A Modifying Autoantigen in Graves' Disease.
Amino Acid Sequence
Animals
Autoantibodies
/ immunology
Autoantigens
/ metabolism
Base Sequence
CHO Cells
Cricetinae
Cricetulus
Graves Disease
/ genetics
HEK293 Cells
Humans
Immunoglobulins, Thyroid-Stimulating
/ immunology
Molecular Dynamics Simulation
Protein Binding
Protein Isoforms
/ chemistry
Receptors, Thyrotropin
/ genetics
Thyrotropin
/ chemistry
Journal
Endocrinology
ISSN: 1945-7170
Titre abrégé: Endocrinology
Pays: United States
ID NLM: 0375040
Informations de publication
Date de publication:
01 05 2019
01 05 2019
Historique:
received:
10
12
2018
accepted:
26
02
2019
pubmed:
2
3
2019
medline:
18
12
2019
entrez:
2
3
2019
Statut:
ppublish
Résumé
The TSH receptor (TSHR) is the major autoantigen in Graves' disease (GD). Bioinformatic analyses predict the existence of several human TSHR isoforms from alternative splicing, which can lead to the coexpression of multiple receptor forms. The most abundant of these is TSHRv1.3. In silico modeling of TSHRv1.3 demonstrated the structural integrity of this truncated receptor isoform and its potential binding of TSH. Tissue profiling revealed wide expression of TSHRv1.3, with a predominant presence in thyroid, bone marrow, thymus, and adipose tissue. To gain insight into the role of this v1.3 receptor isoform in thyroid pathophysiology, we cloned the entire open reading frame into a mammalian expression vector. Immunoprecipitation studies demonstrated that both TSHR-stimulating antibody and human TSH could bind v1.3. Furthermore, TSHRv1.3 inhibited the stimulatory effect of TSH and TSHR-Ab MS-1 antibody on TSHR-induced cAMP generation in a dose-dependent manner. To confirm the antigenicity of v1.3, we used a peptide ELISA against two different epitopes. Of 13 GD samples, 11 (84.6%) were positive for a carboxy terminal peptide and 10 (76.9%) were positive with a junction region peptide. To demonstrate that intracellular v1.3 could serve as an autoantigen and modulate disease, we used double-transfected Chinese hamster ovary cells that expressed both green fluorescent protein (GFP)-tagged TSHRv1.3 and full-length TSHR. We then induced cell stress and apoptosis using a TSHR monoclonal antibody and observed the culture supernatant contained v1.3-GFP protein, demonstrating the release of the intracellular receptor variant by this mechanism.
Identifiants
pubmed: 30822352
pii: 5366832
doi: 10.1210/en.2018-01048
pmc: PMC6455603
doi:
Substances chimiques
Autoantibodies
0
Autoantigens
0
Immunoglobulins, Thyroid-Stimulating
0
Protein Isoforms
0
Receptors, Thyrotropin
0
thyrotropin-binding inhibitory immunoglobulin
0
Thyrotropin
9002-71-5
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1008-1020Subventions
Organisme : BLRD VA
ID : I01 BX000800
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK069713
Pays : United States
Informations de copyright
Copyright © 2019 Endocrine Society.
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