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Thyrocyte targets and effectors of autoimmunity: a role for death receptors?
L J Hammond1, F F Palazzo, M Shattock
1Department of Immunology, St Bartholomew's and Royal London Medical School of Medicine and Dentistry, United Kingdom.
Abstract:
In Hashimoto's thyroiditis, thyrocytes die by apoptosis. Whether this is the result of impaired antiapoptotic gene expression or hyperexpression of proapoptotic 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 cells from different clinical conditions are able to kill Fas-expressing target cells. We have studied whether this effector ability was mediated by Fas/Fas ligand, perforin or other death receptors/ligands, i.e., tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R). We have confirmed that thyroid preparations can kill Fas-expressing HUT78 targets through apoptosis. Cell death was only partially dependent on Fas/Fas ligand but it was trypsin-sensitive. Blocking perforin did not affect Fas-expressing target killing while caspase inhibitors had a consistent although limited effect. Thyroid cells were not sensitive to TRAIL/TRAIL-R. We have also found that both thyrocytes and lymphocytes from Graves' disease thyroids were effective at killing autologous and heterologous Fas-expressing targets. Conversely, killing 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 autologous thyrocyte killing perpetrated by lymphocytes. Death receptors/ligands would appear to play a role. However, a caspase-independent mechanism may also coexist and contribute to cell death in Hashimoto's thyroiditis.
Insights
Thyroid lymphocytes, not thyrocytes, kill target cells in Hashimoto's thyroiditis. This fratricidal killing involves death receptors/ligands and may include caspase-independent pathways, explaining thyrocyte death in this autoimmune condition.
Area of Science:
- Immunology
- Endocrinology
- Cell Biology
Background:
- Thyrocyte apoptosis is a hallmark of Hashimoto's thyroiditis, but the underlying mechanisms remain unclear.
- Previous studies suggest Fas/Fas ligand-mediated fratricidal killing contributes to thyrocyte death.
Purpose of the Study:
- To investigate the mechanisms by which thyroid cells from various conditions kill Fas-expressing target cells.
- To determine if Fas/Fas ligand, perforin, or other death receptors/ligands mediate this cytotoxic activity.
Main Methods:
- Assessment of thyroid cell-mediated cytotoxicity against Fas-expressing HUT78 target cells.
- Evaluation of the roles of Fas/Fas ligand, perforin, and caspase inhibitors in target cell apoptosis.
- Comparison of effector functions between thyrocytes and lymphocytes from Graves' disease and Hashimoto's thyroiditis patients.
Main Results:
- Thyroid preparations effectively killed Fas-expressing targets via apoptosis, partially dependent on Fas/Fas ligand and sensitive to trypsin.
- Perforin blockade did not inhibit killing, while caspase inhibitors showed a limited effect.
- Thyrocytes and lymphocytes from Graves' disease were cytotoxic, whereas only lymphocytes from Hashimoto's thyroiditis exhibited significant killing activity.
Conclusions:
- In Hashimoto's thyroiditis, thyrocytes are functionally impaired, with lymphocytes acting as the primary effectors mediating thyrocyte death.
- Death receptors/ligands likely play a role, alongside potential caspase-independent mechanisms, in thyrocyte apoptosis.
- Lymphocyte-mediated fratricidal killing is proposed as a key mechanism for thyrocyte death in Hashimoto's thyroiditis.