ABNORMAL THYMOCYTE DEVELOPMENT AND GENERATION OF AUTOREACTIVE T-CELLSIN MIXED AND CORTICAL THYMOMAS

To gain insight into the pathogenesis of thymoma-associated myasthenia gravis, thymocyte maturation was investigated in mixed and cortical t hymomas by three-color flow cytometry. Although we detected cells at a ll recognizable stages, we noted an unusual increased percentage of ea rly CD4(+)/CD3(-) thymocytes-especially in mixed thymoma-and a pronoun ced decreased percentage of mature CD4(+)/CD3(+) cells in cortical thy momas as well. The percentage of CD3(+)/CD69(+) cells that arose after positive selection was reduced in both thymoma subtypes compared with control thymuses, which suggests differences in the rate or efficienc y of positive selection particularly in mixed thymomas. Mature T cells in 10 of 11 thymomas were not activated in situ as shown by the absen ce of CD25 expression. After stimulation with recombinant human acetyl choline receptor alpha-subunit fragments, thymocytes from 8 of 11 thym omas of both subtypes proliferated more strongly than those from contr ols, regardless of whether the donors were myasthenic. Responses of re sidual thymus cells to tetanus toroid correlated well with those of au tologous blood T cells, whereas those from the thymomas clearly did no t-implying minimal colonization of thymomas by mature recirculating T cells. In conclusion, our results show that cortical and mixed thymoma s exhibited differences in thymocyte maturation. Nevertheless, both th ymoma subtypes seem to contribute to the pathogenesis of paraneoplasti c myasthenia gravis by generating naive but potentially autoaggressive T cells; in some thymomas, these cells may then be actively immunized inside the tumor.