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1.
J Toxicol Sci ; 45(11): 701-711, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33132244

RESUMO

We aimed to investigate the role of programmed cell death protein 1 (PD-1) and T lymphocytes in the proliferation, apoptosis and secretion of cells from patients and mice with Graves' disease (GD). The levels of serum hormones, related antibodies and inflammatory cytokines in GD patients were determined by electrochemiluminescence immunoassay and ELISA. The percentages of CD4 and CD8 T-lymphocytes and PD-1 expression were examined by flow cytometry. A GD mouse model, a thyroid follicular epithelial cell, and a CD4+PD-1+, CD4+PD-1- and CD8+PD-1+, CD8+PD-1- T lymphocyte co-culture system were constructed. The viability, apoptosis-related markers, serum hormones, related antibodies and inflammatory cytokines in thyroid follicular epithelial cells were determined by CCK-8, Western blot, qTR-PCR, electrochemiluminescence immunoassay and ELISA. Elevated free thyroid hormones (FT3, FT4), thyroid hormone antibodies (TRAb, TPOAb and TGAb), inflammatory cytokines, and inhibited TSH were observed in GD patients. The percentage of CD4+ T cells was increased, while that of CD8+ T cells was reduced in GD patients. PD-1 expression level was lifted in both CD4+ and CD8+ cells from GD patients. In mouse thyroid follicular epithelial cells co-cultured with CD4+PD-1+ and CD8+PD-1+ T lymphocytes, the cell viability, TH and TRAb levels and inflammatory cytokines level were the highest, while the TSH level and apoptosis were the lowest. PD-1 positive T lymphocytes were able to promote viability and inhibit apoptosis of thyroid follicular epithelial cells, which further caused a more accelerated development of GD.


Assuntos
Antígeno B7-H1/imunologia , Antígeno B7-H1/fisiologia , Proliferação de Células , Citocinas/metabolismo , Células Epiteliais/imunologia , Células Epiteliais/fisiologia , Doença de Graves/genética , Doença de Graves/imunologia , Mediadores da Inflamação/metabolismo , Linfócitos/imunologia , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/fisiologia , Glândula Tireoide/citologia , Adulto , Animais , Apoptose , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Progressão da Doença , Feminino , Doença de Graves/patologia , Humanos , Masculino , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade
2.
Autoimmun Rev ; 19(9): 102614, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32663624

RESUMO

Autoimmune thyroid diseases are a group of diseases characterized by a dysfunction of the immune system concerning the thyroid gland, associated with hypothyroidism or hyperthyroidism. The thyroid gland autoimmunity has been recognized as multifactorial. It has been reported that microorganisms may play a role on the pathogenesis of Hashimoto's thyroiditis and Graves´ disease. These could explain the high incidence of the autoimmune thyroid diseases. Helicobacter Pylori (H. pylori) and Hepatitis C virus (HCV) are the microorganisms in which the association with autoimmune thyroid diseases is clearer. The pathophysiologic mechanisms are still not well defined. For H. pylori, molecular mimicry has been the most accepted mechanism. It has been proposed Hepatitis C virus as the trigger of the thyroid autoimmunity by exacerbating the production of thyroid auto-antibodies, while some mention that the real factor that triggers the thyroid autoimmunity is the treatment with Interferon alpha (IFN-alpha) by upregulating MHC class I and inducing ligation of CD40+ cells to thyrocytes. Other microorganisms such as Toxoplasma gondii, Human Immunodeficiency virus, Herpes virus and others have reported information about their association with thyroid autoimmune diseases There are no proposals on how these last microorganisms induce thyroid autoimmunity. There is still a lack of evidence on this topic. Further research must be done to determine the interaction of these microorganisms and the best way to manage these patients.


Assuntos
Autoimunidade , Doença de Graves/imunologia , Doença de Graves/microbiologia , Doença de Hashimoto/imunologia , Doença de Hashimoto/microbiologia , Humanos
4.
Best Pract Res Clin Endocrinol Metab ; 34(1): 101388, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32059832

RESUMO

Graves' disease (GD) is characterized by thyrotoxicosis, caused by the presence of circulating thyroid stimulating antibodies (TSAb), that are determinant also in the pathogenesis of its extrathyroidal manifestations [Graves' ophthalmopathy (GO), pretibial myxedema]. T helper (Th)1 immune response prevails in the immune-pathogenesis of GD and GO, during the active phase, when Th1 chemokines, and their (C-X-C)R3 receptor, play a key role. In GD, the existing treatments are not ideal for hyperthyroidism (long-term remission with anti-thyroid-drugs only in 50% of patients; while radioiodine and surgery cause hypothyroidism). In GD, antigen-specific therapy has been recently published, with the induction of T cell tolerance via an immunization by TSH-R peptides. In GO, rituximab and drugs targeting cytokines have been evaluated. Furthermore, teprotumumab (a human monoclonal anti-IGF-1R blocking antibody) showed to be very effective in GO patients. Further researches are necessary to identify novel effective therapies targeting GD, or GO.


Assuntos
Autoimunidade/fisiologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Doença de Graves , Diagnóstico Diferencial , Doença de Graves/diagnóstico , Doença de Graves/imunologia , Doença de Graves/metabolismo , Doença de Graves/terapia , Oftalmopatia de Graves/diagnóstico , Oftalmopatia de Graves/imunologia , Oftalmopatia de Graves/patologia , Oftalmopatia de Graves/terapia , Humanos , Radioisótopos do Iodo/uso terapêutico , Fatores de Risco
5.
Best Pract Res Clin Endocrinol Metab ; 34(1): 101383, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32088116

RESUMO

Thyroid-associated ophthalmopathy (TAO) remains a vexing autoimmune component of Graves' disease that can diminish the quality of life as a consequence of its impact on visual function, physical appearance and emotional well-being. Because of its relative rarity and variable presentation, the development of highly effective and well-tolerated medical therapies for TAO has been slow relative to other autoimmune diseases. Contributing to the barriers of greater insight into TAO has been the historical absence of high-fidelity preclinical animal models. Despite these challenges, several agents, most developed for treatment of other diseases, have found their way into consideration for use in active TAO through repurposing. Among these, teprotumumab is a fully human inhibitory monoclonal antibody against the insulin-like growth factor I receptor. It has shown remarkable effectiveness in moderate to severe, active TAO in two completed multicenter, double masked, and placebo controlled clinical trials. The drug exhibits a favorable safety profile. Teprotumumab has recently been approved by the U.S. F.D.A, and may rapidly become the first line therapy for this disfiguring and potentially blinding condition.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Oftalmopatia de Graves/tratamento farmacológico , Terapias em Estudo/métodos , Animais , Doença de Graves/tratamento farmacológico , Doença de Graves/imunologia , Oftalmopatia de Graves/imunologia , Oftalmopatia de Graves/metabolismo , Humanos , Imunoterapia/métodos , Imunoterapia/tendências , Qualidade de Vida , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/imunologia , Receptor IGF Tipo 1/metabolismo , Terapias em Estudo/tendências
7.
Medicine (Baltimore) ; 98(50): e18012, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852064

RESUMO

RATIONALE: Hashimoto's encephalopathy (HE) is an autoimmune-mediated encephalopathy rarely seen in Graves' disease, with <20 cases reported previously, associated with elevated concentration of circulating serum anti-thyroid antibodies usually responsive to steroid therapy. PATIENT CONCERNS: We present a HE case (25-year-old male) with Graves' disease, complicated by fever and pancytopenia. The patient presented with fever, gait impairment, delirium, agitation and disorientation. DIAGNOSES: Thyroid-related antibodies were elevated and brain magnetic resonance imaging confirmed symmetrical white-matter lesion. There was no evidence of infection or other reasons to explain all of his clinical manifestations. Hashimoto's encephalopathy (HE) is an autoimmune encephalopathy with various manifestations and the characteristic of elevated anti-thyroid antibodies and has no relationship to thyroid function. INTERVENTIONS: The patient had nonspecific clinical manifestations and excellently respond to glucocorticoid therapy.The symptoms and the radiographic abnormalities disappeared after glucocorticoid therapy. OUTCOMES: We followed up with him for 5 years, in which there was no recurrence and his thyroid function continued to be normal. LESSONS: It is important to evaluate thyroid function and related antibodies in patients present with neuropsychological symptoms to avoid delay in diagnosis.


Assuntos
Autoanticorpos/sangue , Encéfalo/diagnóstico por imagem , Encefalite/etiologia , Doença de Graves/complicações , Doença de Hashimoto/etiologia , Pancitopenia/complicações , Doença Aguda , Adulto , Autoanticorpos/imunologia , Biomarcadores/sangue , Encefalite/diagnóstico , Encefalite/imunologia , Doença de Graves/diagnóstico , Doença de Graves/imunologia , Doença de Hashimoto/diagnóstico , Doença de Hashimoto/imunologia , Humanos , Imagem por Ressonância Magnética , Masculino , Pancitopenia/diagnóstico , Pancitopenia/imunologia , Tomografia Computadorizada por Raios X
8.
Clin Lab ; 65(11)2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31710438

RESUMO

BACKGROUND: Radioimmunoassays, which are often not automated and time-consuming, are gradually being re-placed in medical laboratories by non-radioactive methods that need to be evaluated. The purpose was to compare the measurement of thyroid-stimulating hormone receptor antibodies (TRAb) by the new Brahms' kit using Kryptor TRACE technology and the Brahms' radioimmunoassay. METHODS: We prospectively collected all samples from patients who received thyroid-stimulating hormone receptor antibodies testing in July 2018 at the University Hospital of Brest. The radioimmunoassay used was the Dynotest TRAK human by BRAHMS Diagnostica (Berlin, Germany). The Kryptor method used the BRAHMS TRAK human Kryptor kit performed with the Kryptor Compact Plus system. RESULTS: The inter-assay coefficient variations for the radioimmunological and Kryptor methods were 11.07% and 8.36%, respectively, with the low level quality control and 8.36% and 4.38%, respectively, with the high level quality control. Forty-four patients were included in the study including thirty-two Graves' disease patients in follow-up. The sensitivity of the radioimmunological method for the detection of Graves' disease was 0.94 and the specificity was 0.73. The sensitivity of the Kryptor method was 0.91 and the specificity was 0.91. A non-proportional systematic bias in favor of higher values of TRAb concentrations with the radioimmunological method was observed: slope of 0.93 (0.74 - 1.07, 95% confidence interval) and an intercept of -0.69 IU/L (-1.58 to -0.30, 95% confidence interval). Compared to the Kryptor method, the radioimmunological method tends to overestimate TRAb concentrations by up to 120%. CONCLUSIONS: The fully automated Brahms Kryptor kit using TRACE technology to measure TRAb reduces sampling time and intra- as well as inter-assay variations. The Kryptor kit underestimates the results of TRAb leading to a lower sensitivity and higher specificity compared to the radioimmunoassay. Thus, the new Brahms Kryptor kit has good laboratory performances but the interpretation of the results must still be performed with caution.


Assuntos
Doença de Graves/diagnóstico , Hipotireoidismo/diagnóstico , Imunoglobulinas Glândula Tireoide-Estimulantes/sangue , Radioimunoensaio , Receptores da Tireotropina/imunologia , Tireoidite/diagnóstico , Adulto , Automação Laboratorial , Feminino , Doença de Graves/sangue , Doença de Graves/imunologia , Humanos , Hipotireoidismo/sangue , Hipotireoidismo/imunologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Radioimunoensaio/normas , Reprodutibilidade dos Testes , Tireoidite/sangue , Tireoidite/imunologia , Fluxo de Trabalho
9.
Endocrinol Metab (Seoul) ; 34(3): 268-274, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31565879

RESUMO

BACKGROUND: Graves' disease (GD) is an autoimmune thyroid disorder caused by antibodies stimulating the thyrotropin (TSH) receptor. TSH receptor antibody (TRAb) measurement is useful for predicting GD relapse after antithyroid drug (ATD) treatment. However, the association of other thyroid autoantibodies with GD relapse remains obscure. METHODS: This retrospective study enrolled patients with GD who were initially treated with ATD. TRAb, thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) were measured at the initial diagnosis and at the time of ATD discontinuation. RESULTS: A total of 55 patients were enrolled. The mean age was 49.7 years, and 39 patients (70.9%) were female. Antibody positivity at diagnosis was 90.9%, 69.1%, and 61.9% for TRAb, TPOAb, TgAb, respectively. Median ATD treatment period was 15.1 months. At the time of ATD withdrawal, TRAb titers decreased uniformly overall. Conversely, TPOAb and TgAb showed various changes. After withdrawal of ATD, 19 patients (34.5%) experienced relapse. No clinical features or laboratory results were significantly related to relapse in the overall patient group. However, in the TPOAb positive group at diagnosis, increasing titer of TPOAb or TgAb after ATD treatment was significantly and independently related to relapse free survival (TPOAb: hazard ratio [HR], 17.99; 95% confidence interval [CI], 1.66 to 195.43; P=0.02) (TgAb: HR, 5.73; 95% CI, 1.21 to 27.26; P=0.03). CONCLUSION: Changes in TPOAb or TgAb titers during treatment might be useful for predicting relapse after ATD treatment in patients with positive TPOAb at diagnosis.


Assuntos
Antitireóideos/uso terapêutico , Doença de Graves/diagnóstico , Doença de Graves/imunologia , Iodeto Peroxidase/imunologia , Tireoglobulina/imunologia , Adulto , Autoanticorpos/imunologia , Feminino , Doença de Graves/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos
10.
Endocr J ; 66(10): 843-852, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31434818

RESUMO

Various thyroid diseases are associated with autoimmunity. Major autoimmune thyroid diseases are Graves' disease (GD) and Hashimoto's thyroiditis (HT). Thyrotropin receptor is an autoantigen in GD, and its immunogenicity has been examined. Immune-checkpoint inhibitor (ICI) is recently widely used for treatment of malignant tumors, but cases of thyroid diseases during ICI treatment have been increasing. Thyroid diseases during ICI therapy have been investigated in immunological and clinical aspects, and their Japanese official diagnostic guidelines were established. In addition, serum and tissue immunoglobulin-G4 levels have been examined in association with clinicopathological characteristics in GD, HT, and Riedel's thyroiditis. We review these diseases associated with thyroid autoimmunity and comprehensively discuss their potential application in future research and therapeutic options.


Assuntos
Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Imunoglobulina G/imunologia , Doenças da Glândula Tireoide/imunologia , Animais , Autoantígenos/imunologia , Doença de Graves/imunologia , Antígenos HLA-DR/imunologia , Doença de Hashimoto/imunologia , Humanos , Imunoglobulina G/análise , Imunoterapia/efeitos adversos , Receptores da Tireotropina/antagonistas & inibidores , Receptores da Tireotropina/imunologia , Células Th1/imunologia , Células Th2/imunologia , Tireoidite Autoimune/imunologia
11.
Ann Acad Med Singapore ; 48(6): 181-187, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31377762

RESUMO

INTRODUCTION: Our study aimed to identify the factors associated with successful first-time radioactive iodine (RAI) treatment in patients with Graves' disease (GD). MATERIALS AND METHODS: This is a restrospective study of patients with GD who were treated with RAI. Treatment success was defined as onset of permanent hypothyroidism or euthyroidism after 1 dose of RAI at 1-year follow-up. RESULTS: There were 388 GD patients who underwent RAI treatment between January 2014 and December 2015. Of these, 74% achieved treatment success. Median time to achieve permanent hypothyroidism was 2 months. Male gender, smoking, higher antithyroid drug dosage, lower thyroid stimulating hormone (TSH) level, large goitre size and TSH receptor antibody (TRAb) titre at time of RAI were significantly associated with treatment failure. Multivariate analysis showed that larger goitre size and higher TRAb titre were associated with lower first-time RAI success. CONCLUSION: Larger goitre size and higher TRAb titre predict lower success of RAI therapy in GD patients. Treatment decisions and strategies should be customised for patients who present with these characteristics.


Assuntos
Doença de Graves/radioterapia , Imunoglobulinas Glândula Tireoide-Estimulantes/imunologia , Radioisótopos do Iodo/uso terapêutico , Adulto , Feminino , Bócio/patologia , Doença de Graves/imunologia , Doença de Graves/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Prognóstico , Glândula Tireoide/patologia , Falha de Tratamento
12.
Clin Ter ; 170(4): e285-e290, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31304517

RESUMO

Type-1 helper (Th1) dependent chemokines, such as monokine induced by interferon (IFN)-γ (MIG) seem to contribute to the Graves' disease (GD) pathogenesis. The thyrocytes secrete the chemokine (C-X-C motif) ligand (CXCL)10 under the IFN-γ influence. Therefore, high levels of MIG in peripheral liquids indicate a Th1 orientated immune response and are associated with the active phase of GD in hyperthyroid patients (newly diagnosed and relapsing). Methimazole (MMI), used for the hyperthyroidism treatment, causes a reduction of the MIG secretion by isolated thyrocytes, a decrease of serum MIG levels and leads to a shift from a Th1 to Th2 response in patients with GD in the active phase. The Th1 lymphocytes recruited in the tissues enhance the IFN-γ and tumor necrosis factor (TNF)-α production, that in turn stimulate MIG secretion from these cells; this mechanism originates an amplification feedback loop, causing a perpetuation of the autoimmune process. It has been seen that peroxisome proliferator-activated receptors (PPAR)-γ and PPAR-α activators can modulate the IFN-γ induced MIG secretion in vitro, in GD thyrocytes. More studies are needed to examine the interactions between cytokines and chemokines in the GD pathogenesis and to evaluate the role of MIG as a new therapeutic target.


Assuntos
Quimiocina CXCL9/metabolismo , Doença de Graves/imunologia , Células Th1/metabolismo , Antitireóideos/uso terapêutico , Antivirais/uso terapêutico , Quimiocina CXCL10 , Doença de Graves/tratamento farmacológico , Humanos , Metimazol/uso terapêutico
13.
Endocr J ; 66(11): 1001-1009, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31308303

RESUMO

It is known that there is a relationship between some diseases and blood groups. The objective of our study is to investigate how often ABO and Rh blood groups are seen in benign thyroid diseases, especially in autoimmune-mediated thyroid diseases, and hence whether there is an association between blood groups and thyroid diseases. A total of 958 patients who were followed due to any benign thyroid disease were included in the study. The study population comprised 958 patients, 550 with Hashimoto's hypothyroidism, 160 with non-Hashimoto's hypothyroidism, 103 with iatrogenic hypothyroidism, 93 with central hypothyroidism, and 28 with Graves' and 24 with non-Graves' hyperthyroidism. Of the patients, 47.1% belonged to the O blood group, 30% to the A blood group, 15.2% to the B blood group, and 7.7% to the AB blood group while 90% were Rh-positive. The ratio of those with the O blood group was determined to be significantly higher in the Hashimoto's hypothyroidism group compared to the other disease groups. In the non-Hashimoto's hypothyroidism group, however, the ratio of the AB blood group was statistically significantly higher. While autoimmune diseases were more common in those with the O blood group, they were significantly lower in the AB blood group (p < 0.001). In our study, we determined that the ratio of the O blood group was significantly higher among patients with hypothyroidism due to Hashimoto's thyroiditis. These findings imply that there might be a relation between O blood group and Hashimoto's thyroiditis.


Assuntos
Sistema ABO de Grupos Sanguíneos , Doença de Graves/sangue , Doença de Hashimoto/sangue , Hipotireoidismo/sangue , Sistema do Grupo Sanguíneo Rh-Hr , Adulto , Idoso , Autoanticorpos/imunologia , Feminino , Doença de Graves/imunologia , Doença de Hashimoto/imunologia , Humanos , Hipertireoidismo/sangue , Hipertireoidismo/imunologia , Hipotireoidismo/imunologia , Imunoglobulinas Glândula Tireoide-Estimulantes/imunologia , Iodeto Peroxidase/imunologia , Masculino , Pessoa de Meia-Idade , Turquia
14.
Endocr J ; 66(9): 827-835, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31217394

RESUMO

The novel Graves disease (GD) model was established in BALB/c mice with recombinant adenovirus expressing the full-length human TSHR (Ad-TSHR289) by three times immunizations for nearly three months. Reducing the frequency of immunizations may shorten the modeling time to improve the efficiency of the study. In this study, female BALB/c mice were immunized one time with an adenovirus expressing the autoantigen thyroid-stimulating hormone receptor (Ad-TSHR289). At the 3, 6, 12, 17 weeks after the immunization, mice were sacrificed. The blood was collected and thyroids were removed. T3, T4, TRAB and thyroid weight/body weight (TW/BW) were tested. Compared with the Normal control (NC) group, the incidence of hyperthyroidism at 3, 6, 12 and 17 weeks after immunization were about 66.67%, 100%, 100%, and 100%. Meanwhile, the incidences of goiter were nearly 50%, 83.33%, 100% and 100% at the same stages. Therefore, modeling rates of GD were about 50%, 83.33%, 100%, 100% at 3, 6, 12 and 17 weeks after immunization. T3 in serum continues to increase from 3 weeks to 17 weeks after immunization. Serum TRAb reached to peak at 6 weeks and remained from 12 weeks after immunization, while T4 and TW/BW had kept steady from 6 weeks. There are positive correlations between T3, T4 and TRAb, TRAb and TW/BW, as well as T3, T4 and TW/BW. GD model can be constructed by primary immunization with Ad-TSHR289, which could be detected at 3 weeks and at least until the 17 weeks after primary immunization. It would improve the efficiency of GD research.


Assuntos
Modelos Animais de Doenças , Doença de Graves/etiologia , Doença de Graves/patologia , Imunização , Receptores da Tireotropina/imunologia , Adenoviridae/genética , Animais , Feminino , Doença de Graves/imunologia , Humanos , Hipertireoidismo/imunologia , Hipertireoidismo/patologia , Imunização/métodos , Esquemas de Imunização , Camundongos , Camundongos Endogâmicos BALB C , Receptores da Tireotropina/genética , Glândula Tireoide/imunologia , Glândula Tireoide/patologia
15.
Horm Metab Res ; 51(6): 341-346, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31207654

RESUMO

A rapid and fully automated chemiluminescent immunoassay for the detection of thyrotropin receptor autoantibodies (TSHR-Ab) based on a bridge technology was compared with two bioassays that measure either stimulating (TSAb) or blocking (TBAb) antibodies for the detection and differentiation of TSHR-Ab. A total of 229 patients with various thyroid disorders [151 with Graves' disease (GD), 35 with Hashimoto's thyroiditis (HT), 32 with nodular goiter, and 11 with thyroid cancer] were included. The bridge immunoassay was performed according to the manufacturer's instructions (cut-off>0.55 IU/l). TSAb and TBAb were measured with reporter bioassays. Blocking activity was defined as percent inhibition of luciferase expression relative to induction with bovine TSH alone (cut-off>34% inhibition). TSAb was reported as percentage of specimen-to-reference ratio (> 140 SRR%). The 3 TSHR-Ab assays were negative in all patients with benign euthyroid nodular goiter and differentiated thyroid cancer. In contrast, in all patients with GD, irrespective of the disease duration, TSHR-Ab positivity was present in 127 of 151 (84%) and 140 (93%) for the bridge assay and TSAb bioassay, respectively (p<0.001). Fifteen of 151 (10%) GD samples were positive in the TSAb bioassay but negative in the bridge assay. The bridge assay and the TSAb bioassay correlated positively (r=0.39, p<0.0001) in patients with GD. Both assays detected TSHR-Ab in all ten untreated hyperthyroid patients with GD. In GD patients with a duration of less than six months, 27/29 (93%) and 28 (97%) were TSHR-Ab positive with the bridge and TSAb bioassay, respectively. In comparison, TSHR-Ab were present in two of 35 (6%) and five (14%) HT patients with the bridge and TSAb bio-assay, respectively. TSHR blocking antibodies were present in one (3%) patient with HT and in two (1%) patients with GD; these two GD patients were also bridge assay positive but TSAb bioassay negative. In conclusion, the bridge immunoassay and both bioassays are highly sensitive for the detection of TSHR-Ab. The bridge assay is, however, also positive in the presence of TSHR blocking antibodies detected in a TBAb bioassay.


Assuntos
Anticorpos/imunologia , Doença de Graves/diagnóstico , Doença de Hashimoto/diagnóstico , Imunoensaio/métodos , Imunoglobulinas Glândula Tireoide-Estimulantes/sangue , Receptores da Tireotropina/imunologia , Neoplasias da Glândula Tireoide/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Diferenciação Celular , Feminino , Bócio Nodular/sangue , Bócio Nodular/diagnóstico , Bócio Nodular/imunologia , Doença de Graves/sangue , Doença de Graves/imunologia , Doença de Hashimoto/sangue , Doença de Hashimoto/imunologia , Humanos , Imunoglobulinas Glândula Tireoide-Estimulantes/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/imunologia , Adulto Jovem
16.
Bratisl Lek Listy ; 120(6): 476-480, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223030

RESUMO

AIM: While the ratio of neutrophil-to-lymphocyte (NLR) increases with inflammation, its importance in Graves' disease is not clear. The aim of this study was to evaluate NLR, a marker of chronic inflammmation, in Graves' disease. METHODS: 86 Graves' patients (37 before treatment,49 euthyroid patients after treatment) and 112 controls were enrolled. Hematologic parameters, thyroid function tests, age and gender were recorded. NLRs were calculated. Firstly, groups were composed as Graves' group (Group1) and participants without thyroid disorder as control group (Group2). Secondly, Graves' patients before treatment were considered as Group1a, euthyroid Graves' patients after antithyroid treatment were considered as Group1b. These groups were compared with each other in terms of descriptive data and hematological parameters. RESULTS: Lymphocyte, monocyte, platelet, free T3, and free T4 levels were significantly higher in Graves' group than the controls. TSH and NLR were significantly lower in Graves' group Graves' than the controls. Differences among group1a and group1b for monocyte (p = 0.013), for basophil (p= 0.002), for platelet (p = 0.029), and for NLR (p = 0.029) were statistically significant. CONCLUSION: Unlike other inflammatory diseases, in Graves' disease; hematological parameters may not give information about inflammatory state of the disease. Therefore, NLR should be evaluated with other serum inflammatory markers in Graves' disease (Tab. 2, Fig. 1, Ref. 26).


Assuntos
Doença de Graves , Inflamação , Linfócitos , Neutrófilos , Estudos de Casos e Controles , Doença de Graves/imunologia , Humanos , Contagem de Linfócitos , Tiroxina
17.
Autoimmun Rev ; 18(7): 673-678, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31059842

RESUMO

BACKGROUND: Thyrocytes secrete CXC chemokines, particularly (C-X-C motif) ligand (CXCL)8 and CXCL10; its physiopathological significance remains unclear. This study investigates the modulation of the secretion of CXCL8 vs. CXCL10, in human primary cells cultures of thyroid follicular cells (TFC) in Graves' disease (GD), and fibroblasts (OF) or preadipocytes (OP) from Graves' ophthalmopathy (GO). METHODS: Cells were initially incubated with different concentrations of tumor necrosis factor (TNF)α (1, 5, 10 ng/mL). Then, CXCL8 and CXCL10 were measured in the supernatants of TFC, OF or OP cells basally and after 24 h of treatment with interferon (IFN)γ (1000 IU/mL) and/or TNFα (10 ng/mL), in presence/absence of the peroxisome proliferator activated receptor (PPAR)γ agonist pioglitazone (0, 0.1, 1, 5, 10, 20 µM), or the PPARα agonist fenofibrate (5, 10, 50, 100 µM). RESULTS: CXCL8, not CXCL10, was detected in basal conditions in TFC, OF and OP. CXCL8 secretion increased dose-dependently with increasing concentrations of TNFα. CXCL10 secretion was significantly stimulated by IFNγ (P < 0.01) and not by TNFα, whereas CXCL8 was induced by TNFα (P < 0.01), and inhibited by IFNγ (P < 0.01) in TFC, OF and OP. Combining TNFα and IFNγ, the IFNγ-induced CXCL10 secretion was synergistically increased (P < 0.01) while the TNFα-induced CXCL8 secretion (P < 0.01) was reversed in all cell types. Pioglitazone had no significant effect on the secretion of CXCL8 stimulated by TNFα, while inhibited CXCL10. Fenofibrate, in presence of IFNγ plus TNFα, dose-dependently inhibited both CXCL10 and CXCL8 release. CONCLUSION: We first show that TFC, OF, and OP secrete CXCL8 and CXCL10 differentially, sustained by specific proinflammatory cytokines or their combination. This could reflect a different role of the two chemokines in the course of the disease, as CXCL10 could be associated with the initial phase of the disease when IFNγ is preponderant, while CXCL8 could be associated with a later chronic phase of the disease, when TNFα prevails.


Assuntos
Adipócitos/imunologia , Citocinas/imunologia , Fibroblastos/imunologia , Doença de Graves/imunologia , Oftalmopatia de Graves/imunologia , PPAR gama/imunologia , Células Epiteliais da Tireoide/imunologia , Células Cultivadas , Humanos
18.
PLoS One ; 14(5): e0216941, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31091281

RESUMO

The major histocompatibility complex region has been suggested to play an important role in the development of autoimmune thyroid disease (AITD). In this study, we investigated the associations of human leukocyte antigen (HLA) alleles and amino acid variants of HLA with early-onset AITD. HLA class I and class II genes were analyzed in 116 Korean children with AITDs (Graves' disease [GD]: 71, Hashimoto's disease [HD]: 45) and 142 healthy controls. HLA-B*46:01 (OR = 3.96, Pc = 0.008), -C*01:02 (OR = 2.51 Pc = 0.04), -DPB1*02:02 (OR = 3.99, Pc = 0.04), and -DPB1*05:01 (OR = 4.6, Pc = 0.003) were significantly associated with GD, and HLA-A*02:07 (OR = 4.68, Pc = 0.045) and -DPB1*02:02 (OR = 6.57, Pc = 0.0001) with HD. The frequency of HLA-DPB1*05:01 was significantly higher in GD patients than in HD patients (Pc = 0.0005). Furthermore, differences were found between patients with Thyroid associated ophthalmopathy (TAO) and those without TAO in the distribution of HLA-B*54:01 (8.6% vs. 30.6%, P = 0.04) and -C*03:03 (37.1% vs. 11.1%, P = 0.02). In the analysis of amino acid variants of HLA molecules, both Leu35 (OR = 23.38, P = 0.0002) and Glu55 (OR = 23.38, P = 0.0002) of HLA-DPB1 were strongly associated with GD and showed different distributions between GD and HD (P = 0.001). Our results suggest that HLA alleles, especially amino-acid signatures of the HLA-DP ß chain, might contribute to the molecular pathogenesis of early-onset AITD.


Assuntos
Alelos , Predisposição Genética para Doença , Doença de Graves/genética , Cadeias beta de HLA-DP/genética , Doença de Hashimoto/genética , Polimorfismo Genético , Adolescente , Adulto , Idade de Início , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Expressão Gênica , Frequência do Gene , Doença de Graves/diagnóstico , Doença de Graves/imunologia , Doença de Graves/patologia , Cadeias beta de HLA-DP/classificação , Cadeias beta de HLA-DP/imunologia , Haplótipos , Doença de Hashimoto/diagnóstico , Doença de Hashimoto/imunologia , Doença de Hashimoto/patologia , Humanos , Masculino
19.
J Immunol ; 202(9): 2570-2577, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30944161

RESUMO

Transgenic NOD.H2h4 mice that express the human (h) TSHR A-subunit in the thyroid gland spontaneously develop pathogenic TSHR autoantibodies resembling those in patients with Graves disease. Nanoparticles coupled to recombinant hTSHR A-subunit protein and a tolerogenic molecule (ligand for the endogenous aryl-hydrocarbon receptor; ITE) were injected i.p. four times at weekly intervals into hTSHR/NOD.H2h4 mice with the goal of blocking TSHR Ab development. Unexpectedly, in transgenic mice, injecting TSHR A-subunit-ITE nanoparticles (not ITE-nanoparticles or buffer) accelerated and enhanced the development of pathogenic TSHR Abs measured by inhibition of TSH binding to the TSHR. Nonpathogenic TSHR Abs (ELISA) were enhanced in transgenics and induced in wild-type littermates. Serendipitously, these findings have important implications for disease pathogenesis: development of Graves TSHR Abs is limited by the availability of A-subunit protein, which is shed from membrane bound TSHR, expressed at low levels in the thyroid. The enhanced TSHR Ab response following injected TSHR A-subunit protein-nanoparticles is reminiscent of the transient increase in pathogenic TSHR Abs following the release of thyroid autoantigens after radio-iodine therapy in Graves patients. However, in the hTSHR/NOD.H2h4 model, enhancement is specific for TSHR Abs, with Abs to thyroglobulin and thyroid peroxidase remaining unchanged. In conclusion, despite the inclusion of a tolerogenic molecule, injected nanoparticles coated with TSHR A-subunit protein enhanced and accelerated development of pathogenic TSHR Abs in hTSHR/NOD. NOD.H2h4 These findings emphasize the need for sufficient TSHR A-subunit protein to activate the immune system and the generation of stimulatory TSHR Abs in genetically predisposed individuals.


Assuntos
Autoanticorpos/imunologia , Doença de Graves/imunologia , Tolerância Imunológica/efeitos dos fármacos , Nanopartículas/química , Receptores da Tireotropina/imunologia , Animais , Doença de Graves/patologia , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Compostos Orgânicos/química , Compostos Orgânicos/imunologia , Compostos Orgânicos/farmacologia , Receptores da Tireotropina/química
20.
J Clin Lab Anal ; 33(6): e22904, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31033004

RESUMO

BACKGROUND: Graves' disease (GD) is a common autoimmune disease characterized by genetic and environmental factors. Fcγ receptors (FcγRs) are involved in several autoimmune disorders through recognizing immunoglobulin (Ig) G antibodies and mediating immune response. The study on the expression of FcγRs in GD patients is scarce. The purpose of this study was to evaluate the expression of three different types of FcγRs in patients with active and remissive GD. METHODS: Blood samples of patients and healthy subjects were collected to analyze the percentage of FcγRI (CD64), FcγRII (CD32), and FcγRIII (CD16) on peripheral blood mononuclear cells (PBMCs) and monocytes by flow cytometry and Western blotting. CD32 isotypes were also examined in cases and controls by real-time PCR. RESULTS: The cell percentages expressed CD32 and protein expressions of CD32 on PBMCs, and monocytes from patients with active GD were significantly reduced compared to controls and patients with remissive GD. In particular, the expression of CD32B on PBMC was also decreased in active GD patients. However, the cell percentages expressed CD16 and CD64 from PBMCs and monocytes were comparable between three groups. Besides, the percentages of CD14+ CD32+ cells were negatively correlated with TRAb titers in active GD patients (r = -0.5825, P ï¼œ 0.001). CONCLUSION: These results suggested that CD32 may act as a novel marker for active GDs. The expression of monocytic CD32, in particular CD32B, in GD patients might play a crucial role in maintaining FcγRs function and be a therapeutic target in GD patients.


Assuntos
Doença de Graves/sangue , Receptores de IgG/sangue , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Proteínas Ligadas por GPI/sangue , Doença de Graves/imunologia , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Monócitos/imunologia , Monócitos/metabolismo , Receptores de IgG/genética
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