title: The thymic theme of acetylcholinesterase splice variants in myasthenia gravis.
abstract: 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-betaII. To explore possible causal association of AChE-R changes with thymic composition and function, we used an AChE-R transgenic model and showed smaller thymic medulla compared with strain-matched controls, indicating that AChE-R overexpression interferes with thymic differentiation mechanisms. Interestingly, AChE-R transgenic mice showed increased numbers 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 with 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.
authors.affiliation: Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Adi
authors.initials: A
authors.lastname: Gilboa-Geffen
authors.forename: Paul P
authors.initials: PP
authors.lastname: Lacoste
authors.forename: Lilach
authors.initials: L
authors.lastname: Soreq
authors.forename: Geraldine
authors.initials: G
authors.lastname: Cizeron-Clairac
authors.forename: Rozen
authors.initials: R
authors.lastname: Le Panse
authors.forename: Frederique
authors.initials: F
authors.lastname: Truffault
authors.forename: Iftach
authors.initials: I
authors.lastname: Shaked
authors.forename: Hermona
authors.initials: H
authors.lastname: Soreq
authors.forename: Sonia
authors.initials: S
authors.lastname: Berrih-Aknin
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics* / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D017398:Alternative Splicing; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000235:genetics* / Q000378:metabolism*; D013950:Thymus Gland / Q000201:enzymology* / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D000110:Acetylcholinesterase