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Abnormalities of immune regulation in autoimmune hepatitis and their modulation by TGF-β

自身免疫性肝炎的免疫调节异常及其TGF-β的调节

基本信息

批准号：
09670552
负责人：
SAKAGUCHI Kohsaku
金额：
$ 1.79万
依托单位：
OKAYAMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

Autoimmune hepatitis (AIH) is a chronic active hepatitis, in which abnormalities of immune regulation have been suspected to play a role in the induction of autoimmunity. Recently, the peripheral immune system have been appeared to possess mechanisms to control an autoimmune aberration by the elimination, by apoptosis, of autoreactive or unnecessary lymphocytes activate by antigenic stimuli. The transmembrane protein CD95 (Fas/APO-1) plays a role in the apoptotic death of antigen-activated lymphocytes. In this study, we examined the levels and distributional expressions of CD95 and Bcl-2 on freshly isolated lymphocytes from patients with AIH by flow cytometric analysis. The surface expression of CD95 was significantly high in both the CD4ィイD1+ィエD1 T and CD8ィイD1+ィエD1 T cell subsets derived from the patients with AIH, compared with expression in patients with chronic hepatitis C and normal subjects. The increase in CD95 expression was associated with the phenotypic conversion of native CD45ROィイD1-ィエD1 to primed CD45ROィイD1+ィエD1 T cells. These results indicate that the expanded CD95ィイD1+ィエD1 CD45ROィイD1+ィエD1 primed T cell most likely reflect a continuous activation of T lymphocytes, and/or the persistent presence of activated lymphocytes as a consequence of abnormalities in the peripheral deletion of activated lymphocytes. On the other hands, transforming growth factor-β (TGF-β) has been shown to exert several immunosuppressive effects. We investigated the level of serum TGF-β and the expression of TGF-β receptor II (TβRII) on peripheral blood monocular cells, in order to evaluate the role of TGF-β in the abnormalities of immune regulation. The level of serum TGF-β was significantly greater in the patients with AIH, while the expression of TβRII on PBMC was decreased. The decreased TβRII expression on PBMC suggests that a reduction in TβRII expression on PBMC results in attenuation of immunosuppression signals from TGF-β.

自身免疫性肝炎（Autoimmune hepatitis，AIH）是一种慢性活动性肝炎，其免疫调节异常被怀疑在诱导自身免疫中起作用。最近，外周免疫系统似乎具有通过细胞凋亡消除抗原刺激激活的自身反应性或不必要的淋巴细胞来控制自身免疫畸变的机制。跨膜蛋白CD 95（Fas/APO-1）在抗原激活的淋巴细胞的凋亡中起作用。本研究应用流式细胞术检测了AIH患者外周血淋巴细胞表面CD 95和Bcl-2的表达水平和分布。CD 95在AIH患者CD 4 + CD 4 + CD 1 + T细胞亚群和CD 8 + CD 4 + CD 1 + T细胞亚群中的表达均显著高于慢性丙型肝炎患者和正常人。CD 95表达的增加与天然CD 45 RO CD 45 D1-CD 45 D1向致敏的CD 45 RO CD 45 D1+ CD 45 D1 T细胞的表型转化有关。这些结果表明，扩增的CD 95 γ D1+ γ D1 CD 45 RO γ D1+ γ D1致敏的T细胞最可能反映T淋巴细胞的持续活化，和/或由于活化淋巴细胞的外周缺失异常而持续存在活化淋巴细胞。另一方面，已显示转化生长因子-β（TGF-β）发挥若干免疫抑制作用。本研究通过检测血清TGF-β水平及外周血单核细胞TGF-β受体Ⅱ（TβRII）的表达，探讨TGF-β在免疫调节异常中的作用。AIH患者血清TGF-β水平显著升高，PBMC TβRII表达降低。PBMC上TβRII表达的降低表明PBMC上TβRII表达的降低导致TGF-β的免疫抑制信号减弱。