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1.
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
2.
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
3.
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
4.
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
5.
BMJ Case Rep ; 12(4)2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30954956

RESUMO

We report two women who were diagnosed with hypothyroidism due to what was thought to be Hashimoto's thyroiditis 18 and 16 years ago, respectively. They had been euthyroid on stable doses of levothyroxine for many years, and they presented to our clinic with clinically and biochemically overt hyperthyroidism that persisted even after stopping levothyroxine. Immunological and imaging workups were consistent with Graves' disease. Both patients were treated medically and then received definitive treatment. To our knowledge, the intervals for these two conversions are among the longest conversion intervals reported in the medical literature.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Antitireóideos/uso terapêutico , Doença de Graves/fisiopatologia , Doença de Hashimoto/fisiopatologia , Hipertireoidismo/imunologia , Hipotireoidismo/imunologia , Feminino , Doença de Graves/complicações , Doença de Graves/imunologia , Doença de Graves/terapia , Doença de Hashimoto/complicações , Doença de Hashimoto/imunologia , Doença de Hashimoto/terapia , Humanos , Hipertireoidismo/etiologia , Hipertireoidismo/fisiopatologia , Hipertireoidismo/terapia , Hipotireoidismo/etiologia , Hipotireoidismo/fisiopatologia , Hipotireoidismo/terapia , Metimazol/uso terapêutico , Pessoa de Meia-Idade , Propranolol/uso terapêutico , Tireoidectomia , Tiroxina/efeitos adversos , Tiroxina/uso terapêutico , Resultado do Tratamento
6.
BMC Endocr Disord ; 19(1): 38, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31023276

RESUMO

BACKGROUND: Early diagnosis and relapse prediction in Graves' disease influences treatment. We assessed the abilities of four TSH-receptor antibody tests [TRAb] and one cyclic adenosine monophosphate bioassay to predict relapse of Graves' disease. METHODS: Observational study investigating patients presenting with Graves' disease at a Swiss hospital endocrine referral center or an endocrine outpatient clinic. Main outcomes were diagnosis and relapse of Graves' disease after stop of anti-thyroid drugs. We used Cox regression to study associations of TRAb levels with relapse risk and calculated c-statistics [AUC] to assess discrimination. Blood draws took place as close as possible to treatment initiation. RESULTS: AUCs ranged from 0.90 (TSAb Biossay by RSR) to 0.97 (IMMULITE TSI by Siemens). Highest sensitivity (94.0%) was observed for IMMULITE TSI and RSR TRAb Fast, while the greatest specificity (97.9%) was found with the EliA anti-TSH-R (by Thermo Fisher). In Cox regression analysis comparing the highest versus the lower quartiles, the highest hazard ratio [HR] for relapse was found for BRAHMS TRAK (by Thermo Fisher) (2.98, 95% CI 1.13-7.84), IMMULITE TSI (2.40, 95% CI 0.91-6.35), EliA anti-TSH-R (2.05, 95% CI 0.82-5.10), RSR Fast TRAb (1.80, 95% CI 0.73-4.43), followed by RSR STIMULATION (1.18, 95% CI 0.46-2.99). Discrimination analyses showed respective AUCs of 0.68, 0.65, 0.64, 0.64, and 0.59. CONCLUSION: The assays tested had good diagnostic power and relapse risk prediction with few differences among the new assays. Due to the small sample size and retrospective design with possible selection bias, our data need prospective validation.


Assuntos
Antitireóideos/uso terapêutico , Autoanticorpos/sangue , Biomarcadores/sangue , Doença de Graves/sangue , Receptores da Tireotropina/imunologia , Autoanticorpos/imunologia , Bioensaio , Feminino , Seguimentos , Doença de Graves/tratamento farmacológico , Doença de Graves/imunologia , Doença de Graves/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Prognóstico , Recidiva , Estudos Retrospectivos
7.
Endokrynol Pol ; 70(1): 86-100, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30843179

RESUMO

Thyroid-stimulating hormone receptor (TSHR) is a typical membrane receptor with 7-transmembrane helix domain (7TMR), coupled to the G protein. The mature receptor, present in the cell membrane, is composed of the A subunit comprising a large extracellular domain, and the B subunit, which consists of a short extracellular fragment anchored in the cell membrane and an intracellular part. The TSH receptor is subject to numerous post-translational modifications that determine its final structure and significantly affect its activity. One of them is glycosylation. TSHR is abundantly N-glycosylated, due to the presence of six N-glycosylation sites in the extracellular domain (Asn77, Asn99, Asn113, Asn177, Asn198, Asn302), mostly evolutionarily conserved. N-glycans constitute 30-40% of the receptor molecular weight. The glycans are necessary for the receptor trafficking to the plasma membrane and binding of TSH to the receptor. Fucosylated and sialylated N-oligosaccharides were found on TSHR molecules. The increased sialylation of TSHR glycans correlates positively with the receptor binding ability and prolongs the time of receptor incorporation into the cell membrane. TSHR is the main autoantigen in Graves' disease (GD), one of the thyroid autoimmune diseases. One hypothesis assumes that the higher N-glycosylation of THSR in human compared to animals influences the breaking of autotolerance and GD development. N-oligosaccharides are the important part of THSR molecule, necessary for the proper functioning of receptors and probably involved in thyroid autoimmunity in GD.


Assuntos
Autoantígenos , Doença de Graves/metabolismo , Processamento de Proteína Pós-Traducional , Receptores da Tireotropina/metabolismo , Glicosilação , Doença de Graves/imunologia , Humanos , Receptores da Tireotropina/imunologia
9.
Proc Nutr Soc ; 78(1): 34-44, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30208979

RESUMO

Hashimoto's thyroiditis (HT) and Graves' disease (GD) are examples of autoimmune thyroid disease (AITD), the commonest autoimmune condition. Antibodies to thyroid peroxidase (TPO), the enzyme that catalyses thyroid-hormone production and antibodies to the receptor for the thyroid-stimulating hormone, are characteristic of HT and GD, respectively. It is presently accepted that genetic susceptibility, environmental factors, including nutritional factors and immune disorders contribute to the development of AITD. Aiming to investigate the effect of iodine, iron and selenium in the risk, pathogenesis and treatment of thyroid disease, PubMed and the Cochrane Library were searched for relevant publications to provide a narrative review. Iodine: chronic exposure to excess iodine intake induces autoimmune thyroiditis, partly because highly-iodinated thyroglobulin (Tg) is more immunogenic. The recent introduction of universal salt iodisation can have a similar, although transient, effect. Iron: iron deficiency impairs thyroid metabolism. TPO is a haem enzyme that becomes active only after binding haem. AITD patients are frequently iron-deficient since autoimmune gastritis, which reduces iron absorption and coeliac disease which causes iron loss, are frequent co-morbidities. In two-thirds of women with persistent symptoms of hypothyroidism despite appropriate levothyroxine therapy, restoration of serum ferritin above 100 µg/l ameliorated symptoms. Selenium: selenoproteins are essential to thyroid action. In particular, the glutathione peroxidases remove excessive hydrogen peroxide produced there for the iodination of Tg to form thyroid hormones. There is evidence from observational studies and randomised controlled trials that selenium, probably as selenoproteins, can reduce TPO-antibody concentration, hypothyroidism and postpartum thyroiditis. Appropriate status of iodine, iron and selenium is crucial to thyroid health.


Assuntos
Iodo/imunologia , Ferro/imunologia , Selênio/imunologia , Tireoidite Autoimune/imunologia , Autoantígenos/imunologia , Doença de Graves/imunologia , Doença de Hashimoto/imunologia , Humanos , Hipotireoidismo/imunologia , Imunoglobulinas Glândula Tireoide-Estimulantes/imunologia , Iodeto Peroxidase/imunologia , Proteínas de Ligação ao Ferro/imunologia , Estado Nutricional , Fatores de Risco , Cloreto de Sódio na Dieta
10.
Front Biosci (Landmark Ed) ; 24: 35-47, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30468646

RESUMO

Graves' disease (GD) is the most common cause for hyperthyroidism in iodine-replete areas. The disease is caused by the appearance of stimulating TSH receptor autoantibodies (TRAb) leading to hyperthyroidism. Blocking and neutral TRAb have, however, also been described. TRAb can be measured either by competition assays, assays using a bridge technology or bioassays (for discriminating stimulating vs. blocking antibodies). Therapy of GD with antithyroid drugs belonging to the group of thionamides is the first-line treatment to be continued for 12 up to 18 months. In case of relapse, thyroid ablative therapy including radioiodine therapy or thyroidectomy, respectively, should be performed. Risk factors for relapse are a large thyroid volume, persistence of high TRAb serum titer, smoking, and others. Within this review, we will give insights into the pathogenesis of GD including the pathogenesis of Graves' ophthalmopathy. We also describe recent developments of TRAb measurement, which is used for the diagnosis of GD as well as for outcome prediction. Finally, we discuss therapy aspects as well as the important issue of GD and pregnancy.


Assuntos
Autoanticorpos/imunologia , Doença de Graves/imunologia , Imunoglobulinas Glândula Tireoide-Estimulantes/imunologia , Receptores da Tireotropina/imunologia , Antitireóideos/uso terapêutico , Doença de Graves/patologia , Doença de Graves/terapia , Humanos , Radioisótopos do Iodo/uso terapêutico , Receptores da Tireotropina/metabolismo , Recidiva , Tireoidectomia
11.
J Endocrinol Invest ; 42(4): 471-480, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30132285

RESUMO

BACKGROUND: A role of the insulin-like growth factor-1 receptor (IGF-1R) in the pathogenesis of Graves' orbitopathy (GO) has been proposed, but the existence and function of anti-IGF-1R-antibodies (IGF-1R-Abs) are debated. METHODS: We designed a cross-sectional investigation to measure serum IGF-1R-Abs by a commercial assay in consecutive patients with Graves' disease (GD) compared with healthy subjects and patients with autoimmune thyroiditis (AT). A total of 134 subjects were screened including 27 healthy subjects, 80 GD patients (54 of whom with GO), and 27 AT patients. The main outcome measure was the prevalence of positive serum IGF-1R-Abs in GO, compared with GD without GO and with the other study groups. RESULTS: Having established a cut-off value at 55.2 ng/ml for positive tests, positive IGF-1R-Abs were more frequent in GD (25%), than in AT (3.7%, P = 0.003) and healthy subjects (0%, P = 0.006). Within GD, there was no difference between patients with or without GO. Serum levels of IGF-1R-Abs differed across the study population (P < 0.0001), reflecting their higher concentrations in GD (P < 0.0001 vs both AT and healthy subjects), but with no difference between patients with or without GO. In patients with GO, there was an inverse correlation between serum IGF-1R-Abs and CAS (R = - 0.376, 95% CI: from - 0.373 to - 0.631; P = 0.005), the significance of which remains to be investigated. CONCLUSIONS: Serum autoantibodies against the IFG-1R are present in one-fourth of GD patients, regardless of the presence of GO. Further functional studies are needed to investigate the significance of their inverse correlation with GO activity.


Assuntos
Autoanticorpos/sangue , Biomarcadores/sangue , Doença de Graves/sangue , Oftalmopatia de Graves/sangue , Receptores de Somatomedina/imunologia , Adolescente , Adulto , Idoso , Autoanticorpos/imunologia , Estudos de Casos e Controles , Estudos Transversais , Feminino , Doença de Graves/imunologia , Doença de Graves/patologia , Oftalmopatia de Graves/imunologia , Oftalmopatia de Graves/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
12.
Medicine (Baltimore) ; 97(51): e13486, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30572448

RESUMO

RATIONALE: Insulin autoimmune syndrome (IAS) is a rare endocrine disease characterized by repeated fasting hypoglycemia or episodes of hypoglycemia late after meals, elevated serum insulin, and positivity for insulin autoantibody (IAA) or insulin receptor antibody (IRA). We summarize the clinical manifestations and treatment experiences of 3 patients with IAS. PATIENT CONCERNS: One patient with >20-year history of type 2 diabetes mellitus had irregular episodes of hypoglycemia 2 years of after treatment with insulin. Another patient with a 6-year history of type 2 diabetes mellitus presented irregular episodes of hypoglycemia after 6 months of treatment with insulin. One patient with a history of Graves' disease showed hypoglycemia after administration of thiamazole. DIAGNOSIS: Serum islet cell antibody (ICA) and glutamic acid decarboxylase antibody (GADA) were negative, while antibody insulin autoantibodies were positive in all the 3 patients. Two patients demonstrated diabetes mellitus after an oral glucose tolerance test, while one had normal glucose tolerance. Furthermore, serum insulin levels significantly elevated and did not matched C peptide levels. No abnormalities were found on enhanced MRI of the pancreas, and all 3 patients were clinically diagnosed with IAS. INTERVENTIONS: In case one, insulin aspart 30 injection was withdrawn after admission. In addition, the patient was prescribed sublingual acarbose 3 times daily. Two weeks after admission, prednisone acetate was administered orally once daily at night. In case 2, insulin aspart 30 injection was withdrawn after admission, the patient was prescribed sublingual acarbose 3 times daily with a meal. Five days after admission, oral prednisone acetate was administered once daily at night. In case 3, oral propylthiouracil was prescribed and thiamazole withdrawn after admission, and the patient consumed an extra meal before sleeping. OUTCOMES: At the 3-month follow-up visit, the hypoglycemic episodes had disappeared, serum insulin levels were significantly decreased, and insulin antibody (IA) levels were no longer detectable in all 3 patients. LESSONS: For those patients with high-insulin hypoglycemia, IAA should be evaluated if serum insulin concentrations are inconsistent with C peptide levels. Therapeutically, a lower dose of glucocorticoids with more appropriate medication timing can be used to achieve good results.


Assuntos
Autoanticorpos/sangue , Doenças Autoimunes/sangue , Hipoglicemia/imunologia , Insulina/imunologia , Adulto , Idoso , Antitireóideos/efeitos adversos , Antitireóideos/uso terapêutico , Doenças Autoimunes/etiologia , Doenças Autoimunes/terapia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/imunologia , Feminino , Doença de Graves/sangue , Doença de Graves/tratamento farmacológico , Doença de Graves/imunologia , Humanos , Hipoglicemia/sangue , Hipoglicemia/tratamento farmacológico , Hipoglicemiantes/imunologia , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Insulina/uso terapêutico , Masculino , Metimazol/efeitos adversos , Metimazol/uso terapêutico , Pessoa de Meia-Idade , Síndrome
13.
Expert Rev Clin Pharmacol ; 11(11): 1113-1121, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30417713

RESUMO

INTRODUCTION: Graves' disease (GD) is a disorder, in which auto-immunity against the thyroid- stimulating hormone (TSH) receptor is the pivotal pathogenetic element. This disease may have different clinical manifestations, the most common being thyrotoxicosis. Treatment of this condition differs according to its etiology, but there is currently no evidence-based therapeutic strategy which is universally adopted in all countries. Areas covered: a systematic review of the updates on the management of pediatric GD was performed using the Pubmed data base until March 2018. Systematic reviews with or without meta-analysis were analyzed using the following terms: Antithyroid drugs, Childhood, Hyperthyroidism, Radioactive iodine, Thyroidectomy. Expert commentary: As the best way to manage children with GD remains a matter of debate among pediatric endocrinologists, and there is currently no evidence-based therapeutic strategy which is universally adopted, we confirm that the original and prolonged treatment with anti-thyroid drugs (ATDs) remains the mainstay of treatment for juvenile hyperthyroidism. Alternative treatments include radioiodine (RAI) therapy or surgery (total thyroidectomy). We recommend individualizing the therapeutic approach, without prejudices toward radical therapies that become necessary in case of relapse, adverse effects or poor compliance to ATDs. The optimal approach depends on patient or family preference, and specific patient clinical features.


Assuntos
Antitireóideos/administração & dosagem , Doença de Graves/tratamento farmacológico , Hipertireoidismo/tratamento farmacológico , Antitireóideos/efeitos adversos , Criança , Doença de Graves/imunologia , Doença de Graves/fisiopatologia , Humanos , Hipertireoidismo/imunologia , Hipertireoidismo/fisiopatologia , Radioisótopos do Iodo/uso terapêutico , Recidiva , Tireoidectomia/métodos , Tireotoxicose/tratamento farmacológico , Tireotoxicose/etiologia , Tireotropina/imunologia , Resultado do Tratamento
14.
Nucleic Acids Res ; 46(22): 11898-11909, 2018 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-30407537

RESUMO

MicroRNAs (miRNAs) modulate the post-transcriptional regulation of target genes and are related to biology of complex human traits, but genetic landscape of miRNAs remains largely unknown. Given the strikingly tissue-specific miRNA expression profiles, we here expand a previous method to quantitatively evaluate enrichment of genome-wide association study (GWAS) signals on miRNA-target gene networks (MIGWAS) to further estimate tissue-specific enrichment. Our approach integrates tissue-specific expression profiles of miRNAs (∼1800 miRNAs in 179 cells) with GWAS to test whether polygenic signals enrich in miRNA-target gene networks and whether they fall within specific tissues. We applied MIGWAS to 49 GWASs (nTotal = 3 520 246), and successfully identified biologically relevant tissues. Further, MIGWAS could point miRNAs as candidate biomarkers of the trait. As an illustrative example, we performed differentially expressed miRNA analysis between rheumatoid arthritis (RA) patients and healthy controls (n = 63). We identified novel biomarker miRNAs (e.g. hsa-miR-762) by integrating differentially expressed miRNAs with MIGWAS results for RA, as well as novel associated loci with significant genetic risk (rs56656810 at MIR762 at 16q11; n = 91 482, P = 3.6 × 10-8). Our result highlighted that miRNA-target gene network contributes to human disease genetics in a cell type-specific manner, which could yield an efficient screening of miRNAs as promising biomarkers.


Assuntos
Artrite Reumatoide/genética , Asma/genética , Colite Ulcerativa/genética , Redes Reguladoras de Genes , Genoma Humano , Doença de Graves/genética , MicroRNAs/genética , Algoritmos , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Asma/imunologia , Asma/patologia , Biomarcadores/metabolismo , Estudos de Casos e Controles , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Loci Gênicos , Estudo de Associação Genômica Ampla , Doença de Graves/imunologia , Doença de Graves/patologia , Humanos , MicroRNAs/classificação , MicroRNAs/metabolismo , Herança Multifatorial/genética , Herança Multifatorial/imunologia , Especificidade de Órgãos , Transdução de Sinais
15.
Horm Metab Res ; 50(12): 863-870, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30396220

RESUMO

In the last 3 years, the association of thyrotropin receptor gene (TSHR) variations to Graves' disease (GD) has been confirmed. It is now well established that a 30 Kb region of intron 1 of the TSHR gene is linked to GD predisposition. Elucidating the mechanism(s) by which these polymorphisms confer susceptibility is difficult but would constitute an important advance in endocrine autoimmunity in general. Two hypotheses, both postulating TSHR gene regulatory mechanisms, are discussed. One postulates differential level of expression in the thymus, involving central tolerance. The other postulates a shift in TSHR differential splicing leading to the production of soluble proteins that will have easy access to antigen presenting cells, so it is focused in peripheral tolerance. A combination of the 2 hypothesis is feasible, especially under the light of recent evidence that have identified epigenetic factors acting on TSHR intron 1.


Assuntos
Tolerância Central/imunologia , Estudos de Associação Genética , Doença de Graves/genética , Doença de Graves/imunologia , Receptores da Tireotropina/metabolismo , Autoantígenos/metabolismo , Predisposição Genética para Doença , Humanos , Receptores da Tireotropina/genética
16.
Mutagenesis ; 33(5-6): 351-357, 2018 12 31.
Artigo em Inglês | MEDLINE | ID: mdl-30481337

RESUMO

As apoptosis and genome instability in children with autoimmune diseases (AIDs) are insufficiently investigated, we aimed to analyse them in peripheral blood lymphocytes (PBLs) of children and adolescents with Hashimoto's thyroiditis (HT), Graves' disease (GD) and type 1 diabetes mellitus (T1DM), including possible factors that could affect their occurrence. The study population included 24 patients and 19 healthy controls. Apoptotic cells were detected using an Annexin V-FITC/7-AAD kit. Genome instability was measured as micronuclei (MNs) frequency using the cytokinesis-block MN assay. In addition, comet assay was performed for determination of genome instability as genome damage index (GDI) in new subpopulation of patients with T1DM. The percentage of apoptotic PBLs in patients with AID was significantly lower than in control subjects. There was a positive correlation between thyroid-stimulating homone (TSH) concentration and the proportion of cells in late stage apoptosis in patients with autoimmune thyroid diseases (AITDs). The MN frequency in patients was significantly higher than in controls. Individuals with HT or T1DM had a significantly higher MN frequency than those with GD. Similarly, the value of GDI in patients with T1DM was significantly higher than in controls. The level of apoptosis was positively correlated with MN frequency as well as with GDI in patients with AID. In conclusion, children with AITD (HT and GD) and T1DM have a significantly lower level of apoptosis in PBLs and significantly higher MN frequency as GDI than healthy subjects. Apoptosis and the level of genome instability in these patients with AID are positively correlated.


Assuntos
Apoptose/genética , Doenças Autoimunes/genética , Instabilidade Genômica/genética , Testes para Micronúcleos , Adolescente , Anexina A5/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/fisiopatologia , Criança , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/fisiopatologia , Feminino , Instabilidade Genômica/imunologia , Doença de Graves/genética , Doença de Graves/imunologia , Doença de Graves/fisiopatologia , Doença de Hashimoto/genética , Doença de Hashimoto/imunologia , Doença de Hashimoto/fisiopatologia , Humanos , Linfócitos/patologia , Tireotropina/genética
17.
J Dermatol ; 45(12): 1411-1417, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30222206

RESUMO

An association between alopecia areata (AA) and other autoimmune diseases has been reported. We investigated the associations between AA and overt autoimmune thyroid diseases. A nationwide, population-based, cross-sectional study was performed using the Korea National Health Insurance claims database. We defined patients with AA as those whose records showed at least four physician contacts in which AA, alopecia totalis (AT) or alopecia universalis (AU) was the principal diagnosis. We also established an age- and sex-matched control group without AA. In a subgroup analysis, patients with AT or AU were classified into the severe AA group, and the remainder were classified into the mild to moderate AA group. Patients with AA were at an increased risk of Graves' disease (odds ratio [OR], 1.415; 95% confidence interval [CI], 1.317-1.520) and Hashimoto thyroiditis (OR, 1.157; 95% CI, 1.081-1.237), and the associations were stronger in the severe AA group (Graves' disease: OR, 1.714; 95% CI, 1.387-2.118; Hashimoto thyroiditis: OR, 1.398; 95% CI, 1.137-1.719). In conclusion, AA was significantly associated with overt autoimmune thyroid diseases. Furthermore, the risk was much higher in the severe AA group.


Assuntos
Alopecia em Áreas/epidemiologia , Doença de Graves/epidemiologia , Doença de Hashimoto/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alopecia em Áreas/diagnóstico , Alopecia em Áreas/imunologia , Estudos de Casos e Controles , Criança , Estudos Transversais , Feminino , Doença de Graves/imunologia , Doença de Hashimoto/imunologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Fatores de Risco , Índice de Gravidade de Doença , Adulto Jovem
18.
Viral Immunol ; 31(8): 540-547, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30222515

RESUMO

Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a newly recognized systemic fibroinflammatory disease with characteristic histological findings and high serum IgG4 levels. Epstein-Barr virus (EBV) is a persistent herpesvirus in B lymphocytes, and we previously reported EBV reactivation-induced Ig production. We showed that EBV reactivation induced the production of thyrotropin receptor antibodies, the causative antibodies of Graves' disease. In the present study, we investigated whether EBV reactivation induced IgG4 production and if EBV-positive B cells or IgG4-positive plasma cells are present in the thyroid tissues of Graves' disease patients with lymphoplasmacytic infiltration. EBV-encoded small RNA1 (EBER1) in situ hybridization and immunohistochemistry for IgG and IgG4 were performed on seven resected thyroid tissues with lymphoplasmacytic infiltration collected from the thyroids of 11 Graves' disease patients. We then cultured the lymphocytes of 13 Graves' disease patients and 14 controls and induced EBV reactivation to measure IgG4 levels in culture fluids. We detected EBER1-positive cells and IgG4-positive plasma cells in the same area of thyroid tissues. EBV-reactivated cells with IgG4 on their surface were observed in culture cells, and IgG4 production was detected in culture fluids. The IgG4/IgG percentage was higher than that in normal serum level. A subset of Graves' disease is an IgG4-RD-like condition, not an IgG4-RD. EBV reactivation stimulates IgG4 production, which may result in high serum IgG4 levels and promote IgG4-positive plasma cell infiltration. EBER1 needs to be examined when an increase in IgG4-positive plasma cell numbers is noted.


Assuntos
Linfócitos B/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Doença de Graves/imunologia , Herpesvirus Humano 4/imunologia , Imunoglobulina G/biossíntese , Ativação Viral/imunologia , Adulto , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Linfócitos B/virologia , Estudos de Casos e Controles , Infecções por Vírus Epstein-Barr/complicações , Feminino , Doença de Graves/patologia , Humanos , Imunoglobulina G/análise , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , RNA Viral/análise , RNA Viral/imunologia , Adulto Jovem
19.
J Cell Mol Med ; 22(12): 6386-6390, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30188609

RESUMO

The blood platelets are multifunctional blood cells which are involved in the initiation of atheroma, endothelial dysfunction, and modulation of inflammatory and immune responses in the pathophysiology of many diseases. Because of their multifaceted pro-inflammatory activity, platelets may be involved in the pathogenesis of autoimmune thyroid diseases (AITDs), such as Hashimoto's thyroiditis and Graves' disease. The aim of this study was to assess the level of activation and response ability of platelets in AITDs. We used the flow cytometry technique and kinetic measurement of aggregation to analyse platelet function immediately after blood collection and to demonstrate their activation in the circulation of patients with AITDs. We noted reorganization of platelet subpopulations (normal platelets, microparticles and aggregates) in AITDs, dependent on the degree of cell activation. We proved the elevated expression of the active form of integrin receptor GPIIb/IIIa, responsible for platelet aggregation, and in the kinetic test we confirmed the increased aggregation of platelets in different intracellular signal pathways (dependent on ADP, collagen, arachidonic acid). Our study demonstrates the high platelet activation level found in AITDs.


Assuntos
Doenças Autoimunes/imunologia , Plaquetas/patologia , Doença de Graves/imunologia , Doença de Hashimoto/sangue , Inflamação/imunologia , Doenças Autoimunes/sangue , Doenças Autoimunes/patologia , Plaquetas/imunologia , Micropartículas Derivadas de Células/imunologia , Micropartículas Derivadas de Células/patologia , Feminino , Citometria de Fluxo , Doença de Graves/sangue , Doença de Graves/patologia , Doença de Hashimoto/diagnóstico por imagem , Doença de Hashimoto/imunologia , Doença de Hashimoto/patologia , Humanos , Citometria por Imagem , Inflamação/sangue , Inflamação/patologia , Masculino , Agregação Plaquetária/imunologia , Glândula Tireoide/irrigação sanguínea , Glândula Tireoide/patologia
20.
Neuromuscul Disord ; 28(10): 878-880, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30197184

RESUMO

We report a patient with progressive proximal muscle weakness in her legs, early-onset cataract and perceptive hearing loss, who was recently diagnosed with myotonic dystrophy type 2 (DM2). She also had two autoimmune disorders in her history, namely Graves' disease and celiac disease. Previous studies have shown a high frequency of autoimmune diseases (21%) in patients with DM2. This is the first report of a patient with DM2 and two autoimmune diseases which both have not yet been described in DM2. The cause of this association might be explained at DNA, mRNA and protein levels, including genetic mutation in flanking genes and the toxic effect of the DM2 mutation on proteins involved in inflammation. This case report widens the spectrum of autoimmune diseases in DM2 and has implications both for clinical practice and for research.


Assuntos
Doença Celíaca/complicações , Doença de Graves/complicações , Distrofia Miotônica/complicações , Idoso , Doença Celíaca/diagnóstico , Doença Celíaca/imunologia , Diagnóstico Diferencial , Feminino , Doença de Graves/diagnóstico , Doença de Graves/imunologia , Humanos , Distrofia Miotônica/diagnóstico , Distrofia Miotônica/imunologia
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