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          Institute: MPI für experimentelle Medizin     Collection: Neurogenetics     Display Documents



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ID: 292160.0, MPI für experimentelle Medizin / Neurogenetics
Immune cells contribute to myelin degeneration and axonopathic changes in mice overexpressing proteolipid protein in oligodendrocytes
Authors:Ip, Chi Wang; Kroner, Antje; Bendszus, Martin; Leder, Christoph; Kobsar, Igor; Fischer, Stefan; Wiendl, Heinz; Nave, Klaus-Armin; Martini, Rudolf
Language:English
Date of Publication (YYYY-MM-DD):2006-08
Title of Journal:Journal of Neuroscience
Journal Abbrev.:J. Neurosci.
Volume:26
Issue / Number:31
Start Page:8206
End Page:8216
Review Status:Peer-review
Audience:Experts Only
Abstract / Description:Overexpression of the major myelin protein of the CNS, proteolipid protein (PLP), leads to late-onset degeneration of myelin and pathological changes in axons. Based on the observation that in white matter tracts of these mutants both CD8+ T-lymphocytes and CD11b+ macrophage- like cells are numerically elevated, we tested the hypothesis that these cells are pathologically involved in the primarily genetically caused neuropathy. Using flow cytometry of mutant brains, CD8+ cells could be identified as activated effector cells, and confocal microscopy revealed a close association of the T-cells with MHC-I + ( major histocompatibility complex class I positive) oligodendrocytes. Crossbreeding the myelin mutants with mice deficient in the recombination activating gene-1 (RAG-1) lacking mature T- and B-lymphocytes led to a reduction of the number of CD11b+ cells and to a substantial alleviation of pathological changes. In accordance with these findings, magnetic resonance imaging revealed less ventricular enlargement in the double mutants, partially because of more preserved corpora callosa. To investigate the role of CD8+ versus CD4+ T-lymphocytes, we reconstituted the myelin-RAG-1 double mutants with bone marrow from either CD8-negative (CD4+) or CD4-negative (CD8+) mice. The severe ventricular enlargement was only found when the double mutants were reconstituted with bone marrow from CD8+ mice, suggesting that the CD8+ lymphocytes play a critical role in the immune-related component of myelin degeneration in the mutants. These findings provide strong evidence that a primary glial damage can cause secondary immune reactions of pathological significance as it has been suggested for some forms of multiple sclerosis and other leukodystrophies.
Free Keywords:microglia; macrophages; T-lymphocytes; leukodystrophy; multiple sclerosis; animal model; inflammation INHERITED PERIPHERAL NEUROPATHIES; HEREDITARY SPASTIC PARAPLEGIA; SLOW AXONAL-TRANSPORT; DORSAL-ROOT GANGLIA; MULTIPLE-SCLEROSIS; NERVOUS-SYSTEM; T-CELLS; SCHWANN-CELLS; HETEROZYGOUSLY DEFICIENT; ANIMAL-MODELS
External Publication Status:published
Document Type:Article
Communicated by:Klaus-Armin Nave
Affiliations:MPI für experimentelle Medizin/Neurogenetics
Relations:Has References-DOI:10.1523/JNEUROSCI.1921-06.2006
Identifiers:ISSN:0270-6474 [ID No:1]
ISI:000239477800022 [ID No:2]
ISI:000239477800022 [ID No:3]
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