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)