Thyrocyte targets and effectors of autoimmunity: A role for death receptors?

In Hashimoto's thyroiditis, thyrocytes die by apoptosis. Whether this is th e result of impaired antiapoptotic gene expression or hyperexpression of pr oapoptotic signals or other mechanisms is not fully established. Following the suggestion that thyrocytes from Hashimoto's glands die by a fratricidal killing mediated by Fas/Fas ligand, we have investigated whether thyroid c ells from different clinical conditions are able to kill Fas-expressing tar get cells. We have studied whether this effector ability was mediated by Fa s/Fas ligand, perforin or other death receptors/ligands, i.e., tumor necros is factor-related apoptosis-inducing ligand (TRAIL)/tumor necrosis factor-r elated apoptosis-inducing ligand receptor (TRAIL-R). We have confirmed that thyroid preparations can kill Fas-expressing HUT78 targets through apoptos is. Cell death was only partially dependent on Fas/Fas ligand but it was tr ypsin-sensitive. Blocking perforin did not affect Fas-expressing target kil ling while caspase inhibitors had a consistent although limited effect. Thy roid cells were not sensitive to TRAIL/TRAIL-R. We have also found that bot h thyrocytes and lymphocytes from Graves' disease thyroids were effective a t killing autologous and heterologous Fas-expressing targets. Conversely, k illing of these targets could be shown only with lymphocytes (but not with thyrocytes) from Hashimoto's glands. In Hashimoto's thyroiditis, thyrocytes were poorly functional while lymphocytes were able to operate as effectors . It is envisaged that thyrocyte death in Hashimoto's would result from aut ologous thyrocyte killing perpetrated by lymphocytes. Death receptors/ligan ds would appear to play a role. However, a caspase-independent mechanism ma y also coexist and contribute to cell death in Hashimoto's thyroiditis.