Evidence for Distinct Mechanisms in the Shaping of the CD4 T Cell Repertoire in Histologically Distinct Myasthenia Gravis – Associated Thymomas

Journal of Immunology Research, Aug 2018

The major histocompatibility complex (MHC) class II is involved both in thymocyte maturation and peptide presentation and might thus play a key role in the pathogenesis of paraneoplastic myasthenia gravis (MG) in thymomas. To further investigate this issue, we analyzed and scored the expression of epithelial class II expression in 35 thymomas (medullary, MDT; mixed, MXT; cortical and well differentiated thymic carcinoma, CT / WDTC) and correlated it with the histological tumor subtype, prevalence of MG and thymocyte maturation, which was analyzed by flow cytometry and RT-PCR. Our results show that both MHC class II expression and thymocyte maturation are highly dependent on the histological tumor subtype. CT / WDTC retain features of the normal outer thymic cortex, namely substantial MHC class II expression together with normal early thymocyte maturation until late phases of positive selection, but disturbed terminal thymopoiesis. By contrast, MDT and MXT retain features of the normal inner cortex and the medulla with low to absent class II expression and highly abnormal early thymocyte maturation including impaired positive selection, while terminal T cell maturation in MXT appeared undisturbed. There was no correlation between MHC class II expression and MG status for a given tumor subtype. In conclusion, our results provide evidence for a different histogenesis of cortical thymomas and well differentiated carcinomas on the one hand and mixed and medullary thymomas on the other.

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Evidence for Distinct Mechanisms in the Shaping of the CD4 T Cell Repertoire in Histologically Distinct Myasthenia Gravis – Associated Thymomas

Evidence for Distinct Mechanisms in the Shaping of the CD4 T Cell Repertoire in Histologically Distinct Myasthenia Gravis- Associated Thymomas E STROBEL M. HELMREICH H. KALBACHER H.K. MLLER-HERMELINK A. MARX The major histocompatibility complex (MHC) class II is involved both in thymocyte maturation and peptide presentation and might thus play a key role in the pathogenesis of paraneoplastic myasthenia gravis (MG) in thymomas. To further investigate this issue, we analyzed and scored the expression of epithelial class II expression in 35 thymomas (medullary, MDT; mixed, MXT; cortical and well differentiated thymic carcinoma, CT WDTC) and correlated it with the histological tumor subtype, prevalence of MG and thymocyte maturation, which was analyzed by flow cytometry and RT-PCR. Our results show that both MHC class II expression and thymocyte maturation are highly dependent on the histological tumor subtype. CT WDTC retain features of the normal outer thymic cortex, namely substantial MHC class II expression together with normal early thymocyte maturation until late phases of positive selection, but disturbed terminal thymopoiesis. By contrast, MDT and MXT retain features of the normal inner cortex and the medulla with low to absent class II expression and highly abnormal early thymocyte maturation including impaired positive selection, while terminal T cell maturation in MXT appeared undisturbed. There was no correlation between MHC class II expression and MG status for a given tumor subtype. In conclusion, our results provide evidence for a different histogenesis of cortical thymomas and well differentiated carcinomas on the one hand and mixed and medullary thymomas on the other. Decreased expression levels of MHC class II, although of crucial importance for abnormal intratumorous maturation, are not sufficient to explain the emergence of paraneoplastic MG. Cortical; epithelium; medullary; MHC class II; Myasthenia gravis; Thymoma; Thymus INTRODUCTION Myasthenia gravis (MG) is a neurological disorder characterized by autoantibodies against the acetylcholine receptors at the neuromuscular junction, resulting in generalized muscle weakness. The clinical presentation of MG is almost invariably associated with pathological alterations of the thymus (Marx et al. 1997) . About 10 % of MG cases are related to thymic epithelial tumors (thymomas), which have been subdivided into medullary (MDT), mixed (MXT) and cortical thymomas (CT) and well differentiated thymic carcinomas (WDTC) based on the morphological resemblance of the neoplastic to normal thymic epithelium (Kirchner et al. 1992, Mtiller-Hermelink et al. 1994) . Thymomas characteristically retain organotypic features of the normal thymus, especially the capacity to generate mature T cells. Thus, a maintained but non-tolerogenic intratumorous thymopoiesis plus export of mature T cells from thymomas to peripheral lymphoid organs have been proposed to be a prerequisite for the development of paraneoplastic MG (Mtiller-Hermelink et al. 1997) . However, although thymomas have been shown to be enriched in autoreactive T cells (Sommer et al. 1990; Nenninger 1998, Schultz 1999) , the molecular basis of autoimmunization by thymomas remains largely enigmatic. In recent years, some consistent features of these tumors have been described, including 1) intratumorous overexpression of autoantigen related epitopes (Mygland et al. 1997; Wilisch et al. 1997, Schultz et al. 1999) and 2) impaired intratumorous thymopoiesis, particularly of the CD4 lineage (Takeuchi 1995; Nenninger 1997, 1998) . Cells maturing in the thymus pass two critical checkpoints, positive and negative selection. During positive selection the thymic cortical epithelium presents an evolutionary optimized set of thymic peptides (Chan et al. 1993) bound to major histocompatibility complex (MHC) class I and II molecules to immature thymocytes. Depending on the MHC class recognized by the T cell receptor (TCR), either CD4 or CD8 are engaged and help to further increase the surface expression of the TCR and CD3 (Davis et al 1993) . If the resulting avidity reaches a threshold level, the cell receives a survival signal. However, if the resulting avidity is too high, the cell is eliminated through apoptosis, a mechanism termed negative selection (Bevan 1997; Marrack and Kappler 1997; Williams et al. 1997; Jameson and Bevan 1998) . Only cells surviving these two MHC-dependent checkpoints are allowed to complete maturation and leave the thymus (Janeway and Travers 1994) . Although the MHC is thus critically involved in both thymocyte maturation and antigen presentation, it has not been clarified whether abnormal MHC expression levels are a consistent feature of thymomas (Willcox et al. 1987, Takeuchi et al. 1995, Nenninger et al. 1997) and whether alterations of MHC levels are related to abnormal thymopoiesis. Therefore we tried to further dissect the role of this molecule in intratumo (...truncated)


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P. Ströbel, M. Helmreich, H. Kalbacher, H. K. Müller-Hermelink, A. Marx. Evidence for Distinct Mechanisms in the Shaping of the CD4 T Cell Repertoire in Histologically Distinct Myasthenia Gravis – Associated Thymomas, Journal of Immunology Research, 8, DOI: 10.1155/2001/49127