|
|
|
|
|
|
|
||
© The Rockefeller University Press,
0021-9525/2001//301 $5.00
The Journal of Cell Biology, Volume 152, Number 2,
, 2001 301-308
Original Article |
The Role of Macrophages in Demyelinating Peripheral Nervous System of Mice Heterozygously Deficient in P0
neuk176{at}mail.uni-wuerzburg.de
Mice heterozygously deficient in the p0 gene (P0+/–) are animal models for some forms of inherited neuropathies. They display a progressive demyelinating phenotype in motor nerves, accompanied by mild infiltration of lymphocytes and increase in macrophages. We have shown previously that the T lymphocytes are instrumental in the demyelination process. This study addresses the functional role of the macrophage in this monogenic myelin disorder.
In motor nerves of P0+/– mice, the number of macrophages in demyelinated peripheral nerves was increased by a factor of five when compared with motor nerves of wild-type mice. Immunoelectron microscopy, using a specific marker for mouse macrophages, displayed macrophages not only in the endoneurium of the myelin mutants, but also within endoneurial tubes, suggesting an active role in demyelination. To elucidate the roles of the macrophages, we crossbred the myelin mutants with a spontaneous mouse mutant deficient in macrophage colony-stimulating factor (M-CSF), hence displaying impaired macrophage activation. In the P0-deficient double mutants also deficient in M-CSF, the numbers of macrophages were not elevated in the demyelinating motor nerves and demyelination was less severe. These findings demonstrate an active role of macrophages during pathogenesis of inherited demyelination with putative impact on future treatment strategies.
Key Words: macrophage • macrophage colony-stimulating factor • myelin degeneration • Schwann cell • inherited neuropathies
© 2001 The Rockefeller University Press
 |
Introduction |
|---|
 TopAbstract Introduction Materials and MethodsResultsDiscussionReferences |
|---|
-subunit of the T cell receptor, reflecting a selective involvement of T cells in the pathogenesis of this inherited demyelinating disease (Schmid et al. 2000). Based on these observations, we proposed that a secondary immunopathological mechanism may contribute to nerve pathology (Schmid et al. 2000). In the present study, we focussed on the potential pathogenic impact of macrophages in inherited neuropathies. We demonstrate that in the animal models macrophages are present in a pattern reminiscent of chronic human and experimental inflammatory neuropathies (Schmidt et al. 1996; Ho et al. 1998; Gold et al. 1999). Moreover, myelin mutants with an additional defect in microglia/macrophage activation show less nerve pathology than P0+/– mice with an intact macrophage system. These findings are potentially important in the context of the understanding of pathomechanisms in hereditary neuropathies and designing disease modifying treatments.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
25% of the F1 progeny with the P0+/– op/wt genotype. Phenotypically normal op/wt, wt/wt, and osteopetrotic (op/op) animals with P0+/– genotype (P0+/– op/op) and normal P0+/+ were the F2 product of the double heterozygous mice and were investigated at the age of 6 mo. Later stages have not been investigated, since op/op mice often die at a premature age. To avoid effects of the different genetic backgrounds, only littermates were analyzed. Genotypes of P0 mutants were determined by conventional PCR as described (Schmid et al. 2000). Mice of the op/op genotype were determined by their typical absence of incisivi (Yoshida et al. 1990) and by a PCR protocol generously provided by Dr. S. Oehen (University of Zürich, Zürich, Switzerland). Since op/wt mice display a normal phenotype and behavior, their genotype had to be determined. The presence of wild-type and mutant allele was detected by using oligonucleotides 5'-TGTGTCCCTTCCTCAGATTACA-3' and 5'-GGTCTCATCTATTATGTCTTGTACCAGCCAAAA-3', which introduce an additional BglI restriction site into the mutant allele. The PCR was performed in a final volume of 20 µl; 300 ng genomic DNA was used as template. The reaction product was denaturated at 95°C for 3 min, followed by 5 cycles (94°C, 1 min; 56°C, 45 s; 72°C, 45 s), 35 cycles (94°C, 30 s; 52°C, 30 s; 72°C, 30 s), and a final extension at 72°C for 10 min with a PE Biosystems thermal cycler. The PCR product was digested with BglI (20 IU; Boehringer) for 1 h at 37°C. After digestion, the characteristic fragments indicating the genotypes could be detected on a polyacrylamide gel by autoradiography. The wild-type was represented by a 99- and 96-bp fragment, op/wt mice by a 99-, 96-, 70-, and 30-bp fragment, and op/op-mice by a 96-, 70-, and 30-bp fragment.
Immunohistochemistry and Immunoelectron Microscopy
For histological analyses, we have chosen the two major branches of the femoral nerve, the quadriceps muscle nerve, and the cutaneous saphenous nerve of the mouse. In some experiments, sciatic nerves have been investigated at the level of the sciatic notch. In addition, we investigated the spinal roots of the third and fourth lumbar segment.
For detection and quantification of T lymphocytes, antibodies to CD8 (a gift from R. Zinkernagel, University of Zürich, Zürich, Switzerland) have been used on serial nerve cryosections as described previously (Schmid et al. 2000).
For detection of macrophages, antibodies to mouse F4/80 (1:300; Serotec) were applied overnight on 14-µm-thick serial sections from fresh frozen femoral nerves and spinal roots. To visualize primary antibodies, a biotinylated secondary antibody to rat Igs was applied for 1 h, followed by avidin/biotin reagent (Dako) and staining with diaminobenzidine-HCl and H2O2. For negative control, the primary antibody was omitted. In femoral nerves, immunoreactive profiles were counted on serial cryosections as described (Schmid et al. 2000). In addition, immunolabeling of single fiber preparations of spinal roots from transcardially perfused mice was performed on free-floating tissue as described (Guénard et al. 1996), with the only modification that primary antibodies were detected by biotinylated secondary antibodies, followed by avidin/biotin reagent as indicated above. In some experiments, immunolabeled fibers were embedded on slides and investigated under the light microscope. In other experiments, the immunolabeled fibers were processed for electron microscopy as described (Guénard et al. 1996).
For double immunofluorescence with the monoclonal rat antibodies to mouse F4/80 and mouse major histocompatibility complex (MHC) class II, fresh frozen sections of femoral nerves and spinal roots were first incubated with the MHC class II antibodies (rat anti–mouse I-Ab, 1:400, 1 h; BD PharMingen), followed by incubation with anti–rat Ig antibodies coupled to FITC (1:200, 30 min; Leinco Technologies). Then, incubation with a blocking reagent followed to avoid nonspecific binding of biotin/avidin system reagents (Vector-Sp-2001, 30 min; Vector Laboratories). As a next step, sections were incubated with a biotinylated F4/80 antibody (1:300, 1 h; Serotec), which was visualized with streptavidin coupled to the red fluorescent dye Cy3 (30 min; Dianova). Control experiments were performed omitting primary antibodies, resulting in complete absence of immunoreactivity.
Double immunofluorescence with polyclonal antibodies to neural cell adhesion molecule from rabbit (1:500; Carenini et al. 1999) and with monoclonal antibodies to mouse MHC class I (ER-HR 52, 1:100; Dianova) from rat was performed by simultaneous incubation of primary antibodies for 1.5 h, followed by simultaneous incubation of secondary antibodies (goat anti–rabbit Cy3, 1:500; Dianova; goat anti–rat FITC, 1:500; Leinco Technologies) for 1.5 h. Control experiments were performed omitting primary antibodies resulting in complete absence of immunoreactivity.
For localizing M-CSF receptor expression, double immunofluorescence using rabbit anti–mouse M-CSF receptor antibody (06-175, 1:5,000; UBI) and the macrophage- and microglia-specific rat antibody to mouse Mβ2 integrin (5C6, 1:5,000; Serotec) has been performed as described (Raivich et al. 1998), with the only exception that teased ventral root fibers instead of free-floating brain sections have been used. Digital micrographs of the FITC and Cy3 fluorescence were taken using a Leica TCS 4D confocal laser microscope with a 63x objective in an 8-bit greyscale (b/w), 1,024 x 1,024 pixel format as described in previous studies (Raivich et al. 1998; Kloss et al. 1999). 10 consecutive, equidistant levels spacing 12 µm were recorded and condensed to a single bitmap using the MaxIntens algorithm.
Tissue Preservation for Light and Conventional Electron Microscopy and Morphometry
Femoral nerves and spinal roots of mice were processed for light and electron microscopy as described previously (Schmid et al. 2000). Analysis of the g-ratio (diameter of axons/diameter of fiber) of randomly selected nerve fibers was performed on electron micrographs of the quadriceps nerve and of the ventral roots at a final magnification of 1,600x using Scion Image Software (Scion Corp.).
Statistics
Statistical analysis was performed by using Student's t test or Mann-Whitney U test, when appropriate. P < 0.05 was considered statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Mβ2-positive Macrophages
|
Mβ2. Labeling for M-CSF receptor was exclusively associated with macrophages, whereas Mβ2-negative cells, such as Schwann cells and endoneurial fibroblasts, were never labeled with antibodies to M-CSF receptor (Fig. 2). Macrophages of the P0+/+ mice showed a weak labeling for M-CSF receptor (Fig. 2). Interestingly, P0+/– mice showed some very strongly labeled macrophages in addition to weakly labeled macrophages (Fig. 2). These data show that M-CSF receptor expression is confined to macrophages and that expression levels are increased in some macrophages of the P0+/– mice.
|
3.5-fold at 6 mo, and 5-fold at 12 mo of age (P < 0.001; Fig. 1 C). Macrophage counts in the cutaneous saphenous nerve of P0+/+ mice revealed a similar number as that in the normal, wild-type quadriceps nerves at any age investigated (Fig. 1 C). The number of macrophages in the P0+/– saphenous nerves was normal and did not show an age-dependent increase, a finding in line with the still unexplained lack of demyelinating neuropathy in the sensory nerves of P0+/– mice (Martini et al. 1995; Shy et al. 1997) and of some other myelin mutants (Martini 1997). This divergence between muscular and cutaneous nerves in the P0+/– animals also extended to spinal roots, with the macrophages consistently more numerous in the ventral roots than in the dorsal, or in any nerves from the normal, P0+/+ mice. In addition to differences in number, the F4/80-immunoreactive cells in the quadriceps nerves and ventral roots of P0+/– mice also appeared larger compared with saphenous nerves and dorsal roots of the same genotype, or with spinal roots and femoral nerves of P0+/+ mice (Fig. 1 B). Some of these macrophages from the P0+/– nerves were also laden with lipid vacuoles or with material reminiscent of myelin debris, a finding that we did not observe in the P0+/+ mice or in the P0+/– sensory nerves.
Conventional Electron Microscopy and Immunoelectron Microscopic Localization of Macrophages in Peripheral Nerves of P0+/– Mice
To investigate the spatial relationship of macrophages to demyelinating fibers, we performed conventional electron microscopy and immunoelectron microscopy with F4/80 antibodies in quadriceps nerves and ventral roots of 6-mo-old P0+/– mice.
In ultrathin sections of conventionally prepared quadriceps nerves and ventral roots, endoneurial cells laden with lipid vacuoles or myelin debris were identified as macrophages. They were often found in the endoneurium and were characterized by polymorphic nuclei, abundant heterochromatin, and microvillus-like processes that extended from the surface. Occasionally, such cells were found in the endoneurial tubes, i.e., within the Schwann cell basal laminae (Fig. 3A and Fig. B). In very rare cases, macrophage-like cells were seen just penetrating the basal lamina with a cellular process, reflecting the invasion or leave of the endoneurial tube (Fig. 3 B). However, since Schwann cells can also phagocytose myelin and penetrate basal laminae under pathological conditions, morphological criteria alone appeared insufficient to characterize unequivocally the spatial relationship between macrophages and nerve fibers. Therefore, we performed immunoelectron microscopy using the macrophage-specific antibody F4/80.
|
P0/op Double Mutants: Fewer Macrophages in Femoral Nerves and Less Severe Demyelination
In the current study, we used mice deficient for M-CSF (op/op) and heterozygous for P0 (P0+/–) to investigate the role of macrophages in genetically caused demyelination. Myelin mutant littermates with the normal M-CSF phenotype (P0+/– op/wt or P0+/– wt/wt) served as controls.
In the quadriceps nerve of M-CSF–deficient, P0 heterozygous mice (P0+/– op/op), the number of macrophages was not increased compared with mice with normal P0 dosage (P0+/+ op/wt and P0+/+ op/op; Fig. 4). In contrast, and similar to the findings obtained from P0+/– mice (Fig. 1 C), the number of macrophages in the quadriceps nerve was strongly elevated in P0+/– op/wt mice compared with op mutants with normal P0 gene dosage (P0+/+ op/wt and P0+/+ op/op mice; P = 0.01; Fig. 4). Thus, homozygous deficiency in M-CSF leads to a lack of an age-dependent macrophage increase in the motor nerves of P0+/– mutants.
|
Comparison of semithin sections of quadriceps nerves and ventral roots from 6-mo-old P0+/– op/wt mice with those from the P0+/– op/op littermates revealed that all mice with P0+/– genotype showed pathological alterations indicative of demyelination. However, the severity of the pathological alterations was clearly reduced in mice with the op/op genotype. Thus, an investigator who was not aware of the genotype (R. Martini) could unequivocally distinguish the nerves from P0+/– op/wt mice from those of P0+/– op/op mice.
The thickness of myelin was a particularly striking parameter in the presence or absence of M-CSF. Motor nerves from P0+/– op/op mice always had thicker myelin sheaths than those from the P0+/– op/wt littermates. This difference was strongest in the ventral roots (Fig. 5A and Fig. B), but substantial differences in myelin thickness between P0+/– op/wt and P0+/– op/op mice were also obtained for the quadriceps nerves (not shown). Semithin sections of quadriceps nerves and ventral roots of P0+/+ op/wt and P0+/+ op/op mice were also investigated at the age of 6 mo. These nerves were of normal phenotype with thick myelin and absence of features indicative of demyelination independent of the op genotype (not shown).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Functional Role of Macrophages in P0+/– Mice
Previous studies in M-CSF–deficient (op/op) mice revealed an impaired survival, development, and differentiation of the monocyte hematopoietic cell lineage in the absence of M-CSF (Felix et al. 1990; Metcalf 1991; Witmer-Pack et al. 1993; Stanley et al. 1997; for review see Teitelbaum 2000). In the central nervous system of the op/op mice, microglial activation is severely impaired under various pathological conditions (Raivich et al. 1994; Berezovskaya et al. 1995). In the peripheral nervous system of the osteopetrotic P0+/+ mice, the number of resident macrophages was normal. However, the number of macrophages did not increase in the myelin-deficient osteopetrotic double mutants, which is reminiscent of findings in the injured central nervous system of osteopetrotic single mutants (Raivich et al. 1994). This lack of macrophage reaction upon the diseased peripheral nervous tissue in op/op mice must be considered to be due to a direct and exclusive impairment of the macrophage response, since we show that in P0+/– mice M-CSF receptor was exclusively found on macrophages, a situation similar to the normal and injured central nervous system (Raivich et al. 1998). Thus, our combined findings not only demonstrate that macrophages are pivotal cellular mediators of myelin damage in this primarily genetically caused demyelinating neuropathy, but also that M-CSF is a critical molecule for the activation of these myelin-phagocytosing cells.
Macrophages play important roles under several pathological conditions, including inflammatory disorders of the nervous system (Hartung et al. 1998; Ho et al. 1998; Kiefer et al. 1998; Gold et al. 1999). In the peripheral nervous system, these functions are particularly well characterized in experimental autoimmune neuritis, the animal model for the Guillain-Barré syndrome. In this disease, macrophages present antigen to autoimmune lymphocytes in the context of MHC class II, which results in activation and proliferation of T lymphocytes (Hartung et al. 1998; Gold et al. 1999). Interestingly, in P0+/– mice the previously reported increase of the number of T lymphocytes (Schmid et al. 2000) appears to be lacking when macrophage activation is compromised due to the absence of M-CSF. Since T lymphocytes do not carry M-CSF receptors (Raivich et al. 1998), one has to postulate that the reduced number of antigen-presenting and/or cytokine-secreting macrophages might be the reason for the accompanying lack of increase of T lymphocytes.
Macrophages are also involved in the effector phase of the disorders (Craggs et al. 1984; Jung et al. 1993; Hartung et al. 1998; Gold et al. 1999). In electron microscopy studies of Guillain-Barré syndrome and experimental autoimmune neuritis, activated macrophages are seen in direct contact with myelin (Ballin and Thomas 1969; Lampert 1969; Ho et al. 1998; Smith 1999) which is similar to the macrophage–myelin apposition in our animal model for inherited neuropathies. Apart from the direct physical attack, macrophages also synthesize numerous factors, such as arachidonic acid metabolites, oxygen radicals, nitrous oxide, matrix metalloproteinases, and proinflammatory cytokines that can all act to jeopardize myelin stability and the normal function of the myelin-forming Schwann cell (Banati et al. 1993; Ho et al. 1998; Gold et al. 1999).
The Role of Macrophages in Human Inherited Neuropathies
Similar to our animal model, an increased number of endoneurial macrophages has also been reported in nerve biopsies of patients with inherited peripheral neuropathies (Sommer and Schröder 1995; Schmidt et al. 1996; Stoll et al. 1998). In many forms of CMT the active phase of demyelination occurs during childhood (Gabreëls-Festen et al. 1995; Garcia et al. 1998; Thomas 1999), and nerve biopsies were usually not performed. It is conceivable that circulating monocytes enter the peripheral nerve to clear the myelin debris that results from genetically mediated disintegration of myelin. However, macrophages may also actively help to destroy the myelin produced by the mutant Schwann cells. This notion is clearly supported by the data of the current study in P0 mutant mice, as was suggested previously by noting the close association of macrophages with the myelin at the ultrastructural level of inherited human neuropathy (Vital et al. 1992).
What are the possible implications of the current findings for our understanding of human inherited neuropathies? Only few inherited neuropathies are caused by an abnormal gene dosage of P0 (Nelis et al. 1999), but this does not argue against the possibility that similar mechanisms can take place in demyelinating CMT forms that are unrelated to P0 mutations. Indeed, a similar elevation of macrophage numbers as seen in P0+/– mice has recently been found in Cx32-deficient mice (Kobsar, I., M. Mäurer, and R. Martini, unpublished observations), a model for the X-linked form of CMT (Anzini et al. 1997; Scherer et al. 1998). Most interestingly, in some patients with CMT a rather rapid worsening or even overt inflammation (Gregory et al. 1993; Malandrini et al. 1999) with clinical response to corticosteroid treatment (Bird and Slaky 1991; Crawford and Griffin 1991; Dyck et al. 1982) or plasma exchange (Malandrini et al. 1999) has been described. It is possible that these clinical cases are at the extreme end of an immunopathologic and chronic disease process that may be unnoticed in the majority of cases. Future studies in the mouse models as well as in human biopsies using appropriate macrophage markers (Kiefer et al. 1998) are needed to substantiate our conclusions with the aim to develop treatment strategies that culminate in the impairment of the detrimental immune cells in peripheral nerves of patients.
|
Acknowledgments |
|---|
The study was supported by the Deutsche Forschungsgemeinschaft (SFB 581 to R. Martini and K.V. Toyka; Priority Program "Microglia" MA1053/3-1 and 3-2 to R. Martini; and Ra 486/3-1 to G. Raivich.); Gemmeinnützige Hertie-Stiftung (GHS2/476/98 to R. Martini); by the German Ministry of Research (grant 01KO9703/3 to G. Raivich and Interdisziplinäres Zentrum für klinische Forschung, project C-6, to R. Martini); and by local research funds of the University of Würzburg (to R. Martini).
Submitted: 22 September 2000
Revised: 28 November 2000
Accepted: 4 December 2000
S. Carenini's present address is Novartis-Pharmanalytica, CH-6601 Locarno, Switzerland.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Anzini P., Neuberg D.H.H., Schachner M., Nelles E., Willecke K., Zielasek J., Toyka K.V., Suter U. & Martini R.. Structural abnormalities and deficient maintenance of peripheral nerve myelin in mice lacking the gap junction protein connexin 32, J. Neurosci., 17, 1997, 4545–4551.
Ballin R.H. & Thomas P.K.. Electron microscope observations on demyelination and remyelination in experimental allergic neuritis. I. Demyelination, J. Neurol. Sci, 8, 1969, 1–18.[Medline]
Banati R.B., Gehrmann J., Schubert P. & Kreutzberg G.W.. Cytotoxicity of microglia, Glia, 7, 1993, 111–118.[Medline]
Berezovskaya O., Maysinger D. & Fedoroff S.. The hematopoietic cytokine, colony-stimulating factor 1, is also a growth factor in the CNScongenital absence of CSF-1 in mice results in abnormal microglial response and increased neuron vulnerability to injury, Int. J. Dev. Neurosci, 13, 1995, 285–299.[Medline]
Bird S.J. & Slaky J.T.. Corticosteroid-responsive dominantly inherited neuropathy in childhood, Neurology, 41, 1991, 437–439.
Bolino A., Muglia M., Conforti F.L., LeGuern E., Salih M.A.M., Georgiou A.-M., Christodoulou K., Hausmanowa-Petrusewicz I., Mandich P. & Schenone A.. Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2, Nat. Genet, 25, 2000, 17–19.[Medline]
Carenini S., Montag D., Schachner M. & Martini R.. Subtle roles of N-CAM and MAG during Schwann cell spiralling in P0-deficient mice, Glia, 27, 1999, 203–212.[Medline]
Craggs R.I., King R.H. & Thomas P.K.. The effect of suppression of macrophage activity on the development of experimental allergic neuritis, Acta Neuropathol, 62, 1984, 316–323.[Medline]
Crawford T.O. & Griffin J.W.. Morphometrical and ultrastructural evaluation of the sural nerve in children with Charcot-Marie-Toothimplications for pathogenesis and treatment, Ann. Neurol, 30, 1991, 500.
Dyck P.J., Swanson C.J., Low P.A., Bartleson J.D. & Lambert E.H.. Prednisone-responsive hereditary motor and sensory neuropathy, Mayo Clin. Proc, 57, 1982, 239–246.[Medline]
Felix R., Cecchini M.G., Hofstetter W., Elford P.R., Stutzer A. & Fleisch H.. Impairment of macrophage colony-stimulating factor production and lack of resident bone marrow macrophages in the osteopetrotic op/op mouse, J. Bone Miner. Res, 5, 1990, 781–789.[Medline]
Gabreëls-Festen A.A., Bolhuis P.A., Hoogendijk J.E., Valentijn L.J., Eshuis E.J. & Gabreels F.J.M.. Charcot-Marie-Tooth disease type 1Amorphological phenotype of the 17p duplication versus PMP22 point mutations, Acta Neuropathol, 90, 1995, 645–649.[Medline]
Garcia A., Combarros O., Calleja J. & Berciano J.. Charcot-Marie-Tooth disease type 1A with 17p duplication in infancy and early childhooda longitudinal clinical and electrophysiologic study, Neurology, 50, 1998, 1061–1067.
Gold R., Archelos J.J. & Hartung H.P.. Mechanisms of immune regulation in the peripheral nervous system, Brain Pathol, 9, 1999, 343–360.[Medline]
Gregory R., Thomas P.K., King R.H.M., Hallam P.L.J., Malcolm S., Hughes R.A.C. & Harding A.E.. Coexistence of hereditary motor and sensory neuropathy type Ia and IgM paraproteinemic neuropathy, Ann. Neurol, 33, 1993, 649–652.[Medline]
Guénard V., Montag D., Schachner M. & Martini R.. Onion bulb cells in mice deficient for myelin genes share molecular properties with immature, differentiated non-myelinating and denervated Schwann cells, Glia, 18, 1996, 27–38.[Medline]
Hartung H.P., van der Meche F.G.A. & Pollard J.D.. Guillain-Barre syndrome, CIDP and other chronic immune-mediated neuropathies, Curr. Opin. Neurol, 11, 1998, 497–513.[Medline]
Ho T.W., McKhann G.M. & Griffin J.W.. Human autoimmune neuropathies, Annu. Rev. Neurosci, 21, 1998, 187–226.[Medline]
Jung S., Huitinga I., Schmidt B., Zielasek J., Dijkstra C.D., Toyka K.V. & Hartung H.P.. Selective elimination of macrophages by dichlormethylene diphosphonate-containing liposomes suppresses experimental autoimmune neuritis, J. Neurol. Sci, 119, 1993, 195–202.[Medline]
Kalaydjieva L., Gresham D., Gooding R., Heather L., Baas F., de Jonge R., Blechschmidt K., Angelicheva D., Chandler D. & Worsley P.. N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom, Am. J. Hum. Genet, 67, 2000, 47–58.[Medline]
Kiefer R., Kieseier B.C., Bruck W., Hartung H.P. & Toyka K.V.. Macrophage differentiation antigens in acute and chronic autoimmune polyneuropathies, Brain, 121, 1998, 469–479.
Kloss C.U., Werner A., Klein M.A., Shen J., Menuz K., Probst J.C., Kreutzberg G.W. & Raivich G.. Integrin family of cell adhesion molecules in the injured brainregulation and cellular localization in the normal and regenerating mouse facial motor nucleus, J. Comp. Neurol, 411, 1999, 162–178.[Medline]
Lampert P.W.. Mechanism of demyelination in experimental allergic neuritis. Electron microscopic studies, Lab. Invest, 20, 1969, 127–138.[Medline]
Malandrini A., Villanova M., Dotti M.T. & Frederico A.. Acute inflammatory neuropathy in Charcot-Marie-Tooth disease, Neurology, 52, 1999, 859–861.
Martini R.. Animal models for inherited peripheral neuropathies, J. Anat, 191, 1997, 321–336.[Medline]
Martini R.. Animal models for inherited peripheral neuropathieschances to find treatment strategies?, J. Neurosci. Res, 61, 2000, 244–250.[Medline]
Martini R., Zielasek J., Toyka K.V., Giese K.P. & Schachner M.. P0-deficient mice show myelin degeneration in peripheral nerves characteristic of inherited human neuropathies, Nat. Genet, 11, 1995, 281–286.[Medline]
Mersiyanova I.V., Perepelov A.V., Polyakov A.V., Sidnikov V.F., Dadli E.L., Oparin R.B., Petrin A.N. & Evgrafov O.V.. A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene, Am. J. Hum. Genet, 67, 2000, 37–46.[Medline]
Metcalf D.. The Florey Lecture, 1991. The colony-stimulating factorsdiscovery to clinical use, Philos. Trans. R. Soc. Lond. B Biol. Sci, 333, 1991, 147–173.[Medline]
Nelis E., Haites N. & Van Broeckhoven C.. Mutations in the peripheral myelin genes and associated genes in inherited peripheral neuropathies, Hum. Mutat, 13, 1999, 11–28.[Medline]
Raivich G., Moreno-Flores M.T., Möller J.C. & Kreutzberg G.W.. Inhibition of posttraumatic microglial proliferation in a genetic model of macrophage colony-stimulating factor deficiency in the mouse, Eur. J. Neurosci, 6, 1994, 1615–1618.[Medline]
Raivich G., Haas S., Werner A., Klein M.A., Kloss C. & Kreutzberg G.W.. Regulation of MCSF receptors on microglia in the normal and injured mouse central nervous systema quantitative immunofluorescence study using confocal laser microscopy, J. Comp. Neurol, 395, 1998, 342–358.[Medline]
Scherer S.S., Xu Y.T., Nelles E., Fischbeck K., Willecke K. & Bone L.J.. Connexin32-null mice develop demyelinating peripheral neuropathy, Glia, 24, 1998, 8–20.[Medline]
Schmid C.D., Stienekemeier M., Oehen S., Bootz F., Zielasek J., Gold R., Toyka K.V., Schachner M. & Martini R.. Immune deficiency in mouse models for inherited peripheral neuropathies leads to improved myelin maintenance, J. Neurosci, 20, 2000, 729–735.
Schmidt B., Toyka K.V., Kiefer R., Full J., Hartung H.P. & Pollard J.. Inflammatory infiltrates in sural nerve biopsies in Guillain-Barre syndrome and chronic inflammatory demyelinating neuropathy, Muscle Nerve, 19, 1996, 474–487.[Medline]
Shy M.E., Arroyo E., Sladky J., Menichella D., Jiang H., Xu W., Kamholz J. & Scherer S.S.. Heterozygous P0 knock-out mice develop a peripheral neuropathy that resembles chronic inflammatory demyelinating polyneuropathy (CIDP), J. Neuropathol. Exp. Neurol, 56, 1997, 811–821.[Medline]
Skre H.. Genetic and clinical aspects of Charcot-Marie-Tooth's disease, Clin. Genet, 6, 1974, 98–118.[Medline]
Smith M.E.. Phagocytosis of myelin in demyelinating diseasea review, Neurochem. Res, 24, 1999, 261–268.[Medline]
Sommer C. & Schröder J.M.. HLA-DR expression in peripheral neuropathiesthe role of Schwann cells, resident and hematogenous macrophages, and endoneurial fibroblasts, Acta Neuropathol., 89, 1995, 63–71.[Medline]
Stanley E.R., Berg K.L., Einstein D.B., Lee P.S., Pixley F.J., Wang Y. & Yeung Y.G.. Biology and action of colony-stimulating factor-1, Mol. Reprod. Dev, 46, 1997, 4–10.[Medline]
Stoll G., Gabreëls-Festen A.A.W.M., Jander S., Müller H.W. & Hanemann C.O.. Major histocompatibility complex class II expression and macrophage responses in genetically proven Charcot-Marie-Tooth type 1 and hereditary neuropathy with liability to pressure palsies, Muscle Nerve, 21, 1998, 1419–1427.[Medline]
Suter U. & Snipes G.J.. Biology and genetics of hereditary motor and sensory neuropathies, Annu. Rev. Neurosci, 18, 1995, 45–75.[Medline]
Teitelbaum S.L.. Bone resorption by osteoclasts, Science, 289, 2000, 1504–1508.
Thomas P.K.. Overview of Charcot-Marie-Tooth disease 1A, Ann. NY Acad. Sci, 833, 1999, 1–5.
Vital A., Vital C., Julien J. & Fontan D.. Occurrence of active demyelinating lesions in children with hereditary motor and sensory neuropathy (HMSN) type I, Acta Neuropathol. (Berl, 84, 1992, 433–436.[Medline]
Witmer-Pack M.D., Hughes D.A., Schuler G., Lawson L., McWilliam A., Inaba K., Steinman R.M. & Gordon S.. Identification of macrophages and dendritic cells in the osteopetrotic (op/op) mouse, J. Cell Sci, 104, 1993, 1021–1029.[Abstract]
Yoshida H., Hayashi S.-I., Kunisasa Z., Ogawa M., Nishikawa S., Okamura H., Sudo T., Shultz L.D. & Nishikawa S.. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene, Nature, 345, 1990, 442–444.[Medline]
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
