Biological research for elucidation of molecular mechanisms responsible for thymoma-associated myasthenia gravis

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Although human thymoma is well-known for its frequent association with autoimmune diseases represented by myasthenia gravis, the pathogenesis of paraneoplastic autoimmune diseases associated with thymoma remains to be elucidated. The aim of this study is to reveal the molecular mechanisms resulting in the thymoma-associated paraneoplastic autoimmune diseases.Thymic epithelial cells derived from the human normal thymuses or the human thymoma thymomas were cultured in vitro, and the level of MHC molecules induced by Interferon-γ (IFN-γ) was examined by flow cytometric study. Although there was no difference in the expression level of MHC class I molecules on epithelial cells between the normal thymus and the thymomas, MHC class II expression was significantly lower in thymomas than in the normal thymuses. The expression level of MHC class II molecules was shown to be significantly correlated with the proportion of CD3ィイD1+ィエD1 cells in the CD4ィイD1+ィエD1CD8ィイD1-ィエD1 subset in thymoma, suggesting the relation between down-regulation of MHC class II molecules and the impairemnt of T cell development in thymomas.The molecular mechanism responsible for the impaired expression of IFN-γ dependent MHC class II expression in thymoma was investigated. Gel mobility shift assay was performed to examine the signal transduction from the IFN-γ receptor to the nucleus, and translocation of Stat-1 molecule from the cytoplasm to the nucleus was confirmed in thymomas as well as the normal thymus. Then, the induction of CIITA in response to IFN-γ was evaluated by the method of quantitative RT-PCR. The induction of CIITA was shown to be down-regulated in thymoma epithelial cells compared with that in the normal thymus.These results seem to indicate the possible role of impaired CIITA expression in the abnormal T cell development in thymomas, which results in the onset of paraneoplastic autoimmune diseases.