PMID- 18567864
OWN - NLM
STAT- MEDLINE
DCOM- 20080908
LR  - 20231213
IS  - 0077-8923 (Print)
IS  - 0077-8923 (Linking)
VI  - 1132
DP  - 2008
TI  - Common cellular and diverse genetic basis of thymoma-associated myasthenia 
      gravis: role of MHC class II and AIRE genes and genetic polymorphisms.
PG  - 143-56
LID - 10.1196/annals.1405.018 [doi]
AB  - 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-gamma (IFN-gamma) 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 approximately 
      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-gamma and 
      STAT-1 signaling play a role in MHCII expression in the human thymus and in the 
      pathogenesis of paraneoplastic MG.
FAU - Strobel, Philipp
AU  - Strobel P
AD  - Institute of Pathology, University Hospital Mannheim, University of Heidelberg, 
      Theodor-Kutzer-Ufer 1-3, 68135 Mannheim, Germany. 
      philipp.stroebel@path.ma.uni-heidelberg.de
FAU - Chuang, Wen-Yu
AU  - Chuang WY
FAU - Chuvpilo, Sergei
AU  - Chuvpilo S
FAU - Zettl, Andreas
AU  - Zettl A
FAU - Katzenberger, Tiemo
AU  - Katzenberger T
FAU - Kalbacher, Hubert
AU  - Kalbacher H
FAU - Rieckmann, Peter
AU  - Rieckmann P
FAU - Nix, Wilfred
AU  - Nix W
FAU - Schalke, Berthold
AU  - Schalke B
FAU - Gold, Ralf
AU  - Gold R
FAU - Muller-Hermelink, Hans-Konrad
AU  - Muller-Hermelink HK
FAU - Peterson, Part
AU  - Peterson P
FAU - Marx, Alexander
AU  - Marx A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Ann N Y Acad Sci
JT  - Annals of the New York Academy of Sciences
JID - 7506858
RN  - 0 (Histocompatibility Antigens Class II)
RN  - 0 (STAT1 Transcription Factor)
RN  - 0 (STAT1 protein, human)
RN  - 0 (Transcription Factors)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Cells, Cultured
MH  - Child
MH  - Child, Preschool
MH  - DNA Methylation
MH  - Female
MH  - Gene Expression Regulation/drug effects
MH  - Histocompatibility Antigens Class II/*genetics/*immunology
MH  - Humans
MH  - Infant
MH  - Interferon-gamma/pharmacology
MH  - Male
MH  - Middle Aged
MH  - Myasthenia Gravis/complications/*genetics/*immunology/pathology
MH  - Polymorphism, Genetic/genetics
MH  - Promoter Regions, Genetic/genetics
MH  - STAT1 Transcription Factor/genetics/metabolism
MH  - Signal Transduction/drug effects
MH  - Thymoma/etiology/*genetics/*immunology/pathology
MH  - Transcription Factors/*genetics
MH  - AIRE Protein
EDAT- 2008/06/24 09:00
MHDA- 2008/09/09 09:00
CRDT- 2008/06/24 09:00
PHST- 2008/06/24 09:00 [pubmed]
PHST- 2008/09/09 09:00 [medline]
PHST- 2008/06/24 09:00 [entrez]
AID - 1132/1/143 [pii]
AID - 10.1196/annals.1405.018 [doi]
PST - ppublish
SO  - Ann N Y Acad Sci. 2008;1132:143-56. doi: 10.1196/annals.1405.018.