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Role of MHC Class II and AIRE Genes and Genetic Polymorphisms
a Institutes of Pathology, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany b Institutes of Pathology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan c Institutes of Pathology, University of Würzburg, Würzburg, Germany d Institute of Physiological Chemistry, University of Tübingen, Tübingen, Germany Departments of Neurology, Universities of e Würzburg, f Mainz, g Regensburg, and h Bochum, Germany i Institute of Molecular Pathology, University of Tartu, Tartu, Estonia
Key Words: thymoma • myasthenia gravis • MHCII • CIITA • AIRE • autoimmunity • central tolerance
Address for correspondence: Philipp Ströbel, M.D., Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68135 Mannheim, Germany. Voice: +49-621-383-2556. philipp.stroebel{at}path.ma.uni-heidelberg.de
Generation of autoreactive CD4+ effector T cells and defective production of regulatory CD4+ T cells inside thymomas contribute to the development of myasthenia gravis (MG) in >90% of MG(+) thymomas. The molecular basis of these abnormalities is unknown. We report here that a) expression levels of class II major histocompatibility complex (MHCII) genes are variably decreased in thymomas, most prominently in histological WHO types A and AB; b) epithelial cells of type A and AB thymomas exhibit signal transducer and activator of transcription (STAT-1)-related defects of interferon-
 (IFN-) signaling and human leukocyte antigen (HLA)-DR expression in vitro; c) the promoter III (pIII)- and pIV-driven splice variants of the MHCII transactivator (CIITA) play a key role in MHCII gene expression in thymus and thymomas; and d) the pIV CIITA promoter is heavily methylated in thymomas. Recently, we also found that expression of the autoimmune regulator (AIRE) gene is absent from  95% of thymomas. Among all theses abnormalities, only better preserved expression levels of MHCII (P < 0.001) in thymomas were significantly associated with the presence of MG. Taking the association of a gain-of-function polymorphism of the CTLA-4 and PTPN22 gene with MG in thymomas into account, we conclude that these acquired cellular abnormalities of the thymoma microenvironment in concert with inherited genetic high-risk polymorphisms of immunoregulatory genes have an impact on intratumorous thymopoiesis and appear to tip the balance toward central tolerance failure and development of MG. The findings imply that IFN- and STAT-1 signaling play a role in MHCII expression in the human thymus and in the pathogenesis of paraneoplastic MG.
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