Long-acting Thyroid Stimulator Protector Research Articles

Serum long acting thyroid stimulator (LATS) and LATS-protector (LATS-P) in Graves' disease associated with localized myxedema.

When localized myxedema occurs in Graves' disease, there is often very high serum long acting thyroid stimulator (LATS) activity. However, this association is not invariable and no pathogenetic role for this IgG associated activity is known. Serum LATS protector (LATS-P) is a closely related IgG activity which is present in the majority of cases of untreated Graves' disease. It usually coexists in LATS positive sera in a substantially greater concentration. Its association with localized myxedema has not been studied, nor have serial studies been performed on this activity during the clinical course of the disease. Fourteen patients (13 females, 1 male) with localized myxedema and a history of Graves' disease were examined. In 13 serum LATS was detectable with a wide range of activity from 2.4 to 1,000 units/ml. Serum LATS-P was detected in all including the LATS negative patient with a range of activity from 46 to 4,068 units/ml. Serial studies for at least 2 years were conducted in 8 patients. In two there was no change in either skin lesions or in serum LATS and LATS-P. In 6 the skin lesions partially or completely resolved. In 5 this was associated with statistically significant falls in serum LATS and LATS-P but in one no significant change occurred. The study demonstrated the high prevalence of LATS and LATS-P in localized myxedema. In the sole LATS negative patient there was a high concentration of LATS-P. The role of these activities in the pathogenesis of the disease remains unknown but in serial studies falls in activity were usually associated with clinical improvement.

The prediction of relapse after drug treatment of Graves' disease by assay of long acting thyroid stimulator-protector (LATS-P).

In a study of fifty-two patients with Graves' disease followed for 1 year after stopping antithyroid drugs, a strong relationship has been found between serum LATS-P and relapse. In those with serum LATS-P activity on stopping therapy, twenty-one (88%) out of twenty-four relapsed. In those with no LATS-P activity on stopping antithyroid drugs only eight (29%) out of twenty-eight relapsed and in five LATS-P was detectable at relapse. The overall prevalence of positive assays for LATS-P at relapse (90%) was similar to that seen in untreated Graves' disease.

Serum Long Acting Thyroid Stimulator (Lats) and Lats-Protector (LATS-P) in Graves' Disease Complicated by Localized Myxoedema

When localized myxedema occurs in Graves’ disease, there is often very high serum long acting thyroid stimulator (LATS) activity. However, this association is not invariable and no pathogenetic role for this IgG associated activity is known. Serum LATS protector (LATS-P) is a closely related IgG activity which is present in the majority of cases of untreated Graves’ disease. It usually coexists in LATS positive sera in a substantially greater concentration. Its association with localized myxedema has not been studied, nor have serial studies been performed on this activity during the clinical course of the disease. Fourteen patients (13 females, 1 male) with localized myxedema and a history of Graves’ disease were examined. In 13 serum LATS was detectable with a wide range of activity from 2.4 to 1,000 units/ml. Serum LATS-P was detected in all including the LATS negative patient with a range of activity from 46 to 4,068 units/ml. Serial studies for at least 2 years were conducted in 8 patients. In two there was no change in either skin lesions or in serum LATS and LATS-P. In 6 the skin lesions partially or completely resolved. In 5 this was associated with statistically significant falls in serum LATS and LATS-P but in one no significant change occurred. The study demonstrated the high prevalence of LATS and LATS-P in localized myxedema. I n the sole LATS negative patient there was a high concentration of LATS-P. The role of these activities in the pathogenesis of the disease remains unknown but in serial studies falls in activity were usually associated with clinical improvement.

Relationships Among Immunoglobulin Markers in Graves' Disease*

ABSTRACT TSH-binding inhibitory activity (TBIA), LATS, and LATS-protector (LATS-P) were examined in sera of 17 patients with untreated Graves' disease (UGD), 17 patients treated for Graves' disease (TGD) and rendered euthyroid, 4 TGD cases not yet euthyroid, 12 patients with euthyroid Graves' disease (EGD), 14 patients with Hashimoto's thyroiditis, and 14 euthyroid relatives of Graves' disease patients. TBIA, LATS, and LATS-P were positive in 69%, 29%, and 100% of UGD sera so studied. Frequency of positive TBIA, LATS, or LATS-P was much less in EGD than in UGD. These activities were undetectable in sera of all patients with Hashimoto's thyroiditis. LATS-P was demonstrable in one Graves' relative, while TBIA or LATS were undetectable in all 14 of them so studied. TBIA was strongly positive in all 10 LATS-positive sera (5 UGD, 4 TGD, and 1 EGD) in this study. It was negative, however, in many sera (5 of 12 UGD, all 7 TGD, all 4 EGD, and the 1 Graves' relative) which were positive for LATS-P without LATS. Th...

EVIDENCE THAT BOTH LONG-ACTING THYROID STIMULATOR AND LONG-ACTING THYROID STIMULATOR-PROTECTOR STIMULATE THE HUMAN THYROID GLAND

Thyroid-stimulating immunoglobulins were prepared from two potent sera, one contained long-acting thyroid stimulator (LATS) and the other contained both LATS and LATS-protector (LATS-P). The potencies of the immunoglobulin G (IgG) preparations were estimated in the McKenzie assay. The accumulation of cyclic AMP in mouse thyroid lobes was stimulated only by LATS--IgG; LATS-P--IgG was inactive. In contrast, both LATS-IgG and LATS-P--IgG were equally effective in slices of human thyroid.

Neonatal thyrotoxicosis in four siblings born to a previously thyrotoxic mother.

Neonatal hyperthyroidism is a relatively uncommon disorder. It has been described in infants born to women with active hyperthyroidism and in those born to euthyroid women previously treated medically or surgically for hyperthyroidism. 1 Recent evidence suggests that neonatal hyperthyroidism is due to thyroid stimulation in the fetus by a transplacentally acquired long-acting thyroid stimulation globulin (LATS) or a human specific antibody, LATS-protector (LATS-P), which has been detected in a large number of patients with hyperthyroidism. 2 Although there have been reports of neonatal thyrotoxicosis, this report is the first to our knowledge to describe its consecutive occurrence in four siblings born to a previously thyrotoxic woman. Report of Cases. —The mother is a 40-year-old, gravida 6, para 4, abortus 2 woman who was well until 1950 when, at the age of 16, hyperthyroidism developed and she underwent a partial thyroidectomy and a course of iodine 131 therapy. She

The role of thyroid stimulating immunoglobulins of Graves's disease in neonatal thyrotoxicosis.

SummaryGraves's disease is characterized by hyperthyroidism, a diffuse, uniform enlargement of the thyroid gland and marked eye signs. It is now widely believed that the thyroid overactivity of Graves's disease is a result of the presence in the circulation of abnormal thyroid stimulating immunoglobulins (TSIg). TSIg are transferred from mother to fetus and cause neonatal thyrotoxicosis in around 1 per cent of babies born to mothers who have a history of Graves's disease. Because TSIg may persist in the maternal circulation after successful treatment of Graves's disease by partial thyroidectomy, neonatal thyrotoxicosis may occur in babies born to mothers who have been euthyroid throughout pregnancy. In our study, 9 of 12 examples of neonatal thyrotoxicosis encountered in 96 pregnancies occurred in babies born to mothers who were thought to be thyrotoxic at some stage during the pregnancy. Two main categories of TSIg are recognized: the long‐acting thyroid stimulator (LATS) and LATS‐protector (LATS‐P) both of which were assayed in maternal serum samples withdrawn during the third trimester. Levels in maternal and cord blood were similar. The critical level of TSIg causing neonatal thyrotoxicosis appeared to be 10 units/ml and above 20 units/ml the babies were always thyrotoxic at birth.

EFFECTS OF HUMAN THYROID-STIMULATING HORMONE AND IMMUNOGLOBULINS ON ADENYLATE CYCLASE ACTIVITY AND THE ACCUMULATION OF CYCLIC AMP IN HUMAN THYROID MEMBRANES AND SLICES

The activation of adenylate cyclase and the accumulation of cyclic AMP resulting from the action of human thyroid-stimulating hormone (TSH), long-acting thyroid stimulator (LATS) or LATS-protector (LATS-P) have been investigated in preparations of human thyroid membranes and slices. Human TSH significantly increased adenylate cyclase activity in membranes from non-toxic goitres whereas LATS and LATS-P had no consistent effect. However, pre-incubation of goitrous membranes with LATS--immunoglobulin G inhibited the effect of TSH on adenylate cyclase. When thyroid membranes were prepared from the glands of patients with Graves's disease neither TSH nor thyroid-stimulating immunoglobulins (TSIg) stimulated adenylate cyclase significantly. Whether from non-toxic goitres or thyrotoxic tissue, the concentration of TSH needed to induce half of the maximum response was lower in thyroid slices than in membranes. Both LATS and LATS-P significantly stimulated the accumulation of cyclic AMP in slices of goitrous tissue but thyrotoxic tissue slices did not respond. In goitrous slices, submaximum concentrations of TSH and TSIg caused additive responses in the accumulation of cyclic AMP but TSIg did not increase the maximum response to TSH.

LATS-Protector Activity in Thyrotoxicosis Measured by Thyroidal Intracellular Colloid Droplet Formation*

A modified assay method of LATS and LATS protector (LATSP) was devised employing murine thyroidal intracellular colloid droplet formation. This method is 4- to 8-fold more sensitive to stimulators than is the regular McKenzie bioassay. For the assay of LATSP, IgG to be tested was incubated with human thyroid homogenate, then LATS-IgG was added and it was further incubated. The potency of LATS in the mixture was assayed. The adequacy of the present method for the assay of LATSP was supported by the facts that the LATSP activity was roughly related to the dose of IgG tested and that the inactivation of LATSP was observed when the IgG was pretreated with human thyroid particulate fraction and then assayed. With this method, 7 out of 32 patients with thyrotoxicosis showed LATS and 18 showed LATSP. Changes in LATSP were followed up in 7 cases out of the 18. LATSP activity decreased and then disappeared in 6 out of the 7 cases, when they had been euthyroid for a certain period of time. At 12-20 months after the treatment either by thionamide medication or by subtotal thyroidectomy. LATSP and 131I-thyroid uptake were measured in these 6 patients. In all of the 6, LATSP was negative regardless of thyroid suppressibility.

Thyroid carcinoma and concurrent hyperthyroidism: a study of ten patients.

Ten patients with thyroid carcinoma and co-existing thyrotoxicosis have been studied. In six patients thyroid carcinoma was suspected before thyroidectomy. In three of the four patients in whom neoplasia was not suspected before operation, the lesion was a small papillary carcinoma. In only one of the eight patients in whom serum long acting thyroid stimulator (LATS) and long acting thyroid stimulator protector (LATSP) were assayed was detectable activity found, a low incidence. The possible role of hyperthyroidism in initiating thyroid malignancy is discussed.

Hyperthyroidism in Tasmania following iodide supplementation: measurements of thyroid-stimulating autoantibodies and thyrotropin.

Serum thyroid-stimulating autoantibodies (LATS and LATS protector) and thyrotropin (TSH) concentrations were measured in the serum of 30 patients with hyperthyroidism living in Tasmania who developed their disease following correction of iodine deficiency by addition of iodate to the bread. Patients were grouped according to thyroid scan results. None of 8 patients with autonomous thyroid nodules had thyroid-stimulating autoantibodies. These were present in both of the patients with uniform thyroid scans and 14 of 20 patients (70%) with irregular scans without demonstrated localized autonomy. Serum TSH, measured by immunoassay of concentrated serum extracts, was 0.15 muU/ml or less in all patients, below the range of 0.35 to 2.60 muU/ml found in normal subjects. Only 6 (20%) of the 30 patients failed to show either localized autonomy or thyroid-stimulating autoantibodies. In most regards these patients resembled those with antonomous nodules. The findings support the conclusion that the increased incidence of phyerthyroidism in Tasmania was due to an increased supply of iodine to patients with latent hyperthyroidism whose thyroid glands, due to the presence of toxid nodule(s) or thyroid-stimulating autoantibodies, were unresponsive to control by TSH deprivation. There was no evidence for additional pathogenic mechanisms

LATS and human-specific thyroid stimulator; their relation to graves' disease

Graves' disease is characterised by many autoimmune features (see Table 1). Whether or not it can be accurately classified as an autoimrnune disease depends on whether any of these features can be shown to be causative. Notable is the presence of thyroid-specific autoantibodies; some of these have little functional significance but others may be responsible for the hyperthyroidism and perhaps also for the extrathyroidal manifestations of the disease. They are therefore of significance in the pathogenesis of the disease and the cell-stimulating effect of these antibodies is of considerable immunological interest. The first of these thyroid-stimulating autoantibodies, long-acting thyroid stimulator (LATS), has now been extensively studied. It is a thyroid-specific autoantibody which stimulates the thyroid, but LATS is not alone responsible for the hyperthyroidism of Graves' disease. The evidence concerning LATS and its pathogenic significance is reviewed. Human-specific thyroid stimulator (HSTS) is probably identical to LATSprotector (LATS-P). Much less is known about LATS-P than about LATS but the subject of LATS-P and HSTS is dealt with in some detail because of its present interest. Lastly the relevance of these findings is discussed in relation to the pathogenesis of Graves' disease as a whole.

Autoimmunity in the pathogenesis of endocrine exophthalmos

It is now fully acceptable that thyroid stimulating antibodies (TSAb) include long-acting thyroid stimulator (LATS) which stimulates the thyroid and adrenal glands in the mouse (El Kabir et al, 1971) and other animals but may have no effect on the human glands, and LATS-protector (LATS-P) or human-specific thyroid-stimulating antibody (HTS) which is probably responsible for the hyperactivity of the thyroid in Graves' disease (Adams, Kennedy and Stewart, 1974; Adams et al, 1974). As in other autoimmune systems there is a larger group of closely allied antibodies, reactive with TSHsensitive receptors in other tissues. Particularly important in this respect are the ophthalmopathic immunoglobulins (O-Ig) which cross-react with the harderian gland in guinea pigs and with adipose tissue cells in several species including man. Such antibodies are cell-stimulating in character as opposed to being cytotoxic, as are thyroid microsomal antibodies. They could be responsible for the proliferation of retro-orbital tissue in exophthalmos; related but not identical antibodies might cause subcutaneous lesions in pretibial myxoedema. There are indications that fibroblasts also proliferate in the orbit and other sites in these conditions but it is uncertain that TSHreceptors exist on connective tissue cells so their stimulation could be due to other mechanisms related to inflammation and repair. Two separate lesions in endocrine exophthalmos are the myositis of the extraocutar muscles and the increased bulk of retrobulbar fat and/or connective tissue. Together these lesions give rise to the diplopia, raised orbital pressure, oedema and proptosis characteristic of the syndrome (Werner, 1972). Autoimmune mechanisms of a different nature are probably involved in the two types of dysfunction. Other factors such as venous stasis play a part in the clinical picture but will not be discussed. The spasm of the levator palpebrae muscle which causes lid retraction and lid lag, is still attributed to the effects of excess circulating thyroid hormones and adrenergic potentiation, and has not so far been implicated immunologically.

Placental transmission of thyroid-stimulating immunoglobulins.

Long-acting thyroid stimulator (LATS) and LATS protector (LATS-P) were assayed at or near delivery in serum from 18 pregnant women with a history of past or present thyrotoxicosis. The results suggested that neonatal thyrotoxicosis may be predicted prenatally if maternal serum LATS and LATS-P concentrations near delivery are above certain levels.

Letter: Neonatal hyperthyroidism and long-acting thyroid stimulator protector.

Neonatal hyperthyroidism has been thought to result from transplacental passage of long-acting thyroid stimulator (L.A.T.S.) from a mother with Graves's disease. A case is presented here in which no L.A.T.S. was detected in the mother or neonate but another immunoglobulin, L.A.T.S. protector, a specific human thyroid stimulator, was shown to be present in the mother's serum. This stimulator may have been the cause of the neonatal hyperthyroidism.

Association of the long-acting thyroid stimulator protector with the immunoglobulin G fraction of serum from patients with thyrotoxicosis

Both the long-acting thyroid stimulator and the long-acting thyroid stimulator protector are associated with the immunoglobulin G fraction of human serum proteins. Fractionation of globulins by (NH 4) 2SO 4 precipitation and DEAE-cellulose chromatography showed that the protector activity was associated with subfractions of differing electrophoretic mobility. Attempts to concentrate the protector in immunochemically pure immunoglobulin G prepared in this way may fail because of loss of protector activity with other immunoglobulin G fractions. Gel filtration on Sephadex G-150 indicated that protector activity was associated with 7-S proteins.

Neonatal hyperthyroidism and long-acting thyroid stimulator protector.

Neonatal hyperthyroidism has been thought to result from transplacental passage of long-acting thyroid stimulator (L.A.T.S.) from a mother with Graves's disease. A case is presented here in which no L.A.T.S. was detected in the mother or neonate but another immunoglobulin, L.A.T.S. protector, a specific human thyroid stimulator, was shown to be present in the mother's serum. This stimulator may have been the cause of the neonatal hyperthyroidism.

Some factors affecting the detection of long-acting thyroid stimulator protector using the McKenzie bioassay.

SUMMARY The long-acting thyroid stimulator (LATS) protector may be detected by its property of blocking the binding of LATS to LATS absorbing activity (LAA). This study confirmed that the sensitivity of LATS protector detection was largely determined by the choice of reference mixture of LATS and LAA. Optimal sensitivity was achieved when: (a) the reference concentration of LATS activity gave a response at the upper end of the linear part of the dose–response curve; (b) the reference LATS-containing serum required a minimum of LAA for LATS binding; (c) the reference LAA preparation was free of thyroglobulin; (d) the concentration of LAA in the reference mixture was that which almost abolished the response to the reference concentration of LATS; (e) the reference LAA preparation was incubated with LATS protector before the addition of the reference LATS.

Stimulation of the human thyroid by infusions of plasma containing LATS protector.

LATS protector was tested for ability to stimulate the human thyroid gland by infusing plasma containing LATS protector into human volunteers. Infusions of plasma from normal, euthyroid subjects served as controls. Before receiving the infusions the recipients had been given tracer doses of 125I (100–300 μCi) and were taking triiodothyronine (80–100 μg daily). Levels of 125I in blood and urine were followed by counting plasma samples and urine samples. Three strong LATS protector plasmas caused a significant increase in the blood 125I level and had a variable effect on the urinary excretion. A weak LATS protector plasma had a negligible effect. Three infusions of plasma from normal people had no effect. The infused LATS protector plasmas showed no detectable LATS (mouse bioassay) in 10-fold immunoglobulin concentrates. It was calculated that the levels of LATS protector attainedin the volunteer subjects were 1/10th to 1/18th of the levels in the thyrotoxic patients from whom the LATS protector plasmas were obtained. We conclude that LATS protector stimulates the human thyroid gland.

Correlation between long-acting thyroid stimulator protector level and thyroid 131-I uptake in thyrotoxicosis.

Out of 50 consecutive untreated patients with diffuse toxic goitre 15 showed long-acting thyroid stimulator (LATS), 30 showed LATS protector only, and five showed neither. LATS protector was present in all the patients with LATS. Infiltrative ophthalmopathy was less common in patients with LATS protector only (40%) than in patients with LATS also (67%), but the difference was not significant. There was a correlation between LATS protector level and thyroid (131)I uptake rate factor (k(1)), the coefficient (r) being 0.68 (P < 0.001). LATS level showed no such correlation. The results support the hypothesis that LATS protector is a pathogenic thyroid stimulator in patients with diffuse toxic goitre.