scholarly journals The Role of the Microbiota in Graves’ Disease and Graves’ Orbitopathy

2021 ◽  
Vol 11 ◽  
Author(s):  
Jueyu Hou ◽  
Yunjing Tang ◽  
Yongjiang Chen ◽  
Danian Chen
Keyword(s):  
Gut Microbiota ◽  
Negative Impact ◽  
Bifidobacterium Longum ◽  
Autoimmune Disorder ◽  
Thyroid Stimulating Hormone ◽  
Clinical Syndrome ◽  
Graves Disease ◽  
Material Transfer ◽  
T Helper 17 ◽  
Graves Orbitopathy

Graves‘ disease (GD) is a clinical syndrome with an enlarged and overactive thyroid gland, an accelerated heart rate, Graves’ orbitopathy (GO), and pretibial myxedema (PTM). GO is the most common extrathyroidal complication of GD. GD/GO has a significant negative impact on the quality of life. GD is the most common systemic autoimmune disorder, mediated by autoantibodies to the thyroid-stimulating hormone receptor (TSHR). It is generally accepted that GD/GO results from complex interactions between genetic and environmental factors that lead to the loss of immune tolerance to thyroid antigens. However, the exact mechanism is still elusive. Systematic investigations into GD/GO animal models and clinical patients have provided important new insight into these disorders during the past 4 years. These studies suggested that gut microbiota may play an essential role in the pathogenesis of GD/GO. Antibiotic vancomycin can reduce disease severity, but fecal material transfer (FMT) from GD/GO patients exaggerates the disease in GD/GO mouse models. There are significant differences in microbiota composition between GD/GO patients and healthy controls. Lactobacillus, Prevotella, and Veillonella often increase in GD patients. The commonly used therapeutic agents for GD/GO can also affect the gut microbiota. Antigenic mimicry and the imbalance of T helper 17 cells (Th17)/regulatory T cells (Tregs) are the primary mechanisms proposed for dysbiosis in GD/GO. Interventions including antibiotics, probiotics, and diet modification that modulate the gut microbiota have been actively investigated in preclinical models and, to some extent, in clinical settings, such as probiotics (Bifidobacterium longum) and selenium supplements. Future studies will reveal molecular pathways linking gut and thyroid functions and how they impact orbital autoimmunity. Microbiota-targeting therapeutics will likely be an essential strategy in managing GD/GO in the coming years.

scholarly journals Probiotic Bifidobacterium longum supplied with methimazole improved the thyroid function of Graves’ disease patients through the gut-thyroid axis

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Dongxue Huo ◽  
Chaoping Cen ◽  
Haibo Chang ◽  
Qianying Ou ◽  
Shuaiming Jiang ◽  
...  
Keyword(s):  
Thyroid Function ◽  
Intestinal Microbiota ◽  
Bifidobacterium Longum ◽  
Autoimmune Disorder ◽  
Graves Disease ◽  
Metagenomic Sequencing ◽  
Treatment Groups ◽  
Black Bean ◽  
Thyrotropin Receptor Antibody ◽  
Thyroid Axis

AbstractGraves’ disease (GD) is an autoimmune disorder that frequently results in hyperthyroidism and other symptoms. Here, we designed a 6-month study with patients divided into three treatment groups, namely, methimazole (MI, n = 8), MI + black bean (n = 9) and MI + probiotic Bifidobacterium longum (n = 9), to evaluate the curative effects of probiotics supplied with MI on thyroid function of patients with GD through clinical index determination and intestinal microbiota metagenomic sequencing. Unsurprisingly, MI intake significantly improved several thyroid indexes but not the most important thyrotropin receptor antibody (TRAb), which is an indicator of the GD recurrence rate. Furthermore, we observed a dramatic response of indigenous microbiota to MI intake, which was reflected in the ecological and evolutionary scale of the intestinal microbiota. In contrast, we did not observe any significant changes in the microbiome in the MI + black bean group. Similarly, the clinical thyroid indexes of patients with GD in the probiotic supplied with MI treatment group continued to improve. Dramatically, the concentration of TRAb recovered to the healthy level. Further mechanistic exploration implied that the consumed probiotic regulated the intestinal microbiota and metabolites. These metabolites impacted neurotransmitter and blood trace elements through the gut-brain axis and gut-thyroid axis, which finally improved the host’s thyroid function.

scholarly journals Neurological manifestations of Graves’ disease: A case report and review of the literature

2016 ◽  
Vol 7 (01) ◽  
pp. 153-156 ◽  
Author(s):  
Swayamsidha Mangaraj ◽  
Arun Kumar Choudhury ◽  
Binoy Kumar Mohanty ◽  
Anoj Kumar Baliarsinha
Keyword(s):  
Similar Case ◽  
Clinical Manifestations ◽  
Autoimmune Disorder ◽  
Thyroid Stimulating Hormone ◽  
Graves Disease ◽  
Diagnostic Dilemma ◽  
Ocular Manifestations ◽  
Thyroid Associated Ophthalmopathy ◽  
Organ Specific ◽  
High Degree

ABSTRACTGraves’ disease (GD) is characterized by a hyperfunctioning thyroid gland due to stimulation of the thyroid-stimulating hormone receptor by autoantibodies directed against it. Apart from thyrotoxicosis, other clinical manifestations include ophthalmopathy, dermopathy, and rarely acropachy. GD is an organ-specific autoimmune disorder, and hence is associated with various other autoimmune disorders. Myasthenia gravis (MG) is one such disease, which is seen with patients of GD and vice versa. Though the association of GD and myasthenia is known, subtle manifestations of latter can be frequently missed in routine clinical practice. The coexistence of GD and ocular MG poses a significant diagnostic dilemma to treating physicians. The ocular manifestations of myasthenia can be easily missed in case of GD and falsely attributed to thyroid associated ophthalmopathy due to closely mimicking presentations of both. Hence, a high degree of the clinical vigil is necessary in such cases to appreciate their presence. We present a similar case which exemplifies the above said that the clinical challenge in diagnosing coexistent GD and ocular myasthenia.

scholarly journals Thyroid-stimulating hormone receptor (TSHR) fusion proteins in Graves’ disease

2020 ◽  
Vol 246 (2) ◽  
pp. 135-147
Author(s):  
Hans-Peter Holthoff ◽  
Kerstin Uhland ◽  
Gabor Laszlo Kovacs ◽  
Andreas Reimann ◽  
Kristin Adler ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fusion Proteins ◽  
Recombinant Adenovirus ◽  
Disease Model ◽  
Autoimmune Disorder ◽  
Thyroid Stimulating Hormone ◽  
Graves Disease ◽  
Serum Samples

Graves’ disease is an autoimmune disorder, which is characterized by stimulatory antibodies targeting the human thyrotropin receptor (TSHR), resulting in hyperthyroidism and multiple organ damage. We systematically investigated monomeric and dimeric fusion proteins of the A subunit of TSHR for efficacy to bind to the monoclonal patient antibody M22, to interact with Graves’ patient serum samples, and to impact on anti-TSHR antibody titers, hyperthyroidism, tachycardia and other in vivo read-outs in a long-term mouse model of Graves’ disease induced by immunization with a recombinant adenovirus encoding TSHR A. Binding assays and functional measurements of TSHR-dependent cAMP formation showed binding of monomeric TSHR-His and dimeric TSHR-Fc to the anti-TSHR antibody M22 at low-effective concentrations (EC50 of 5.7 nmol/L and 8.6 nmol/L) and inhibition of the effects of this antibody at high efficiencies (IC50 values of 16–20 nmol/L). Both proteins also block the effects of polyclonal anti-TSHR antibodies occurring in Graves’ patient sera with somewhat lower average efficiencies (mean IC50 values of 29 nmol/L and 68 nmol/L). However, in vivo characterization of epicutaneous patch administrations of TSHR-Fc at doses of 0.3 and 0.6 mg/kg body weight in a murine Graves’ disease model did not result in any improvement of disease parameters. In conclusion, high affinity binding of TSHR-Fc to pathological anti-TSHR antibodies was not matched by efficacy to improve Graves’ disease parameter in a long-term mouse model.

scholarly journals Decreased Treg Cell and TCR Expansion Are Involved in Long-Lasting Graves’ Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Ziyi Chen ◽  
Yufeng Liu ◽  
Shiqian Hu ◽  
Meng Zhang ◽  
Bingyin Shi ◽  
...  
Keyword(s):  
T Cell ◽  
Treg Cell ◽  
Flow Cytometric Analysis ◽  
Autoimmune Disorder ◽  
Cell Receptor ◽  
Treg Cells ◽  
Thyroid Stimulating Hormone ◽  
Graves Disease ◽  
Rna Seq ◽  
Flow Cytometric

Graves’ disease (GD) is a T cell-mediated organ-specific autoimmune disorder. GD patients who have taken anti-thyroid drugs (ATDs) for more than 5 years with positive anti-thyroid stimulating hormone receptor autoantibodies value were defined as persistent GD (pGD). To develop novel immunotherapies for pGD, we investigated the role of T cells in the long-lasting phase of GD. Clinical characteristics were compared between the pGD and newly diagnosed GD (nGD) (N = 20 respectively). Flow cytometric analysis was utilized to determine the proportions of Treg and Th17 cells (pGD, N = 12; nGD, N = 14). T cell receptor sequencing (TCR-seq) and RNA sequencing (RNA-seq) were also performed (pGD, N = 13; nGD, N = 20). Flow cytometric analysis identified lower proportions of Th17 and Treg cells in pGD than in nGD (P = 0.0306 and P = 0.0223). TCR-seq analysis revealed a lower diversity (P = 0.0025) in pGD. Specifically, marked clonal expansion, represented by an increased percentage of top V-J recombination, was observed in pGD patients. Interestingly, pGD patients showed more public T cell clonotypes than nGD patients (2,741 versus 966). Meanwhile, RNA-seq analysis revealed upregulation of the inflammation and chemotaxis pathways in pGD. Specifically, the expression of pro-inflammatory and chemotactic genes (IL1B, IL13, IL8, and CCL4) was increased in pGD, whereas Th17 and Treg cells associated genes (RORC, CARD9, STAT5A, and SATB1) decreased in pGD. Additionally, TCR diversity was negatively correlated with the expression of pro-inflammatory or chemotactic genes (FASLG, IL18R1, CCL24, and CCL14). These results indicated that Treg dysregulation and the expansion of pathogenic T cell clones might be involved in the long-lasting phase of GD via upregulating chemotaxis or inflammation response. To improve the treatment of pGD patients, ATDs combined therapies, especially those aimed at improving Treg cell frequencies or targeting specific expanded pathogenic TCR clones, are worth exploring in the future.

scholarly journals Clinical profiles of thyroid dermopathy: a dermato-endocrinology minireview

2020 ◽  
Vol 8 (6) ◽  
pp. 125-127
Author(s):  
Taoreed Adegoke Azeez ◽  
Ayobami Chioma Egbu
Keyword(s):  
Local Therapy ◽  
Hashimoto Thyroiditis ◽  
Thyroid Stimulating Hormone ◽  
Clinical Syndrome ◽  
Graves Disease ◽  
Thyroid Disorders ◽  
Whole Process ◽  
Excessive Secretion ◽  
Activated Fibroblasts ◽  
Thyroid Dermopathy

Background: Thyroid disorders sometimes have extra-thyroidal manifestations. Hyperthyroidism is a clinical syndrome resulting from excessive secretion of thyroid hormones. The commonest cause is Graves’ disease. About 0.5 – 4.3% of patients with Graves’ disease have an infiltrative dermopathy called thyroid dermopathy. It is due to excessive deposition of glycosaminoglycans from activated fibroblasts. Skin fibroblasts are activated by thyroid stimulating hormone receptor antibodies and the whole process is initiated by T lymphocytes. Thyroid dermopathy is rarely also found in other thyroid disorders such as Hashimoto thyroiditis. The diffuse non-pitting oedema variant is the commonest clinical presentation. Other variants include the nodular, plaque, mixed and elephantiasis types. The main concerns of the patients usually are cosmetic, discomfort and difficulty in wearing shoes. Thyroid dermopathy usually presents after the diagnosis of Graves diseases but it may present together or sometime after. Rarely, thyroid dermopathy presents before the diagnosis of Graves’ disease is made. Apart from the shin and feet, other sites that can be affected include arms, forearms, back, thighs, pinna and nose. Conclusion: The management is multidisciplinary, involving Dermatologists and Endocrinologists. Usually, controlling the thyroid dysfunction does not translate into regression of the skin lesion. However, many patients have their thyroid dermopathy regressing spontaneously while others usually require local therapy. Other therapeutic options include systemic therapy such as pentoxifylline, compressive physiotherapy and surgery.

scholarly journals Gut Microbiota as Regulators of Th17/Treg Balance in Patients With Myasthenia Gravis

2021 ◽  
Vol 12 ◽  
Author(s):  
Pan Chen ◽  
Xiangqi Tang
Keyword(s):  
Gut Microbiota ◽  
Myasthenia Gravis ◽  
Autoimmune Disorder ◽  
Treg Cells ◽  
Microbial Metabolites ◽  
T Helper ◽  
T Helper 17 ◽  
Microbial Dysbiosis ◽  
Genetic And Environmental Factors ◽  
Immune Imbalance

Myasthenia gravis (MG) is an acquired neurological autoimmune disorder characterized by dysfunctional transmission at the neuromuscular junction, with its etiology associated with genetic and environmental factors. Anti-inflammatory regulatory T cells (Tregs) and pro-inflammatory T helper 17 (Th17) cells functionally antagonize each other, and the immune imbalance between them contributes to the pathogenesis of MG. Among the numerous factors influencing the balance of Th17/Treg cells, the gut microbiota have received attention from scholars. Gut microbial dysbiosis and altered microbial metabolites have been seen in patients with MG. Therefore, correcting Th17/Treg imbalances may be a novel therapeutic approach to MG by modifying the gut microbiota. In this review, we initially review the association between Treg/Th17 and the occurrence of MG and subsequently focus on recent findings on alterations of gut microbiota and microbial metabolites in patients with MG. We also explore the effects of gut microbiota on Th17/Treg balance in patients with MG, which may provide a new direction for the prevention and treatment of this disease.

Diagnosis of Graves’ disease – laboratory tests and possible difficulties in interpretation

2019 ◽  
Vol 55 (2) ◽  
pp. 121-128
Author(s):  
Agata Maria Kalicka
Keyword(s):  
Autoimmune Disorder ◽  
Laboratory Diagnosis ◽  
Iodine Intake ◽  
Thyroid Stimulating Hormone ◽  
Graves Disease ◽  
Free Triiodothyronine ◽  
Disease Diagnostics ◽  
Assay Methods ◽  
Receptor Antibodies ◽  
Tsh Receptor Antibodies

Graves’ disease is an autoimmune disorder and the most common cause of hyperthyroidism in areas with sufficient iodine intake. Laboratory diagnosis of thyroid function disorders is based on the performance of tests assessing the thyroid hormone activity, and thus the concentration of thyroid-stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3). In order to confirm diagnosis of Graves’ disease, it is necessary to obtain the positive titre of TSH receptor antibodies (TRAb). Despite the continuous improvement of available assay methods, there are still situations causing difficulties in interpretation. Abnormal structure of the TSH molecule, heterophile antibodies, drugs or systemic diseases affect the concentrations of the hormones. In the following review article the above-mentioned parameters as well as limitations and difficulties of interpretation offered by Graves’ disease diagnostics was discussed.

scholarly journals Acute Drug-Induced Cholestatic Syndrome in Basedow Graves’ Disease

2020 ◽  
Vol 5 (2) ◽  
pp. 81-85 ◽  
Author(s):  
Robert Aurelian Tiucă ◽  
Alina Mioara Boeriu ◽  
Rareș Adrian Georgescu ◽  
Ionela Maria Pașcanu
Keyword(s):  
Liver Damage ◽  
Therapeutic Option ◽  
Autoimmune Disorder ◽  
Thyroid Stimulating Hormone ◽  
Antithyroid Drugs ◽  
Graves Disease ◽  
Drug Induced ◽  
Immune Mediated ◽  
Viral Hepatitis A ◽  
Cholestatic Syndrome

AbstractIntroduction: Graves’ disease (GD), an autoimmune disorder caused by high levels of auto-antibodies against the thyroid-stimulating hormone receptor, is considered the most common cause of thyrotoxicosis, characterized by features such as goiter, ophthalmopathy and dermopathy. In our country, the administration of antithyroid drugs (ATD) is the first line of treatment in this disease. Side effects are rare but some of them, such as agranulocytosis or liver damage, may become serious.Case presentation: We report the case of a 20-year-old female patient who was diagnosed with GD after being previously diagnosed with viral hepatitis A. Treatment was initiated with methimazole 30 mg/day, and three weeks later she developed intense hepatic cytolysis and cholestatic syndrome, therefore the ATD was stopped. A suspicion of autoimmune liver disease was raised, and a liver biopsy was performed in order to establish the diagnosis. The next therapeutic option for hyperthyroidism was radioactive iodine (RAI). Three months following RAI, the patient presented severe hypothyroidism, thereupon treatment with levothyroxine was initiated.Conclusions: Although severe acute liver injury is rare, mild liver dysfunction is quite common in patients with GD. The overproduction of thyroid hormones, or the treatment with ATD through immune mediated processes or drug reactions, represent possible mechanisms responsible for liver damage.

scholarly journals Clinical Profiles of Thyroid Dermopathy: A Dermato-Endocrinological Perspective

2020 ◽  
Vol 5 (4) ◽  
pp. 159-161
Author(s):  
Taoreed Adegoke Azeez ◽  
Ayobami Chioma Egbu
Keyword(s):  
Local Therapy ◽  
Hashimoto Thyroiditis ◽  
Skin Lesions ◽  
Thyroid Stimulating Hormone ◽  
Clinical Syndrome ◽  
Graves Disease ◽  
Thyroid Disorders ◽  
Whole Process ◽  
Excessive Secretion ◽  
Thyroid Dermopathy

AbstractThyroid disorders sometimes have extra-thyroidal manifestations. Hyperthyroidism is a clinical syndrome resulting from excessive secretion of thyroid hormones. The most common cause is Graves’ disease. About 0.5–4.3% of patients with Graves’ disease have an infiltrative dermopathy called thyroid dermopathy, which is due to excessive deposition of glycosaminoglycans from activated fibroblasts. Skin fibroblasts are activated by thyroid stimulating hormone receptor antibodies the whole process being initiated by T lymphocytes. Rarely, thyroid dermopathy is also found in other thyroid disorders such as Hashimoto thyroiditis. The diffuse non-pitting edema variant is the most common clinical presentation. Other variants include the nodular, plaque, mixed, and elephantiasis types. Usually, the main concerns of the patients are cosmetic, discomfort, and difficulty in wearing shoes. Thyroid dermopathy usually presents after the diagnosis of Graves’ disease, but it may also present together or sometime after this condition. Rarely, thyroid dermopathy presents before the diagnosis of Graves’ disease is made. Apart from the shin and feet, other sites that can be affected include the arms, forearms, back, thighs, pinna, and nose. The management is multidisciplinary, involving dermatologists and endocrinologists. Usually, controlling the thyroid dysfunction does not translate into regression of the skin lesions. However, many patients have their thyroid dermopathy regress spontaneously, while others usually require local therapy. Other therapeutic options include systemic therapy such as pentoxifylline, compressive physiotherapy, and surgery.

scholarly journals Modulating gut microbiota in a mouse model of Graves’ orbitopathy and its impact on induced disease

Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Sajad Moshkelgosha ◽  
◽  
Hedda Luise Verhasselt ◽  
Giulia Masetti ◽  
Danila Covelli ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Thyroid Autoimmunity ◽  
Treg Cells ◽  
Material Transfer ◽  
Disease Heterogeneity ◽  
Brown Adipose ◽  
Probiotic Treatment ◽  
Autoimmune Condition ◽  
Graves Orbitopathy ◽  
The Impact

Abstract Background Graves’ disease (GD) is an autoimmune condition in which autoantibodies to the thyrotropin receptor (TSHR) cause hyperthyroidism. About 50% of GD patients also have Graves’ orbitopathy (GO), an intractable disease in which expansion of the orbital contents causes diplopia, proptosis and even blindness. Murine models of GD/GO, developed in different centres, demonstrated significant variation in gut microbiota composition which correlated with TSHR-induced disease heterogeneity. To investigate whether correlation indicates causation, we modified the gut microbiota to determine whether it has a role in thyroid autoimmunity. Female BALB/c mice were treated with either vancomycin, probiotic bacteria, human fecal material transfer (hFMT) from patients with severe GO or ddH2O from birth to immunization with TSHR-A subunit or beta-galactosidase (βgal; age ~ 6 weeks). Incidence and severity of GD (TSHR autoantibodies, thyroid histology, thyroxine level) and GO (orbital fat and muscle histology), lymphocyte phenotype, cytokine profile and gut microbiota were analysed at sacrifice (~ 22 weeks). Results In ddH2O-TSHR mice, 84% had pathological autoantibodies, 67% elevated thyroxine, 77% hyperplastic thyroids and 70% orbital pathology. Firmicutes were increased, and Bacteroidetes reduced relative to ddH2O-βgal; CCL5 was increased. The random forest algorithm at the genus level predicted vancomycin treatment with 100% accuracy but 74% and 70% for hFMT and probiotic, respectively. Vancomycin significantly reduced gut microbiota richness and diversity compared with all other groups; the incidence and severity of both GD and GO also decreased; reduced orbital pathology correlated positively with Akkermansia spp. whilst IL-4 levels increased. Mice receiving hFMT initially inherited their GO donors’ microbiota, and the severity of induced GD increased, as did the orbital brown adipose tissue volume in TSHR mice. Furthermore, genus Bacteroides, which is reduced in GD patients, was significantly increased by vancomycin but reduced in hFMT-treated mice. Probiotic treatment significantly increased CD25+ Treg cells in orbital draining lymph nodes but exacerbated induced autoimmune hyperthyroidism and GO. Conclusions These results strongly support a role for the gut microbiota in TSHR-induced disease. Whilst changes to the gut microbiota have a profound effect on quantifiable GD endocrine and immune factors, the impact on GO cellular changes is more nuanced. The findings have translational potential for novel, improved treatments.

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