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Abstract
Thymic T cell development is characterized by sequential selection processes to ensure generation of a self-tolerant, immuncompetent mature T cell repertoire. Malfunction of any of these selection processes may potentially result in either immunodeficiency or autoimmunity. Myasthenia gravis (MG) is a typical autoimmune manifestation of thymic epithelial tumors (thymomas) and is related to the capacity of these tumors to generate and export mature T cells. Analysis of the factors that lead to autoimmunization in thymomas will help to understand the mechanisms that prevent MG under physiological conditions in humans. In a comparison of MG(+) and MG(-) thymomas, we could show that only thymomas capable of generating mature CD45RA+CD4+ T cells are associated with MG (p< 0.0001), while terminal thymopoiesis was abrogated in MG(-) thymomas. In particular, acquisition of the CD27+CD45RA+ phenotype appears to be a critical checkpoint of late T cell development in the human thymus and may play an important role in the prevention of autoimmunity. Moreover, MG(-) thymomas were virtually depleted of regulatory (CD4+CD25+) T cells (regT), while regT were readily detectable in MG(+) thymomas, albeit at significantly reduced numbers compared to control thymuses. Thus, in MG(+) thymoma patients, thymectomy apparently also results in removal of a regulatory T cell pool and may explain the frequent temporary postoperative deterioration of MG in these patients.
Highlights
Myasthenia gravis (MG) is an autoimmune disease mediated by anti-acetylcholine receptor autoantibodies that cause muscle weakness by impairing neuromuscular transmission (Lindstrom et al, 1998)
On Chi-Square-test, presence of MG was significantly linked to high levels of mature naıve CD4þ T cells ð p, 0:01Þ: Preliminary results of a TUNEL analysis showed that the subtotal loss of the mature naive CD4 T cell subset is due to deletion/apoptosis (Fig. 2)
Earlier studies on terminal thymopoiesis in humans suggest (a) that late T cell development is an MHC-independent process (Vanhecke et al, 1997) and (b) that it occurs after acquisition of CD27 (Vanhecke et al, 1995)
Summary
Myasthenia gravis (MG) is an autoimmune disease mediated by anti-acetylcholine receptor autoantibodies that cause muscle weakness by impairing neuromuscular transmission (Lindstrom et al, 1998). MG-associated thymomas retain many functional features of the normal thymus, namely the capacity to generate and export mature T cells from immature precursors. All known thymocyte maturation stages in terms of CD3, CD69, CD4 and CD8 expression can be detected in virtually all MG(þ ) and MG(2 ) thymomas (Takeuchi et al, 1995; Nenninger et al, 1998). This study suggested a role of thymoma-derived CD4þ T cells in the pathogenesis of paraneoplastic MG. It did not resolve the underlying pathophysiology at the level of intratumorous thymopoiesis. To address these questions, we analyzed the intratumorous generation of mature naive CD45RAþ thymocyte subsets (Vanhecke et al, 1995) in thymomas
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