ArticleThe Journal of clinical endocrinology and metabolism2009
Evidence that shed thyrotropin receptor A subunits drive affinity maturation of autoantibodies causing Graves' disease.
Article in The Journal of clinical endocrinology and metabolism, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 48 citations in OpenAlex.
- Significance of pathological changes and chemokine expression in various organs in a Graves' disease animal model.Journal of molecular histology · 2025Article
- Exploring antigenic variation in autoimmune endocrinopathy.Frontiers in immunology · 2025Review
- Recent Advances in Folates and Autoantibodies against Folate Receptors in Early Pregnancy and Miscarriage.Nutrients · 2023Review
- Cepharanthine blocks TSH receptor peptide presentation by HLA-DR3: Therapeutic implications to Graves' disease.Journal of autoimmunity · 2020Article
- Review
- Structural-Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work.Frontiers in endocrinology · 2017Review
- TSH Receptor Cleavage Into Subunits and Shedding of the A-Subunit; A Molecular and Clinical Perspective.Endocrine reviews · 2016Review
- Withdrawn: TSH Receptor Cleavage Into Subunits and Shedding of the A-Subunit; A Molecular and Clinical Perspective.Endocrine reviews · 2016Review
- Thyrotropin Receptor Epitope and Human Leukocyte Antigen in Graves' Disease.Frontiers in endocrinology · 2016Review
- Bioassays for TSH Receptor Autoantibodies, from FRTL-5 Cells to TSH Receptor-LH/CG Receptor Chimeras: The Contribution of Leonard D. Kohn.Frontiers in endocrinology · 2016Review
- Deleting the Redundant TSH Receptor C-Peptide Region Permits Generation of the Conformationally Intact Extracellular Domain by Insect Cells.Endocrinology · 2015Article
- Evidence that TSH Receptor A-Subunit Multimers, Not Monomers, Drive Antibody Affinity Maturation in Graves' Disease.The Journal of clinical endocrinology and metabolism · 2015Article
- A unique mouse strain that develops spontaneous, iodine-accelerated, pathogenic antibodies to the human thyrotrophin receptor.Journal of immunology (Baltimore, Md. : 1950) · 2015Article
- Crystal structure of a TSH receptor monoclonal antibody: insight into Graves' disease pathogenesis.Molecular endocrinology (Baltimore, Md.) · 2015Article
- Novel insights on thyroid-stimulating hormone receptor signal transduction.Endocrine reviews · 2013Review
- Negative correlation between bone mineral density and TSH receptor antibodies in long-term euthyroid postmenopausal women with treated Graves' disease.Thyroid research · 2013Article
- Probing structural variability at the N terminus of the TSH receptor with a murine monoclonal antibody that distinguishes between two receptor conformational forms.Endocrinology · 2013Article
- Thyrotropin-blocking autoantibodies and thyroid-stimulating autoantibodies: potential mechanisms involved in the pendulum swinging from hypothyroidism to hyperthyroidism or vice versa.Thyroid : official journal of the American Thyroid Association · 2013Review
- The thyrotropin receptor hinge region as a surrogate ligand: identification of loci contributing to the coupling of thyrotropin binding and receptor activation.Endocrinology · 2012Article
- Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
contextIn Graves' disease, thyroid-stimulating antibodies (TSAb) activate the TSH receptor (TSHR) causing hyperthyroidism. Serum polyclonal TSAb are difficult to study because of their extremely low serum levels.
objectiveOur objective was to determine whether monoclonal TSAb possess characteristics previously reported for polyclonal autoantibodies in Graves' sera.
designWe studied monoclonal TSAb from three laboratories: six generated from mice with induced hyperthyroidism; and one, M22, a human autoantibody obtained from Graves' B cells.
resultsAll TSAb with one exception were potent activators of TSHR-mediated cAMP generation, with relatively similar half-maximal stimulatory concentrations. Like polyclonal autoantibodies, monoclonal TSAb were largely neutralized by conformationally "active" (but not "inactive") recombinant TSHR A subunits (the N-terminal cleavage product of the TSHR). Chimeric substitutions of TSHR amino acids 25-30 (the extreme N terminus after removal of the 21 residue signal peptide) abrogated the binding and function of all monoclonal TSAb but with one antibody (TSAb4) revealing a nonidentical epitope. Remarkably, these residues are uninvolved in the M22 epitope determined by x-ray analysis. Finally, flow-cytometric dose-response analyses, not previously possible with polyclonal TSAb, revealed that all monoclonal TSAb, human and murine, bound with lower affinity to their in vivo target, the TSH-holoreceptor, than to the isolated TSHR ectodomain.
conclusionsTSAb function does not require antibodies with identical epitopes, and human autoantibody M22 may, therefore, not represent the full epitopic repertoire of polyclonal TSAb in Graves' disease. Most important, we provide strong evidence that the shed ectodomain (primarily the A subunit) is the primary antigen driving affinity maturation of TSAb producing B cells.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.