Immune Complex-Induced Inflammation as a Mechanism of Inhibition of Peripheral Nerve Regeneration (IN1-2.002)

Abstract

Objective: To investigate if immune complex formation and Fc gamma receptors (FcγRs) participate in anti-ganglioside antibody-mediated inhibition of axon regeneration. Background Anti-ganglioside antibodies (Abs) are the most commonly recognized autoimmune markers in all forms of Guillain-Barre syndrome (GBS) and these Abs are associated with poor recovery. Extent of axonal injury and failure of axonal regeneration are critical determinants of recovery after GBS. In this clinical context, we have shown that anti-ganglioside Abs adversely affect axon regeneration after peripheral nerve injury in an animal model, in complement-independent fashion. Therefore, we asked whether immune complexe formation and Fc gamma receptors (FcγRs)-induced inflammation participates in this Ab-mediated inhibition of axon regeneration. Design/Methods: A well characterized antibody passive transfer and sciatic nerve crush model was used to study the anti-ganglioside Ab-mediated inhibition of axon regeneration in wild type and various transgenic mice lacking specific FcγRs. Outcome measures included electrophysiology, morphometry, immunocytochemistry, quantitative real-time PCR, and western blotting. Results: We found that there was a highly significant upregualtion of FcγRs with nerve crush/injury. Notably, anti-ganglioside Ab-mediated inhibition of axon regeneration was entirely dependent on the expression of specific activating FcγRs as transgenic mice lacking specific FcγRs were completely immune to Ab-mediated inhibition of axon regeneration. Conclusions: Our results demonstrate that immune complex formation and engagement of specific FcγRs leads to inhibition of peripheral nerve regeneration. The current studies are relevant not only to acute and chronic immune neuropathies but to other neurological conditions including multiple sclerosis and traumatic spinal cord and brain injuries as recent studies have emphasized the role of anti-neural Abs and FcγRs in secondary central nervous system injury in experimental models. Supported by: NIH/NINDS (NS42888 and NS54962) and GBS/CIDP Foundation. Disclosure: Dr. Sheikh has nothing to disclose. Dr. Zhang has nothing to disclose. Dr. Bogdanova has nothing to disclose. Dr. Gao has nothing to disclose. Dr. Guo has nothing to disclose. Dr. Massaad has nothing to disclose. Dr. Kotha has nothing to disclose.