TSH Receptor Autoantibodies Research Articles

The ATA guidelines of thyrotoxicosis

The authors of guidelines provide 100 recommendations describing many intensively discussed issues. Among them is hepatotoxicity of PTU and limitation of PTU treatment mainly to the first trimester of pregnancy. Methimazole becomes first line ATD for patients with new onset of Graves’ disease. Graves’ orbitopathy (GO) is classified according to its clinical activity and severity. Deterioration of GO after radioactive iodine (RAI) treatment and beneficial effects of steroids to prevent RAI induced exacerbation of GO are described. All patients with subclinical thyrotoxicosis who are older than 65 years and those who are below age 65 and have risk factors or hyperthyroid symptoms should be treated. It is proposed to measure TSH receptor autoantibodies in pregnant women with a previous history of autoimmune thyroid disease. The information about thyroid ultrasonography with the colour-flow Doppler for the rapid differentiation between the two main types of amiodarone-induced thyrotoxicosis, and its help for accurate treatment of these conditions is provided.

Regulation of TSH Receptor Autoantibodies by a long Non-Coding RNA (Heg) and Cdk1- A Review

Regulation of TSH Receptor Autoantibodies by a long Non-Coding RNA (Heg) and Cdk1- A Review

Thyrotropin Receptor Antibody Assays

In this issue of the Journal , Leschik and colleagues1 compare the analytical performance and the clinical utility of a commercially available thyroid-stimulating immunoglobulin (TSI) reporter bioassay with an automated thyrotropin-binding inhibitory immunoglobulin (TBII) electrochemiluminescent immunoassay. The TSI reporter bioassay is a cell-based assay (or “bioassay”) that uses a genetically engineered cell line capable of specifically detecting serum TSI using cyclic AMP–dependent luciferase activity as the readout. The TBII assay is an anti–thyrotropin receptor (TSHR) electrochemiluminescent immunoassay that uses a porcine TSHR and human anti-TSHR autoantibody M22. The authors report that the TSI bioassay is able to detect lower levels of anti-TSHR autoantibodies than the TBII assay and exhibits better precision, but they do not present data indicating whether either assay is more predictive than the other in determining patients’ responses to antithyroid treatment. However, they clearly establish the sensitivity of both assays. TSHR autoantibody (TRAb) measurements (as either TSI or TBII) generally have few potential clinical applications: confirming the diagnosis of Graves disease, the prediction of risk for Graves disease in a neonate born to a mother with Graves disease in pregnancy or in the past, and the prediction of relapse in the medical treatment of Graves disease. In most patients, the diagnosis of Graves disease can be made in the clinical setting of thyrotoxicosis, diffuse goiter, ophthalmopathy (exophthalmos), and dermopathy (pretibial myxedema).2,3 The diagnosis is easily confirmed in most patients with a low thyroid-stimulating hormone (TSH) concentration and an elevated FT4 concentration. In early Graves disease, if T4 levels are normal the …

Analytical Performance and Clinical Utility of a Bioassay for Thyroid-Stimulating Immunoglobulins

The analytical performance and the clinical utility of a thyrotropin receptor (TSHR)-stimulating immunoglobulin (TSI) bioassay were compared with those of a TSHR-binding inhibitory immunoglobulin (TBII) assay. Limits of detection (LoD) and quantitation (LoQ), assay cutoff, and the half-maximal effective concentration (EC(50)) were measured. Dilution analysis was performed in sera of hyperthyroid patients with Graves disease (GD) during antithyroid treatment (ATD). Titer was defined as the first dilution step at which measurement of TSI or TBII fell below the assay cutoff. The LoD, LoQ, cutoff, and EC(50) of the bioassay were 251-, 298-, 814-, and 827-fold lower than for the TBII assay. There were 22%, 42%, 23%, and 14% more positive samples in the TSI bioassay at dilutions of 1:3, 1:9, 1:27, and 1:81 (P < .0001), respectively. Responders to ATD demonstrated marked differences in titers compared with nonresponders. The bioassay detected lower levels of TSHR autoantibodies, and the dilution analysis provided similar predictive values of both assays in GD.

Regulation of TSH Receptor Autoantibodies by a long Non-Coding RNA (Heg) and Cdk1- A Review

Aims: A substantialpartofthegenome istranscribedinnon-codingRNAs. We review ourfinding of along non-coding RNA (designatedHeg)in mononuclearcells(MNC) and regulation of TSHreceptorautoantibodies(TRAb). Results:The Heg RNA transcriptinMNC isnegatively correlatedwithTRAb inpatients withearlyand untreatedGravesdisease.In treatedpatients andincontrolsHeg correlatednegativelywithCD14 mRNA. Transfection studieswithfragments ofHeg added toMNC (exogenous Heg)decreased CD14 mRNA in MNC and increasedgene expressionofRIG-I,TLR7 and IFN-�≥ .Heg islikelyto activate TLR7 receptors. CD14 isa co-receptorofTLR7. Decrease ingene expressionofCD14 afterHeg isa signof differentiationofMNC todendriticcells.Thismay reduce surfaceexpressionof CD14, cytokineresponses and the responsiveness to TSH receptorantigens. Thusthe relationshipbetween TRAb and lncHeg RNA ismost likelyexplainedbyreceptorcross- interference.Cdk1 mRNA (an indexofcellcycleactivity)ispositivelyrelatedwithTRAb. Cdk1 mRNA and TRAb butnotHeg decreased significantlyduringantithyroidtreatment. Cdk1 decreased tovaluesbelownormal. Conclusion: Thus bothHeg RNA and Cdk1 may regulatethe level ofTRAb but by two different mechanisms.

Correlation between TSH Receptor Antibody Assays and Clinical Manifestations of Graves' Orbitopathy

PurposeTo investigate an association between the levels of serum thyroid-stimulating hormone (TSH)-receptor autoantibodies (TRAbs) and Graves' orbitopathy (GO) activity/severity scores, and compare the performance of three different TRAb assays in assessing the clinical manifestations of GO.Materials and MethodsCross-sectional study. Medical records of 155 patients diagnosed with GO between January 2008 and December 2010 were reviewed. GO activity was assessed by clinical activity score (CAS) and severity graded with the modified NOSPECS score by a single observer. Serum TRAb was measured by three different methods: 1st generation thyrotropin-binding inhibitor immunoglobulin (TBII) assay (TRAb1st); 3rd generation TBII assay (TRAb3rd); and biological quantitative assay of thyroid-stimulating immunoglobulin (TSI) using Mc4-CHO cells (Mc4-CHO TSI assay). Results were correlated with scores of activity/severity of thyroid eye disease.ResultsAll three assays (TRAb1st, TRAb3rd, and Mc4-CHO TSI) yielded results that were significantly positively correlated with CAS (β=0.21, 0.21, and 0.46, respectively; p<0.05) and proptosis (β=0.38, 0.34, and 0.33, respectively; p<0.05). Mc4-CHO TSI bioassay results were significantly positively correlated with all GO severity indices (soft tissue involvement, proptosis, extraocular muscle involvement, and total eye score; β=0.31, 0.33, 0.25, and 0.39, respectively; p<0.05).ConclusionMc4-CHO TSI bioassay was superior over the two TBIIs in assessing active inflammation and muscle restriction due to GO, whereas TBII assay would be sufficient for evaluation of patients with proptosis.

The phenomenon of associated Graves' and Plummer's disease: A case report

We have presented the case of a female patient with the simultaneous occurrence of autoimmune hyperthyroidism (Graves' disease) and autonomous hyperthyroidism (Plummer's disease). She has been under our care for euthyroid goiter for many years, but when last seen it was noted that she showed signs of 'hyperthyroid syndrome'. We carried out extensive examination and testing. The diagnosis of associated two types of hyperthyroidisms was based on the following criteria: features of clinical hypermetabolic state, maximal suppression of TSH, raised 'free' thyroxin and presence of TSH receptor autoantibodies, associated with scintigraphic findings of 'hot' nodules with partially suppressed paranodal tissue. In this paper we discussed our previous experiences and compared them to those of other authors.

Rare Presentation of Marine-Lenhart Syndrome

The combination of autoimmune Graves’ disease with a solitary hot thyroid nodule suppressing the remainder of the thyroid gland is rare. We report a case of Graves’ disease associated with a single hyperfunctioning nodule with suppression of the remaining gland. A 45 year old male patient with past medical history of autoimmune Graves’ disease with severe ophthalmopathy was referred to endocrine clinic. His symptoms started with dry eyes several years ago without associated hypermetabolic symptoms. Further investigation revealed hyperthyroidism; he was started on methimazole. Thyroid stimulating immunoglobulin was 484 %( reference: <140%, Method: immunoassay). Thyroid scan with I-123 sodium iodide showed uptake of 28.3 percent at 24 hours, and showed a large area of intense activity mid and lower left thyroid lobe with suppression of uptake in the rest of the thyroid gland. Thyroid ultrasound showed a heterogeneous well-defined 1.3x1.0x1.0 cm left mid lower pole nodule. These findings are suggestive of a rare variant of Marine-Lenhart syndrome. Graves’ hyperthyroidism is thought to be caused by autoantibodies stimulating the TSH receptors. Thyroid nodules associated with Graves’ disease have been reported with the incidence between 25 to 30%, most of which are cold nodules. The incidence of Graves’ disease accompanied by hot nodules ranges from 2.7 to 4.1%.These rare cases of Graves’ disease with accompanying functioning thyroid nodules are known as Marine-Lenhart syndrome. Most reported cases of Marine-Lenhart syndrome are Graves’ disease with multiple hyperfunctioning nodules. Our case represents an unusual variety in which Graves’ disease with a hyperfunctioning solitary nodule was associated with suppression of the remaining gland. Acquired mutations resulting in constitutively activated TSH receptors and the presence of anti TSH receptor autoantibodies might be responsible for the development of Marine-Lenhart syndrome. Keywords: Marine-Lenhart, autoimmune, Graves’ disease, solitary thyroid nodule. Read more →

Autoimmune Thyrotoxicosis: Diagnostic Challenges

Autoimmune thyrotoxicosis or Graves' disease (GD) is the most common cause of hyperthyroidism in the United States (full text available online: http://education.amjmed.com/pp1/249). GD occurs more often in women (ratio 5:1) and has a population prevalence of 1-2%. A genetic determinant to the susceptibility to GD is suspected because of familial clustering of the disease, a high sibling recurrence risk, and the familial occurrence of thyroid autoantibodies. GD is a systemic autoimmune thyroid disorder characterized by the infiltration of immune effector cells and thyroid-antigen-specific T cells into the thyroid and thyroid stimulating hormone receptor (TSHR) expressing tissues, i.e. orbit, skin, with the production of autoantibodies to well-defined thyroidal antigens. Stimulatory autoantibodies in GD activate the TSHR leading to thyroid hyperplasia and unregulated thyroid hormone production and secretion. Diagnosis of GD is straightforward in a patient with a diffusely enlarged, heterogeneous, hypervascular (increased Doppler flow on neck ultrasound) thyroid gland, associated orbitopathy, biochemically confirmed thyrotoxicosis, positive TSHR autoantibodies, and often a family history of autoimmune disorders.

A TSHr-LH/CGr Chimera that Measures Functional TSAb in Graves' Disease

Stimulating thyrotropin receptor (TSHr) autoantibodies (TSAb) are the cause of hyperthyroidism in Graves' disease. In a patient's serum, TSAb can coexist with antagonist TSHr autoantibodies that block TSAb stimulatory activity (TSBAb); both can vary in amount and time. The objective of the study was to create a functional assay that detects only TSAb, thus having an increased accuracy for diagnosing Graves' disease. A TSHr chimera (Mc4) that retains an agonist-sensitive TSAb epitope but replaces a TSBAb epitope was stably transfected in cells to establish the Mc4 assay. The study was conducted at the Chieti University (Outpatient Endocrine Clinic) and the University of Pisa (the Department of Endocrinology). The assay was validated using sera from 170 individuals with Graves' disease, Hashimoto's thyroiditis, and nonautoimmune hyperthyroidism and normal subjects from Chieti University. A second blinded study evaluated sera from 175 patients with autoimmune thyroid disease (mainly Graves' disease) from the University of Pisa. Interventions included the assessment of patients' sera using human wild-type TSHr (WT-TSHr), Mc4 chimera, and binding (TRAb) assays. The Mc4 assay has the best accuracy for diagnosing Graves' disease. The Mc4 assay has a better diagnostic accuracy than WT-TSHr and second-generation TRAb assays. Indeed, the sensitivity of the WT-TSHr, TRAb, and Mc4 assays was 97.3, 86.5, and 100%, respectively, whereas the specificity was 93.1, 97, and 98.5%, respectively. The Mc4 assay is a functional assay with improved sensitivity and specificity for the detection of TSAb and is clinically useful in diagnosing Graves' disease.

Blocking type TSH receptor antibodies.

TSH receptor (TSHR) autoantibodies (TRAbs) play a key role in the pathogenesis of Graves’ disease. In the majority of patients, TRAbs stimulate thyroid hormone synthesis via activation of the TSHR (stimulating TRAbs, TSHR agonists). In some patients, TRAbs bind to the receptor but do not cause activation (blocking TRAbs, TSHR antagonists). Isolation of human TSHR monoclonal antibodies (MAbs) with either stimulating (M22 and K1-18) or blocking activities (5C9 and K1-70) has been a major advance in studies on the TSHR. The binding characteristics of the blocking MAbs, their interaction with the TSHR and their effect on TSHR constitutive activity are summarised in this review. In addition, the binding arrangement in the crystal structures of the TSHR in complex with the blocking MAb K1-70 and with the stimulating MAb M22 (2.55 Å and 1.9 Å resolution, respectively) are compared. The stimulating effect of M22 and the inhibiting effect of K1-70 on thyroid hormone secretion in vivo is discussed. Furthermore the ability of K1-70 to inhibit the thyroid stimulating activity of M22 in vivo is shown. Human MAbs which act as TSHR antagonists are potentially important new therapeutics. For example, in Graves’ disease, K1-70 may well be effective in controlling hyperthyroidism and the eye signs caused by stimulating TRAb. In addition, hyperthyroidism caused by autonomous TSH secretion should be treatable by K1-70, and 5C9 has the potential to control hyperthyroidism associated with TSHR activating mutations. Furthermore, K1-70 has potential applications in thyroid imaging as well as targeted drug delivery to TSHR expressing tissues.

PDGF Enhances Orbital Fibroblast Responses to TSHR Stimulating Autoantibodies in Graves' Ophthalmopathy Patients

Thyroid-stimulating hormone receptor (TSHR) stimulating autoantibodies are associated with Graves' ophthalmopathy (GO), the orbital manifestation of Graves' disease (GD). TSHR autoantibody levels and orbital TSHR expression levels correlate positively with GO disease activity. Platelet-derived growth factors (PDGF) are increased in GO and potently activate orbital fibroblast effector functions. We investigated the possible relationship between PDGF and TSHR expression on orbital fibroblasts and how that influences the immunopathological effects of TSHR autoantibodies on orbital fibroblast activity. Orbital fibroblasts were stimulated with PDGF-AA, PDGF-AB, and PDGF-BB, and TSHR expression was determined by flow cytometry. Stimulatory effects of bovine TSH and GD immunoglobulins on orbital fibroblasts (with or without PDGF-BB preincubation) were determined by IL-6, IL-8, chemokine (C-C motif) ligand (CCL)-2, CCL5, CCL7, and hyaluronan ELISA. The TSHR blocking antibody K1-70 and the cAMP inhibitor H89 were used to determine involvement of TSHR signaling. PDGF-AB and PDGF-BB stimulation increased TSHR expression on orbital fibroblasts, whereas PDGF-AA did not. Furthermore, stimulation with bovine TSH and immunoglobulins from GD patients induced IL-6, IL-8, CCL2, and hyaluronan production by orbital fibroblasts, and PDGF-BB preincubation enhanced this response of orbital fibroblasts. Blocking studies with a TSHR blocking antibody and a cAMP inhibitor inhibited these effects, indicating the involvement of TSHR signaling and thus of TSHR stimulating autoantibodies herein. These findings indicate that PDGF-B containing PDGF isoforms amplify the immunopathological effects of TSHR-stimulating autoantibodies in GO patients by stimulating TSHR expression on orbital fibroblasts.

A Stimulatory Thyrotropin Receptor Antibody Enhances Hyaluronic Acid Synthesis in Graves' Orbital Fibroblasts: Inhibition by an IGF-I Receptor Blocking Antibody

Graves' ophthalmopathy (GO) is characterized by expanded volume of the orbital fat and extraocular muscle tissues and elevated levels of TSH receptor autoantibodies (TRAb). The expansion of orbital tissues involves accumulation of hyaluronic acid (HA) within the orbit. The objective of the study was to determine whether a monoclonal stimulatory TRAb (M22) impacts HA synthesis in GO orbital cells and, if so, whether this might be blocked by an IGF-I receptor (IGF-IR)-blocking antibody (1H7) or inhibitors of various downstream signaling cascades. GO orbital fibroblast cultures (n = 6) were treated with M22, bovine TSH (bTSH), or IGF-I in serum-free medium. Some cultures also received 1H7, LY294002, rapamycin, or protein kinase A inhibitor. HA production and phosphorylated Akt levels in media or immunoblotting for phosphorylated Akt were measured. M22 or bTSH stimulated HA synthesis (2.1-fold with 100 ng/ml M22 and 1.9-fold with 10 U/liter bTSH; P < 0.05 each). M22-induced HA synthesis was inhibited by LY294002 or rapamycin but not by protein kinase inhibitor. HA synthesis stimulated by M22 or IGF-I was inhibited by 1H7 (mean 36.6 ± 5.6% and mean 45.8 ± 7.6%, respectively; P < 0.05 each). Similarly, M22- or IGF-I-stimulated Akt phosphorylation was inhibited by 1H7 (mean 54 ± 9.6 and 36.1 ± 8.8%, respectively; P = 0.01 each). The stimulatory TRAb M22 increases HA production in undifferentiated GO orbital fibroblasts via phosphoinositide 3-kinase/phosphorylated AKT/mammalian target of rapamycin activation. Blockade of IGF-IR inhibits both HA synthesis and Akt phosphorylation induced by M22 or IGF-I in these cells, suggesting that TSH receptor and IGF-IR signaling may be closely linked in the GO orbit.

Similar Clinical Performance of a Novel Chimeric Thyroid-Stimulating Hormone Receptor Bioassay and an Automated Thyroid-Stimulating Hormone Receptor Binding Assay in Graves' Disease

Graves' disease (GD) is caused by the continuous stimulation of the thyroid gland by autoantibodies directed against the thyroid-stimulating hormone receptor (TSHR). Two frequent assays for the measurement of TSHR autoantibodies (TSHRAb) were compared, one measuring stimulation of cyclic adenosine monophosphate (cAMP) production and one measuring inhibition of TSH binding, with regard to diagnostic accuracy for GD as well as whether there was an existence of their discordant results in patients with GD and painless thyroiditis (PT). Using 106 sera from untreated GD and 80 sera from autoimmune PT, we compared the diagnostic performance of two TSHRAb assays that have been recently developed. The first one is a bioreporter assay using chimera TSHR (Mc-4), which detects a stimulation signal of cAMP level in cultured CHO cells (Mc4-TSAb assay). The second is a binding inhibition assay using the extracelluar domain of porcine TSHR and a monoclonal antibody (M22) closely mimicking the binding to TSH (M22-TRAb assay). In addition, we compared both assays by using eight sera from eight GD subjects becoming spontaneously hypothyroid due to appearance of thyroid blocking autoantibodies (TBAb) that were measured with inhibition rates of TSH-stimulated cAMP in porcine cells. The Mc4-TSAb assay and the M22-TRAb assay were positive in 94.3% and 92.5% of the GD patients, respectively, whereas they were negative in 95.0% and 98.8% of the PT subjects. However, 10 of 106 GD sera (9.4%) showed discordant results. Six of 106 cases with untreated GD (5.7%) were Mc4-TSAb positive and M22-TRAb negative. In contrast, 4 of 106 sera (3.8%) were Mc4-TSAb negative but M22-TRAb positive. Two cases of untreated GD were negative for both Mc4-TSAb and M22-TRAb. In eight GD subjects with TBAb and hypothyroidism, the binding assay was highly positive, although Mc4-TSAb was negative. Similar and excellent performance was noted for the Mc4-TSAb and M22-TRAb assays in a large group of patients with GD. However, there was 9.4% discordance with regard to false negatives for GD and 3.8% discordance between the two tests with regard to false positives for PT. With regard to the relatively high rate of discordancy, a combination of both assays could reduce the presence of TSHRAb-seronegative GD.

In vivo effects of a human thyroid-stimulating monoclonal autoantibody (M22) and a human thyroid-blocking autoantibody (K1-70).

PurposeTo study in vivo effects of the human monoclonal TSH receptor (TSHR) autoantibodies M22 (stimulating type) and K1-70 (blocking type) on thyroid hormone levels in rats.MethodsSerum levels of total T4, free T4, M22 and K1-70 were measured following intramuscular injection of M22 IgG (2–4 μg/animal), K1-70 IgG (10–200 μg/animal) or both into rats. Thyroid pathology was assessed in M22-injected rats.ResultsSerum levels of total T4 and free T4 increased in a dose-dependent manner following injection of M22 IgG. Thyroid follicular cell hypertrophy was dependent on the dose of M22 IgG. K1-70 IgG caused a dose dependent decrease of total T4 and free T4 levels in rats receiving K1-70 only. The stimulating effects of M22 IgG on T4 levels in rats were completely inhibited by K1-70 IgG.ConclusionM22 is a potent stimulator of thyroid hormone secretion in vivo. In contrast, K1-70 inhibits thyroid hormone secretion in vivo. Furthermore, K1-70 has the ability to inhibit the stimulating activity of M22 in vivo and as such has potential as a new drug to block TSHR stimulation by autoantibodies in Graves’ disease.

A genome-wide association study identifies two new risk loci for Graves' disease

Graves' disease is a common autoimmune disorder characterized by thyroid stimulating hormone receptor autoantibodies (TRAb) and hyperthyroidism. To investigate the genetic architecture of Graves' disease, we conducted a genome-wide association study in 1,536 individuals with Graves' disease (cases) and 1,516 controls. We further evaluated a group of associated SNPs in a second set of 3,994 cases and 3,510 controls. We confirmed four previously reported loci (in the major histocompatibility complex, TSHR, CTLA4 and FCRL3) and identified two new susceptibility loci (the RNASET2-FGFR1OP-CCR6 region at 6q27 (P(combined) = 6.85 × 10(-10) for rs9355610) and an intergenic region at 4p14 (P(combined) = 1.08 × 10(-13) for rs6832151)). These newly associated SNPs were correlated with the expression levels of RNASET2 at 6q27, of CHRNA9 and of a previously uncharacterized gene at 4p14, respectively. Moreover, we identified strong associations of TSHR and major histocompatibility complex class II variants with persistently TRAb-positive Graves' disease.

Decrease in TSH Receptor Autoantibodies during Antithyroid Treatment: Relationship with a Long Noncoding Heg RNA and Cdk1 mRNA in Mononuclear Cells

We have previously shown that a long noncoding RNA transcript Heg is negatively correlated with TSH receptor autoantibodies (TRAb) in patients with untreated Graves' disease and with CD14 mRNA in treated patients and controls. Thus patients with high concentrations of Heg RNA have low levels of TRAb or CD14 mRNA, respectively. Here we show that an additional factor, gene expression of Cdk1 in mononuclear cells, is positively related to concentrations of TRAb in patients with untreated Graves' disease. Cdk1 mRNA is very important for regulation of cell cycle activity. It is well known that TRAb decrease significantly during treatment with antithyroid drugs. This decrease during treatment cannot be explained by Heg RNA, which remains unchanged. Cdk1 mRNA decreased significantly during treatment to values below values obtained in normal subjects. Thus both Heg RNA and Cdk1 mRNA may influence the level of TSH receptor autoantibodies but by different mechanisms.

Graves' Disease: Diagnostic and Therapeutic Challenges (Multimedia Activity)

Graves' disease is the most common cause of hyperthyroidism in the United States. Graves' disease occurs more often in women with a female:male ratio of 5:1 and a population prevalence of 1% to 2%. A genetic determinant to the susceptibility to Graves' disease is suspected because of familial clustering of the disease, a high sibling recurrence risk, the familial occurrence of thyroid autoantibodies, and the 30% concordance in disease status between identical twins. Graves' disease is an autoimmune thyroid disorder characterized by the infiltration of immune effector cells and thyroid antigen-specific T cells into the thyroid and thyroid-stimulating hormone receptor expressing tissues, with the production of autoantibodies to well-defined thyroidal antigens, such as thyroid peroxidase, thyroglobulin, and the thyroid-stimulating hormone receptor. The thyroid-stimulating hormone receptor is central to the regulation of thyroid growth and function. Stimulatory autoantibodies in Graves' disease activate the thyroid-stimulating hormone receptor leading to thyroid hyperplasia and unregulated thyroid hormone production and secretion. Below-normal levels of baseline serum thyroid-stimulating hormone receptor, normal to elevated serum levels of T4, elevated serum levels of T3 and thyroid-stimulating hormone receptor autoantibodies, and a diffusely enlarged, heterogeneous, hypervascular (increased Doppler flow) thyroid gland confirm diagnosis of Graves' disease (available at: http://supplements.amjmed.com/2010/hyperthyroid/faculty.php). This Resource Center is also available through the website of The American Journal of Medicine (www.amjmed.com). Click on the “Thyroid/Graves' Disease” link in the “Resource Centers” section, found on the right side of the Journal homepage.

Endokrine Orbitopathie aus internistischer Sicht

Graves' orbitopathy (GO) is the most frequently observed extrathyroidal manifestation of Graves' disease occurring in up to 40% of patients. Most patients with Graves' orbitopathy are tested positive for TSH receptor autoantibodies (TRAb), which are pathognomonic for Graves' disease and also play a central pathogenetic role in the development of GO. For the diagnosis of Graves' disease, symptoms of hyperthyroidism, low TSH and high fT3 and/or fT4 levels and positive TRAbs are typical. All patients with Graves' disease must be regularly examined for extrathyroidal manifestations, especially for Graves' orbitopathy. For hyperthyroidism, treatment with antithyroidal drugs, such as thiamazole or propylthiouracil is initiated to quickly restore euthyroidism, which also frequently leads to improvement of Graves' orbitopathy. Smoking cessation is also heavily mandated. In cases of relapse or ineffective antithyroidal treatment, radioiodine therapy or thyroid surgery is a further definitive therapeutic option to treat hyperthyroidism. The management of Graves' orbitopathy remains clinically challenging and demands involvement of a multidisciplinary team including endocrinologists, ophthalmologists, surgeons, radiotherapists and nuclear medicine specialists.

Impairment of Regulatory Capacity of CD4+CD25+ Regulatory T Cells Mediated by Dendritic Cell Polarization and Hyperthyroidism in Graves’ Disease

Graves' disease (GD) is one of the most common autoimmune diseases. The immune dysfunction in GD involves the generation of thyroid-stimulating hormone receptor (TSHR) autoantibodies that presumably arise consequent to interactions among dendritic cells (DCs), T cells, and regulatory T (Treg) cells. However, the immunological mechanisms of interactions between them that lead to the induction and regulation of this autoimmune disease are poorly defined. In this study, we investigated whether DCs are the main cause of the defective activity of Treg cells in GD patients. We found a significant decrease in the percentage of circulating CD4(+)CD25(+)FOXP3(+) Treg cells in untreated GD patients (uGD), which was negatively correlated with the concentration of TSHR autoantibodies. uGD-derived DCs were polarized to increase the number of plasmacytoid DCs (pDCs) and conferred the ability to abrogate the suppressive function of Treg cells through inducing apoptosis of CD4(+)CD25(+) Treg cells in an IFN-α-dependent manner, and elevated thyroid hormones further exacerbated the effect. The nucleotide UDP, which inhibits IFN-α secretion of pDCs through P2Y6 receptor signaling, restored the suppressive function of CD4(+)CD25(+) Treg cells. Collectively, uGD-derived DCs through pDC polarization and elevated thyroid hormones act in concert to impair the regulatory capacity of Treg cells, facilitating the production of TSHR autoantibodies in the pathogenesis of GD.