Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
The thyrotropin receptor autoantigen in Graves disease is the culprit as well as the victim
Chun-Rong Chen, … , Basil Rapoport, Sandra M. McLachlan
Chun-Rong Chen, … , Basil Rapoport, Sandra M. McLachlan
Published June 15, 2003
Citation Information: J Clin Invest. 2003;111(12):1897-1904. https://doi.org/10.1172/JCI17069.
View: Text | PDF
Article Autoimmunity

The thyrotropin receptor autoantigen in Graves disease is the culprit as well as the victim

  • Text
  • PDF
Abstract

Graves disease, a common organ-specific autoimmune disease affecting humans, differs from all other autoimmune diseases in being associated with target organ hyperfunction rather than organ damage. Clinical thyrotoxicosis is directly caused by autoantibodies that activate the thyrotropin receptor (TSHR). The etiology of Graves disease is multifactorial, with nongenetic factors playing an important role. Of the latter, there is the intriguing possibility that the molecular structure of the target antigen contributes to the development of thyroid-stimulatory autoantibodies (TSAb’s). Among the glycoprotein hormone receptors, only the TSHR undergoes intramolecular cleavage into disulfide-linked subunits with consequent shedding of some of the extracellular, autoantibody-binding A subunits. Functional autoantibodies do not arise to the noncleaving glycoprotein hormone receptors. Recently, TSAb’s were found to preferentially recognize shed, rather than attached, A subunits. Here we use a new adenovirus-mediated animal model of Graves disease to show that goiter and hyperthyroidism occur to a much greater extent when the adenovirus expresses the free A subunit as opposed to a genetically modified TSHR that cleaves minimally into subunits. These data show that shed A subunits induce or amplify the immune response leading to hyperthyroidism and provide new insight into the etiology of Graves disease.

Authors

Chun-Rong Chen, Pavel Pichurin, Yuji Nagayama, Francesco Latrofa, Basil Rapoport, Sandra M. McLachlan

×

Figure 3

Options: View larger image (or click on image) Download as PowerPoint
Goiter and histology in TSHR-adenovirus–injected mice. (a) Thyroid lobe ...
Goiter and histology in TSHR-adenovirus–injected mice. (a) Thyroid lobe areas measured by planimetry in mice immunized with adenoviruses expressing TSHR-289, TSHR-D1NET, TSHR-WT, and control adenovirus (Con). The gray area indicates the mean ± 2 SD of values for control mice. The number of animals with goiters was significantly higher in mice injected with adenovirus TSHR-289 versus control (Con) adenovirus (**P = 0.002) and in adenovirus TSHR-289 versus adenovirus TSHR-D1NET–injected mice (*P = 0.005) (Fisher exact test). (b) Thyroid histology in representative mice from the control adenovirus (euthyroid animal) and TSHR-289-Ad (hyperthyroid animal) groups. Entire thyroids cannot be shown because the ×40 magnification was the lowest possible with this microscope. Thyroid epithelial morphology is evident at higher magnification (×200). Thyrocytes in the adenovirus-TSHR-289–immunized animal are more columnar and vacuolated, consistent with hyperthyroidism.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts