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.

A novel GJB1 frameshift mutation produces a transient CNS symptom of X-linked Charcot–Marie–Tooth disease

“…In mice deficient in Cx32, a model for CMT1X, T-lymphocytes and macrophages were induced, and macrophages showed close apposition to degenerating myelin, suggesting that involvement of T-lymphocytes and macrophages is a common pathogenetic feature in various forms of slowly progressive inherited neuropathies [19,20]. Another study revealed that Cx32-deficient mice crossbred with mice deficient in mature T-and B-lymphocytes (RAG-1-deficient mice) showed less severe myelin degeneration in the absence of lymphocytes [21].…”

Altered Ion Channels in an Animal Model of Charcot-Marie-Tooth Disease Type IA

“…Because we did not detect widespread Nav1.8 expression in developing nerves (data not shown), it is unlikely that its increased expression in Trembler-J nerves represents a persistence/recapitulation of development, as has been argued for Nav1.2 in the CNS (see above). The nodal expression of Nav1.8 could be related to inflammatory changes that occur in demyelinating neuropathies (Maurer et al, 2002), as Nav1.8 expression increases after nerve injury (Akopian et al, 1999;Gold et al, 2003;Roza et al, 2003). This possibility seems unlikely because there were no obvious differences in the number of Nav1.8-positive neurons in the lumbar ganglia or in the intensity of immunostaining of unmyelinated axons between Trembler-J and WT mice (data not shown) (cf.…”

The causes of Charcot-Marie-Tooth disease

“…However, the signals that mediate this cell-to-cell communication are largely unknown. Loss of trophic support by damaged Schwann cells may contribute, and recent data suggest that inflammation is involved [206]. Further work will focus on the identification of other genes that can cause CMT.…”