title: Role of immune cells in animal models for inherited neuropathies: facts and visions.
abstract: Mice heterozygously deficient in the peripheral myelin adhesion molecule P0 (P0+/- mice) are models for some forms of Charcot-Marie-Tooth (CMT) neuropathies. In addition to the characteristic hallmarks of demyelination, elevated numbers of CD8-positive T-lymphocytes and F4/80-positive macrophages are striking features in the nerves of these mice. These immune cells increase in number with age and progress of demyelination, suggesting that they might be functionally related to myelin damage. In order to investigate the pathogenetic role of lymphocytes, the myelin mutants were cross-bred with recombination activating gene 1 (RAG-1)-deficient mice, which lack mature T- and B-lymphocytes. The immunodeficient myelin mutants showed a less severe myelin degeneration. The beneficial effect of lymphocyte-deficiency was reversible, since demyelination worsened in immunodeficient myelin-mutants when reconstituted with bone marrow from wild-type mice. Ultrastructural analysis revealed macrophages in close apposition to myelin and demyelinated axons. We therefore cross-bred the P0+/- mice with spontaneous osteopetrotic (op) mutants deficient in the macrophage colony-stimulating factor (M-CSF), hence displaying impaired macrophage activation. In the corresponding double mutants the numbers of macrophages were not elevated in the peripheral nerves, and the demyelinating phenotype was less severe than in the genuine P0+/- mice, demonstrating that macrophages are also functionally involved in the pathogenesis of genetically mediated demyelination. We also examined other models for inherited neuropathies for a possible involvement of immune cells. We chose mice deficient in the gap junction component connexin 32, a model for the X-linked form of CMT. Similar to P0-deficient mice, T-lymphocytes and macrophages were elevated and macrophages showed a close apposition to degenerating myelin. We conclude that the involvement of T-lymphocytes and macrophages is a common pathogenetic feature in various forms of slowly progressive inherited neuropathies.
authors.affiliation: Department of Neurology, University of Würzburg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Mäurer
authors.forename: Igor
authors.initials: I
authors.lastname: Kobsar
authors.forename: Martin
authors.initials: M
authors.lastname: Berghoff
authors.forename: Christoph D
authors.initials: CD
authors.lastname: Schmid
authors.forename: Stefano
authors.initials: S
authors.lastname: Carenini
authors.forename: Rudolf
authors.initials: R
authors.lastname: Martini
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000276:immunology*; D018932:Chemokine CCL2 / Q000235:genetics; D004195:Disease Models, Animal; D017353:Gene Deletion; D007107:Immune System / Q000502:physiology*; D008262:Macrophage Activation / Q000502:physiology; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008818:Mice, Neurologic Mutants; D009046:Motor Neurons / Q000502:physiology; D018993:Myelin P0 Protein / Q000235:genetics; D009186:Myelin Sheath / Q000502:physiology*; D012583:Schwann Cells / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology
chemical_list: D018932:Chemokine CCL2; D018993:Myelin P0 Protein; D016173:Macrophage Colony-Stimulating Factor