Serum Thyroid-stimulating Immunoglobulin Research Articles

Epidemiology of thyroid-stimulating immunoglobulin in recent-onset symptomatic thyroid eye disease.

This study aims to report correlations between thyroid-stimulating immunoglobulin (TSI) and both clinical and radiological parameters in recent-onset symptomatic thyroid eye disease (TED) patients. A prospective cohort study of TED patients managed at the Chinese University of Hong Kong from January 2014 to May 2022. Serum TSI levels were determined with the functional assay. Outcomes included the Clinical Activity Score (CAS), marginal reflex distance1 (MRD1), extraocular muscle motility restriction (EOMy), exophthalmos, and diplopia. The radiological assessment included cross-sectional areas and signal of extraocular muscles on STIR-sequence MRI. A total of 255 (197 female) treatment-naive patients, with an average onset age of 50 ± 14 years (mean ± s.d.), were included. Elevated pre-treatment TSI level was observed in 223 (88%) patients. There was a weak positive correlation between TSI and CAS (r = 0.28, P = 0.000031), MRD1 (r = 0.17, P = 0.0080), and the size of the levator palpebrae superioris/superior rectus complex (r = 0.25, P = 0.018). No significant correlation existed between TSI and STIR signals. The AUC and optimal cut-off value for clinical active TED were 0.67 (95% CI: 0.60-0.75) and 284% (specificity: 50%, sensitivity: 85%). In total, 64 patients received intravenous methylprednisolone (IVMP) during the study interval, and they had a higher baseline TSI level than those who did not have IVMP (P = 0.000044). Serial post-IVMP TSI among the 62 patients showed a significant reduction compared to the baseline level (P < 0.001). Both the baseline and post-IVMP TSI levels, and percentages of TSI changes were comparable between patients who responded and did not respond to the first course of IVMP. TSI can be a serum biomarker for the diagnosis, prognosis, and treatment response of TED. Further validation should be warranted.

Elevated serum thyroid stimulating immunoglobulin linked to failure of first-line intravenous methylprednisolone monotherapy in moderate-to-severe thyroid eye disease.

To assess factors associated with failure of intravenous methylprednisolone (IVMP) monotherapy as the first-line treatment for thyroid eye disease (TED) and to identify patients who might benefit from supplementing mycophenolate mofetil (MMF) to IVMP. Data for all patients with TED treated with IVMP according to the EUGOGO protocol in our center between 2016-2021 were retrospectively analysed. Forty-seven patients (mean age 51.32 ± 14 years, 27 females) were enrolled. The mean time from first reported symptoms to first IVMP treatment was 12.1 ± 5.59 months (range 0-120). The mean clinical activity score (CAS) before treatment and at a mean of 5 and 12.2 weeks after treatment initiation was 6.00, 2.96, and 1.81, respectively (P < 0.01). Twenty-one patients (44.68%) were recommended second-line treatment: nine due to no response or worsening of CAS, six due to partial response, four with good response but early relapse after completion of treatment, and one due to late relapse. Eighteen of those 21 patients received second-line treatment which included rituximab (n = 7), MMF (n = 6), a second course of IVMP (n = 4), and tocilizumab (n = 1). Serum thyroid-stimulating immunoglobulin (TSI) levels were higher in patients who received second-line treatment compared with patients who responded well to first-line IVMP monotherapy at presentation (2135% vs 1159%, P = 0.05) and after completion of first-line treatment (2201% vs. 986%, P = 0.043). TED patients requiring second-line treatment after failed IVMP monotherapy had higher baseline and post-first-line treatment serum TSI levels. Those with elevated TSI may benefit from dual therapy (IVMP and MMF) and require closer monitoring.

THU670 Serum TSI Concentration In Patients With Graves’ Disease Undergoing Maintenance-dose Of Antithyroid Drug (ATD) And Its Relationship With Disease Relapse After ATD Withdrawal

Abstract Disclosure: P.V. Nguyen: None. K.T. Nguyen: None. Background: Graves' disease (GD) is an autoimmune disorder in which thyroid-stimulating immunoglobulin (TSI) plays a key role in its pathogenesis. TSI assays have been recently optimized in their accuracy, and the procedure has also been simplified, which can potentially replace TRAb measured by conventional TSH-binding inhibitory immunoglobulins (TBII) assays in routine clinical practice. Objectives: Our objective was to study the serum TSI concentration in patients with Graves’ disease undergoing maintenance-dose ATD. We also aimed to assess the predictive value of TSI immunoassay, as well as the clinical signs and thyroid function tests in predicting Graves’ disease relapse following ATD discontinuation. Finally, follow-up would be continued to check for relapse or long term euthyroid status. Methods: Retrospective follow-up study of 352 patients with hyperthyroidism due to GD, treated at the endocrine outpatient clinic of Medic Medical Center, Ho Chi Minh City from January 2000 to April 2021. TSI was measured several times during the course of treatment when planning to stop the medication (at the discretion of the attending physician). ATD withdrawal would be considered when the patients achieved clinical euthyroidism with normal FT4 tests for at least 3 months with minimal dose of ATD. The decision to withdraw ATD was also based on TSI concentration, as well as the goiter’s characteristics and parenchymal vascularity observed via thyroid Doppler ultrasound. Results: The median TSI concentration of patients with GD undergoing maintenance-dose ATD was 1.45 IU/L (normal range &amp;lt;0.10 IU/L), and their thyroid function measured at the same time tended to be euthyroid in our study. TSI cut-off level at ATD withdrawal to predict the recurrence of GD was 1.31 IU/L which corresponded with the sensitivity, specificity, positive and negative predictive values of 63.64%, 78,79%, 50% and 86.67%, respectively. Multiple logistic regression analysis showed that the following factors were associated with an increased risk of relapse after the end of medical treatment: Graves' ophthalmopathy (GO), OR 3.69 (95% CI: 1.06-12.87; p=0.04), treatment duration less than 18 months, OR 7.77 (95% CI: 1.92-31.42; p&amp;lt;0.01), TSI level before ATD withdrawal ≥1.31 IU/L, OR 9.92 (95% CI: 2.77-35.42; p&amp;lt;0.01). Conclusion: At the time of ATD withdrawal, while normal FT4 levels were observed, high TSI levels were indicative of an ongoing immune process. These findings suggest that TSI measurements, in addition to clinical and ultrasound evaluations, may aid in the prediction of GD relapse after ATD discontinuation. In addition, GO, treatment duration of less than 18 months and TSI level before ATD withdrawal ≥1.31 IU/L were associated with an increased risk of relapse of GD after ATD discontinuation. Our study contributes to the expanding literature supporting the clinical utility of TSI assay in the management of GD. Presentation: Thursday, June 15, 2023

Changes in Clinical Activity, Serum Autoantibody Levels, and Chorioretinal Vessels After Systemic Glucocorticoid Therapy in Thyroid Eye Disease.

The aim of this study was to investigate changes in the Clinical Activity Score, serum thyroid-stimulating hormone receptor antibody and thyroid-stimulating immunoglobulin levels, chorioretinal blood vessels, and extraocular muscle thickness in patients with thyroid eye disease following systemic steroid treatment. This prospective observational study enrolled 57 patients with active thyroid eye disease who received systemic intravenous glucocorticoids for 12weeks. Demographics, clinical activity scores, optical coherence tomography images, and serum thyroid-stimulating immunoglobulin and thyroid-stimulating hormone receptor antibody levels were assessed at baseline, at 6 and 12weeks after intravenous (IV) GC therapy initiation, and 2months after IV GC therapy termination. The extraocular muscle thickness, choroidal thickness, and choroidal vascularity index were measured. The clinical activity scores showed a significant decrease. Serum thyroid-stimulating immunoglobulin levels dropped continuously for 2months. The thyroid-stimulating hormone receptor antibody level decreased until 12weeks after treatment but returned to within the normal range in 75% of patients after 77 and 126days, respectively. The choroidal thickness decreased at all time points. The thickness of the medial and inferior rectus muscles decreased at 2months after treatment. The clinical activity score decreased to < 3 points in 50% of patients after 78days. Intravenous glucocorticoid therapy improved the clinical activity score, chorioretinal blood flow, and extraocular muscle thickness. The serum autoantibody levels were normalized in patients with active thyroid eye disease 2 months after IV GC termination. The serum thyroid-stimulating immunoglobulin and thyroid-stimulating hormone receptor antibody levels correlated with restoration of chorioretinal capillary perfusion and improved clinical symptoms and muscle thickness. Non-invasive optical coherence tomography findings and serologic factors predict the response to intravenous glucocorticoid therapy.

Clinical relevance of thyroid-stimulating immunoglobulin as a biomarker of the activity of thyroid eye disease.

Although it has been reported that thyroid-stimulating immunoglobulin (TSI) is associated with the clinical characteristics of thyroid eye disease (TED), there is a paucity of literature regarding the role of TSI in diagnosing active TED. This study investigated the relationship between the level of TSI and the activity of TED and assessed the cut-off value of TSI discriminating active TED from inactive TED. This cross-sectional study included 101 patients with TED. TSI was quantitatively measured with a cell-based bioassay using a chimeric TSH receptor and a cyclic adenosine monophosphate response element-dependent luciferase. The association between TSI and a variety of demographic and clinical features of TED was analysed. Multivariate regression analysis was performed to determine possible independent factors affecting the level of TSI. TSI level was higher in males than in females (p = 0.023) and smokers than in nonsmokers (p = 0.004). TSI level was inversely correlated with the duration of ocular symptoms (r = -0.295, p = 0.003). The level of TSI was also significantly different when compared to the thyroid function (p = 0.003), TED activity (p < 0.001), and TED severity (p = 0.001). Multivariate regression analysis revealed a significant relationship between TED activity and thyroid function jointly and the TSI level. The cut-off level of TSI for predicting active TED was a specimen-to-reference ratio of 406.7 (p < 0.001, area under the curve = 0.847, sensitivity 77.4%, specificity 81.3%). TSI was a functional biomarker strongly associated with TED activity even after being adjusted by other clinical characteristics. Serum TSI level may help identify patients with active TED in clinics.

Proinflammatory Effects of Calprotectin in Graves’ Orbitopathy

ABSTRACT Purpose: Early detection and control of inflammation are important to manage Graves’ orbitopathy (GO). We investigated the effects of calprotectin (S100A8/A9) on orbital fibroblast inflammation and GO pathogenesis. Methods: We measured serum calprotectin, S100A8 and S100A9 mRNA expression in orbital fat/connective tissue from GO patients and healthy controls, and proinflammatory cytokines in primary cultured orbital fibroblasts. Results: The serum levels of S100A8/A9 and the expression of S100A8/A9 mRNA in orbital tissue were higher in the GO patients than in the healthy controls. The serum calprotectin levels positively correlated with the clinical activity score and serum thyroid-stimulating immunoglobulin levels. In cultured GO orbital fibroblasts, S100A8/A9 increased the expression of interleukin (IL)-6, IL-8, and monocyte chemotactic protein-1, as well as the phosphorylation of extracellular signal-regulated kinase and nuclear factor-κB. Conclusion: We demonstrated the potential of calprotectin as a biomarker of GO severity and proinflammatory responses to S100A8/A9 in GO orbital fibroblasts.

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 …

Hipertiroidismo

Hyperthyroidism is caused by an excess of circulating thyroid hormones. Its prevalence is approximately 1.3% (0.5% clinical and 0.7% subclinical). Excess thyroid hormone may be due to sustained production or overproduction of the thyroid hormone release into the circulation or preformed by extrathyroidal production. The most common causes are Graves' disease, toxic multinodular goitre and toxic adenoma. The clinical findings of hyperthyroidism include metabolic and cardiovascular manifestations. The determination of T3 and/or free T4 and TSH serum levels allows diagnosis of thyrotoxicosis. Additional evidence for the etiologic diagnosis include ultrasound scan and the serum thyroid-stimulating immunoglobulin, thyroid peroxidase antibodies and thyroglobulin. There are three treatment options: iodine-131, surgery, and antithyroid drugs. The choice of treatment modality is dictated by the cause of thyrotoxicosis and patient profile.

Relationship between thyroid stimulating hormone and thyroid stimulating immunoglobulin in Graves’ hyperthyroidism

In Graves' hyperthyroidism, suppression of serum TSH after restoration of normal serum T4 and T3 with treatment has been attributed to binding of TSH-receptor antibodies to TSH receptors in the pituitary. Accordingly, the relationship between TSH and serum thyroid stimulating immunoglobulin (TSI) was examined during follow-up of patients with Graves' hyperthyroidism. 23 patients with Graves' hyperthyroidism were identified who met the inclusion criteria of at least 24 months follow-up after initiation of methimazole and availability of concurrent measurements of serum TSH and TSI. TSI disappeared in 12 patients (Group A) and persisted in 11 patients (Group B). Initial T4 was not significantly different between the 2 groups. However, TSI was significantly lower in Group A than Group B [median (interquartile range) 179 (152-212)% vs 255 (208-369)%, p=0.0009]. In Group A, TSH normalized during treatment, and this anteceded disappearance of TSI by a significant time interval [median (interquartile range) 6 (3-8) months vs 15 (11-20) months, p=0.005]. In Group B, TSI persisted in all patients during follow-up ranging from 24 to 73 months. No correlation was found to exist between serum TSH and TSI, and for Group B TSI at final follow-up was not significantly different from the initial value [median (interquartile range) 255 (208-369)% vs 236 (160-310)%, p=0.4]. These findings do not support the suggestion that TSI has a direct suppressive effect on TSH secretion.

Serum Thyrotropin in Graves’ Disease: A More Reliable Index of Circulating Thyroid-Stimulating Immunoglobulin Level than Thyroid Function?

To assess the relationship between serum thyrotropin (thyroid-stimulating hormone or TSH) on one hand and thyroid-stimulating immunoglobulin (TSI), free thyroxine (T4), and triiodothyronine (T3) levels on the other in Graves' disease, inasmuch as TSH may be suppressed in the presence of TSI because TSI may bind to the TSH receptor on the thyroid gland membrane and thus eliminate the need for circulating TSH for stimulating the thyroid gland. We determined serum TSI levels in 37 women and 13 men with Graves' disease, stratified into 4 groups on the basis of serum TSH levels irrespective of serum free T4 and T3 levels. Our reference ranges were 0.72 to 1.74 ng/dL for free T4, 80 to 200 ng/dL for T3, and 0.4 to 4.0 micro/mL for TSH. Mean serum TSI concentrations were highest (215% +/- 28%) in patients with undetectable TSH levels (<0.03 micro/mL) and lowest (103% +/- 9%) in those with supernormal TSH concentrations (>4.0 micro/mL). TSI levels were intermediate in the other study groups: 157% +/- 16% in patients with subnormal though detectable TSH levels (0.03 to 0.39 micro/mL) and 125% +/- 12% in those with normal TSH levels (0.4 to 4.0 micro/mL). Moreover, a progressive decline in TSI levels with increasing serum TSH concentrations was noted, along with a significant negative correlation (r = -0.45; P<0.01) between serum TSI and TSH concentrations. Finally, relationships between free T4 and T3 levels on one hand and TSI or TSH levels on the other were not significant, with a considerable variability in free T4 and T3 levels being noted in individual study groups. Serum TSH is frequently suppressed after treatment with antithyroid drugs or radioiodine (131I), irrespective of clinical thyroid function as expressed by increased, normal, or decreased free T4 and T3 concentrations. In an individual patient with Graves' disease, the serum TSH level may be more reflective of the circulating TSI concentration than is thyroid gland function as expressed by free T4 and T3 concentrations and therefore may be as reliable a predictor of remission as TSI.

The aftermath of orbital radiotherapy for graves’ ophthalmopathy

Objective To determine whether long-term improvement could be observed after orbital radiotherapy for Graves’ disease; in addition, to evaluate ancillary treatments needed for those who have received radiotherapy, to search for late-emerging adverse consequences of radiotherapy, and to relate orbital changes to serum levels of thyroid-stimulating immunoglobulin (TSI). Design Three-year follow-up of noncomparative interventional case series. Participants Forty-two patients. Intervention All patients had received orbital radiotherapy within 6 months of study entry. Twelve months after study entry, patients were free to select any additional treatment for their ophthalmopathy. Main outcome measures Need for surgery, steroid therapy, volume of extraocular muscles and fat, proptosis, area of diplopia fields and range of extraocular muscle motion, volume changes after decompression and correlations of eye findings with serum TSI levels, retinal status. Results Half of the patients elected to have a surgical procedure on their eyes or orbits. Among patients who were not decompressed, we found only slight improvement in some of the main outcome measures. TSI did not positively correlate with baseline status or with any observed change in major outcome measures. After orbital decompression, the volumes of both muscle and fat increase, but bony orbital volume increases more and proptosis diminishes. Retinal microvascular abnormalities consistent with radiation retinopathy developed de novo in five eyes of three patients within 3 years of radiation therapy. Conclusions In this 3-year uncontrolled follow-up phase, limited evidence for a clinically significant improvement was observed, which may be the result of treatment or of natural remission. In either case, the changes are of little clinical significance. Because it is neither effective nor innocuous, radiotherapy does not seem to be indicated for treatment of mild to moderate ophthalmopathy.

The relationship between maternal serum thyroid-stimulating immunoglobulin and fetal and neonatal thyrotoxicosis

OBJECTIVE: To estimate whether the risk of neonatal thyrotoxicosis was related to the value of maternal thyroid-stimulating immunoglobulin in women with Graves disease. METHODS: The records of pregnant women undergoing testing for thyroid-stimulating immunoglobulin over a 10-year period were analyzed. Neonatal thyrotoxicosis was defined as the presence of tachycardia, goiter, hydrops, tremulousness, voracious appetite, irritability, cardiomegaly, or congestive heart failure, with elevated thyroid hormone levels. The relationship between maternal thyroid-stimulating immunoglobulin values and the development of thyrotoxicosis was examined. The sensitivity, specificity, and positive and negative predictive values were calculated using an arbitrarily chosen cutoff for thyroid-stimulating immunoglobulin. RESULTS: Twenty-nine women with a history of Graves disease and positive thyroid-stimulating immunoglobulin values were available for analysis. Of the 35 live births, there were six cases of neonatal thyrotoxicosis (17.1%). A maternal thyroid-stimulating immunoglobulin value at least 5 index units predicted neonatal thyrotoxicosis with a sensitivity of 100%, specificity of 76.0%, positive predictive value of 40.0%, and negative predictive value of 100%. CONCLUSION: Pregnancies complicated by high values of maternal thyroid-stimulating immunoglobulin appear to be at risk of developing neonatal thyrotoxicosis.

TSH Receptor Antibody in Hyperthyroid Patients due to Graves' Disease Treated with Antithyroid Drugs

As an immunologic process, TSH receptor antibody (TRab) may be synthesized by the lymphocytes within the thyroid gland. Two techniques were devised to express this TRap activity: a) thyroid stimulating immunoglobulin (TSI) expressed as thyroid c AMP synthesis and b) TSH binding inhibiting immunoglobulin (TBII) expressed as TSH displacement. In general, serum TSI and TBII activity correlated well with each other in hyperthyroid patients. Measurement of TSI and TBII is useful to assess improvement of immunologic abnormality induced by antithyroid drugs. The data so far gathered indicated that TRab disappears from the blood in about 70-80% of hyperthyroid patients in response to antithyroid drugs. However, this does not indicate that intrathyroidal TRab synthesis has ceased, since thyroglobulin is still secreted supernormally and T3 fails to suppress the thyroid in some patients. On the other hand, normalization of thyroglobulin and absence of TRab in the blood indicated complete normalization in the patients as evidenced by positive T3 suppressibility. By using a number of new drugs, further efforts must be made to completely normalize immunologic abnormality in 100% of patients. Recurrence of hyperthyroidism of Graves' disease is generally associated with re-appearance of TRab in the blood in most of the recurrent patients after discontinuation of antithyroid drugs.

Evidence against the importance in the disease process of antibodies to bovine thyroid-stimulating hormone found in some patients with Graves' disease.

The antibody to TSH (TSH-Ab) found in some patients with Graves' disease may be either an antiidiotype (anti-id-Ab) to the TSH receptor antibody (TRAb) or the antigen (idiotype) for which the anti-id-Ab is in fact TRAb. Four groups have found antibodies to bovine TSH (bTSH-Ab) in Graves' disease patients in a TSH binding-inhibiting immunoglobulin (TBII) RRA that uses [125I]bTSH. In this assay serum samples containing bTSH-Ab give highly negative TBII values. The purpose of this study was to look for any clinical significance of potential idiotypic-antiidiotypic network regulation related to bTSH-Ab. Twenty-one (0.49%) of 4285 Graves' disease patients had TBII values less than the mean -4 SD of normal subjects. In all 21, bTSH-Ab was found by incubation of [125I]bTSH with the patient's serum, and significant inhibition of binding of bTSH-Ab to bTSH by human TSH was found in only 3 of these serum samples. We investigated next whether the binding site of the anti-TSH-Ab mimicked the TSH receptor-binding site. Binding of [125I]bTSH to bTSH-Ab-positive serum was not inhibited by bTSH-Ab-negative, thyroid-stimulating immunoglobulin-positive [(+)], and/or TBII(+) immunoglobulin G. In one patient with human TSH-Ab, TSH-Ab appeared and disappeared, and when TSH-Ab was negative, TBII was positive. Inhibition of [125I]bTSH binding to TSH-Ab by the same patient's serum when that patient was serum thyroid-stimulating immunoglobulin(+), TBII(+), and TSH-Ab-negative was sought but not found. Changes in serum TSH-Ab activity and disease activity were not correlated in this patient. In six untreated patients with Graves' hyperthyroidism with bTSH-Ab, the serum T3 and T4 concentrations and the time required to become euthyroid during antithyroid drug treatment were not significantly different from those in 52 such patients without bTSH-Ab. These data suggest that bTSH-Ab is not an anti-id-Ab to TRAb and that TSH-Ab does not directly modulate the activity of Graves' disease.

Toxic multinodular goiter: a variant of autoimmune hyperthyroidism.

The aim of this study was to examine whether at least a subgroup of patients with toxic multinodular goiter may have autoimmune thyroid disease. Thyroid-stimulating immunoglobulin (TSI) activity, measured by a sensitive bioassay employing cultured human thyroid cells, was determined in patients with toxic multinodular goiter and other thyroid disorders. All patients with active Graves' disease (n = 47) had detectable serum TSI activity, whereas TSI was undetectable in patients with thyroid disease not believed to be of autoimmune origin: toxic adenoma (n = 13), cold nodule (n = 5), and nontoxic goiter (n = 19), with a single exception in the latter group. Toxic multinodular goiter (n = 26) was diagnosed based on clinical and laboratory evidence of hyperthyroidism associated with a multinodular goiter on palpation and scintiscan. The toxic multinodular goiter group was then subclassified according to scintiscan pattern (type A, diffuse but uneven distribution of technetium uptake; type B, multiple discrete nodules of varying size and function). All but 1 of the 11 TSI-positive toxic multinodular goiter patients had a type A scintiscan pattern. The patients with the type A scintiscan pattern were younger and more often had elevated antithyroid antibody titers, ophthalmopathy, and concurrent development of goiter and hyperthyroidism (rather than long-standing goiter preceding hyperthyroidism) compared to the type B patients. Thus, a subgroup of patients with clinically defined toxic multinodular goiter (type A) probably have autoimmune hyperthyroidism (a variant of Graves' disease), while in another subgroup (type B) hyperthyroidism is not related to an autoimmune etiology (a variant of toxic adenoma).

Rabbits immunized with thyroid-stimulating hormone produce autoantiidiotypic thyroid-stimulating antibodies.

We immunized rabbits with thyroid-stimulating hormone (TSH) to investigate the hypothesis that such immunization could result in production of thyroid-stimulating autoantiidiotypic antibodies to anti-TSH. Thyroid-stimulating immunoglobulin (TSI) appeared in the serum of several rabbits after immunization. At 160 d, TSI equivalent to 6-18 microU TSH/1.5 mg IgG was present in two of six human (h)TSH-, two of six hTSH beta chain-, and two of the four surviving bovine (b)TSH-immunized animals. Control (human serum albumin-immunized rabbits) serum TSI was 4.3 +/- 0.4 (mean +/- SD) at this time. Antiidiotypic antibodies that could bind to monoclonal anti-hTSH were found in the sera of the bTSH-immunized rabbits. The peak TSI activity occurred 3 mo after a TSH booster immunization and declined gradually during subsequent weeks. Evidence that antiidiotypic antibodies to anti-TSH can cause thyroid stimulation strengthens the notion that such antibodies may be the cause of Graves' hyperthyroidism.