with subclinical-hypothyroidism when compared to both euthyroid patients and healthy controls (p < 0.001 for both oxysterols). After restoration of euthyroidism, concentrations of 7-ketocholesterol and cholestane-3ß,5α,6ß-triol decreased significantly and reached similar concentrations observed in healthy controls (p < 0.001 for both oxysterols). CONCLUSIONS: Auto-oxidized oxysterol species are higher in patients with mild thyroid dysfunction, and supported the rationale for treating subclinical-hypothyroidism.
Assuntos
Hipotireoidismo/metabolismo , Oxisteróis/metabolismo , Adulto , Doenças Assintomáticas , Colestanóis/sangue , Cromatografia Líquida , Feminino , Humanos , Hipotireoidismo/complicações , Hipotireoidismo/tratamento farmacológico , Cetocolesteróis/sangue , Masculino , Pessoa de Meia-Idade , Oxirredução , Estresse Oxidativo , Estudos Prospectivos , Espectrometria de Massas em Tandem , Tireoidite Autoimune/complicações , Tireoidite Autoimune/tratamento farmacológico , Tireoidite Autoimune/metabolismo , Tireotropina/metabolismo , Tiroxina/uso terapêuticoRESUMO
Vitamin D is one of the most important nutrients required by the human body. It is a steroid hormone that plays an important role in regulating calcium and phosphorus metabolism, and bone health. Epidemiological studies have revealed a close correlation between vitamin D and many common chronic diseases. Additionally, vitamin D has recently been shown to act as an immunomodulatory hormone, and, accordingly, vitamin D deficiency was uncovered as a risk factor for autoimmune thyroid diseases, although the underlying mechanisms are still unknown. It is therefore necessary to disclose the role and mechanism of action of vitamin D in the occurrence and development of autoimmune thyroid diseases. This knowledge will help design intervention and early treatment strategies for patients with autoimmune thyroid diseases who present with low levels of vitamin D.
Assuntos
Doença de Hashimoto/metabolismo , Fatores Imunológicos/metabolismo , Tireoidite Autoimune/metabolismo , Deficiência de Vitamina D/metabolismo , Vitamina D/metabolismo , Doença de Hashimoto/fisiopatologia , Doença de Hashimoto/prevenção & controle , Humanos , Fatores Imunológicos/uso terapêutico , Receptores de Calcitriol/metabolismo , Fatores de Risco , Testes de Função Tireóidea , Tireoidite Autoimune/fisiopatologia , Tireoidite Autoimune/prevenção & controle , Vitamina D/sangue , Vitamina D/uso terapêutico , Deficiência de Vitamina D/prevenção & controle , Vitaminas/sangue , Vitaminas/metabolismo , Vitaminas/uso terapêuticoRESUMO
OBJECTIVE: Mercury and other toxic metals have been suggested to be involved in thyroid disorders, but the distribution and prevalence of mercury in the human thyroid gland is not known. We therefore used two elemental bio-imaging techniques to look at the distribution of mercury and other toxic metals in the thyroid glands of people over a wide range of ages. MATERIALS AND METHODS: Formalin-fixed paraffin-embedded thyroid tissue blocks were obtained from 115 people aged 1-104 years old, with varied clinicopathological conditions, who had thyroid samples removed during forensic/coronial autopsies. Seven-micron sections from these tissue blocks were used to detect intracellular inorganic mercury using autometallography. The presence of mercury was confirmed using laser ablation-inductively coupled plasma-mass spectrometry which can detect multiple elements. RESULTS: Mercury was found on autometallography in the thyroid follicular cells of 4% of people aged 1-29 years, 9% aged 30-59 years, and 38% aged 60-104 years. Laser ablation-inductively coupled plasma-mass spectrometry confirmed the presence of mercury in samples staining with autometallography, and detected cadmium, lead, iron, nickel and silver in selected samples. CONCLUSIONS: The proportion of people with mercury in their thyroid follicular cells increases with age, until it is present in over one-third of people aged 60 years and over. Other toxic metals in thyroid cells could enhance mercury toxicity. Mercury can trigger genotoxicity, autoimmune reactions, and oxidative damage, which raises the possibility that mercury could play a role in the pathogenesis of thyroid cancers, autoimmune thyroiditis, and hypothyroidism.
Assuntos
Monitoramento Ambiental , Hipotireoidismo/metabolismo , Mercúrio/metabolismo , Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Tireoidite Autoimune/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
We have reviewed the available literature on thyroid diseases and coronavirus disease 2019 (COVID-19), and data from the previous coronavirus pandemic, the severe acute respiratory syndrome (SARS) epidemic. We learned that both SARS and COVID-19 patients had thyroid abnormalities. In the limited number of SARS cases, where it was examined, decreased serum T3, T4 and TSH levels were detected. In a study of survivors of SARS approximately 7% of the patients had hypothyroidism. In the previous evaluation evidence was found that pituitary function was also affected in SARS. Others suggested a hypothalamic-pituitary-adrenal axis dysfunction. One result published recently indicates that a primary injury to the thyroid gland itself may play a key role in the pathogenesis of thyroid disorders in COVID-19 patients, too. Subacute thyroiditis, autoimmune thyroiditis and an atypical form of thyroiditis are complications of COVID-19. Thyroid hormone dysfunction affects the outcome by increasing mortality in critical illnesses like acute respiratory distress syndrome, which is a leading complication in COVID-19. Angiotensin-converting enzyme 2 is a membrane-bound enzyme, which is also expressed in the thyroid gland and the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) uses it for docking, entering as well as replication. Based on the available results obtained in the SARS-CoV-2 pandemic, beside others, we suggest that it is necessary to monitor thyroid hormones in COVID-19.
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COVID-19/fisiopatologia , Doença de Graves/fisiopatologia , Hipotireoidismo/fisiopatologia , Síndrome do Desconforto Respiratório/fisiopatologia , Tireoidite/fisiopatologia , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/complicações , COVID-19/metabolismo , Doença de Graves/etiologia , Doença de Graves/metabolismo , Humanos , Hipotireoidismo/etiologia , Hipotireoidismo/metabolismo , Mortalidade , Prognóstico , Receptores de Coronavírus/metabolismo , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/metabolismo , SARS-CoV-2/metabolismo , Síndrome Respiratória Aguda Grave/complicações , Síndrome Respiratória Aguda Grave/metabolismo , Síndrome Respiratória Aguda Grave/fisiopatologia , Glândula Tireoide/metabolismo , Tireoidite/etiologia , Tireoidite/metabolismo , Tireoidite Autoimune/etiologia , Tireoidite Autoimune/metabolismo , Tireoidite Autoimune/fisiopatologia , Tireoidite Subaguda/etiologia , Tireoidite Subaguda/metabolismo , Tireoidite Subaguda/fisiopatologia , Tireotropina/metabolismo , Tiroxina/metabolismo , Tri-Iodotironina/metabolismoRESUMO
PURPOSE: To evaluate factors influencing the insulin and levothyroxine requirement in patients with autoimmune polyglandular syndrome type 3 (APS-3) vs. patients with type 1 diabetes mellitus (T1DM) and autoimmune hypothyroidism (AH) alone, respectively. METHODS: Fifty patients with APS-3, 60 patients with T1DM and 40 patients with AH were included. Anthropometric, clinical and biochemical parameters were evaluated in all patients. Insulin requirement was calculated in patients with APS-3 and T1DM, while levothyroxine requirement was calculated in APS-3 and AH. RESULTS: Patients with APS-3 showed higher age (p = 0.001), age of onset of diabetes (p = 0.006) and TSH (p = 0.004) and lower total insulin as U/day (p < 0.001) and U/Kg (p = 0.001), long-acting insulin as U/day (p = 0.030) and U/kg (p = 0.038) and irisin (p = 0.002) compared to T1DM. Patients with APS-3 had higher waist circumference (p = 0.008), duration of thyroid disease (p = 0.020), levothyroxine total daily dose (p = 0.025) and mcg/kg (p = 0.006), triglycerides (p = 0.007) and VAI (p = 0.010) and lower age of onset of thyroid disease (p = 0.007) than AH. At multivariate analysis, levothyroxine treatment and VAI were associated with insulin and levothyroxine requirement in APS-3, respectively. VAI was independently associated with insulin requirement in T1DM. Circulating irisin levels were independently associated with levothyroxine requirement in AH. CONCLUSION: Patients with APS-3 show lower insulin requirement and higher levothyroxine requirement than T1DM and AH alone, respectively. Levothyroxine treatment and VAI affect insulin and levothyroxine requirement, respectively, in APS-3. In T1DM, adipose tissue dysfunction, indirectly expressed by high VAI, is associated with an increased insulin requirement, while circulating irisin levels influence the levothyroxine requirement in AH.
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Biomarcadores/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Doença de Hashimoto/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Poliendocrinopatias Autoimunes/tratamento farmacológico , Tireoidite Autoimune/tratamento farmacológico , Tiroxina/uso terapêutico , Adolescente , Adulto , Idoso , Glicemia/análise , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Feminino , Seguimentos , Doença de Hashimoto/metabolismo , Doença de Hashimoto/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Poliendocrinopatias Autoimunes/metabolismo , Poliendocrinopatias Autoimunes/patologia , Prognóstico , Tireoidite Autoimune/metabolismo , Tireoidite Autoimune/patologia , Adulto JovemRESUMO
INTRODUCTION: Oxidative stress has been proposed as one of the factors concurring in the pathophysiology of autoimmune thyroid diseases. Reactive oxygen species are the main expression of oxidative stress in biological systems, and their production can overcome antioxidant defenses ultimately leading to cell damage, apoptosis, and death. The present review was aimed at describing the state of the art of the relationships between oxidative stress and autoimmune thyroiditis. The most used biomarkers of oxidative stress and their correlation with thyroid function are reported. EVIDENCE ACQUISITION: We conducted a search of the literature in the English language starting from 2000, using the following search terms: "Hashimoto thyroiditis," "autoimmune thyroiditis," "hypothyroidism," "hyperthyroidism," "oxidative stress," "oxidants," "antioxidant," "advanced glycation end products." Both clinical studies and animal models were evaluated. EVIDENCE SYNTHESIS: Data form clinical studies clearly indicate that the balance between oxidants and antioxidants is shifted towards the oxidative side in patients with autoimmune thyroiditis, suggesting that oxidative stress may be a key event in the pathophysiology of the disease, irrespective of thyroid function. Studies in animal models, such as the NOD.H2h4 mouse, confirm that thyroidal accumulation of ROS plays a role in the initiation and progression of autoimmune thyroiditis. CONCLUSIONS: Oxidant/antioxidant imbalance represent a key feature of thyroid autoimmunity. Oxidative stress parameters could be used as biochemical markers of chronic inflammation, to better predict the disease evolution along its natural history. Dietary habits and antioxidant supplements may provide protection from autoimmunity, opening new perspectives in the development of more tailored therapies.
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Estresse Oxidativo , Tireoidite Autoimune/metabolismo , Biomarcadores/sangue , Humanos , Tireoidite Autoimune/sangueRESUMO
The essential biological action of vitamin D is regulation of calcium and phosphorus metabolism and preserving bone health. In recent years there have been reports about the extraskeletal actions of vitamin D and its role in the regulation of immune system. Vitamin D supplementation appears to reduce the incidence of cardiovascular diseases, cancer, and infections and be able to reduce all-cause mortality. Deficiency of vitamin D has been found to correlate with the increased incidence of autoimmune diseases, including type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis. Autoimmune thyroid diseases (AITD), including Graves' disease, Hashimoto's thyroiditis are relatively common autoimmune disorders affecting more than 5% of general population. It has been shown that vitamin D receptors (VDR) and 1-alpha hydroxylase are expressed in papillary thyroid cancer and normal thyroid tissue, suggesting local synthesis of 1,25(OH)2D in the thyroid. While VDR gene polymorphism has been found in much research to be associated with AITDs, very few studies have examined the impact of vitamin D deficiency on the incidence of AITDs in humans with conflicting results. This review focuses on the association between vitamin D and autoimmune thyroid diseases and summarizes the results of vitamin D supplementation studies in patients with AITD.
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Doença de Graves/metabolismo , Doença de Hashimoto/metabolismo , Tireoidite Autoimune/metabolismo , Deficiência de Vitamina D/metabolismo , Vitamina D/metabolismo , Doença de Graves/tratamento farmacológico , Doença de Graves/epidemiologia , Doença de Hashimoto/tratamento farmacológico , Doença de Hashimoto/epidemiologia , Humanos , Receptores de Calcitriol/metabolismo , Tireoidite Autoimune/tratamento farmacológico , Tireoidite Autoimune/epidemiologia , Vitamina D/análogos & derivados , Vitamina D/uso terapêutico , Deficiência de Vitamina D/epidemiologia , Vitaminas/uso terapêuticoRESUMO
Because of contradictory results, clinical significance of elevated levels of macroprolactin (macroprolactinemia) remains unclear. The aim of this study was to investigate whether macroprolactinemia determines levothyroxine action on hypothalamic-pituitary-thyroid axis activity and thyroid antibody titers in women with autoimmune hypothyroidism. The study population included 2 age-, body mass index-, hormone-, and thyroid antibody-matched groups of premenopausal women with untreated autoimmune subclinical hypothyroidism: 15 subjects with coexisting macroprolactinemia and 29 individuals with prolactin levels within the reference range. All included patients were then treated with levothyroxine for 6 months. Serum levels of thyrotropin, free thyroid hormones, prolactin and 25-hydroxyvitamin D, titers of thyroid peroxidase and thyroglobulin antibodies, as well as macroprolactin content were assessed at the beginning and at the end of the study. Except for 25-hydroxyvitamin D levels and macroprolactin content, there were no significant differences between both study arms in the investigated markers. All participants completed the study. In both treatment arms, levothyroxine treatment decreased thyrotropin levels, increased free thyroxine and free triiodothyronine levels, as well as reduced thyroid peroxidase titers, but this effect was less pronounced in women with macroprolactinemia. In women with normal prolactin levels, levothyroxine reduced also thyroglobulin antibody titers and increased 25-hydroxyvitamin D levels. In this group of patients, treatment-induced changes in hormone levels and thyroid antibody titers correlated with treatment-induced changes in 25-hydroxyvitamin D levels. The obtained results suggest that macroprolactin excess attenuates the impact of levothyroxine on hypothalamic-pituitary-thyroid axis activity and thyroid autoimmunity.
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Doença de Hashimoto/tratamento farmacológico , Doença de Hashimoto/metabolismo , Hiperprolactinemia/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Glândula Tireoide/efeitos dos fármacos , Tireoidite Autoimune/tratamento farmacológico , Tireoidite Autoimune/metabolismo , Tiroxina/farmacologia , Adulto , Autoanticorpos/sangue , Autoantígenos/sangue , Autoimunidade/efeitos dos fármacos , Feminino , Doença de Hashimoto/sangue , Doença de Hashimoto/complicações , Humanos , Hiperprolactinemia/sangue , Hiperprolactinemia/complicações , Iodeto Peroxidase/sangue , Proteínas de Ligação ao Ferro/sangue , Pessoa de Meia-Idade , Prolactina/sangue , Hormônios Tireóideos/sangue , Tireoidite Autoimune/sangue , Tireoidite Autoimune/complicações , Tireotropina/sangue , Vitamina D/análogos & derivados , Vitamina D/sangue , Adulto JovemRESUMO
Background: Despite advances in targeted kinase inhibitor development for patients with medullary thyroid cancer (MTC), most patients develop resistance and would benefit from alternative approaches. Immune-based therapies are now considered for patients with progressive MTC. This study is the first comprehensive assessment of the immune milieu, immune-suppressive molecules, and potential tumor antigens in patients with MTC. Methods: Primary and/or regionally metastatic tumor tissues from 46 patients with MTC were screened for immune infiltrates by using standard immunohistochemistry (IHC) and further analyzed by multispectral imaging for T cell and myeloid markers. RNASeq expression profiling was performed in parallel. RNASeq, targeted sequencing, and IHC techniques identified cancer-associated mutations and MTC-enriched proteins. Results: Organized immune infiltration was observed in 49% and 90% of primary and metastatic tumors, respectively. CD8+ cells were the dominant T cell subtype in most samples, while CD163+ macrophages were most frequent among myeloid infiltrates. PD-1+ T cells were evident in 24% of patients. Myeloid subsets were largely major histocompatibility complex II (MHCII-), suggesting a dysfunctional phenotype. Expression profiling confirmed enrichment in T cell, macrophage, and inflammatory profiles in a subset of samples. PD-L1 was expressed at low levels in a small subset of patients, while the immune regulatory molecules CD155 and CD47 were broadly expressed. Calcitonin, GRP, HIST1H4E, NOMO3, and NPIPA2 were highly and specifically expressed in MTC. Mutations in tumor suppressors, PTEN and p53, and mismatch repair genes, MSH2 and MSH6, may be relevant to disease progression and antigenicity. Conclusions: This study suggests that MTC is a more immunologically active tumor that has been previously reported. Patients with advanced MTC should be screened for targetable antigens and immune checkpoints to determine their eligibility for current clinical trials. Additional studies are necessary to fully characterize the antigenic potential of MTC and may encourage the development of adoptive T cells therapies for this rare tumor.
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Antígenos de Neoplasias/metabolismo , Carcinoma Neuroendócrino/imunologia , RNA-Seq , Neoplasias da Glândula Tireoide/imunologia , Calcitonina/metabolismo , Carcinoma Neuroendócrino/metabolismo , Ensaios Clínicos como Assunto , Análise Mutacional de DNA , Progressão da Doença , Perfilação da Expressão Gênica , Humanos , Sistema Imunitário , Imuno-Histoquímica , Leucócitos/metabolismo , Macrófagos/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , Mutação , Receptores Virais/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Tireoidite Autoimune/metabolismo , Estados UnidosRESUMO
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.