Mice heterozygously de®cient for myelin protein zero (P0) mimicking human Charcot±Marie±Tooth (CMT) disease 1B show T-lymphocyte and macrophage upregulation in peripheral nerves, which aggravates and modulates the genetically mediated demyelinating neuropathy. In connexin32 (cx32)-de®cient (cx32 def ) mice, which mimic the X-linked dominant form of CMT (CMTX), T-lymphocyte and macrophage numbers are also signi®cantly elevated in peripheral nerves. To test the hypothesis that immune cells are

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... eed pathogenic in this model, we cross-bred cx32 def mice with recombination activating gene-1 (RAG-1)-de®cient mice, which lack mature T-and B-lymphocytes. In these immunoincompetent double mutants, the number of endoneurial macrophages was reduced. Furthermore, features indicative of myelin degeneration and axonopathic changes were mitigated in the RAG-1-de®cient double mutants, whereas enlarged periaxonal Schwann cell collars, a hallmark speci®c for cx32-mutants, were not reduced. Since both cx32-and P0 de®ciency lead to similar immunopathogenic processes, we conclude that immune-mediated demyelination may be a feature common to many CMT-like neuropathies independent of the genetic origin. Abbreviations: CMT = Charcot±Marie±Tooth; CMTX = X-linked Charcot±Marie±Tooth; cx32 = connexin32; cx32 def = connexin32 de®cient; cx32 wt = connexin32 wild type; nf = neuro®lament; P0 = myelin protein zero; RAG-1 = recombination activating gene-1 ã Guarantors of Brain 2003