RESUMO
PURPOSE: Autoimmune Thyroiditis (AIT) is the most common thyroid disease; however, there were no measures to prevent the progression of the disease. The present study attempts to identify that Notch signaling regulates the differentiation of T helper 17 (Th17) cells by activating downstream Phosphatidylinositol-3 kinase/protein kinase/mechanistic target of rapamycin complex 1 (PI3K/AKT/mTORC1) pathway participating in the thyroid injury of the experimental autoimmune thyroiditis (EAT). METHODS: In vivo experiments, mice were randomly divided into 4 groups: a control group, an EAT group, and two groups with LY294002 treatment (pTg plus 25 mg/kg or 50 mg/kg LY294002, respectively). The degrees of thyroiditis were evaluated, and the percentage of Th17 cells, expression of interleukin-17A (IL-17A), and the main components of the Notch-PI3K signaling pathway were detected in different groups. In vitro experiments, two different dosages of LY294002 (25 and 50 µM) were used to intervene splenic mononuclear cells (SMCs) from EAT mice to further evaluate the regulatory effect of Notch-PI3K pathway on Th17 cells. RESULTS: Our data demonstrate that the infiltration of Th17 cells and the expressions of IL-17A, Notch, hairy and split 1 (Hes1), pAKT (Ser473), pAKT (Thr308), pmTOR (Ser2448), S6K1, and S6K2 increased remarkably in EAT mice. After PI3K pathway was blocked, the degrees of thyroiditis were significantly alleviated, and the proportion of Th17 cells, the expression of IL-17A, and the above Notch-PI3K pathway-related molecules decreased in a dose-dependent manner. Additionally, the proportion of Th17 cells was positively correlated with the concentration of serum thyroglobulin antibody (TgAb), IL-17A, and Notch-PI3K pathway-related molecules mRNA levels. CONCLUSIONS: Notch signal promotes the secretion of IL-17A from Th17 cells by regulating the downstream PI3K/AKT/mTORC1 pathway through Hes-Phosphatase and tensin homolog (PTEN) and participates in thyroid autoimmune damage, and the PI3K pathway inhibitor may play important effects on AIT by affecting Th17 cells differentiation.
Assuntos
Diferenciação Celular , Alvo Mecanístico do Complexo 1 de Rapamicina , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Receptores Notch , Transdução de Sinais , Células Th17 , Tireoidite Autoimune , Animais , Células Th17/metabolismo , Camundongos , Diferenciação Celular/efeitos dos fármacos , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Tireoidite Autoimune/metabolismo , Tireoidite Autoimune/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Interleucina-17/metabolismo , Glândula Tireoide/patologia , Glândula Tireoide/metabolismo , Feminino , Cromonas/farmacologia , Morfolinas/farmacologiaRESUMO
Autoimmune thyroid disorders (AITD) represent the most frequent of all autoimmune disorders. Their aetiopathogenesis is incompletely understood, but most likely multifactorial. Early life stress can have long-lasting effects on the immune system. The aim of the present study was to investigate, for the first time, whether patients with AITD are more frequently affected by early life stress. A total of N = 208 women were recruited into a case-control study. Of these, n = 78 (median age: 53, interquartile range: 15) were patients recruited from a thyroid outpatient clinic with confirmed Hashimoto's thyroiditis, Graves' disease, or AITD not otherwise specified. The remaining n = 130 age- and BMI-matched women (median age: 53, interquartile range: 12) were recruited from the general population. Early life stress was measured with the Childhood Trauma Questionnaire. Patients with AITD did not differ from controls regarding sexual abuse, physical abuse, and physical neglect. However, a greater number of patients reported emotional neglect (29.7% vs. 19.5%) and emotional abuse (41.3% vs. 32%). This study provides initial evidence for emotional neglect and abuse as potential risk factors for the development of AITD. Prospective confirmation of these findings could pave the way for the development of interventions to prevent AITD in predisposed individuals.
Assuntos
Experiências Adversas da Infância , Doenças Autoimunes , Doença de Graves , Doença de Hashimoto , Tireoidite Autoimune , Humanos , Feminino , Criança , Pessoa de Meia-Idade , Tireoidite Autoimune/patologia , Estudos de Casos e Controles , Estudos Prospectivos , Doença de Hashimoto/complicações , Doenças Autoimunes/complicações , Doença de Graves/complicaçõesRESUMO
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) damages multiple organs, including the thyroid, by direct invasion and cell entry via angiotensin-converting enzyme 2 or indirectly by promoting excessive inflammation in the body. The immune system is a critical factor in antiviral immunity and disease progression. In the context of SARS-CoV-2 infection, the immune system may become overly activated, resulting in a shift from regulatory to effector responses, which may subsequently promote the development and progression of autoimmune diseases. The incidence of autoimmune thyroid diseases, such as subacute thyroiditis, Graves' disease, and Hashimoto's thyroiditis, increases in individuals with COVID-19 infection. This phenomenon may be attributed to aberrant responses of T-cell subtypes, the presence of autoantibodies, impaired regulatory cell function, and excessive production of inflammatory cytokines, namely interleukin (IL)-6, IL-1ß, interferon-γ, and tumor necrosis factor-α. Therefore, insights into the immune responses involved in the development of autoimmune thyroid disease according to COVID-19 can help identify potential therapeutic approaches and guide the development of effective interventions to alleviate patients' symptoms.
Assuntos
COVID-19 , Doença de Graves , Tireoidite Autoimune , Tireoidite , Humanos , Tireoidite Autoimune/patologia , SARS-CoV-2 , Doença de Graves/tratamento farmacológico , Doença de Graves/patologiaRESUMO
Autoimmune toxicity occurs in up to 60% of patients treated with immune checkpoint inhibitor (ICI) therapy for cancer and represents an increasing clinical challenge for expanding the use of these treatments. To date, human immunopathogenic studies of immune-related adverse events (IRAEs) have relied on sampling of circulating peripheral blood cells rather than affected tissues. Here, we directly obtained thyroid specimens from individuals with ICI-thyroiditis, one of the most common IRAEs, and compared immune infiltrates with those from individuals with spontaneous autoimmune Hashimoto's thyroiditis (HT) or no thyroid disease. Single-cell RNA sequencing revealed a dominant, clonally expanded population of thyroid-infiltrating cytotoxic CXCR6+ CD8+ T cells (effector CD8+ T cells) present in ICI-thyroiditis but not HT or healthy controls. Furthermore, we identified a crucial role for interleukin-21 (IL-21), a cytokine secreted by intrathyroidal T follicular (TFH) and T peripheral helper (TPH) cells, as a driver of these thyrotoxic effector CD8+ T cells. In the presence of IL-21, human CD8+ T cells acquired the activated effector phenotype with up-regulation of the cytotoxic molecules interferon-γ (IFN-γ) and granzyme B, increased expression of the chemokine receptor CXCR6, and thyrotoxic capacity. We validated these findings in vivo using a mouse model of IRAEs and further demonstrated that genetic deletion of IL-21 signaling protected ICI-treated mice from thyroid immune infiltration. Together, these studies reveal mechanisms and candidate therapeutic targets for individuals who develop IRAEs.
Assuntos
Tireoidite , Humanos , Linfócitos T CD8-Positivos/metabolismo , Doença de Hashimoto , Interleucinas , Tireoidite Autoimune/genética , Tireoidite Autoimune/patologia , Tireoidite/induzido quimicamente , Tireoidite/imunologiaRESUMO
In recent years, Hashimoto's thyroiditis (HT) has become the most common autoimmune thyroid disease. It is characterized by lymphocyte infiltration and the detection of specific serum autoantibodies. Although the potential mechanism is still not clear, the risk of Hashimoto's thyroiditis is related to genetic and environmental factors. At present, there are several types of models of autoimmune thyroiditis, including experimental autoimmune thyroiditis (EAT) and spontaneous autoimmune thyroiditis (SAT). EAT in mice is a common model for HT, which is immunized with lipopolysaccharide (LPS) combined with thyroglobulin (Tg) or supplemented with complete Freund's adjuvant (CFA). The EAT mouse model is widely established in many types of mice. However, the disease progression is more likely associated with the Tg antibody response, which may vary in different experiments. SAT is also widely used in the study of HT in the NOD.H-2h4 mouse. The NOD.H2h4 mouse is a new strain obtained from the cross of the nonobese diabetic (NOD) mouse with the B10.A(4R), which is significantly induced for HT with or without feeding iodine. During the induction, the NOD.H-2h4 mouse has a high level of TgAb accompanied by lymphocyte infiltration in the thyroid follicular tissue. However, for this type of mouse model, there are few studies to comprehensively evaluate the pathological process during the induction of iodine. A SAT mouse model for HT research is established in this study, and the pathologic changing process is evaluated after a long period of iodine induction. Through this model, researchers can better understand the pathological development of HT and screen new treatment methods for HT.
Assuntos
Iodo , Tireoidite Autoimune , Camundongos , Animais , Tireoidite Autoimune/genética , Tireoidite Autoimune/patologia , Autoanticorpos , Camundongos Endogâmicos NOD , Suplementos Nutricionais , Modelos Animais de DoençasRESUMO
Purpose: To investigate whether the Notch signaling pathway participates in the occurrence and development of experimental autoimmune thyroiditis (EAT) by affecting the differentiation and function of Th17 cells. Materials and Methods: Experimental mice were randomly divided into a control group, an EAT-A group (porcine thyroid immunoglobulin- (pTg-) treated mice) and an EAT-B group (treated with the DAPT γ-secretase inhibitor before pTg). HE staining, IHC staining, flow cytometry, RT-qPCR, and ELISA were used to evaluate the degrees of thyroiditis, detect the percentage of Th17 cells and measure the expression of retinoic acid-related orphan receptor gamma t (RORγt), interleukin-17A (IL-17A), and the main components of the Notch signaling pathway. Results: The degrees of thyroiditis, the proportions of Th17 cells, and the expression of RORγt and IL-17A were significantly decreased in the EAT-B group after blocking the Notch signaling pathway by DAPT, and these parameters were significantly increased in the EAT-A group compared to the control group (all P < 0.05). Additionally, the Th17 cell percentages and IL-17A concentrations in spleen mononuclear cells (SMCs) from EAT-A mice decreased in a dose-dependent manner after DAPT treatment in vitro (all P < 0.01). Correlation analyses revealed that the Th17 cell percentages were positively correlated with the serum TgAb titers, Notch pathway-related mRNA expression levels, and IL-17A concentrations in EAT mice (all P < 0.05). Conclusions: The expression of Notch signaling pathway components was upregulated in EAT mice, but blockade of the Notch signaling pathway alleviated the degree of thyroiditis, decreased the Th17 cell proportions, and downregulated the IL-17A effector cytokine both in vivo and in vitro. These findings suggested that the Notch signaling pathway may be involved in the pathogenesis of thyroid autoimmune injury in EAT mice by promoting the differentiation of Th17 cells.
Assuntos
Doença de Hashimoto , Tireoidite Autoimune , Camundongos , Animais , Tireoidite Autoimune/patologia , Interleucina-17/metabolismo , Células Th17/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Diferenciação Celular , Transdução de SinaisRESUMO
This review on the 100th anniversary of the American Thyroid Association summarizes the remarkable progress attained during the past century regarding the pathogenesis and treatment of thyroid autoimmune diseases. Indeed, the general concept of autoimmune diseases in humans was established 70 years ago by thyroid investigators. Graves' disease is a paradigm for the rare occurrence of how autoimmunity can cause disease by stimulating rather than destroying an organ system. Therapeutic advances in the mid 20th century involving administration of thyroid hormones, thionamide drugs, and radioiodine have been hugely beneficial for human health. However, these approaches can only treat, but not cure, thyroid autoimmunity. Investigation of these diseases is facilitated by the identification of a limited number of specific autoantigens, whose molecular cloning has provided much information on their structure. This knowledge has led to highly sensitive and specific diagnostic tests, provided insight into novel aspects regarding the pathogenesis of thyroid autoimmunity, and has opened avenues for the development of new therapeutic agents. Immunotherapy for a cure as opposed to therapy of Graves' disease and Hashimoto's thyroiditis remains the holy grail for the 21st century.
Assuntos
Tireoidite Autoimune , Humanos , Tireoidite Autoimune/patologia , Tireoidite Autoimune/terapia , Aniversários e Eventos Especiais , Estados Unidos , Sociedades MédicasRESUMO
IgG4-related disease is a rare chronic pathology manifested by lymphoplasmacytic infiltration of one or more organs, the formation of storiform fibrosis, tissue edema, and an increase of IgG4 in the blood. This disease was singled out as an independent nosological unit only in 2001. The incidence is less than 1 in 100,000 people per year. Almost any organ can be affected in IgG4-related disease. The association of Riedel's thyroiditis with IgG4 was established in 2010. Riedel's thyroiditis is an extremely rare inflammatory disease of the thyroid gland, which diagnosis is complicated by an atypical course and the absence of characteristic symptoms. Less than 300 clinical cases of the disease have been described in the world, only two from them were in children. This article presents a clinical case of a 6-year-old boy with Riedel's thyroiditis.
Assuntos
Doença Relacionada a Imunoglobulina G4 , Imunoglobulina G , Humanos , Criança , Masculino , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Doença Relacionada a Imunoglobulina G4/patologia , Doença Relacionada a Imunoglobulina G4/diagnóstico , Doença Relacionada a Imunoglobulina G4/tratamento farmacológico , Glândula Tireoide/patologia , Glândula Tireoide/imunologia , Tireoidite Autoimune/imunologia , Tireoidite Autoimune/diagnóstico , Tireoidite Autoimune/patologia , Tireoidite Autoimune/complicações , Tireoidite Autoimune/sangueRESUMO
OBJECTIVES: The association of autoimmune thyroiditis (AIT) with papillary thyroid carcinoma (PTC) has been studied for over 60 years, yet their causal relationship has not been elucidated. Most published papers report a better prognosis of the patients with tumour in the field of thyroiditis. In our work we aimed to find out the differences in the clinical behaviour of PTC depending on the presence of autoimmune inflammation. METHODS: We retrospectively analysed a group of 1,201 patients with PTC dispensed in St. Elisabeth Cancer Institute and Faculty of Medicine from 2000 to 2015. We divided patients with AIT according to the time of diagnosis of inflammation into the AIT1 subgroup, which included patients monitored for AIT before tumour detection. In them, we assumed that the factor of long-term endocrinological monitoring could speed up the diagnosis of the tumour and thus improve the prognosis. The AIT2 subgroup consisted of patients with both tumour and inflammation diagnosed simultaneously, thus eliminating the factor of prior monitoring. RESULTS: PTC in the AIT1 subgroup had better prognostic parameters (TNM stage, persistence, disease remission). Patients in the AIT2 group had all monitored parameters comparable with patients with tumours without autoimmune inflammation. CONCLUSION: AIT alone does not have a protective effect on the course of PTC, the cause of a better prognosis in the AIT1 subgroup is a different pathomechanism of carcinogenesis, as well as previous endocrinological monitoring and earlier detection of malignancy (Tab. 4, Fig. 2, Ref. 27).
Assuntos
Carcinoma Papilar , Doença de Hashimoto , Neoplasias da Glândula Tireoide , Tireoidite Autoimune , Humanos , Câncer Papilífero da Tireoide/complicações , Tireoidite Autoimune/complicações , Tireoidite Autoimune/diagnóstico , Tireoidite Autoimune/patologia , Neoplasias da Glândula Tireoide/complicações , Neoplasias da Glândula Tireoide/diagnóstico , Estudos Retrospectivos , Prognóstico , Inflamação , Doença de Hashimoto/complicações , Doença de Hashimoto/diagnósticoRESUMO
PURPOSE: Autoimmune thyroiditis (AIT) is one of the most common autoimmune endocrine diseases. The currently recognized causes are genetic susceptibility, environmental factors and immune disorders. It is important to clarify the pathogenesis for the prevention, diagnosis, treatment of AIT and scientific iodine supplementation. This study analyzed the DNA methylation levels of PRKAA2, ITGA6, PRL and THEM4 genes related to PI3K-AKT signaling pathway, compared the DNA methylation levels between cases and controls from different water iodine levels in Shandong Province of China, and evaluated the contribution of PI3K-AKT signaling pathway-related genes in AIT. METHODS: A total of 176 adult AIT patients were included from three different water iodine areas, and 176 healthy controls were included according to gender, age and BMI. According to the results of the Illumina Methylation 850 K BeadChip in our previous research, the significant methylation differences of genes on the PI3K-AKT signaling pathway related to AIT were determined. The MethylTarget™ assay was used to detect the methylation levels of the target genes, and real-time PCR experiments were used to verify the mRNA expression levels. RESULTS: Compared with the control group, PRKAA2_3 and 15 CpG sites were hyper-methylated. ITGA6 gene and 2 CpG sites were hypo-methylated in AIT cases. The mRNA expression of ITGA6 gene was negatively correlated with the DNA methylation levels of ITGA6 gene and 2 CpG sites. Compared with cases and controls in areas with different water iodine levels, methylation differences were mainly in PRKAA2 and ITGA6 genes. The methylation levels of PRKAA2_1 and PRKAA2_3 were positively correlated with age. The methylation levels of PRL and THEM4 genes were negatively correlated with age. The methylation level of PRKAA2_3 was positively correlated with FT4. CONCLUSION: In summary, we identified aberrant DNA methylation levels of PRKAA2 and ITGA6 genes related to PI3K-AKT signaling pathway in the blood of AIT patients. Both iodine supplementation after long-term iodine deficiency and iodine excess can affect the DNA methylation levels of PRKAA2 and ITGA6 genes, and the former affects more obviously. In ITGA6 gene, this aberrant epigenetic modification is associated with the increased mRNA expression.
Assuntos
Doença de Hashimoto , Iodo , Tireoidite Autoimune , Adulto , Metilação de DNA , Humanos , Integrina alfa6/genética , Integrina alfa6/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais , Tireoidite Autoimune/genética , Tireoidite Autoimune/patologia , ÁguaRESUMO
Autoimmune thyroiditis is a group of organ-specific autoimmune thyropathies, which are caused by a genetically determined defect in immune tolerance to thyroid antigens, as a result of which its autoimmune damage occurs. The aim of the study was to analyze literature data on the pathogenetic role of genetic and biochemical parameters in patients with autoimmune thyroiditis.
Assuntos
Tireoidite Autoimune , Humanos , Tireoidite Autoimune/genética , Tireoidite Autoimune/patologiaRESUMO
INTRODUCTION/OBJECTIVES: The prevalence of thyroid disorders is high in Saudi Arabia. Among the disorders, goiter and thyroiditis are the most common and have unique ultrasound (US) features, underscoring the need for US screening for thyroid pathologies. This study aimed to determine the prevalence of thyroiditis and thyroid nodules in patients attending the Family and Community Medicine Center of Imam Abdulrahman Bin Faisal University. METHODS: This registry-based cross-sectional study analyzed laboratory and US data from 240 patients who attended the Family and Community Medicine Center of Imam Abdulrahman Bin Faisal University from January 2020 to December 2021. Abnormalities of the thyroid gland were categorized according to laboratory and US data. Associations between different types of thyroid pathology and clinical and laboratory findings were assessed using appropriate statistical methods. RESULTS: The majority of participants were Saudi women. The prevalence of thyroiditis in the study population was 43%. Approximately 25% of these patients had more than 1 nodule, and fine-needle aspiration biopsy showed that most nodules were benign. Most nodules were found in clinically euthyroid patients. Thyroiditis might be associated with abnormal thyroid function. CONCLUSIONS: Thyroiditis and thyroid nodules were common in our cohort. Vitamin D deficiency, other autoimmune diseases, and a family history of thyroid disorders were associated with thyroiditis and thyroid nodules. US is useful for identifying the type of thyroid disease.
Assuntos
Neoplasias da Glândula Tireoide , Nódulo da Glândula Tireoide , Tireoidite Autoimune , Tireoidite , Estudos Transversais , Medicina de Família e Comunidade , Feminino , Humanos , Estudos Retrospectivos , Arábia Saudita/epidemiologia , Neoplasias da Glândula Tireoide/complicações , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/complicações , Nódulo da Glândula Tireoide/diagnóstico por imagem , Nódulo da Glândula Tireoide/epidemiologia , Tireoidite/complicações , Tireoidite Autoimune/complicações , Tireoidite Autoimune/patologiaRESUMO
OBJECTIVE: The aim: To evaluate the pathomorphological features of the esophageal mucous membrane in young people with GERD and autoimmune thyroiditis. PATIENTS AND METHODS: Materials and methods: 120 patients with GERD and AIT and 45 people with isolated GERD matched for age, gender and social status were examined. Esophagogastroduodenoscopy, histological study and comparative morphometry of the esophageal mucosa were performed. RESULTS: Results: The frequency of erosive GERD in the examined groups of patients did not statistically differ. At the same time, integral analysis of the structure of erosive forms of GERD revealed statistically significant redistribution of grades of esophagitis towards its enhancement in patients with comorbid pathology. The histological study showed that in patients with GERD and AIT all the morphometric parameters studied had a significantly more severe course and exceeded similar indicators of the group with isolated GERD: epithelium total thickness, epithelium basal layer thickness, connective tissue papillae height, intercellular space. The analysis of morphological changes frequency showed that epithelium basal layer hyperplasia, dystrophic changes and epithelial edema, elongation of papillae and dilation of intercellular space were significantly more frequent in the group with comorbid pathology. CONCLUSION: Conclusions: GERD and euthyroid AIT comorbidity in the student population is accompanied by a statistically significant redistribution of esophagitis grades towards its aggravation. The presence of concomitant euthyroid AIT in patients with non-erosive GERD leads to statistically more pronounced disorganization of esophageal mucosal epithelium.
Assuntos
Refluxo Gastroesofágico , Doença de Hashimoto , Tireoidite Autoimune , Adolescente , Refluxo Gastroesofágico/complicações , Refluxo Gastroesofágico/epidemiologia , Doença de Hashimoto/patologia , Humanos , Mucosa/patologia , Tireoidite Autoimune/complicações , Tireoidite Autoimune/epidemiologia , Tireoidite Autoimune/patologiaRESUMO
BACKGROUND: Primary thyroid lymphoma (PTL) is a rare disease frequently arising against a background of autoimmune thyroiditis. It has recently been reported that the inactivation of the NF-κB negative regulator A20 by deletion and/or mutation could be involved in the pathogenesis of subsets of B-cell lymphomas. This study investigated the clinicopathologic characteristics and A20 mutation in patients with PTL. METHODS: We analyzed the characteristics of 45 PTL patients (14 men and 31 women), with a median age of 71 (range, 35-90) years. A20 mutations were analyzed in DNA extracted from 20 samples consisting of 19 tumor tissue samples and 1 sample from Hashimoto's thyroiditis. RESULTS: Thirty-five patients (82%) had a history of Hashimoto's thyroiditis, and 29 (64%) had diffuse large B-cell lymphoma (DLBCL) and presented with larger tumors including bulky mass, elevated soluble interleukin-2 receptor levels, and a longer history of Hashimoto's thyroiditis than that of patients with mucosa-associated lymphoid tissue (MALT) lymphoma (n=16). A20 mutations were identified in 3 of 19 PTL patients (16%), in 2 of the 10 (20%) with DLBCL and in 1 of the 9 (11%) with MALT lymphoma. Interestingly, all patients with A20 mutations had Hashimoto's thyroiditis. Furthermore, they had a common missense variant in exon 3 (rs2230926 380T>G; F127C), which reduces the ability of A20 to inhibit NF-κB signaling. CONCLUSION: Our study suggests that the histological features of PTL affect clinical outcomes and that A20 mutations are related to PTL pathogenesis in some patients with Hashimoto's thyroiditis.
Assuntos
Doença de Hashimoto , Linfoma de Zona Marginal Tipo Células B , Linfoma Difuso de Grandes Células B , Neoplasias da Glândula Tireoide , Tireoidite Autoimune , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Doença de Hashimoto/complicações , Doença de Hashimoto/genética , Doença de Hashimoto/patologia , Humanos , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma Difuso de Grandes Células B/complicações , Masculino , Pessoa de Meia-Idade , Mutação , NF-kappa B/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Tireoidite Autoimune/complicações , Tireoidite Autoimune/genética , Tireoidite Autoimune/patologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genéticaRESUMO
AIM: Patients with chronic hepatitis C are frequently treated with interferon (IFN)-α. Autoimmune thyroid disease occurs in 20% ~ 40% of IFN-α-treated patients. In this study, the effects of IFN-α administration on triggering and regulating autoimmune thyroiditis in various animal models were evaluated. MAIN METHODS: Exogenous IFN-α was given to naive CBA mice, and both thyroglobulin (TG) immunization-induced (CBA) and spontaneous autoimmune thyroiditis (NOD·H-2 h4) models. Thyroid function, and anti-thyroglobulin antibody (ATA) and B-cell-activating factor (BAFF) levels were measured. Alterations in transcriptome profiles were analyzed. KEY FINDINGS: In the TG-induced thyroiditis model, IFN-α administration reduced plasma free thyroxine levels but did not alter ATA titers, BAFF levels, or the severity of histological changes. Interestingly, even without changes in thyroid functions, four of eight mice in the IFN-α alone group exhibited thyroiditis compared to the control group. Immunologically, mice in the IFN-α group exhibited profound CD3+ cell infiltration in the thyroid and higher plasma BAFF levels compared to the control group. Meanwhile, pathological and serological alterations after IFN-α administration were not observed in the NOD·H-2 h4 model. An RNA sequencing analysis revealed that immunoregulatory signatures were not excited by IFN-α treatment in naive CBA mice. Meanwhile, innate and adaptive immunity, inflammatory cytokine, chemokine, and cell-killing signaling pathways were all stimulated by IFN-α administration after TG immunization of CBA mice. SIGNIFICANCE: We confirmed the remarkable effects of IFN-α in both initiating thyroid immunity and modulating thyroid function and immunoregulatory signatures in established autoimmune thyroiditis. We suggest that IFN-α should be administered with caution in clinical settings.
Assuntos
Fatores Imunológicos/toxicidade , Interferon-alfa/toxicidade , Tireoglobulina/toxicidade , Tireoidite Autoimune/patologia , Animais , Modelos Animais de Doenças , Imunização , Camundongos , Camundongos Endogâmicos CBA , Camundongos Endogâmicos NOD , Tireoidite Autoimune/etiologia , Tireoidite Autoimune/imunologiaRESUMO
In previous studies we have demonstrated that the expression of the Major Histocompatibility Complex (MHC) class I gene in thyrocytes is controlled by several hormones, growth factors, and drugs. These substances mainly act on two regions of the MHC class I promoter a "tissue-specific" region (-800 to -676 bp) and a "hormone/cytokines-sensitive" region (-500 to -68 bp). In a previous study, we have shown that the role of the "tissue-specific" region in the MHC class I gene expression is dominant compared to that of the "hormone/cytokines-sensitive" region. In the present report we further investigate the dominant role of the "tissue-specific" region evaluating the effect of thyroid stimulating hormone (TSH), methimazole (MMI), phenylmethimazole (C10), glucose and thymosin-α1. By performing experiments of electrophoretic mobility shift assays (EMSAs) we show that TSH, MMI and C10, which inhibit MHC class I expression, act on the "tissue-specific" region increasing the formation of a silencer complex. Glucose and thymosin-α1, which stimulate MHC class I expression, act decreasing the formation of this complex. We further show that the silencer complex is formed by two distinct members of the transcription factors families activator protein-1 (AP-1) and nuclear factor-kB (NF-kB), c-jun and p65, respectively. These observations are important in order to understand the regulation of MHC class I gene expression in thyroid cells and its involvement in the development of thyroid autoimmunity.
Assuntos
Genes MHC Classe I/genética , Hormônios/fisiologia , Glândula Tireoide/fisiologia , Animais , Antitireóideos/farmacologia , Linhagem Celular , Ensaio de Desvio de Mobilidade Eletroforética , Regulação da Expressão Gênica/efeitos dos fármacos , Genes MHC Classe I/efeitos dos fármacos , Glucose/farmacologia , Metimazol/análogos & derivados , Metimazol/farmacologia , Ratos , Tionas/farmacologia , Timosina/farmacologia , Glândula Tireoide/citologia , Glândula Tireoide/efeitos dos fármacos , Tireoidite Autoimune/genética , Tireoidite Autoimune/patologia , Tireotropina/farmacologia , Fatores de Transcrição/genéticaRESUMO
Hashimoto thyroiditis (HT) is a pathology that often causes a gradual thyroid insufficiency in affected patients due to the autoimmune destruction of this gland. The cellular immune response mediated by T helper lymphocytes TH1 and TH17 can induce the HT disease. In this pathologic condition, there is an imbalance between the TH17 and Treg lymphocytes as well as a gut microbiota dysfunction. The objective of this work was to describe the interactions of the cell subpopulations that participate in HT. To achieve this goal, we generated a mathematical model that allowed the simulation of different scenarios for the dynamic interaction between thyroid cells, the immune system, and the gut microbiota. We used a hypothetical-deductive design of mathematical modeling based on a system of ordinary differential equations, where the state variables are the TH1, TH17, and Treg lymphocytes, the thyrocytes, and the bacteria from gut microbiota. This work generated a compartmental model of the cellular immune response occurring in the thyroid gland. It was observed that TH1 and TH17 lymphocytes could increase the immune cells' activity, as well as activate effector cells directly and trigger the apoptosis and inflammation processes of healthy thyrocytes indirectly. Likewise, the model showed that a reduction in Treg lymphocytes could increase the activity of TH17 lymphocytes when an imbalance of the gut microbiota composition occurred. The numerical results highlight the TH1, TH17, and bacterial balance of the gut microbiota activities as important factors for the development of HT disease.
Assuntos
Doença de Hashimoto/imunologia , Doença de Hashimoto/patologia , Modelos Teóricos , Animais , Simulação por Computador , Microbioma Gastrointestinal/imunologia , Microbioma Gastrointestinal/fisiologia , Doença de Hashimoto/microbiologia , Humanos , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Células Epiteliais da Tireoide/imunologia , Células Epiteliais da Tireoide/patologia , Tireoidite Autoimune/imunologia , Tireoidite Autoimune/microbiologia , Tireoidite Autoimune/patologiaRESUMO
Introduction: Both polycystic ovary syndrome (PCOS) and autoimmune thyroiditis (AT) are considered to be among the most common endocrinopathies in young women, and they are classified as diseases that affect many processes in the human body. Their role in the development of metabolic disorders and diseases of the cardiovascular system in adult women is also emphasized. However, there are no data available to assess such risk in the teenage girl population. The aim of the study was to assess the hormonal and metabolic profile of adolescent girls with PCOS, additionally diagnosed with AT, as well as to identify possible risk factors for the coexistence of AT and PCOS. Material and Methods: 80 euthyroidic PCOS patients were qualified for the study (chronological age 16.54 ± 1.00 years, BMI 24.60 ± 4.16 kg/m2). Eighteen girls diagnosed with AT were included in the study group and 62 girls without AT-in the control group. Each patient had biochemical and hormonal tests performed. Additionally, to diagnose AT, the level of antibodies against thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-TG), as well as the image of the thyroid gland on ultrasound examination, were taken into account. Results: Estradiol concentration was significantly higher in the study than in the control group (203.00 ± 217.00 vs. 152.00 ± 78.50 pmol/L, p=0.02). Higher DHEAS concentrations were also observed in the AT group compared with the group without AT (391.28 ± 176.40 vs. 317.93 ± 114.27 µg/dl, p=0.04). Moreover, there was a positive correlation between AT and estradiol concentration (ry=0.27; p=0.04). It was also shown that there is a tendency toward statistical significance for the positive correlation between the positive anti-TPO titer and the glucose concentration at 120 min OGTT (rÆ´=0.26; p=0.07) and girls with PCOS and AT had higher glucose levels in 120 min OGTT (115.29±41.70 vs. 98.56±28.02 mg/dl, p=0.08). Conclusion: The study results showed no difference in the metabolic profile between the groups. The high concentration of estradiol found in girls with PCOS and AT may indicate the role of this hormone in the development of the autoimmune process. However, the numbers are small, and more research is needed to confirm our findings.