Role of immune cells in animal models for inherited peripheral neuropathies

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Neuromolecular Med. 2006;8(1-2):175-90.

Role of immune cells in animal models for inherited peripheral

neuropathies.

Wang Ip C, Kroner A, Fischer S, Berghoff M, Kobsar I, Maurer M,

i R.

Department of Neurology, Developmental Neurobiology, University of

Wuerzburg, f-Schneider-Str. 11, D-97080 Wuerzburg, Germany.

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.