Pathomechanisms of paraneoplastic myasthenia gravis.
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.
Institute of Pathology, University of Wuerzburg, Josef-Schneider-Strasse 2, 97080, Wuerzburg, Germany. path036@mail.uni-wuerzburg.de
Philipp
P
Ströbel
Tobias
T
Preisshofen
Markus
M
Helmreich
Hans Konrad
HK
Müller-Hermelink
Alexander
A
Marx
D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002648:Child; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D020287:In Situ Nick-End Labeling; D038041:Lymphopoiesis; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000276:immunology*; D010257:Paraneoplastic Syndromes / Q000276:immunology*; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013934:Thymectomy; D013945:Thymoma / Q000276:immunology* / Q000473:pathology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*
D000911:Antibodies, Monoclonal