Bone Marrow Transfer From Wild‐type Mice Reverts the Beneficial Effect of Genetically Mediated Immune Deficiency in Myelin Mutants

Abstract

Inherited demyelinating neuropathies are chronically disabling human disorders caused by various genetic defects, including deletions, single site mutations, and duplications in the respective myelin genes. We have shown in a mouse model of one distinct hereditary demyelinating neuropathy (heterozygous PO‐deficiency, PO±) that an additional null mutation in the recombination activating gene‐1 (RAG‐1‐‐) leads to a substantially milder disorder, indicating a disease modifying role of T‐lymphocytes. In the present study, we addressed the role of lymphocytes in the mouse model by reconstituting bone marrow of PO±/RAG‐1‐‐ mice with bone marrow from immunocompetent wild‐type mice. We compared the pathology and nerve conduction in double mutant mice (PO±/RAG‐1‐‐ on a C57BL/6 background) with that in double mutants after receiving a bone marrow transplant. We found that the milder demyelination seen in the lymphocyte‐deficient PO±/RAG‐1‐‐ mutants was reverted to the more severe pathology by reestablishing a competent immune system by bone marrow transfer. These data corroborate the concept that the immune system contributes substantially to the pathologic process in this mouse model and may open new avenues to ameliorate human hereditary neuropathies by exploiting immunosuppressive treatments.

Myelin protein zero mutation His39Pro: hereditary motor and sensory neuropathy with variable onset, hearing loss, restless legs and multiple sclerosis

“…7 Hearing loss and pupillary reflex abnormalities have been described in families with late-onset motor and sensory neuropathy-2 associated with the Thr124Met MPZ mutation. 3 20 Hearing loss without pupillary abnormalities presenting years before the onset of neuropathy has also been reported in association with a Glu97Val mutation.…”

“…[7][8][9] Rare mutations of the peripheral myelin proteins (PMP22) and connexin 32 have been associated with changes in the central nervous system (CNS) on imaging, characteristic of multiple sclerosis and acute disseminated encephalomyelitis, respectively. [10][11][12][13][14] In this report, we present data on a large family with the MPZ mutation His39Pro and describe the varied phenotypes seen in the kindred, including one case of acute-onset painful neuropathy, hearing loss, restless legs and relapsing remitting multiple sclerosis.…”

Immune Cells Contribute to Myelin Degeneration and Axonopathic Changes in Mice Overexpressing Proteolipid Protein in Oligodendrocytes

“…Bone marrow transplantation from wild-type, CD4Ϫ/Ϫ, or CD8Ϫ/Ϫ donor mice into PLP/RAG-1Ϫ/Ϫ mutants (hosts) has been performed in analogy to previous experiments in P0ϩ/Ϫ/RAG-1Ϫ/Ϫ mutants (Mäurer et al, 2001). Control experiments were performed by transplanting wild-type bone marrow into PLP-wt mice.…”

Molecular cell biology of Charcot-Marie-Tooth disease

“…Indeed, myelin degeneration and impairment of nerve conduction properties were less severe when the immune system is T-cell deficient [147]. This effect can be reverted back to the more-severe pathology of the heterozygous Mpz knock-out mice by transplantation of bone marrow of a wt mouse into these mutant animals [148]. Analogously, the influence of macrophages was addressed with similar beneficial results [149].…”