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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.
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Article Autoimmunity

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

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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

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Figure 2

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Serum T4 in mice immunized with adenovirus expressing different structur...
Serum T4 in mice immunized with adenovirus expressing different structural forms of the TSHR. BALB/c mice were immunized with adenovirus expressing the shed A subunit (TSHR-289) and the noncleaving receptor (TSHR-D1NET). As controls, mice were also injected with adenovirus expressing the WT TSHR (TSHR-WT) or β-gal (Con). Data shown are the individual values for mice in each group (number shown in parentheses). The shaded area indicates the mean ± 2 SD of values for 15 control adenovirus-immunized mice. Serum T4 levels were measured in mice after two adenovirus injections (a and b) and at euthanasia after the third adenovirus injections (c and d). Immunization with TSHR-289 adenovirus increased serum T4 levels in more mice than immunization with TSHR-D1NET adenovirus. *P = 0.005; **P = 0.002; ***P < 0.001 (Fisher exact test).
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