Immune-mediated components of hereditary demyelinating neuropathies: lessons from animal models and patients

Martini, Rudolf; Toyka, Klaus V.

doi:10.1016/s1474-4422(04)00822-1

Cited by 78 publications

(48 citation statements)

References 72 publications

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“…We found CD8ϩ T-lymphocytes and CD11bϩ macrophage-like cells elevated in white matter tracts of the mutants. The macrophage-like cells thereby outnumber the T-lymphocytes by a factor of ϳ20, which is similar to our previous observations in demyelinating mutants of the peripheral nervous system (Schmid et al, 2000;Kobsar et al, 2003;Martini and Toyka, 2004;Ip et al, 2006). The CD8ϩ T-lymphocytes could often be found in close contact to MHC-Iϩ oligodendrocytes, which is highly reminiscent of the interaction of cytotoxic T-lymphocytes with their target structure.…”

Section: Discussionsupporting

confidence: 88%

“…Moreover, the remaining macrophages contain less myelin debris than in PLP mutants with an intact immune system, reflecting a lower activation status than in the presence of T-lymphocytes. Similar observations have been made in RAG-1-deficient myelin mutants of the peripheral nervous system (Schmid et al, 2000;Kobsar et al, 2003;Martini and Toyka, 2004;Ip et al, 2006). A direct proof that macrophage-like cells are pathogenetically relevant in our CNS mutants is provided by recent investigations focusing on PLP mutants that have been crossbred to mice deficient in the gene for the cell adhesion molecule sialoadhesin Oetke et al, 2006).…”

Section: Discussionsupporting

confidence: 66%

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

et al. 2006

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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.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 66%

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

et al. 2006

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“…This observation is prevalent in hereditary motor and sensory neuropathies (Suter and Scherer, 2003), in PelizaeusMerzbacher disease/spastic paraplegia type-2 due to proteolipid protein 1 (PLP1) mutations, and mouse models thereof Nave, 2010). Immunological components may accentuate the disease phenotypes (Martini and Toyka, 2004;Kroner et al, 2010). A particular example in this regard is multiple sclerosis (MS) (Compston and Coles, 2008).…”

Section: Introductionmentioning

confidence: 99%

Genetically Induced Adult Oligodendrocyte Cell Death Is Associated with Poor Myelin Clearance, Reduced Remyelination, and Axonal Damage

Pohl¹,

Porcheri²,

Mueggler³

et al. 2011

J. Neurosci.

128

118

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Loss of oligodendrocytes is a feature of many demyelinating diseases including multiple sclerosis. Here, we have established and characterized a novel model of genetically induced adult oligodendrocyte death. Specific primary loss of adult oligodendrocytes leads to a well defined and highly reproducible course of disease development that can be followed longitudinally by magnetic resonance imaging. Histological and ultrastructural analyses revealed progressive myelin vacuolation, in parallel to disease development that includes motor deficits, tremor, and ataxia. Myelin damage and clearance were associated with induction of oligodendrocyte precursor cell proliferation, albeit with some regional differences. Remyelination was present in the mildly affected corpus callosum. Consequences of acutely induced cell death of adult oligodendrocytes included secondary axonal damage. Microglia were activated in affected areas but without significant influx of B-cells, T-helper cells, or T-cytotoxic cells. Analysis of the model on a RAG-1 (recombination activating gene-1)-deficient background, lacking functional lymphocytes, did not change the observed disease and pathology compared with immunecompetent mice. We conclude that this model provides the opportunity to study the consequences of adult oligodendrocyte death in the absence of primary axonal injury and reactive cells of the adaptive immune system. Our results indicate that if the blood-brain barrier is not disrupted, myelin debris is not removed efficiently, remyelination is impaired, and axonal integrity is compromised, likely as the result of myelin detachment. This model will allow the evaluation of strategies aimed at improving remyelination to foster axon protection.

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“…Their actions have a major impact on the course of the disease (Bruck, 1997;Griffin et al, 1990Griffin et al, , 1992Kiefer et al, 2001;Martini and Toyka, 2004). Although the invasion of hematogenous macrophages into injured nerves is well described (Bruck, 1997), less attention has been paid to a resident endoneurial macrophage pool, which appears to be predetermined for an early modulation of the ongoing pathogenetic process (Arvidson, 1977;Bonnekoh et al, 1989;Oldfors, 1980).…”

Section: Discussionmentioning

confidence: 99%

“…In neuropathies, macrophages are the main effector cells and have additional disease-modulating functions (Bruck, 1997;Griffin et al, 1990Griffin et al, , 1992Kiefer et al, 2001;Kieseier et al, 2006;Martini and Toyka, 2004). It is widely believed that macrophages involved in the pathogenesis of neuropathies are of hematogenous origin (Bruck et al, 1996;Stoll and Muller, 1999) and infiltrate the endoneurium during the disease process.…”

Section: Introductionmentioning

confidence: 99%

Further evidence for a crucial role of resident endoneurial macrophages in peripheral nerve disorders: Lessons from acrylamide‐induced neuropathy

Müller

Wacker

Getts

et al. 2008

Glia

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Endoneurial macrophages are crucially involved in the pathogenesis of neuropathies. Historically, the macrophage response in neuropathies is believed to be of hematogenous origin. However, recent studies could demonstrate an intrinsic generation of the early macrophage response by resident endoneurial macrophages after traumatic nerve injury and in a model of hereditary neuropathy. We hypothesized that the local macrophage response might suffice to generate an appropriate macrophage response in mild neuropathies, supplemented by infiltrating macrophages only in severe nerve pathology. To clarify this assumption, we investigated the macrophage response in acrylamide-induced neuropathy as a model of a slowly progressive neuropathy with a defined onset. We induced the neuropathy in bone marrow chimeric mice carrying green fluorescent protein transgenic bone marrow, allowing the differentiation of resident (GFP(-)) and invading hematogenous endoneurial (GFP(+)) macrophages. Quantification of GFP(-) and GFP(+) endoneurial macrophages in the sciatic nerve revealed an increase only of resident macrophages in proximal parts, whereas in distal parts a minor additional influx of hematogenous macrophages was observed. The immunohistochemical profile of GFP(-) and GFP(+) macrophages was similar but distal GFP(-) macrophages were differentially activated than their GFP(+) counterparts. Characterization of CCR2-deficient mice revealed a function for this chemokine system in attracting hematogenous macrophages but not in generating the intrinsic macrophage response. In conclusion, we provide evidence for a role of resident macrophages in acrylamide-induced neuropathy. Resident endoneurial macrophages intrinsically generate the macrophage response in this slowly progressive neuropathy, which only becomes supplemented by hematogenous macrophages in distal areas of more pronounced damage.

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Immune-mediated components of hereditary demyelinating neuropathies: lessons from animal models and patients

Cited by 78 publications

References 72 publications

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

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

Genetically Induced Adult Oligodendrocyte Cell Death Is Associated with Poor Myelin Clearance, Reduced Remyelination, and Axonal Damage

Further evidence for a crucial role of resident endoneurial macrophages in peripheral nerve disorders: Lessons from acrylamide‐induced neuropathy

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