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Graves' immunoglobulins activate phospholipase A2 by recognizing specific epitopes on thyrotropin receptor
A Di Cerbo1, R Di Paola, C Menzaghi
1Division and Research Unit of Endocrinology, Istituto di Ricovero e Cura a Carattere Scientifico Casa Sollievo della Sofferenza General Hospital, San Giovanni Rotondo (Foggia), Italy. adicerb@tin.it
The Journal of Clinical Endocrinology and Metabolism
|September 16, 1999
Summary
Graves' disease patients have diverse thyroid-stimulating antibodies that activate adenylyl cyclase (AC) and phospholipase A2 (PLA2) pathways. The N-terminal region of the TSH receptor is crucial for both AC and PLA2 activation by these autoantibodies.
Area of Science:
- Endocrinology
- Immunology
- Molecular Biology
Background:
- Thyroid-stimulating immunoglobulins (IgG) in Graves' disease activate thyroid cells via TSH receptor (TSHR) signaling.
- Both adenylyl cyclase (AC) and phospholipase A2 (PLA2) pathways are implicated in thyroid growth and function.
- Evidence suggests distinct IgG subpopulations activate AC or PLA2, with dual activation linked to larger goiters.
Purpose of the Study:
- To investigate the role of the N-terminal extracellular domain of the human TSHR (hTSHR) in mediating PLA2 activation by Graves' IgG.
- To characterize the heterogeneity of Graves' IgG in activating AC and PLA2 pathways.
- To correlate autoantibody activity with disease severity in Graves' disease.
Main Methods:
- Used stably transfected Chinese hamster ovary (CHO) cells expressing wild-type hTSHR and a chimera (Mc1+2) with substituted N-terminal residues.
- Measured PLA2 activity via arachidonic acid (AA) release in response to Graves' IgG.
- Compared AC and PLA2 activation by IgG in wild-type and chimera-transfected cells.
Main Results:
- 72% of Graves' patients had IgG that stimulated PLA2 activity in wild-type hTSHR-expressing cells.
- PLA2 stimulation by Graves' IgG was significantly reduced in cells expressing the hTSHR chimera (Mc1+2).
- 63% of patients had IgG stimulating both AC and PLA2; some IgG showed selective AC or PLA2 activation.
- Autoantibodies active in both pathways were associated with higher thyroid hormone levels and larger goiters.
Conclusions:
- The N-terminal extracellular domain of the hTSHR is essential for both PLA2 and AC activation by Graves' IgG.
- Graves' disease involves heterogeneous autoantibodies with selective or dual pathway activation.
- Dual AC and PLA2 activating autoantibodies may indicate more severe Graves' disease.