The interaction of graves' IgG with the thyrotrophin receptor

Rickards, Carole R.; Buckland, Paul Robert; Smith, Bernard Rees; Hall, R.

doi:10.1016/0014-5793(81)80330-4

Cited by 32 publications

(18 citation statements)

References 18 publications

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“…9,No. 1 unable to demonstrate the formation of a termolecular complex between TSH, TSH receptor, and TRAb (4,10,113,114). If the receptor had more than one binding site for either ligand, or the antibody and hormone interacted with different regions of the receptor, the formation of such a complex would clearly be expected.…”

Section: Valency Of the Tsh Receptor For Tsh And Trabmentioning

confidence: 84%

“…These problems were essentially overcome by using detergent-solubilized thyroid membranes which showed virtually no nonspecific interference from normal IgG preparations or unextracted serum (8,9). Furthermore, the inhibition of labeled TSH binding to detergentsolubilized TSH receptors by TRAb shows a steeper dose-response relationship than that using particulate membrane preparations (10). This is due, at least in part, to the slower dissociation rate of the complex formed between detergent-solubilized receptors and labeled TSH (11).…”

Section: A Receptor Assaysmentioning

confidence: 97%

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Autoantibodies to the Thyrotropin Receptor

1988

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This review considers recent developments in our understanding of the properties of TRAb, particularly measurement of the antibodies and their sites of action and synthesis. Two new assay methods have allowed considerable improvements in the sensitivity, specificity, precision, and ease of measuring TRAb. In particular: 1) receptor assays based on inhibition of receptor-purified labeled TSH binding to detergent-solubilized TSH receptors and 2) bioassays based on stimulation of cAMP release from monolayer cultures of isolated thyroid cells. Detailed studies with the two assays indicate that TSH receptor antibodies nearly always act as TSH agonists in patients with a history of Graves' hyperthyroidism. Studies in areas of dietary iodine sufficiency suggest that measurement of the antibodies at various stages in the course of treating Graves' disease can be of value in predicting the outcome of therapy. However, in areas of iodine deficiency, difficulties in the ability of patients' thyroid tissue to recover from the effects of antithyroid drugs may prevent the receptor antibodies from causing a relapse of thyrotoxicosis. Consequently, the predictive value of receptor antibody measurements would be expected to be lower in these geographical areas. Although patients with a history of Graves' hyperthyroidism nearly always have TRAb which act as TSH agonists, about 20% of patients with frank hypothyroidism due to autoimmune destruction of the thyroid have TRAb which act as TSH antagonists (blocking antibodies). There is some evidence that these blocking antibodies can cause hypothyroidism particularly in the neonate. With regard to the site of synthesis of TRAb, there is now direct evidence that they are synthesized by thyroid lymphocytes, particularly the lymphocytes in close proximity to thyroid follicular cells. This is consistent with the well established effects of antithyroid treatment (drugs, radioiodine, or surgery) on TRAb levels in addition to their effects on thyroid hormone synthesis. Recent studies using affinity labeling with 125I-labeled TSH have enabled elucidation of the structure of the TSH receptor. TSH receptors in human, porcine, and guinea pig thyroid tissue have a two-chain structure in which the TSH binding site is formed on the outside surface of the cell membrane by a water-soluble A subunit (Mr approximately 50 K). The A subunit is linked by a disulfide bridge and weak noncovalent bonds to the amphiphilic B subunit (Mr approximately 30 K). This subunit, which penetrates the lipid bilayer, probably forms the site for interaction of the receptor with the regulatory subunits of adenylate cyclase.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Valency Of the Tsh Receptor For Tsh And Trabmentioning

confidence: 84%

Section: A Receptor Assaysmentioning

confidence: 97%

Autoantibodies to the Thyrotropin Receptor

1988

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“…Even if the receptor was univalent and occupied by hormone, it seemed likely to us that polyclonal Graves' immunoglobulin would precipitate the complex. Nevertheless, Rickards et al (23) failed in attempts to immunoprecipitate complexes between receptor and TSH, an outcome which led them to conclude that Graves' immunoglobulins and TSH interact at the same site. Our findings clearly demonstrate that Graves' immunoglobulins lead to the precipitation of either unoccupied or occupied TSH receptors.…”

Section: Resultsmentioning

confidence: 99%

“…Purification and structural characterization of the TSH receptor has been attempted mainly by the use of TSH affinity chromatography, but there is a lack of consensus regarding the molecular size of the TSH binding species, with estimates ranging from 15,000 to 500,000 (23,(28)(29)(30). There are no full reports characterizing the molecular species recognized by Graves' immunoglobulins.…”

Section: Resultsmentioning

confidence: 99%

“…It is noteworthy that two of these bands are similar in size to those of molecular weight of 88,000 and 66,000 isolated by Koizumi et al (30) using TSH affinity chromatography. Kohn et al (31) have recently reported a 50-55,000 species as well as [18][19][20][21][22][23]000 species precipitated by a monoclonal antibody to the thyroid TSH receptor. Smaller molecular weight species may have been precipitated by the autoantibodies but would not have been resolved by our gel system.…”

Section: Resultsmentioning

confidence: 99%

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Precipitation of the thyrotropin receptor and identification of thyroid autoantigens using Graves' disease immunoglobulins.

Heyma¹,

Harrison²

1984

J. Clin. Invest.

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A bstract. The thyrotropin (TSH) receptor is a putative target for autoantibodies in Graves' hyperthyroidism and therefore, should be capable of being identified, isolated, and structurally characterized by immunological means. To this end, four sera from patients with hyperthyroidism, three of which inhibited the binding of '25I-TSH to Triton-solubilized human thyroid membranes, were used to isolate TSH receptors by immunoprecipitation. To account for an effect of TSH binding or receptor occupancy on the ability of Graves' immunoglobulins to precipitate TSH receptors, two approaches were taken: (a) specific '25I-TSH binding activity was measured after solubilized thyroid membranes had been incubated with Graves' sera followed by precipitation with Staphylococcus protein A ("receptor depletion"); (b) TSH binding sites were labeled with '251-TSH and the complexes were precipitated using Graves' sera and Staphylococcus protein A ("receptor precipitation").The three sera which inhibited 1251-TSH binding depleted '251-TSH binding activity between 30-80%. Preformed complexes between Staphylococcus protein A and immunoglobulins in these sera were also able to deplete '25I-TSH binding activity. However, after receptor depletion, the one serum that did not inhibit '25I-TSH binding was associated with a significant increase in 125I1

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Thyrotropin-Receptor Autoantibodies in Children and Young Adults With Graves' Disease

Brown¹

1986

Arch Pediatr Adolesc Med

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The interaction of graves' IgG with the thyrotrophin receptor

Cited by 32 publications

References 18 publications

Autoantibodies to the Thyrotropin Receptor

Autoantibodies to the Thyrotropin Receptor

Precipitation of the thyrotropin receptor and identification of thyroid autoantigens using Graves' disease immunoglobulins.

Thyrotropin-Receptor Autoantibodies in Children and Young Adults With Graves' Disease

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