It is known that thyrocyte apoptosis is significantly more pronounced in Hashimoto's thyroiditis (HT) than in Graves' Disease (GD)1. In their recent contribution to Nature Immunology2, Stassi and coworkers confirmed higher thyrocyte apoptosis in HT than in GD thyroids. However, they also found that Fas and Fas ligand (FasL) expression were only moderately reduced in seven GD-affected versus five HT-affected thyroids, suggesting that other mechanisms may affect apoptosis. They propose that differences in the production of cytokines by infiltrating lymphocytes can explain the differences in thyroid follicular cell (TFC) apoptosis that are observed in HT and GD.

In contrast to the findings of Stassi et al.2, we found that Fas expression was invariably higher in HT and lower in GD thyrocytes.3 Immunohistochemical analysis showed limited areas of Fas+ TFCs in GD, which were most often observed near to mononuclear infiltrates, the majority of follicles being Fas−. TFC apoptosis was accordingly minimal. These findings suggest that the homophilic interaction between Fas and its ligand, expressed by thyrocytes, is far more likely to occur in HT than in GD glands.

After TFC depletion, we found significant differences in the expression of Fas by infiltrating lymphocytes in HT and GD glands. Fas expression in intrathyroidal lymphocytes was higher in GD, as shown by quantitative mRNA, immunoblotting and cytofluorimetric analyses. We also observed marked differences in the proportion of apoptotic lymphocytes, which were far higher in GD than in HT. Comparative immunohistochemical analysis of GD and HT specimens by double-staining with CD3 mAbs and TUNEL, or cytokeratin mAb and TUNEL, showed that apoptosis was mainly present in infiltrating lymphocytes in GD and in TFCs in HT.

Stassi et al.2 show that infiltrating lymphocytes are more prone to apoptosis in GD than in HT. We propose that FasL expression by GD thyrocytes may promote lymphocyte apoptosis. This hypothesis is consistent with the previously proposed concept4 that TH1 cells are expected to be more sensitive to Fas-mediated apoptosis than TH2 cells. Thus, in GD thyrocytes may preferentially stimulate apoptosis in TH1 lymphocytes, whereas the surviving TH2 cells may promote TFC resistance to apoptosis via the up-regulation of cFLIP and Bcl-xL. In contrast, we did not observe significant apoptosis in lymphocytes infiltrating HT glands, which suggests that the HT microenvironment does not promote lymphocyte apoptosis. We also found that the expression of the anti-apoptotic molecule Bcl-2 is increased in HT lymphocytes and reduced in thyrocytes.

In conclusion, it is conceivable that T cell–derived cytokines play a crucial role in regulating TFC apoptosis in GD and HT, as shown by the elegant experiments by Stassi and coworkers. However, our findings suggest that thyrocytes are likely to play a crucial role in regulating intrathyroidal T cell survival and selection, which supports the concept that the interaction between tissue-specific epithelial cells and infiltrating lymphocytes plays a major role in autoimmune disease.

See Response to 'Thyrocytes — not innocent bystanders in autoimmune disease' by Giorgio Stassi and the Control of target cell survival in thyroid autoimmunity by T helper cytokines via regulation of apoptotic proteins. by Giorgio Stassi.