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Fcγ receptor-mediated inflammation inhibits axon regeneration.

Zhang G, Bogdanova N, Gao T, Song JJ, Cragg MS, Glennie MJ, Sheikh KA - PLoS ONE (2014)

Bottom Line: Anti-glycan/ganglioside antibodies are the most common immune effectors found in patients with Guillain-Barré Syndrome, which is a peripheral autoimmune neuropathy.These findings have clinical implications for nerve repair and recovery in antibody-mediated immune neuropathies.Our results add to the complexity of axon regeneration in injured peripheral and central nervous systems as adverse effects of B cells and autoantibodies on neural injury and repair are increasingly recognized.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Texas Medical School at Houston, Houston, Texas, United States of America.

ABSTRACT
Anti-glycan/ganglioside antibodies are the most common immune effectors found in patients with Guillain-Barré Syndrome, which is a peripheral autoimmune neuropathy. We previously reported that disease-relevant anti-glycan autoantibodies inhibited axon regeneration, which echo the clinical association of these antibodies and poor recovery in Guillain-Barré Syndrome. However, the specific molecular and cellular elements involved in this antibody-mediated inhibition of axon regeneration are not previously defined. This study examined the role of Fcγ receptors and macrophages in the antibody-mediated inhibition of axon regeneration. A well characterized antibody passive transfer sciatic nerve crush and transplant models were used to study the anti-ganglioside antibody-mediated inhibition of axon regeneration in wild type and various mutant and transgenic mice with altered expression of specific Fcγ receptors and macrophage/microglia populations. Outcome measures included behavior, electrophysiology, morphometry, immunocytochemistry, quantitative real-time PCR, and western blotting. We demonstrate that the presence of autoantibodies, directed against neuronal/axonal cell surface gangliosides, in the injured mammalian peripheral nerves switch the proregenerative inflammatory environment to growth inhibitory milieu by engaging specific activating Fcγ receptors on recruited monocyte-derived macrophages to cause severe inhibition of axon regeneration. Our data demonstrate that the antibody orchestrated Fcγ receptor-mediated switch in inflammation is one mechanism underlying inhibition of axon regeneration. These findings have clinical implications for nerve repair and recovery in antibody-mediated immune neuropathies. Our results add to the complexity of axon regeneration in injured peripheral and central nervous systems as adverse effects of B cells and autoantibodies on neural injury and repair are increasingly recognized.

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Anti-glycan Ab-mediated inhibition of axon regeneration was independent of inhibitory FcγRIIB.Sciatic nerve micrographs from Fcgr2b- mice treated with sham Ab or GD1a/GT1b-2b mAb (A). MF counts in sciatic (B) or tibial (C) nerves from WT or Fcgr2b- mice treated with sham Ab or GD1a/GT1b-2b mAb. Quantitative electrophysiological data showing CMAP amplitudes in WT mice or Fcgr2b- mutants treated with sham Ab or GD1a/GT1b-2b mAb (D). *p < 0.001 (Two-way ANOVA, Tukey’s multiple comparisons test). N  =  12 per group. Error bars, s.e.m. Scale bar, 10 µm. WT  =  wild type; NS  =  not significant; MF  =  myelinated nerve fibers.
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pone-0088703-g005: Anti-glycan Ab-mediated inhibition of axon regeneration was independent of inhibitory FcγRIIB.Sciatic nerve micrographs from Fcgr2b- mice treated with sham Ab or GD1a/GT1b-2b mAb (A). MF counts in sciatic (B) or tibial (C) nerves from WT or Fcgr2b- mice treated with sham Ab or GD1a/GT1b-2b mAb. Quantitative electrophysiological data showing CMAP amplitudes in WT mice or Fcgr2b- mutants treated with sham Ab or GD1a/GT1b-2b mAb (D). *p < 0.001 (Two-way ANOVA, Tukey’s multiple comparisons test). N  =  12 per group. Error bars, s.e.m. Scale bar, 10 µm. WT  =  wild type; NS  =  not significant; MF  =  myelinated nerve fibers.

Mentions: The inhibition of axon regeneration induced by GD1a/GT1b-2b was abrogated in Fcer1g- mice, which exclusively express inhibitory FcγRIIB. This led to the hypothesis that the inhibitory FcγRs are not involved in the anti-glycan Ab-mediated inhibition. Availability of Fcgr2b - mice (which lack inhibitory FcγRIIB but express all activating FcγRs) allowed reconstitution studies. We found that axon regeneration in Fcgr2b - mice was severely inhibited by GD1a/GT1b-2b mAb. The numbers of regenerating MF in sciatic (57±19) and tibial (9±8) nerves in GD1a/GT1b-2b-treated Fcgr2b - mice were significantly decreased compared with those in sham Ab-treated sciatic (2177±225) and tibial (678±97) nerves (Figures 5A-5C). GD1a/GT1b-2b induced even more severe inhibition of axonal regeneration in Fcgr2b - mice (SN, 57±19 and TN, 9±8) than what it did in the control animals (SN, 299±22 and TN, 36±6). Electrophysiological studies were consistent with morphological findings showing that the treatment with GD1a/GT1b-2b mAb abolished evoked CMAP responses in Fcgr2b - mutants (Figure 5D). These studies in Fcer1g- and Fcgr2b - mice indicated that anti-glycan Ab-mediated inhibition of axon regeneration in this model was completely dependent on the expression of activating FcγRs.


Fcγ receptor-mediated inflammation inhibits axon regeneration.

Zhang G, Bogdanova N, Gao T, Song JJ, Cragg MS, Glennie MJ, Sheikh KA - PLoS ONE (2014)

Anti-glycan Ab-mediated inhibition of axon regeneration was independent of inhibitory FcγRIIB.Sciatic nerve micrographs from Fcgr2b- mice treated with sham Ab or GD1a/GT1b-2b mAb (A). MF counts in sciatic (B) or tibial (C) nerves from WT or Fcgr2b- mice treated with sham Ab or GD1a/GT1b-2b mAb. Quantitative electrophysiological data showing CMAP amplitudes in WT mice or Fcgr2b- mutants treated with sham Ab or GD1a/GT1b-2b mAb (D). *p < 0.001 (Two-way ANOVA, Tukey’s multiple comparisons test). N  =  12 per group. Error bars, s.e.m. Scale bar, 10 µm. WT  =  wild type; NS  =  not significant; MF  =  myelinated nerve fibers.
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pone-0088703-g005: Anti-glycan Ab-mediated inhibition of axon regeneration was independent of inhibitory FcγRIIB.Sciatic nerve micrographs from Fcgr2b- mice treated with sham Ab or GD1a/GT1b-2b mAb (A). MF counts in sciatic (B) or tibial (C) nerves from WT or Fcgr2b- mice treated with sham Ab or GD1a/GT1b-2b mAb. Quantitative electrophysiological data showing CMAP amplitudes in WT mice or Fcgr2b- mutants treated with sham Ab or GD1a/GT1b-2b mAb (D). *p < 0.001 (Two-way ANOVA, Tukey’s multiple comparisons test). N  =  12 per group. Error bars, s.e.m. Scale bar, 10 µm. WT  =  wild type; NS  =  not significant; MF  =  myelinated nerve fibers.
Mentions: The inhibition of axon regeneration induced by GD1a/GT1b-2b was abrogated in Fcer1g- mice, which exclusively express inhibitory FcγRIIB. This led to the hypothesis that the inhibitory FcγRs are not involved in the anti-glycan Ab-mediated inhibition. Availability of Fcgr2b - mice (which lack inhibitory FcγRIIB but express all activating FcγRs) allowed reconstitution studies. We found that axon regeneration in Fcgr2b - mice was severely inhibited by GD1a/GT1b-2b mAb. The numbers of regenerating MF in sciatic (57±19) and tibial (9±8) nerves in GD1a/GT1b-2b-treated Fcgr2b - mice were significantly decreased compared with those in sham Ab-treated sciatic (2177±225) and tibial (678±97) nerves (Figures 5A-5C). GD1a/GT1b-2b induced even more severe inhibition of axonal regeneration in Fcgr2b - mice (SN, 57±19 and TN, 9±8) than what it did in the control animals (SN, 299±22 and TN, 36±6). Electrophysiological studies were consistent with morphological findings showing that the treatment with GD1a/GT1b-2b mAb abolished evoked CMAP responses in Fcgr2b - mutants (Figure 5D). These studies in Fcer1g- and Fcgr2b - mice indicated that anti-glycan Ab-mediated inhibition of axon regeneration in this model was completely dependent on the expression of activating FcγRs.

Bottom Line: Anti-glycan/ganglioside antibodies are the most common immune effectors found in patients with Guillain-Barré Syndrome, which is a peripheral autoimmune neuropathy.These findings have clinical implications for nerve repair and recovery in antibody-mediated immune neuropathies.Our results add to the complexity of axon regeneration in injured peripheral and central nervous systems as adverse effects of B cells and autoantibodies on neural injury and repair are increasingly recognized.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Texas Medical School at Houston, Houston, Texas, United States of America.

ABSTRACT
Anti-glycan/ganglioside antibodies are the most common immune effectors found in patients with Guillain-Barré Syndrome, which is a peripheral autoimmune neuropathy. We previously reported that disease-relevant anti-glycan autoantibodies inhibited axon regeneration, which echo the clinical association of these antibodies and poor recovery in Guillain-Barré Syndrome. However, the specific molecular and cellular elements involved in this antibody-mediated inhibition of axon regeneration are not previously defined. This study examined the role of Fcγ receptors and macrophages in the antibody-mediated inhibition of axon regeneration. A well characterized antibody passive transfer sciatic nerve crush and transplant models were used to study the anti-ganglioside antibody-mediated inhibition of axon regeneration in wild type and various mutant and transgenic mice with altered expression of specific Fcγ receptors and macrophage/microglia populations. Outcome measures included behavior, electrophysiology, morphometry, immunocytochemistry, quantitative real-time PCR, and western blotting. We demonstrate that the presence of autoantibodies, directed against neuronal/axonal cell surface gangliosides, in the injured mammalian peripheral nerves switch the proregenerative inflammatory environment to growth inhibitory milieu by engaging specific activating Fcγ receptors on recruited monocyte-derived macrophages to cause severe inhibition of axon regeneration. Our data demonstrate that the antibody orchestrated Fcγ receptor-mediated switch in inflammation is one mechanism underlying inhibition of axon regeneration. These findings have clinical implications for nerve repair and recovery in antibody-mediated immune neuropathies. Our results add to the complexity of axon regeneration in injured peripheral and central nervous systems as adverse effects of B cells and autoantibodies on neural injury and repair are increasingly recognized.

Show MeSH
Related in: MedlinePlus