Paraneoplastic Autoimmunity in Thymus Tumors

Abstract

Autoimmune phenomena are more frequent in thymic epithelial tumors (TET) than in any other human tumor. Mysthenia gravis (MG) is by far the most common autoimmune disease in thymoma patients. MG is characterized by muscle weakness due to autoantibodies against the acetylcholine receptor (AChR), and CD4 AChR-specific T cells play a pivotal role for the production of these autoantibodies. About 10% of MG patients have a thymoma and, interestingly, only such thymomas exhibit an MG association that maintains thymuslike morphological and functional features with respect to the homing and differentiation of immature T cells. Since AChR protein is not expressed in thymomas, the specificity of the autoimmunity in thymoma-associated MG is thought to be determined by nonreceptor proteins with AChR epitopes. Such proteins are overexpressed in cortical-type MG-associated thymomas, and medullary thymomas express these proteins at barely detectable levels. Aside from this quantitative difference, the pathogenesis of anti-AChR autoimmunity might be qualitatively different in these thymoma subtypes. Our findings suggest that an antigen-specific abnormal Tcell selection,by cortical-type TET may contribute to the pathogenesis of paraneoplastic MG. In contrast, an abnormal (intratumorous) activation of autoreactive T cells may be operative in medullary thymomas.

The Role of Thymomas in the Development of Myasthenia Gravis

“…Some type A (medullary) thymomas, which are rarely associated with MG, have been found to harbor increased numbers of activated CD25+CD4+ mature T cells compared to the normal thymus 63. By contrast, almost all type AB, B2, and B3 thymomas (that collectively are frequently MG‐associated) were devoid of activated CD4+ T cells 64,94. These findings argue for a different pathogenesis of paraneoplastic MG in type A versus type AB and B thymomas (see below).…”

Biological implications of thymectomy for myasthenia gravis

“…In 1939, Blalock et al reported the remission of MG after removing a thymoma, 4 following which frequent associations of thymic abnormalities in MG patients suggested the involvement of the thymus in the pathogenesis of this disease. [5][6][7] Furthermore, thymectomy has been reported to result in remission and palliation of symptoms in many MG patients. 8 The oncologic implications of resecting the thymus and an associated thymoma are understood; however, the role of thymectomy for treating patients with nonthymomatous MG is still unclear, as the perceived effectiveness of that procedure is largely based on retrospective reviews of clinical experience.…”

Two thymus-related autoimmune disorders: a case report and review of the literature

“…tTG is the known target in celiac disease, deaminating gliadin peptide, leading to increased presentation to T-cells, and thereby stimulating the immune system 10. Some studies reported autoimmune enteropathy in association with thymoma, but there are few studies addressing the association of celiac disease and thymoma 15,16. Also, association between aplastic anemia and celiac disease have rarely been reported, and it is supposed that this relation to share an underlying immune pathological mechanism that destroys tissue with T-cell mediation 13,14,17.…”