Submitted July 19, 2006
Accepted October 27, 2006
The thymic theme of acetylcholinesterase splice variants in Myasthenia gravis
Adi Gilboa-Geffen, Paul P Lacoste, Lilach Soreq, Geraldine Cizeron-Clairac, Rozen Le Panse, Frederique Truffault, Iftach Shaked, Hermona Soreq*, and Sonia Berrih-Aknin
The Hebrew University of Jerusalem, Israel
CNRS-UMR 8162, Institute Paris-Sud Cytokines, Universite Paris XI, Hopital Marie Lannelongue, France
* Corresponding author; email: soreq{at}cc.huji.ac.il.
Cholinergic signaling and acetylcholinesterase (AChE) influence immune response and inflammation. Autoimmune Myasthenia gravis (MG) is mediated by antibodies to the acetylcholine receptor and current therapy is based on anti-AChE drugs. MG is associated with thymic hyperplasia, showing signs of inflammation. The objectives of this study were to analyze the involvement of AChE variants in thymic hyperplasia. We found lower hydrolytic activities in the MG thymus compared with adult controls, accompanied by translocation of AChE-R from the cytoplasm to the membrane and increased expression of the signaling protein kinase PKC-
II. To explore possible causal association of AChE-R changes with thymic composition and function, we employed an AChE-R transgenic model and showed smaller thymic medulla compared to strain-matched controls, indicating that AChE-R overexpression interferes with thymic differentiation mechanisms. Interestingly, AChE-R transgenic mice showed increased number of CD4+CD8+ cells, that were considerably more resistant in vitro to apoptosis than normal thymocytes, suggesting possibly altered positive selection. We further analyzed microarray data of MG thymic hyperplasia compared to healthy controls and found continuous and discrete changes in AChE-annotated GO categories. Together, these findings show that modified AChE gene expression and properties are causally involved in thymic function and development.
