Wang Ip Chi, Kroner Antje, Fischer Stefan, Berghoff Martin, Kobsar Igor, Mäurer Mathias, Martini Rudolf
Department of Neurology, Developmental Neurobiology, University of Wuerzburg, Josef-Schneider-Str. 11, D-97080 Wuerzburg, Germany.
Neuromolecular Med. 2006;8(1-2):175-90. doi: 10.1385/nmm:8:1-2:175.
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.
表达正常剂量一半的蛋白零的小鼠（P0+/-小鼠）或完全缺乏缝隙连接蛋白连接蛋白32的-/-小鼠，分别模拟遗传性神经病的脱髓鞘形式，如1B型夏科-马里-图斯（CMT）神经病和1X型CMT神经病。在这两种模型中，在生命的最初几个月观察到几乎正常的髓鞘形成，随后是缓慢进展的脱髓鞘性神经病。在这两种模型中，脱髓鞘神经内的CD8+T淋巴细胞和巨噬细胞大量增加。最近，在轻度过表达人类外周髓鞘蛋白22 kD的小鼠中也观察到了这种情况，该小鼠模拟了最常见的CMT形式，即1A型CMT。在所有脱髓鞘模型中，巨噬细胞与完整的髓鞘或脱髓鞘轴突密切接触，表明这些细胞在髓鞘变性中起积极作用。此外，成纤维细胞样细胞与巨噬细胞接触，表明成纤维细胞样细胞在巨噬细胞激活中起功能作用。通过将P0+/-和缝隙连接蛋白连接蛋白32-/-小鼠与免疫缺陷的重组激活基因-1缺陷突变体杂交，观察到脱髓鞘表型有显著缓解。同样，将P0+/-小鼠与巨噬细胞激活缺陷的突变体杂交也导致表型缓解。这些发现表明免疫系统参与了脱髓鞘性神经病的发病机制。相比之下，在P0-/-小鼠中，从发病开始就表现出髓鞘紧密化受损和轴突丢失，免疫细胞似乎具有神经保护作用，因为与重组激活基因-1突变体杂交会导致轴索性病变加重。在本综述中，我们讨论了免疫系统对遗传性脱髓鞘和髓鞘形成异常的影响，涉及疾病机制和可能的临床意义。
