Neutral Antibodies to the TSH Receptor Are Present in Graves’ Disease and Regulate Selective Signaling Cascades

摘要

TSHR Abs by competition assay with N-mAbs. On examining signaling cascades, we found that N-mAbs induced signal transduction, primarily via the protein kinase A Il cascade. In addition to the activation of phosphatidyl- inositol 3/Akt, N-mAbs, unlike TSH, had the ability to exclusively activate the mammalian target of rapamycin/S6K, nuclear factor- ?B, and MAPK-ERK1/2/p38a signaling cascades and their down- stream effectors ribosomal kinase/Mnk1/mitogen/stress-acti- vated kinase-1 and N-mAbs activated all forms of protein kinase C isozymes. To define the downstream effector mechanisms pro- duced by these signaling cascades, cytokine production, prolif- eration, and apoptosis in thyrocytes were investigated. Although N-mAbs produced less cytokines and proliferation compared with TSH, they had the distinction of inducing thyroid cell apoptosis under the experimental conditions used. When dissecting out possible mechanisms of apoptosis, we found that activation of multiple oxidative stress markers was the primary mechanism or- chestrating the death signals. Therefore, using oxidative stress- induced apoptosis, N-mAbs may be capable of exacerbating the autoimmune response in GD via apoptotic cells inducing antigen- driven mechanisms. This may help explain the inflammatory na- ture of this common disorder.