title: Role of immune cells in animal models for inherited peripheral neuropathies.
abstract: Mice expressing half of the normal dose of protein zero (P0+/- mice) or completely deficient gap-junction protein connexin 32 -/- mice mimic demyelinating forms of inherited neuropathies, such as Charcot-Marie-Tooth (CMT) neuropathies type 1B and CMT type 1X, respectively. In both models, an almost normal myelin formation is observed during the first months of life, followed by a slowly progressing demyelinating neuropathy. In both models, there is a substantial increase of CD8+ T-lymphocytes and macrophages within the demyelinating nerves. Recently, this has also been observed in mice mildly overexpressing human peripheral myelin protein 22 kD mimicking the most common form of CMT, CMT type 1A. In all demyelinating models, the macrophages show close contacts with intact myelin sheaths or demyelinated axons, suggesting an active role of these cells in myelin degeneration. Additionally, fibroblast-like cells contact macrophages, suggesting a functional role of fibroblast-like cells in macrophage activation. By cross-breeding P0+/- and gap-junction protein connexin 32-/- mice with immunodeficient recombination activating gene-1-deficient mutants, a substantial alleviation of the demyelinating phenotype was observed. Similarly, cross-breeding of P0+/- mice with mutants with a defect in macrophage activation led to an alleviated phenotype as well. These findings demonstrate that the immune system is involved in the pathogenesis of demyelinating neuropathies. In contrast, in P0-/- mice, which display a compromised myelin compaction and axonal loss from onset, immune cells appear to have a neuroprotective effect because cross-breeding with recombination activating gene-1 mutants leads to an aggravation of axonopathic changes. In the present review, we discuss the influence of the immune system on inherited de- and dysmyelination regarding disease mechanisms and possible clinical implications.
authors.affiliation: Department of Neurology, Developmental Neurobiology, University of Wuerzburg, Josef-Schneider-Str. 11, D-97080 Wuerzburg, Germany.
authors.forename: Chi
authors.initials: C
authors.lastname: Wang Ip
authors.forename: Antje
authors.initials: A
authors.lastname: Kroner
authors.forename: Stefan
authors.initials: S
authors.lastname: Fischer
authors.forename: Martin
authors.initials: M
authors.lastname: Berghoff
authors.forename: Igor
authors.initials: I
authors.lastname: Kobsar
authors.forename: Mathias
authors.initials: M
authors.lastname: Mäurer
authors.forename: Rudolf
authors.initials: R
authors.lastname: Martini
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000648:ultrastructure; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D003711:Demyelinating Diseases / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D016654:Genes, RAG-1; D006801:Humans; D008264:Macrophages / Q000276:immunology* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic; D018993:Myelin P0 Protein / Q000235:genetics / Q000378:metabolism; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D010523:Peripheral Nervous System Diseases / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D000097002:Gap Junction beta-1 Protein
chemical_list: D017630:Connexins; D018993:Myelin P0 Protein; D009185:Myelin Proteins; D000097002:Gap Junction beta-1 Protein; C489545:Pmp22 protein, mouse