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

Abstract

Overexpression of the major myelin protein of the CNS, proteolipid protein (PLP), leads to late-onset degeneration of myelin and pathological changes in axons. Based on the observation that in white matter tracts of these mutants both CD8ϩ T-lymphocytes and CD11bϩ macrophage-like cells are numerically elevated, we tested the hypothesis that these cells are pathologically involved in the primarily genetically caused neuropathy. Using flow cytometry of mutant brains, CD8ϩ cells could be identified as activated effector cells, and confocal microscopy revealed a close association of the T-cells with MHC-Iϩ (major histocompatibility complex class I positive) oligodendrocytes. Crossbreeding the myelin mutants with mice deficient in the recombination activating gene-1 (RAG-1) lacking mature T-and B-lymphocytes led to a reduction of the number of CD11bϩ cells and to a substantial alleviation of pathological changes. In accordance with these findings, magnetic resonance imaging revealed less ventricular enlargement in the double mutants, partially because of more preserved corpora callosa. To investigate the role of CD8ϩ versus CD4ϩ T-lymphocytes, we reconstituted the myelin-RAG-1 double mutants with bone marrow from either CD8-negative (CD4ϩ) or CD4-negative (CD8ϩ) mice. The severe ventricular enlargement was only found when the double mutants were reconstituted with bone marrow from CD8ϩ mice, suggesting that the CD8ϩ lymphocytes play a critical role in the immune-related component of myelin degeneration in the mutants. These findings provide strong evidence that a primary glial damage can cause secondary immune reactions of pathological significance as it has been suggested for some forms of multiple sclerosis and other leukodystrophies.

Interactions between Schwann cells and macrophages in injury and inherited demyelinating disease

“…In these mouse mutants, macrophages enter the endoneurial tubes, associate with myelin, and eventually phagocytose it, leaving the demyelinated axons intact (Ip et al, 2006). Typically, these macrophages acquire a morphology resembling ''foamy'' macrophages containing myelin debris.…”

“…The pivotal function of macrophages in the pathogenesis of inherited myelin degeneration was revealed by crossbreeding the myelin mutants with mice deficient in molecules involved in macrophage activation (Ip et al, 2006). So far, sialoadhesin, M-CSF and MCP-1 have been identified as important mediators (see Fig.…”

GLIA Edinburgh 2017: Abstracts Oral Presentations, Posters, Indexes

“…Accordingly, the pathogenic relevance of inflammation and the reason for failure of immunomodulatory therapies are unclear. Previous studies from our group have shown that secondary inflammation amplifies neural damage and disease outcome in models of primarily genetically-mediated disorders of the CNS, such as distinct forms of neuronal ceroid lipofuscinoses (Groh et al, 2013) and PLP1-related leukodystrophies (Ip et al, 2006). To further investigate the potential impact of secondary neuroinflammation, we generated mouse models carrying PLP1 point mutations previously found in patients displaying clinical features of PMS (Groh et al, 2016).…”

Molecular triggers of neuroinflammation in mouse models of demyelinating diseases

“…This was experimentally shown by crossbreeding either Plp 66/+ transgenic or Mpz heterozygous mice with recombinase RAG-1 deficient mice, which lack functional B and T cells. This led in both lines to a reduction in the degree of demyelination in the optic and peripheral nerves, and allowed more axons to survive (Ip et al, 2006a;2006b). It is therefore surprising that a similar lack of B and T cells did not affect peripheral demyelination in a Pmp22 transgenic mouse model of CMT1A (Kohl et al, 2010).…”

“…In all transgenics the degree of dysmyelination/demyelination is proportional to Plp1 gene dosage (Readhead et al, 1994). In the CNS of 12 months-old Plp 66/+ mice, corpus callosum, cerebellum, spinal cord, and optic nerves are filled with numerous (CD11b + ) leukocytes (Ip et al, 2006a). Moreover, CD11b + and CD45 + inflammatory cells are detected in the optic nerve where active demyelination is associated with axonopathy (Edgar et al, 2010;Ip et al, 2006a).…”