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Stimulatory TSH-Receptor Antibodies and Oxidative Stress in Graves Disease
Tanja Diana1, Andreas Daiber2, Matthias Oelze2
1Molecular Thyroid Research Laboratory, Department of Medicine I, Johannes Gutenberg University Medical Center, Mainz Germany.
Context:
We hypothesized that TSH-receptor (TSHR) stimulating antibodies (TSAbs) are involved in oxidative stress mechanisms in patients with Graves disease (GD).
Methods:
Nicotinamide adenine dinucleotide phosphate oxidase, isoform 2 (NOX2); oxidative parameters; and oxidative burst were measured in serum, urine, and whole blood from patients with GD and control subjects. Superoxide production was investigated in human embryonic kidney (HEK)-293 cells stably overexpressing the TSHR. Lipid peroxidation was determined by immunodot-blot analysis for protein-bound 4-hydroxy-2-nonenal (4-HNE) in human primary thyrocytes and HEK-293-TSHR cells.
Results:
Serum NOX2 levels were markedly higher in hyperthyroid untreated vs euthyroid treated patients with GD, hyperthyroid patients with toxic nodular goiter, and euthyroid healthy control subjects (all P < 0.0001). Urine oxidative parameters were increased in patients with GD vs patients with toxic goiter (P < 0.01) and/or control subjects (P < 0.001). The maximum of the zymosan A- and phorbol 12,13-dibutyrate-induced respiratory burst of leukocytes was 1.5-fold higher in whole blood from hyperthyroid patients with GD compared with control subjects (P < 0.001 and P < 0.05). Monoclonal M22 TSAbs stimulated cAMP (HEK cells) in a dose-dependent manner. M22 (P = 0.0082), bovine TSH (P = 0.0028), and sera of hyperthyroid patients with GD (P < 0.05) increased superoxide-specific 2-hydroxyethidium levels in HEK-293 TSHR cells after 48-hour incubation vs control subjects. In contrast, triiodothyronine (T3) did not affect reactive oxygen species (ROS) production. In primary thyrocytes, the 4-HNE marker was higher in patients with GD vs control subjects at 6 and 48 hours (P = 0.02 and P = 0.04, respectively). Further, after 48-hour incubation of HEK-293 TSHR cells with patient sera, 4-HNE was higher in patients with untreated GD compared with control subjects (P < 0.05).
Conclusions:
Monoclonal M22 and polyclonal serum TSAbs augment ROS generation and/or induce lipid peroxidation.
Insights
TSH-receptor stimulating antibodies (TSAbs) in Graves disease patients contribute to oxidative stress by increasing reactive oxygen species (ROS) and lipid peroxidation. This study reveals a direct link between TSAbs and oxidative damage in Graves disease.
Area of Science:
- Endocrinology
- Immunology
- Oxidative Stress Research
Background:
- Graves disease (GD) is an autoimmune disorder characterized by hyperthyroidism.
- TSH-receptor stimulating antibodies (TSAbs) are key drivers of GD pathogenesis.
- The role of oxidative stress in GD remains incompletely understood.
Purpose of the Study:
- To investigate the involvement of TSH-receptor stimulating antibodies (TSAbs) in oxidative stress mechanisms in patients with Graves disease (GD).
- To assess oxidative parameters and superoxide production in relation to TSAbs and TSHR activity.
Main Methods:
- Measured nicotinamide adenine dinucleotide phosphate oxidase (NOX2), oxidative parameters, and oxidative burst in serum, urine, and whole blood from GD patients and controls.
- Investigated superoxide production in HEK-293 cells overexpressing TSHR.
- Determined lipid peroxidation marker 4-HNE in thyrocytes and HEK-293-TSHR cells.
Main Results:
- Elevated serum NOX2 levels and increased urine oxidative parameters were observed in GD patients.
- Leukocyte respiratory burst activity was significantly higher in hyperthyroid GD patients.
- TSAbs and GD patient sera increased superoxide production and lipid peroxidation in TSHR-expressing cells.
Conclusions:
- Monoclonal M22 TSAbs and polyclonal serum TSAbs augment reactive oxygen species (ROS) generation.
- TSAbs are implicated in inducing lipid peroxidation in the context of Graves disease.
- These findings highlight the contribution of TSAbs to oxidative stress in GD.
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