Search

Papillary thyroid carcinoma (PTC) is characterized by T cell infiltration and frequently by the presence of anti-thyroglobulin antibodies (TgAbs). The role of cellular immunity and of TbAbs in this context is a matter of debate. The aim of our study was to correlate the presence of TgAbs, tumor epitope-specific T cells and the clinical outcome of PTC patients. We studied n=183 consecutive patients with a diagnosis of PTC which were treated with total thyroidectomy plus 131 I ablation. During a follow-up of in mean 97 months, most of the PTC patients had no signs of tumor relapse (n=157 patients). In contrast, one patient had serum Tg levels above the detection limit and<1 ng/ml, two patients Tg serum levels≥1 ng/ml and<2 ng/ml and n=23 patients had Tg serum levels≥2 ng/ml. Morphological signs of tumor recurrence were seen in 14 patients; all of these patients had serum Tg levels≥2 ng/ml. Importantly, with the exception of one patient, all TgAb positive PTC patients (n=27) had no signs of tumor recurrence as the serum Tg levels were below the assays functional sensitivities. Tetramer analyses revealed a higher number of tumor epitope-specific CD8+T cells in TgAb positive patients compared to TgAb negative PTC patients. In summary, we show that the occurrence of TgAbs may have an impact on the clinical outcome in PTC patients. This might be due to a tumor epitope-specific cellular immunity in PTC patients., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

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.

TSH receptor antibodies (TRAbs) are characteristic indicators for the common autoimmune thyroid disease Graves disease (GD). In almost all patients stimulating TRAbs are found leading to hyperthyroidism as these antibodies act in an agonistic manner to TSH. Besides stimulating TRAbs, other TRAbs are also frequently found leading to inhibition of TSH receptor signaling (blocking TRAbs) or to the activation of different signaling cascades resulting in e.g. thyrocyte apoptosis (cleavage antibodies). Patients' sera may contain all three types of TRAbs. Dependent on the activity of these particular TSHR autoantibodies clinical symptoms might change. Within this review we summarize current genetic and environmental factors that are generally accepted for GD's etiology. Binding sides to the TSH receptor as well as the resulting signaling cascades are described just as the current used assay methods for TRAb measurement. Finally, we illustrate the clinical impact of TRAbs in the follow-up of GD patients with special focus on GD patients suffering from Graves' ophthalmopathy.

Objective: We related organ-specific autoantibodies, including diabetes-associated autoantibodies (DAAs) and non-DAAs to systemic cytokines/chemokines in type 1 and type 2 diabetes., Research Design and Methods: From the European Action LADA (latent autoimmune diabetes in adults) cohort, patients with adult-onset type 1 diabetes (n = 80, of whom 50 had LADA and 30 had classic type 1 diabetes) and type 2 diabetes (n = 626) were analyzed for DAAs (GAD antibody [GADA], IA-2 antigen, islet cell antibody, and zinc transporter T8), non-DAAs (transglutaminase, thyroid peroxide autoantibodies, parietal cell antibodies), and 10 immune mediator concentrations (measured by LUMINEX)., Results: Type 1 diabetes patients (whether having classic type 1 diabetes or LADA), apart from their clinical phenotype, could not be distinguished by either autoantibodies (both DAAs and non-DAAs) or immune mediators. In type 1 diabetes, most immune mediators (9 of 10) were negatively correlated with DAA titers. Type 2 diabetes patients, who by definition were without DAAs, had fewer non-DAAs (P < 0.0005), but had higher levels of proinflammatory immune mediators, especially compared with patients with type 1 diabetes who had high GADA titers (interleukin [IL]-6 [P < 0.001], soluble E-selectin [P < 0.01], and IL-1 receptor antagonist [P = 0.052], for trend)., Conclusions: Patients with type 1 diabetes had more DAAs and non-DAAs than did those with type 2 diabetes, whereas the frequency and nature of these autoantibodies was broadly similar in classic type 1 diabetes and LADA. Systemic immune mediator levels, in the main, were negatively correlated with DAA titers, and, for some, were higher in patients with type 2 diabetes, especially when compared with patients who had high GADA titers. Differences in the clinical classification of diabetes are associated with graded differences in adaptive and innate immune reactivity., (© 2016 by the American Diabetes Association.)

Context: Hashimoto's thyroiditis (HT) is a common autoimmune disease leading to thyroid destruction due to lymphocytic infiltration. Only rare data are available regarding the recognition of specific cellular antigens, e.g. of thyroperoxidase (TPO) and thyroglobulin (Tg)., Objective: The aim of this study was to quantify and characterize TPO- and Tg-epitope-specific CD8-positive T cells of HT patients., Design: Six different human leukocyte antigen (HLA)-A2 restricted, TPO- or Tg-specific tetramers were synthesized and used for measuring CD8-positive T cells in HT patients and controls., Results: The frequency of peripheral TPO- and Tg-specific CD8-positive T cells was significantly higher in HLA-A2-positive HT patients (2.8 ± 9.5%) compared with HLA-A2-negative HT patients (0.5 ± 0.7%), HLA-A2-positive nonautoimmune goiter patients (0.2 ± 0.4%), and HLA-A2-positive healthy controls (0.1 ± 0.2%). The frequency of Tg-specific T cells (3.0%) was very similar to those of TPO-specific CD8-positive T cells (2.9%). Subgroup analyses revealed a steady increase of the number of epitope-specific CD8-positive T cells from 0.6 ± 1.0% at initial diagnosis up to 9.4 ± 18.3% in patients with long-lasting disease. Analyses of the number of thyroid-infiltrating cells as well as the cytotoxic capacity revealed a similar picture for TPO- and Tg-specific T cells., Conclusion: We here report for the first time that both antigens, TPO and Tg, are recognized by CD8-positive T cells and are involved in the thyroid destruction process leading to clinical disease manifestation.

Background: Most recently, a new rapid and fully automated electrochemiluminescence immunoassay for the determination of TSH receptor autoantibodies (TRAb) based on the ability of TRAb to inhibit the binding of a human thyroid-stimulating monoclonal antibody (M22) has been established., Objective: To evaluate this assay system in clinical routine based on an international multicentre trial and to compare the results with other established TRAb assays., Patients and Measurements: Totally 508 Graves' disease (GD), 142 autoimmune thyroiditis, 107 subacute thyroiditis, 109 nonautoimmune nodular goitre, 23 thyroid cancer patients and 446 normal controls were retrospectively evaluated., Results: ROC plot analysis revealed an area under curve of 0.99 (95% CI: 0.99-1.0) indicating a high assay sensitivity and specificity. The highest sensitivity (99%) and specificity (99%) was seen at a cut-off level of 1.75 IU/l. Here, the calculated positive predictive value was 95%, whereas the negative predictive value was 100%. Applying the ROC plot-derived cut-off of 1.75 IU/l we found a sensitivity for TRAb positivity within the group of newly diagnosed GD patients of 97% which is in accordance to the sum of different nonautomated porcine TSH receptor-based assays with a sensitivity of 94% indicating an excellent analytical performance of the new assay format. Detailed comparison of the automated and the sum of manual assays revealed a near identical specificity., Conclusion: Our results demonstrate that this new assay system has a high sensitivity for detecting GD and specificity for discriminating from other thyroid diseases. This assay may represent the future technology for rapid fully automated TRAb detection.

Graves' disease (GD) is the only autoimmune disease where autoantibodies stimulate the target organs. Among the most common clinical manifestations are hyperthyroidism and orbitopathy (GO). To ensure the diagnosis of autoimmune hyperthyroidism, activity of TSH receptor autoantibodies (TRAb) should be determined. Because of their significantly improved sensitivity and equal specificity, second-generation TRAb assays (activity given in IU/l) should be preferred over first-generation assays (activity given in U/l). During follow-up of antithyroid drug therapy it is possible to predict outcome for some patients with high chances if TRAb levels are high. On this basis, thyreoablative treatment (operation or radioiodine) can already be indicated before the 1st year of antithyroid drug treatment has passed. If TRAb antibody titers are > 10 IU/l, it is possible to predict outcome as early as 6 months after initiation of antithyroid drug therapy. Below a certain threshold, depending on the time point of measurement, no representative risk analyses are available for TRAbs. TRAb measurement is also helpful to determine the course of GO. This may guide the physician through crucial treatment decisions, especially if the patient is at risk of deterioration.

Background: Graves' disease (GD) is mediated by autoantibodies which bind to the TSH receptor (TRAb). The aim of the present study was to evaluate the technical performance of the first fully automated immunoassay for TRAb detection., Methods: The Elecsys Anti-TSHR immunoassay utilizes a porcine TSH receptor (TSHR) and the human thyroid stimulating monoclonal TSHR autoantibody M22., Results: Intraassay and total imprecision CV were determined between 1.4%-14.9%, and 2.4%-28.8%, respectively. Using the 20% CV criteria the functional sensitivity was found at 0.73 IU/L. The median CV at the cut-off (1.75 IU/L) was found to be 11%. Comparison studies with five TRAb immunoassays yielded slopes and intercepts between 1.02-1.48, and -0.74-0.56, respectively. Correlation coefficients were determined between 0.895 and 0.978. ROC plot analysis of patients with GD, patients with other thyroid disorders and healthy controls revealed an AUC of 0.99 resulting in a sensitivity of 97% and a specificity of 99% at a TRAb level of 1.75 IU/L., Conclusion: The evaluation of the TRAb immunoassay generated homogeneous performance data and demonstrated a high degree of comparability to established TRAb assays. The automated TRAb assay represents a major improvement of thyroid testing in clinical practice.

Clinical thyrotoxicosis in Graves' disease patients is caused by thyrotropin receptor (TSHR)-stimulating autoantibodies. The molecular mechanisms of TSHR post-translational modification, TSHR signaling and TSHR-autoantibody interaction are still debatable, and the precise interaction of stimulating and blocking autoantibodies with TSHR is unclear. Recent TSHR epitope studies indicate that binding sites for stimulating and blocking autoantibodies are close together, not on distinct or distant parts of the molecule. Furthermore, new methods to detect TSHR autoantibodies and their clinical use are addressed. Highly sensitive TSHR autoantibody assays are widely available and cost efficient, and their routine clinical use might help in the differential diagnosis of hyperthyroidism and disease outcome prediction in patients with high levels of TSHR autoantibodies.

Abstract: Commercial assays to measure thyroid stimulating hormone (TSH) receptor (TSHR) autoantibodies (TRAb) have been available for the serological diagnosis of autoimmune thyroid diseases (AITD) for several years. The widespread assessment of this parameter has identified Graves'' disease (GD) as a common organ-specific autoimmune disease. Within the present article we aim to review immunobiological and epidemiological aspects as well as diagnostic methods available for the detection of TRAb. Over the last decade, TRAb detection in GD became more sensitive since TRAb assays were being largely improved by named research groups. Therefore, functional assay (fas) and diagnostic sensitivity of current TRAb assays will be discussed. Within the second part of this review we will focus on clinical applications of TRAb measurement for outcome prediction of GD as well as the importance of this method to distinguish GD from other AITD. [Copyright &y& Elsevier]