title: Fcγ receptor-mediated inflammation inhibits axon regeneration.
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.
authors: Department of Neurology, University of Texas Medical School at Houston, Houston, Texas, United States of America.
authors: Gang
authors: G
authors: Zhang
authors: Department of Neurology, University of Texas Medical School at Houston, Houston, Texas, United States of America.
authors: Nataliia
authors: N
authors: Bogdanova
authors: Department of Neurology, University of Texas Medical School at Houston, Houston, Texas, United States of America.
authors: Tong
authors: T
authors: Gao
authors: Department of Neurology, University of Texas Medical School at Houston, Houston, Texas, United States of America.
authors: Julia J
authors: JJ
authors: Song
authors: Antibody and Vaccine Group, Cancer Sciences Division, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors: Mark S
authors: MS
authors: Cragg
authors: Antibody and Vaccine Group, Cancer Sciences Division, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors: Martin J
authors: MJ
authors: Glennie
authors: Department of Neurology, University of Texas Medical School at Houston, Houston, Texas, United States of America.
authors: Kazim A
authors: KA
authors: Sheikh
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001369:Axons / Q000276:immunology / Q000473:pathology*; D001522:Behavior, Animal; D003167:Complement Activation; D004195:Disease Models, Animal; D005732:Gangliosides / Q000276:immunology; D020275:Guillain-Barre Syndrome / Q000276:immunology; D007249:Inflammation / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009416:Nerve Regeneration; D010525:Peripheral Nerves / Q000276:immunology / Q000473:pathology; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*; D012584:Sciatic Nerve / Q000473:pathology
chemical_list: D001323:Autoantibodies; C522404:Fcgr4 protein, mouse; D005732:Gangliosides; D017452:Receptors, IgG