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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 Abs induced inhibition of axon regeneration in C3- mice.Light micrographs of sciatic nerve from sham Ab- or GD1a/GT1b-2b-treated C3- mice (A). Regenerating MF counts in sciatic and tibial nerves from C3- mice treated with sham Ab or GD1a/GT1b-2b mAb (B). *p<0.05; **p<0.001 (Student’s t-test). N  =  12 per group. Error bars, s.e.m. Scale bar, 10 µm. MF  =  myelinated nerve fibers.
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pone-0088703-g010: Anti-glycan Abs induced inhibition of axon regeneration in C3- mice.Light micrographs of sciatic nerve from sham Ab- or GD1a/GT1b-2b-treated C3- mice (A). Regenerating MF counts in sciatic and tibial nerves from C3- mice treated with sham Ab or GD1a/GT1b-2b mAb (B). *p<0.05; **p<0.001 (Student’s t-test). N  =  12 per group. Error bars, s.e.m. Scale bar, 10 µm. MF  =  myelinated nerve fibers.

Mentions: Complement-fixing pathogenic Abs can cause nerve injury through the activation of classical complement pathway. We previously demonstrated that membrane attack complex (C5b-9) is not involved in anti-glycan Ab-induced inhibition of axon regeneration [14]. In this study we examined the role of C3 complement component, a critical component of classical complement pathway, in Ab-mediated inhibition. The effect of anti-glycan mAb, GD1a/GT1b-2b, was examined in C3- mice. We found that GD1a/GT1b-2b mAb produced severe inhibition of axon regeneration in C3- mice (Figure 10). The numbers of regenerating MF in GD1a/GT1b-2b-treated sciatic (354±90) and tibial (42±9) nerves were significantly reduced compared with that in sham Ab treated sciatic (1501±84) and tibial (409±25) nerves. These data provide further evidence that complement is not involved in this Ab-mediated inhibition of axon regeneration in our models.


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 Abs induced inhibition of axon regeneration in C3- mice.Light micrographs of sciatic nerve from sham Ab- or GD1a/GT1b-2b-treated C3- mice (A). Regenerating MF counts in sciatic and tibial nerves from C3- mice treated with sham Ab or GD1a/GT1b-2b mAb (B). *p<0.05; **p<0.001 (Student’s t-test). N  =  12 per group. Error bars, s.e.m. Scale bar, 10 µm. MF  =  myelinated nerve fibers.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3921223&req=5

pone-0088703-g010: Anti-glycan Abs induced inhibition of axon regeneration in C3- mice.Light micrographs of sciatic nerve from sham Ab- or GD1a/GT1b-2b-treated C3- mice (A). Regenerating MF counts in sciatic and tibial nerves from C3- mice treated with sham Ab or GD1a/GT1b-2b mAb (B). *p<0.05; **p<0.001 (Student’s t-test). N  =  12 per group. Error bars, s.e.m. Scale bar, 10 µm. MF  =  myelinated nerve fibers.
Mentions: Complement-fixing pathogenic Abs can cause nerve injury through the activation of classical complement pathway. We previously demonstrated that membrane attack complex (C5b-9) is not involved in anti-glycan Ab-induced inhibition of axon regeneration [14]. In this study we examined the role of C3 complement component, a critical component of classical complement pathway, in Ab-mediated inhibition. The effect of anti-glycan mAb, GD1a/GT1b-2b, was examined in C3- mice. We found that GD1a/GT1b-2b mAb produced severe inhibition of axon regeneration in C3- mice (Figure 10). The numbers of regenerating MF in GD1a/GT1b-2b-treated sciatic (354±90) and tibial (42±9) nerves were significantly reduced compared with that in sham Ab treated sciatic (1501±84) and tibial (409±25) nerves. These data provide further evidence that complement is not involved in this Ab-mediated inhibition of axon regeneration in our models.

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