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（FasL）在甲状腺细胞中表达，在使正常甲状腺组织成为“免疫排斥部位”中起重要作用。“由于IL-1β在Graves'甲状腺组织中强烈表达，我们试图确定IL-1β在Graves'病过程中可能参与甲状腺细胞和T细胞之间的Fas/FasL相互作用。免疫组织化学分析显示，Graves'甲状腺中FasL阳性甲状腺细胞的百分比低于正常甲状腺。相比之下，格雷夫斯病中的许多甲状腺细胞表达Fas分子。IL-1β体外处理甲状腺细胞可增加Fas表达，但明显降低FasL表达。在IL-1β刺激的甲状腺细胞中，体外活化的T细胞强表达FasL，诱导Fas介导的细胞凋亡，Graves甲状腺组织中可见大量的CD 4 ^+ T细胞浸润。Western blotting分析显示，甲状腺浸润的CD 4 ^+ T细胞的FasL表达明显强于外周血（PB）CD 4 ^+ T细胞。虽然PB CD 4 ^+ T细胞对IL-1β刺激的甲状腺细胞的杀伤活性很弱，但Graves病甲状腺浸润的CD 4 ^+ T细胞明显诱导Fas介导的IL-1β刺激的甲状腺细胞凋亡。在甲状腺浸润的CD 4 ^+ T细胞中Fas表达也明显增加，但这些细胞对Fas介导的凋亡具有抵抗性，这可能与Bcl-x2表达增加有关。既往研究表明，IL-1β可增加粘附分子的表达，刺激活化的T细胞从外周血向甲状腺组织迁移。另外，IL-1β可增强Fas介导的CD 4 ^+ T细胞诱导的甲状腺细胞凋亡的敏感性，这可能是由于IL-1β破坏了Graves病甲状腺组织中“免疫排斥位点”的形成。

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.