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1.
Int J Mol Sci ; 20(18)2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31514388

RESUMO

The thyroid is a major component of the endocrine system and its pathology can cause serious diseases, e.g., papillary carcinoma (PC). However, the carcinogenic mechanisms are poorly understood and clinical useful biomarkers are scarce. Therefore, we determined if there are quantitative patterns of molecular chaperones in the tumor tissue and circulating exosomes that may be useful in diagnosis and provide clues on their participation in carcinogenesis. Hsp27, Hsp60, Hsp70, and Hsp90 were quantified by immunohistochemistry in PC, benign goiter (BG), and normal peritumoral tissue (PT). The same chaperones were assessed in plasma exosomes from PC and BG patients before and after ablative surgery, using Western blotting. Hsp27, Hsp60, and Hsp90 were increased in PC in comparison with PT and BG but no differences were found for Hsp70. Similarly, exosomal levels of Hsp27, Hsp60, and Hsp90 were higher in PC than in BG, and those in PC were higher before ablative surgery than after it. Hsp27, Hsp60, and Hsp90 show distinctive quantitative patterns in thyroid tissue and circulating exosomes in PC as compared with BG, suggesting some implication in the carcinogenesis of these chaperones and indicating their potential as biomarkers for clinical applications.


Assuntos
Exossomos/metabolismo , Proteínas de Choque Térmico/metabolismo , Glândula Tireoide/imunologia , Glândula Tireoide/patologia , Carcinoma Papilar/imunologia , Carcinoma Papilar/metabolismo , Carcinoma Papilar/patologia , Exossomos/ultraestrutura , Feminino , Bócio/metabolismo , Bócio/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Glândula Tireoide/metabolismo
2.
EBioMedicine ; 46: 381-386, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31371192

RESUMO

BACKGROUND: Alemtuzumab is approved for the treatment of active relapsing-remitting multiple sclerosis (RRMS). Alemtuzumab-related secondary autoimmune disorders (sAID) are common, with thyroid sAID being the most frequent, and fundamentally affect the risk-benefit ratio. Therefore, biomarkers indicating the development of sAID are urgently needed to instruct clinical decisions. METHODS: We evaluated whether the anti-thyroid autoantibodies (ThyAb) anti-thyroglobulin (anti-TG) and anti-thyroid-peroxidase (anti-TPO) detected at baseline by standard testing are able to indicate increased risk for thyroid sAID following alemtuzumab treatment in a multicentre prospective cohort of 106 alemtuzumab-treated RRMS patients. We here present an interim-analysis with a median follow-up of 36 months. FINDINGS: Baseline characteristics demonstrated no significant differences between patients with or without thyroid sAID. 29/106 (27·4%) patients developed thyroid sAID between 5 and 51 months following alemtuzumab treatment initiation. 14/29 patients (48·3%) were positive for ThyAb at baseline and developed thyroid sAID. Hazard ratio for time to thyroid autoimmunity was 12.15 (95% CI 4.73-31.2) indicating a highly increased risk for ThyAb positive patients. Baseline ThyAb were associated with shorter time to sAID, but not with a specific disease entity of thyroid sAID. Hazard ratios for age, sex, previous treatment, disease duration, disability and smoking status demonstrated no significant association with thyroid autoimmunity. INTERPRETATION: Standard ThyAb-testing for anti-TPO and anti-TG antibodies at baseline was able to indicate increased risk for clinically manifest thyroid sAID and should therefore be used in clinical decisions concerning alemtuzumab treatment initiation. FUND: German Ministry of Education, Science, Research and Technology and the German Research foundation.


Assuntos
Alemtuzumab/efeitos adversos , Autoanticorpos/farmacologia , Autoimunidade/efeitos dos fármacos , Glândula Tireoide/imunologia , Adulto , Antineoplásicos Imunológicos/efeitos adversos , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/mortalidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais
3.
Horm Metab Res ; 51(6): 347-352, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31207655

RESUMO

Various cut-offs have been proposed for thyroid peroxidase antibodies (TPOAb) positivity. Considering that the long-term trend of TPOAb levels and its positivity incidence is not clearly understood, we conducted the current study to determine the longitudinal variations of TPOAb in a population-based cohort study. We followed 5783 individuals of Tehran Thyroid cohort Study (TTS) for 10 years (4 phases). After exclusions, data of 3493 euthyroid participants remained for analyses. The baseline prevalence rates of TPOAb positivity were 19.8, 17, and 11.4% and the annual incidence rates (95% CI) of TPOAb positivity were 8.53 (8.29-8.77), 7.59 (7.37-7.80) and 6.79 (6.60-6.98) per 1000 persons for the 3 proposed cut-offs of 14.77, 18.38, and 40 U/l; respectively. Although a slightly increasing trend was observed for TPOAb levels (p=0.001) and its conventional positivity (TPOAb>40U/l), the recently proposed cut-offs of 14.77 and 18.38 U/l showed constant TPOAb positivity over 10 years. The time trends of the TPOAb levels among younger participants were significantly different from older participants (time×age effect p=0.004), with the former having an increasing trend and the latter, a relatively decreasing trend. Although the prevalence of TPOAb positivity was significantly (p<0.001) higher among women as compared to men, the longitudinal changes of TPOAb were similar in men and women. TPOAb positivity along with TSH values between 2.5 and 5.0 mU/l or free T4 values between 0.93 and 1.7 ng/dl exerted a significantly increased risk of subclinical or overt hypothyroidism. In an iodine sufficient population, an increasing trend in TPOAb levels was observed in line with the increasing incidence of subclinical and overt hypothyroidism.


Assuntos
Autoanticorpos/sangue , Hipertireoidismo/diagnóstico , Hipertireoidismo/epidemiologia , Hipotireoidismo/diagnóstico , Hipotireoidismo/epidemiologia , Iodeto Peroxidase/imunologia , Glândula Tireoide/imunologia , Adulto , Autoanticorpos/imunologia , Estudos de Casos e Controles , Feminino , Humanos , Hipertireoidismo/sangue , Hipertireoidismo/imunologia , Hipotireoidismo/sangue , Hipotireoidismo/imunologia , Incidência , Irã (Geográfico)/epidemiologia , Masculino , Prognóstico , Estudos Prospectivos , Testes de Função Tireóidea
4.
Int Immunopharmacol ; 73: 333-342, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31129420

RESUMO

PURPOSE: Growth arrest-specific protein 6 (Gas6) is a vitamin K-dependent protein that plays an important role in the pathogenesis of autoimmune diseases. The purpose of this study was to explore the expression of Gas6 and its effects on autoimmune thyroiditis (AIT). METHOD: A total of 24 male NOD.H-2h4 mice were randomly assigned to three groups: (1) a control group supplied with regular water; (2) a sodium iodide (NaI) group supplied with 0.005% sodium iodide water; and (3) a group treated with recombinant mouse Gas6 (rmGas6) after iodine supplementation (NaI + Gas6 group). The severity of lymphocytic infiltration in the thyroid was measured through histopathology. Serum levels of tumor necrosis factor α (TNF-α), interleukin (IL) 6 and IL-1ß, as well as anti-thyroglobulin antibody (TgAb) titers were measured using an enzyme-linked immunosorbent assay. In addition, the expression of Gas6, Caspase 3, TAM receptors (Axl and MerTK), nuclear factor κB (NF-κB) and I-kappa-B α (IκB-α) were measured by Western blotting. Finally, the proportions of T cells were determined in the splenocytes of NOD.H-2h4 mice by flow cytometry. RESULTS: The mRNA and protein expression of Gas6 was significantly lower in the NaI group compared to the control group. Serum levels of TgAb, TNF-α, IL-6 and IL-1ß were also significantly higher in the NaI group but were dramatically reduced after rmGas6 injection. The prevalence of thyroiditis and the infiltration of lymphocytes were significantly lower in the NaI + Gas6 group compared to the NaI group. The protein expression of cleaved-Caspase 3, phosphorylation of MerTK, and NF-κB and IκB-α in the thyroid gland were significantly reduced after rmGas6 administration. The proportion of Th1, Th2 and Th17 cells in splenocytes were also significantly reduced after rmGas6 treatment, whereas there was a dramatic increase in the proportion of Treg cells. CONCLUSION: Gas6 exerts an anti-inflammatory effect in a mouse model of AIT and may therefore be a potential therapeutic target.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Tireoidite Autoimune/imunologia , Animais , Apoptose , Autoanticorpos/sangue , Citocinas/sangue , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Iodo , Masculino , Camundongos , Proteínas Recombinantes/farmacologia , Glândula Tireoide/imunologia , Tireoidite Autoimune/sangue
5.
Horm Metab Res ; 51(5): 296-301, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31071734

RESUMO

Hashimoto's thyroiditis (HT) is the most prevalent autoimmune disorder characterized by the destruction of thyroid cells caused by leukocytes and antibody-mediated immune processes accompanied by hypothyroidism. In recent years, evidence has emerged pointing to various roles for vitamin D, including, proliferation and differentiation of normal and cancer cells, cardiovascular function, and immunomodulation. Vitamin D deficiency has been especially demonstrated in HT patients. The aim of this study was to investigate the effect of vitamin D on circulating thyroid autoantibodies and thyroid hormones profile (T4, T3, and TSH) in females with HT. Forty-two women with HT disease were enrolled in this randomized clinical trial study and divided into vitamin D and placebo groups. Patients in the vitamin D and placebo groups received 50 000 IU vitamin D and placebo pearls, weekly for 3 months, respectively. The serum levels of 25-hydroxy vitamin D [25(OH) D], Ca++ion, anti-thyroperoxidase antibody (anti-TPO Ab), anti-thyroglobulin antibody (anti-Tg Ab), T4, T3, and TSH were measured at the baseline and at the end of the study using enzyme-linked immunosorbent assays. The results of this study showed a significant reduction of anti-Tg Ab and TSH hormone in the Vitamin D group compared to the start of the study; however, there was a no significant reduction of anti-TPO Ab in the Vitamin D group compared to the placebo group (p=0.08). No significant changes were observed in the serum levels of T3 and T4 hormones. Therefore, vitamin D supplementation can be helpful for alleviation of the disease activity in HT patients; however, further well controlled, large, longitudinal studies are needed to determine whether it can be introduced in clinical practice.


Assuntos
Autoanticorpos/imunologia , Suplementos Nutricionais , Doença de Hashimoto/tratamento farmacológico , Doença de Hashimoto/imunologia , Glândula Tireoide/imunologia , Hormônios Tireóideos/sangue , Vitamina D/uso terapêutico , Adulto , Feminino , Doença de Hashimoto/sangue , Humanos , Tiroxina/uso terapêutico
6.
PLoS One ; 14(5): e0216954, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31086392

RESUMO

BACKGROUND: Blocking the PD-1 pathway induces immune-related adverse events (irAEs) which often involve the thyroid gland (thyroid irAEs). Clinical features of a thyroid irAE including its predictability and relationship to prognosis remain to be elucidated. METHODS: Two hundred consecutive patients treated with nivolumab at Kyoto University Hospital between September 1, 2014 and August 31, 2017 were included in a retrospective cohort study. We systematically determined and classified subclinical and overt thyroid irAEs based on data collected of serum free T4 and TSH levels. Baseline characteristics and detailed clinical data were analyzed, and analyses of overall survival (OS) excluded patients censored within 1 month from the first administration of nivolumab. RESULTS: Sixty-seven patients (33.5%) developed thyroid irAEs and these were divided into a subclinical thyroid irAE group (n = 40, 20.0%) and an overt thyroid irAE group (n = 27, 13.5%). Patients with thyroid uptake of FDG-PET before treatment showed high incidences of overt thyroid irAE (adjusted odds ratio 14.48; 95% confidence interval [CI] 3.12-67.19), while the same relationship was not seen with subclinical thyroid irAE. Regarding the total cohort, the thyroid irAE (+) group had a significantly longer median OS than the thyroid irAE (-) group (16.1 versus 13.6 months, hazard ratio [HR] 0.61; 95% CI 0.39-0.93). In 112 non-excluded patients with lung cancer, the thyroid irAE (+) group similarly had a longer median OS than the thyroid irAE (-) group (not reached versus 14.2 months, HR 0.51; 95% CI 0.27-0.92). However, this observation was not seen in 41 non-excluded patients with malignant melanoma (12.0 versus 18.3 months, HR 1.54; 95% CI 0.67-3.43). CONCLUSIONS: By thyroid uptake of FDG-PET, overt thyroid irAEs could be predicted before nivolumab therapy. Thyroid irAEs related to good prognosis in lung cancer but might be inconclusive in malignant melanoma.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Melanoma/diagnóstico por imagem , Nivolumabe/efeitos adversos , Neoplasias Cutâneas/diagnóstico por imagem , Glândula Tireoide/efeitos dos fármacos , Tireoidite/diagnóstico por imagem , Idoso , Antineoplásicos Imunológicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Fluordesoxiglucose F18/farmacocinética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Masculino , Melanoma/tratamento farmacológico , Melanoma/imunologia , Melanoma/mortalidade , Pessoa de Meia-Idade , Nivolumabe/administração & dosagem , Tomografia por Emissão de Pósitrons , Prognóstico , Compostos Radiofarmacêuticos/farmacocinética , Estudos Retrospectivos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Análise de Sobrevida , Glândula Tireoide/imunologia , Glândula Tireoide/patologia , Tireoidite/induzido quimicamente , Tireoidite/mortalidade , Tireoidite/patologia , Tireotropina/sangue , Tiroxina/sangue , Tri-Iodotironina/sangue
7.
Eur J Clin Invest ; 49(7): e13122, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31034586

RESUMO

BACKGROUND: Osteopontin (OPN) is recognized as a potent immunoregulator of autoimmune disease. In the study, we tried to explore the association of serum OPN levels with autoimmune thyroid disease, including Graves' disease (GD) and Hashimoto's thyroiditis (HT), in an ethnic Chinese population. MATERIALS AND METHODS: We enrolled 131 patients with GD, 33 patients with HT and 123 healthy controls. Serum OPN, B cell-activating factor (BAFF) and interferon (IFN)-α levels were quantified. Graves' disease patients with high thyroid function at the time of sample collection were defined as having active GD, while the other patients were defined as having inactive GD. RESULTS: Serum OPN levels were higher in active GD than in inactive GD and the control groups (P = 0.001 and P = 0.018, respectively). In GD, significant associations of OPN levels with thyroid-stimulating hormone receptor antibody (TSHRAb) levels were observed in women (r = -0.344, P = 0.002, and r = 0.440, P = 0.004, respectively) but not in men. Osteopontin levels were associated with BAFF levels only in women with GD or HT (r = 0.506, P < 0.001 and r = 0.430, P = 0.025, respectively), but not in men with GD or HT. CONCLUSIONS: Serum OPN levels were upregulated in active GD, and serum OPN levels were associated with thyroid function and TSHRAb levels in GD. Additionally, OPN levels were correlated with BAFF levels in GD and HT. The associations of OPN levels with clinical phenotypes of GD and BAFF levels showed a dimorphic pattern.


Assuntos
Fator Ativador de Células B/metabolismo , Doença de Graves/sangue , Doença de Hashimoto/sangue , Osteopontina/metabolismo , Adulto , Autoanticorpos/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Interferon-alfa/metabolismo , Masculino , Caracteres Sexuais , Glândula Tireoide/imunologia , Tireotropina/metabolismo , Tiroxina/metabolismo , Regulação para Cima/fisiologia
8.
Int J Mol Sci ; 20(4)2019 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-30791371

RESUMO

The role of autoantibodies in in vitro fertilization (IVF) has been discussed for almost three decades. Nonetheless, studies are still scarce and widely controversial. The aim of this study is to provide a comprehensive systematic review on the possible complications associated to autoantibodies (AA) impeding the chances of a successful IVF cycle. An Embase, PubMed/Medline and Cochrane Central Database search was performed on 1 December 2018, from 2006 until that date. From the 598 articles yielded in the search only 44 relevant articles ultimately fulfilled the inclusion criteria and were qualitatively analyzed. Five subsets of results were identified, namely, thyroid related AA, anti-phospholipid antibodies, anti-nuclear antibodies, AA affecting the reproductive system and AA related to celiac disease. It may be implied that the majority of auto-antibodies exert a statistically significant effect on miscarriage rates, whereas the effects on clinical pregnancy and live birth rates differ according to the type of auto-antibodies. While significant research is performed in the field, the quality of evidence provided is still low. The conduction of well-designed prospective cohort studies is an absolute necessity in order to define the impact of the different types of autoantibodies on IVF outcome.


Assuntos
Autoanticorpos/imunologia , Fertilização In Vitro , Infertilidade/terapia , Anticorpos Antinucleares/imunologia , Anticorpos Antifosfolipídeos/imunologia , Especificidade de Anticorpos/imunologia , Doenças Autoimunes/complicações , Doenças Autoimunes/imunologia , Doença Celíaca/complicações , Doença Celíaca/imunologia , Feminino , Fertilização In Vitro/efeitos adversos , Fertilização In Vitro/métodos , Humanos , Infertilidade/etiologia , Gravidez , Glândula Tireoide/imunologia , Glândula Tireoide/metabolismo , Resultado do Tratamento
9.
Dev Med Child Neurol ; 61(8): 984-988, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30720202

RESUMO

Epidemiological studies, animal models, and case-control studies indicate maternal immune activation may be an important factor involved in disease expression of autism spectrum disorder (ASD), Tourette syndrome, and obsessive-compulsive disorder (OCD). We report eight children (mean age 6y 6mo [range 4-15y]; six males and two females) referred over a 2-year period with at least one of these neurodevelopmental disorders plus a maternal history of thyroid autoimmunity. Seven of eight children presented with an abrupt onset of neuropsychiatric symptoms (OCD [n=6], tics [n=5], and/or psychosis [n=1]), associated with an autistic or global regression. Four children had a pre-existing diagnosis of ASD. Six presentations were preceded by infection, and symptoms followed a relapsing-remitting course in seven children. All children responded to immunomodulatory treatment as indicated by a reduction in psychiatric symptoms, and seven children were also managed with conventional treatment with additional improvement. We propose that maternal autoimmunity can activate fetal microglia or alter transcription of neurodevelopmental vulnerability and/or immune genes in utero, and is an environmental factor that increases the expression and severity of neurodevelopmental problems, and susceptibility to deteriorations after infectious or stress stimuli. WHAT THIS PAPER ADDS: Maternal thyroid autoimmunity may represent a risk factor for neuropsychiatric disorders in offspring. Atypical neuropsychiatric features in these children may be due to maternal immune activation in utero.


Assuntos
Transtornos de Ansiedade/imunologia , Transtorno do Espectro Autista/imunologia , Doença de Hashimoto/imunologia , Transtornos do Neurodesenvolvimento/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Glândula Tireoide/imunologia , Transtornos de Tique/imunologia , Adolescente , Transtornos de Ansiedade/psicologia , Transtorno do Espectro Autista/psicologia , Criança , Pré-Escolar , Feminino , Doença de Hashimoto/psicologia , Humanos , Masculino , Transtornos do Neurodesenvolvimento/psicologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/psicologia , Transtornos de Tique/psicologia
10.
Endocr J ; 66(2): 193-198, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30568076

RESUMO

There is a great deal of research interest regarding the underlying causes of slightly elevated TSH values in patients with subclinical hypothyroidism (SH) without abnormal findings on ultrasonography or anti-thyroid antibodies. Twelve infertile women with thyroglobulin antibody (TGAb) and thyroid peroxidase antibody (TPOAb)-negative nongoitrous SH were referred to our department of endocrinology between September 2007 and September 2015. None had been diagnosed with autoimmune thyroid disease or had any possible causes of SH. In all cases, LT4 was prescribed to bring TSH value below 2.5 mIU/L. Among those with infertility treatments, six (50%) became pregnant and gave birth to infants. Here, we report three of these six women who successfully became pregnant with infertility treatments and were found to have thyroid autoimmunity on data obtained during the postpartum period. Two developed postpartum thyroiditis, and the remaining one woman was temporarily weakly positive for TPOAb at 9 months postpartum. We describe three infertile subclinically hypothyroid women without goiter or anti-thyroid antibodies with potential thyroid autoimmunity. Thyroid autoimmunity is one of the most important issues for management of pregnant women, and thus, our findings are noteworthy for the care of infertile women with SH. This report provides valuable insights into the presence of autoimmunity in nongoitrous thyroid-associated antibody-negative SH patients.


Assuntos
Autoanticorpos/imunologia , Hipotireoidismo/complicações , Infertilidade Feminina/complicações , Glândula Tireoide/imunologia , Tireoidite Autoimune/complicações , Adulto , Autoimunidade/imunologia , Feminino , Humanos , Hipotireoidismo/imunologia , Infertilidade Feminina/imunologia , Iodeto Peroxidase/imunologia , Tireoglobulina/imunologia , Tireoidite Autoimune/imunologia
12.
J Clin Pharm Ther ; 44(1): 102-108, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30306604

RESUMO

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.


Assuntos
Suplementos Nutricionais , Selenometionina/administração & dosagem , Tireoidite Autoimune/terapia , Adolescente , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , Masculino , Glândula Tireoide/imunologia , Glândula Tireoide/fisiopatologia , Tireoidite Autoimune/fisiopatologia , Resultado do Tratamento
13.
Mol Cell Endocrinol ; 480: 97-106, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30393005

RESUMO

Autoimmune thyroid disease (AITD) mainly includes Graves' disease (GD) and Hashimoto's thyroiditis (HT), and its pathogenesis is not clearly defined. This study was designed to explore risk loci for AITD. Genome-wide genetic data were analyzed to identify important risk loci for GD, and a case-control study with 845 AITD patients and 694 healthy controls was also conducted. The functional role of possible risk loci for GD was explored by analyzing the correlations of Centrosomal protein 128 (CEP128) expression level with intrathyroidal immune cells and key genes for candidate immune cells in GD thyroid tissues. CEP128 was identified as an important risk locus for GD in the genome-wide genetic analysis, and it was located near TSHR without obvious linkage disequilibrium with TSHR. Two tag single-nucleotide variants in CEP128 including a missense variant rs327463 were substantially related to genetic predisposition to GD and HT in the case-control study. CEP128 rs327463 was substantially related to GD under the allele model (OR = 1.31, 95%CI 1.08-1.59, P = 0.006) and the dominant model (OR = 1.37, 95%CI 1.09-1.72, P = 0.008), and it was related to HT under the recessive model (OR = 1.85, P = 0.031) and the homozygous model (OR = 1.91, P = 0.025). Moreover, CEP128 was substantially correlated with the frequencies of T-follicular helper (Tfh) cell and M1 macrophages in GD tissues. Gene set enrichment analysis suggested that CEP128 was related to several common immune pathways involved in GD pathogenesis, such as interferon-γ mediated signaling pathway and toll-like receptor signaling pathway. This study highlight the crucial role of CEP128 in the pathogenesis of GD, and polymorphisms in CEP128 contribute to genetic predisposition to both GD and HT.


Assuntos
Doenças Autoimunes/genética , Loci Gênicos , Predisposição Genética para Doença , Proteínas dos Microtúbulos/genética , Doenças da Glândula Tireoide/genética , Estudos de Casos e Controles , Cromossomos Humanos/genética , Frequência do Gene/genética , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação/genética , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Risco , Glândula Tireoide/imunologia , Glândula Tireoide/patologia
14.
J Cell Physiol ; 234(3): 2204-2216, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30246383

RESUMO

Autoimmune thyroid disease (AITD) is one of the most common organ-specific autoimmune disorders. It mainly manifests as Hashimoto's thyroiditis (HT) and Graves' disease (GD). HT is characteristic of hypothyroidism resulting from the destruction of the thyroid while GD is characteristic of hyperthyroidism due to excessive production of thyroid hormone induced by thyrotropin receptor-specific stimulatory autoantibodies. T lymphocytes and their secretory cytokines play indispensable roles in modulating immune responses, but their roles are often complex and full of interactions among distinct components of the immune system. Dysfunction of these T cells or aberrant expressions of these cytokines can cause the breakdown of immune tolerance and result in aberrant immune responses during the development of AITDs. This review summarizes recently identified T subsets and related cytokines and their roles in the pathogenesis of AITDs with the hope to provide a better understanding of the precise roles of notably identified T subsets in AITDs and facilitate the discovery of functional molecules or novel immune therapeutic targets for AITDs.


Assuntos
Doenças Autoimunes/imunologia , Doença de Graves/imunologia , Doença de Hashimoto/imunologia , Doenças da Glândula Tireoide/imunologia , Doenças Autoimunes/patologia , Citocinas/imunologia , Doença de Graves/patologia , Doença de Hashimoto/patologia , Humanos , Linfócitos T/imunologia , Linfócitos T/patologia , Células Th1/imunologia , Células Th1/patologia , Células Th2/imunologia , Células Th2/patologia , Doenças da Glândula Tireoide/patologia , Glândula Tireoide/imunologia , Glândula Tireoide/patologia
15.
J Formos Med Assoc ; 118(1 Pt 2): 347-353, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29898820

RESUMO

BACKGROUND/PURPOSE: Our previous study found that 9 of 63 recurrent aphthous stomatitis (RAS)/Behcet's disease (BD) patients have serum gastric parietal cell antibody (GPCA) positivity. This study assessed whether serum GPCA positivity or RAS/BD itself was a significant factor causing hematinic deficiencies and hyperhomocysteinemia in GPCA-positive RAS/BD (GPCA+RAS/BD) or gastric and thyroid autoantibodies-negative RAS/BD (Abs-RAS/BD) patients. METHODS: The mean blood hemoglobin (Hb), iron, vitamin B12, folic acid, and homocysteine levels were measured and compared between any two of three groups of 9 GPCA+RAS/BD patients, 41 Abs-RAS/BD patients, and 126 healthy control subjects. RESULTS: GPCA+RAS/BD patients had significantly lower mean blood Hb (for men only), iron (for men only), and vitamin B12 levels as well as a significantly higher mean serum homocysteine level than 126 healthy control subjects. Moreover, GPCA+RAS/BD patients had significantly greater frequencies of blood Hb, iron, and vitamin B12 deficiencies and of hyperhomocysteinemia than healthy control subjects. GPCA+RAS/BD patients did have a significantly lower mean serum vitamin B12 level and a significantly higher mean serum homocysteine level as well as significantly greater frequencies of vitamin B12 deficiency and of hyperhomocysteinemia than Abs-RAS/BD patients. Moreover, Abs-RAS/BD patients did have significantly lower mean blood Hb, iron, and folic acid levels and significantly greater frequencies of blood Hb and iron deficiencies than healthy control subjects. CONCLUSION: The GPCA is a major factor causing vitamin B12 deficiency and hyperhomocyteinemia in GPCA+RAS/BD patients. RAS/BD itself does play a significant role in causing anemia and hematinic deficiencies in both GPCA+RAS/BD and Abs-RAS/BD patients.


Assuntos
Autoanticorpos/sangue , Síndrome de Behçet/sangue , Hiper-Homocisteinemia/sangue , Estomatite Aftosa/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Ácido Fólico/sangue , Deficiência de Ácido Fólico/sangue , Hematínicos , Hemoglobinas/análise , Humanos , Ferro/sangue , Masculino , Pessoa de Meia-Idade , Células Parietais Gástricas/imunologia , Estômago/imunologia , Taiwan , Glândula Tireoide/imunologia , Vitamina B 12/sangue , Deficiência de Vitamina B 12/sangue , Adulto Jovem
16.
Autoimmunity ; 51(5): 228-237, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30486698

RESUMO

BACKGROUND: The aim was to determine prevalence and age at seroconversion of thyroid autoimmunity in relation to islet autoantibodies, gender and HLA-DQ genotypes in children with increased risk for type 1 diabetes followed from birth. METHODS: In 10-year-old children (n = 1874), blood samples were analysed for autoantibodies against thyroid peroxidase (TPOAb), thyroglobulin (TGAb), glutamic acid decarboxylase 65 (GADA), Zink transporter 8 (ZnT8R/W/QA), insulinoma-associated protein-2 (IA-2A), insulin (IAA) and HLA-DQ genotypes. Prospectively collected samples from 2 years of age were next analysed for TPOAb, and TGAb and, finally, in confirming samples at 11-16 years of age along with TSH and FT4. Frequencies were tested with Chi-square or Fischer's exact tests, autoantibody levels with Wilcoxon and correlations between autoantibody levels with Spearman's rank correlation test. RESULTS: The prevalence of thyroid autoimmunity was 6.9%, overrepresented in girls (p < .001) also having higher TPOAb levels at 10 years (p = .049). TPOAb was associated with GADA (p = .002), ZnT8R/W/QA (p = .001) and IA-2A (p = .001) while TGAb were associated with ZnT8R/W/QA (p = .021). In boys only, TPOAb were associated with GADA (p = .002), IA-2A (p = .001), ZnT8R/W/QA (p = .001) and IAA (p = .009), and TGAb with GADA (p = .013), IA-2A (p = .005) and ZnT8R/W/QA (p = .003). Levels of IA-2A correlated to both TPOAb (p = .021) and to TGAb (p = .011). In boys only, levels of GADA and TGAb correlated (p = .009 as did levels of IA-2A and TPOAb (p = .013). The frequency and levels of thyroid autoantibodies increased with age. At follow-up, 22.3% had abnormal thyroid function or were treated with thyroxine. CONCLUSIONS: Thyroid autoimmunity and high TPOAb levels were more common in girls. In contrast, in boys only, there was a strong association with as well as correlation between levels of thyroid and islet autoantibodies. It is concluded that while girls may develop autoimmune thyroid disease (AITD) independent of islet autoantibodies, the risk for thyroid disease in boys may be linked to concomitant islet autoimmunity.


Assuntos
Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Ilhotas Pancreáticas/imunologia , Glândula Tireoide/imunologia , Tireoidite Autoimune/diagnóstico , Adolescente , Fatores Etários , Autoanticorpos/imunologia , Autoantígenos/imunologia , Autoantígenos/metabolismo , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/imunologia , Feminino , Seguimentos , Antígenos HLA-DQ/sangue , Antígenos HLA-DQ/imunologia , Humanos , Lactente , Recém-Nascido , Iodeto Peroxidase/imunologia , Iodeto Peroxidase/metabolismo , Proteínas de Ligação ao Ferro/imunologia , Proteínas de Ligação ao Ferro/metabolismo , Ilhotas Pancreáticas/metabolismo , Masculino , Prognóstico , Estudos Prospectivos , Soroconversão , Fatores Sexuais , Suécia , Glândula Tireoide/metabolismo , Tireoidite Autoimune/sangue , Tireoidite Autoimune/imunologia , Transportador 8 de Zinco/imunologia , Transportador 8 de Zinco/metabolismo
17.
PLoS One ; 13(10): e0206652, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30372494

RESUMO

OBJECTIVE: Although there are substantial data linking thyroid autoimmunity (TAI) and infertility, data regarding assisted reproductive technology (ART) outcomes and TAI markers in follicular fluid (FF) of women undergoing ART are scarce. Objective of the study was to assess the association of the levels of thyroid autoantibodies in FF and ART outcome expressed as the achieved pregnancies. METHODS: This study enrolled 52 women undergoing ART (26 TAI positive subjects and 26 age and body mass index matched TAI negative controls). Blood samples were drawn before the initiation of protocol for controlled ovarian stimulation, and thyrotropin (TSH), free triiodothyronine (fT3), free thyroxine (fT4), thyroid peroxidase antibodies (TPOAbs) and thyroglobulin antibodies (TgAbs) levels were measured. TSH, fT4, TPOAbs, TgAbs and progesterone levels were also measured in FF. RESULTS: There were no significant differences between the groups regarding mean levels of FF TSH and FF fT4. Statistically significant correlation was discovered regarding the levels of serum and FF TPOAbs (0,961, p<0.001 in TAI positive, 0,438, p = 0.025 in TAI negative group) and TgAbs (0,945, p<0.001 in TAI positive, 0,554, p = 0.003 in TAI negative group). Pregnancies rates per initiated cycle and per embryotransfer cycle were significantly different between TAI positive and TAI negative group, (30.8% vs 61.5%), p = 0.026 and (34.8% vs 66.7%), p = 0.029, respectively. Multivariate analysis showed that TAI positive women had less chance to achieve pregnancy (p = 0.004, OR = 0.036, 95% CI 0.004-0.347). CONCLUSIONS: Higher levels of thyroid autoantibodies in FF of TAI positive women are strongly correlated with serum levels and may have effect on the post-implantation embryo development.


Assuntos
Autoanticorpos/imunologia , Líquido Folicular/imunologia , Técnicas de Reprodução Assistida , Glândula Tireoide/imunologia , Tireotropina/sangue , Tiroxina/sangue , Adulto , Autoanticorpos/sangue , Estudos de Casos e Controles , Feminino , Humanos , Gravidez , Estudos Prospectivos , Técnicas de Reprodução Assistida/estatística & dados numéricos , Tri-Iodotironina/sangue , Adulto Jovem
18.
Autoimmunity ; 51(7): 352-359, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30345813

RESUMO

OBJECTIVE: Hashimoto's thyroiditis (HT) is characterized by autoantibodies targeting the thyroid. Abnormal CD4+CXCR5+T cell levels were previously shown to be associated with HT. However, Tfh cells consist of heterogeneous subpopulations, and which T follicular helper (Tfh) cell subpopulation participates in the pathogenesis of HT remains poorly understood. METHODS: Thirty healthy controls (HCs) and 52 HT patients were enrolled in the study. The percentages of Tfh, ICOS+Tfh, PD1+Tfh, Tfh1, Tfh2, Tfh17, effector Tfh, resting Tfh, effector memory Tfh, central memory Tfh, and naïve Tfh cells in the peripheral blood were all determined via flow cytometry, and the associations between the percentages of these cells and thyroid function indices were also investigated. RESULTS: The percentage of Tfh cells was significantly higher in HT patients than in HCs. Examination of the Tfh cell subsets revealed that the percentages of Tfh1, Tfh2, and resting Tfh cells were significantly decreased, while those of the ICOS+Tfh, PD1+Tfh, Tfh17, and effector Tfh cells were significantly increased in HT patients. No significant differences in effector memory, central memory or naïve Tfh cell percentages were noted between the HC and HT groups. Furthermore, the percentage of PD1+Tfh cells was positively correlated with anti-thyroglobulin antibody levels. Most importantly, only Tfh17 cell percentages were positively correlated with anti-thyroglobulin and anti-thyroid peroxidase antibody levels and were negatively correlated serum free T3 and free T4 levels in HT patients. CONCLUSIONS: Increased circulating Tfh17 cell and PD1+Tfh percentages are associated with higher autoantibody levels in HT patients, which imply that Tfh17 or PD1+Tfh cells may play a pathogenic role in the development of HT.


Assuntos
Autoanticorpos/sangue , Doença de Hashimoto/sangue , Receptor de Morte Celular Programada 1/metabolismo , Células Th17/imunologia , Adulto , Autoanticorpos/imunologia , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Estudos de Casos e Controles , Feminino , Doença de Hashimoto/imunologia , Voluntários Saudáveis , Humanos , Linfonodos/citologia , Linfonodos/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/imunologia , Células Th17/metabolismo , Glândula Tireoide/imunologia
19.
Horm Metab Res ; 50(12): 840-852, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30357776

RESUMO

After investigating thyroid autoimmunity for more than 40 years, we present a personal perspective on the field. Despite effective therapies for Graves' hyperthyroidism and Hashimoto's thyroiditis, cures are elusive. Novel forms of therapy are being developed, such as small molecule inhibitors of the TSH receptor (TSHR), but cure will require immunotherapy. This goal requires advances in understanding the pathogenesis of thyroid autoimmunity, the 'keys' for which are the thyroid antigens themselves. Presently, however, greater investigative focus is on non-thyroid specific immune cell types and molecules. Thyroid autoantigens are the drivers of the autoimmune response, a prime example being the TSHR. In our view, the TSHR is the culprit as well as the victim in Graves' disease because of its unique structure. Unlike the closely related gonadotropin receptors, the TSHR cleaves into subunits and there is strong evidence that its shed extracellular A-subunit, not the holoreceptor, is the major antigen driving pathogenic thyroid stimulating autoantibodies (TSAb) development. There is no Graves' disease of the gonads. Studies of potential antigen-specific immunotherapies require an animal model. Such models have been developed in which TSAb can be induced or, more importantly, arise spontaneously. Not appreciated until recently by thyroid investigators is that B cell surface autoantibodies are highly efficient 'antigen receptors' and the epitope to which an autoantibody binds influences antigen processing and which peptide is presented to T cells. These animal models and recombinant human autoantibodies cloned from Graves' and Hashimoto's B cells (plasma cells) are available for study by future generations.


Assuntos
Autoimunidade , Glândula Tireoide/imunologia , Animais , Autoanticorpos/metabolismo , Autoantígenos/metabolismo , Humanos , Receptores da Tireotropina/metabolismo
20.
Cancer Sci ; 109(11): 3583-3590, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30230649

RESUMO

Thyroid dysfunction (TD) induced by immune checkpoint inhibitors is not sufficiently understood. The purpose of this retrospective observational study was to identify risk factors and the clinical course of TD induced by nivolumab. Patients with advanced solid tumors who were treated with nivolumab from March 2009 through to March 2016 at the National Cancer Center Hospital (Tokyo, Japan) were included. Thyroid function and antithyroid Abs from serum samples among all patients were evaluated at baseline and during nivolumab treatment. Overt hypothyroidism was defined as low serum-free T4 together with elevated thyroid-stimulating hormone (TSH) >10 µIU/mL. Thyrotoxicosis was defined as low TSH with elevated free T4 and/or free T3. We defined thyroid autoimmunity as the presence of antithyroid Abs at baseline, including antithyroid peroxidase Abs and antithyroglobulin Abs (TgAb). Twenty-three (14%) of a total of 168 patients developed TD, including 17 cases of hypothyroidism and 20 of thyrotoxicosis. Thyrotoxicosis followed by hypothyroidism occurred in 14 cases. Fourteen of 35 patients (40%) with thyroid autoimmunity developed TD vs 9 of 133 (7%) without (odds ratio 9.19; 95% confidence interval [CI], 3.53-23.9). In multivariate analysis, elevated TSH and TgAb at baseline were significantly associated with the development of TD, with odds ratio of 7.36 (95% CI, 1.66-32.7) and 26.5 (95% CI, 8.18-85.8), respectively. Association between TD and elevated antithyroid peroxidase Abs at baseline was not significant. These results suggest that patients with pre-existing TgAb and elevated TSH at baseline are at high risk of TD.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Autoanticorpos/metabolismo , Doenças da Glândula Tireoide/epidemiologia , Glândula Tireoide/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/epidemiologia , Hipotireoidismo/imunologia , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Nivolumabe , Razão de Chances , Estudos Retrospectivos , Doenças da Glândula Tireoide/induzido quimicamente , Doenças da Glândula Tireoide/imunologia , Glândula Tireoide/metabolismo , Tireotoxicose/induzido quimicamente , Tireotoxicose/epidemiologia , Tireotoxicose/imunologia , Tireotropina/metabolismo , Adulto Jovem
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