title: Thymic Atrophy and Apoptosis of CD4+CD8+ Thymocytes in the Cuprizone Model of Multiple Sclerosis.
abstract: Previous studies on the degenerative animal model of multiple sclerosis suggested that the copper-chelator cuprizone might directly suppress T-cell functions. Peripheral T-cell function in the cuprizone model has already been explored; therefore, in the present study, we investigated, for the first time, how cuprizone feeding affects the thymus, the organ of T-cell maturation and selection. We found that even one week of cuprizone treatment induced significant thymic atrophy, affecting the cortex over the medulla. Fluorescent microscopy and flow-cytometric analyses of thymi from cuprizone- and vehicle-treated mice indicated that eradication of the cluster of the differentiation-4 (CD4)-CD8 double-positive T-cell subset was behind the substantial cell loss. This result was confirmed with CD3-CD4-CD8 triple-staining experiments. Ultrastructurally, we observed degraded as well as enlarged mitochondria, myelin-bodies, large lipid droplets, and large lysosomes in the thymi of cuprizone-treated mice. Some of these features were similar to those in physiological and steroid-induced accelerated aging. According to our results, apoptosis was mainly of mitochondrial origin mediated by both caspase-3- and apoptosis inducing factor-mediated mechanisms. Additionally, mitogen activated protein kinase activation and increased pro-apoptotic B cell lymphoma-2 family protein expression were the major underlying processes. Our results do not indicate a functional relationship between cuprizone-induced thymus involution and the absence of inflammatory responses or the selective demyelination observed in the cuprizone model. On the other hand, due to the reversible nature of cuprizone's deleterious effects, the cuprizone model could be valuable in studying thymus regeneration as well as remyelination processes.
authors.affiliation: Department of Biochemistry and Medical Chemistry, University of Pecs, Pecs, Hungary.
authors.forename: Izabella
authors.initials: I
authors.lastname: Solti
authors.affiliation: Department of Pharmaceutical Biotechnology, University of Pecs, Pecs, Hungary.
authors.forename: Krisztian
authors.initials: K
authors.lastname: Kvell
authors.affiliation: Karolinska Institutet, Department of Biosciences and Nutrition, NOVUM, Huddinge, Sweden.
authors.forename: Gergely
authors.initials: G
authors.lastname: Talaber
authors.affiliation: Department of Biochemistry and Medical Chemistry, University of Pecs, Pecs, Hungary.
authors.forename: Sara
authors.initials: S
authors.lastname: Veto
authors.affiliation: Department of Neurology, University of Pecs, Pecs, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Acs
authors.affiliation: Department of Biochemistry and Medical Chemistry, University of Pecs, Pecs, Hungary; MTA-PTE Nuclear-Mitochondrial Research Group, Pecs, Hungary; Szentagothai Research Center, University of Pecs, Pecs, Hungary.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Gallyas
authors.affiliation: Department of Neurology, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Illes
authors.affiliation: Department of Biochemistry and Medical Chemistry, University of Pecs, Pecs, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Fekete
authors.affiliation: Department of Biochemistry and Medical Chemistry, University of Pecs, Pecs, Hungary.
authors.forename: Petra
authors.initials: P
authors.lastname: Zalan
authors.affiliation: Department of Urology, University of Pecs, Pecs, Hungary.
authors.forename: Arpad
authors.initials: A
authors.lastname: Szanto
authors.affiliation: Department of Biochemistry and Medical Chemistry, University of Pecs, Pecs, Hungary.
authors.forename: Zita
authors.initials: Z
authors.lastname: Bognar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001284:Atrophy; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D003471:Cuprizone / Q000009:adverse effects; D004195:Disease Models, Animal; D016130:Immunophenotyping; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009103:Multiple Sclerosis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D060168:Thymocytes / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D003471:Cuprizone; D020928:Mitogen-Activated Protein Kinases