Role of Fas mediated apoptosis in the process of autoimmune thyroid diseases : possible involvement of Fas ligand (FasL) expression in breakdown of "immunoprevileged site" formation

Fas配体(Fas Ligand，FasL)在甲状腺细胞中表达，在使正常甲状腺组织成为“免疫缺陷部位”方面起着重要作用。由于IL-1β在Graves病的甲状腺组织中有较强的表达，我们试图从甲状腺细胞与T细胞之间的Fas/Fas L相互作用的角度来探讨IL-1β在Graves病发病过程中的可能作用。与之相反，Graves病的许多甲状腺细胞表达Fas分子。体外培养的甲状腺细胞经IL-1β处理后，Fas的表达增加，而FasL的表达明显降低。体外激活的T细胞强烈表达Fas L，可诱导IL-1β刺激的甲状腺细胞发生Fas介导的细胞凋亡。免疫印迹分析显示，浸润性T细胞的FasL表达明显强于外周血(PB)。虽然外周血中CD4+T细胞对IL-1β刺激的甲状腺细胞的杀伤活性很弱，但Graves病患者甲状腺组织中的CD4+T细胞对IL-1β刺激的甲状腺细胞有明显的诱导Fas介导的细胞凋亡作用。浸润性T细胞中Fas的表达也显著增加，但细胞对Fas介导的细胞凋亡具有抵抗作用，这可能是由于Bclx2的表达增加所致。以往的研究表明，IL-1β增加了黏附分子的表达，刺激活化的T细胞从外周血向甲状腺组织迁移。此外，我们的研究结果表明，IL-1β增加了CD4~+T细胞诱导的Fas介导的甲状腺细胞凋亡的敏感性，这可能与Graves病甲状腺组织中“免疫缺陷部位”形成的破坏有关。

Fas ligand (FasL) is expressed in thyrocytes, and appear to plays an important role to make normal thyroid tissue to be "immunoprevileged site." Since IL-1β is strongly expressed in Graves' thyroid tissue, we tried to determine the possible involvement of IL-1β in the process of Graves' disease regarding Fas/FasL interaction between thyrocytes and T cells.Immunohistochemical analysis has shown that the percentage of FasL-positive thyrocytes in Graves' thyroids was less than in normal thyroids. In contrast, many thyrocytes in Graves' disease expressed Fas molecule. Treatment of thyrocytes with IL-1β in vitro increased Fas expression but markedly reduced FasL expression. Activated T cells in vitro, which strongly expressed FasL, induced Fas-mediated apoptosis in IL-1β stimulated thyrocytes.Massive CD4^+ T cell infiltration has been demonstrated in Graves' thyroid tissue. Western blotting analysis revealed that FasL expression of thyroid infiltrating CD4^+ T cells was significantly intense than that of peripheral blood (PB) CD4^+ T cells. Although the cytotoxic activity of PB CD4^+ T cells toward IL-1β stimulated thyrocytes was very week, thyroid infiltrating CD4^+ T cells of Graves' disease apparently induced Fas mediated apoptosis toward IL-1β stimulated thyrocytes. Fas expression was also markedly increased in thyroid-infiltrating CD4^+ T cells, however, the cells were resistant to Fas-mediated apoptosis, probably due to the increased expression of Bcl-x2.Previous studies have shown that IL-1β increases the expression of adhesion molecules and stimulates the migration of activated T cells from peripheral blood into thyroid tissues. In addition, our present results indicate that IL-1β increases the sensitivity of Fas mediated apoptosis of thyrocytes induced by CD4^+ T cells, which may attribute to the breakdown of "immunoprevileged site" formation in thyroid tissues of Graves' disease.