Deficiency of adaptive immunity does not interfere with Wallerian degeneration

Abstract

Following injury, distal axons undergo the process of Wallerian degeneration, and then cell debris is cleared to create a permissive environment for axon regeneration. The innate and adaptive immune systems are believed to be critical for facilitating the clearance of myelin and axonal debris during this process. However, immunodeficient animal models are regularly used in transplantation studies investigating cell therapies to modulate the degenerative/regenerative response. Given the importance of the immune system in preparing a permissive environment for regeneration by clearing debris, animals lacking, in part or in full, a functional immune system may have an impaired ability to regenerate due to poor myelin clearance, and may, thus, be poor hosts to study modulators of regeneration and degeneration. To study this hypothesis, three different mouse models with impaired adaptive immunity were compared to wild type animals in their ability to degenerate axons and clear myelin debris one week following sciatic nerve transection. Immunofluorescent staining for axons and quantitation of axon density with nerve histomorphometry of the distal stump showed no consistent discrepancy between immunodeficient and wild type animals, suggesting axons tended to degenerate equally between the two groups. Debris clearance was assessed by macrophage density and relative myelin basic protein expression within the denervated nerve stump, and no consistent impairment of debris clearance was found. These data suggested deficiency of the adaptive immune system does not have a substantial effect on axon degeneration one week following axonal injury.

Egr2 overexpression in Schwann cells increases myelination frequency in vitro

“…cyclosporine, which would have been required in immune competent mice and its efficacy would have added another factor of variation between individual mice. A study in our lab found axonal regeneration and myelin debris clearance to be comparable between three different mouse strains with deficiencies in the adaptive immune system to that of wild type mice (Cashman and Höke 2017). Naïve cells were used as the control as our in vitro results did not show a significant effect on myelination frequency, proliferation, or apoptosis between naïve and non-transduced cells (Fig.…”

Next-generation RNA sequencing elucidates transcriptomic signatures of pathophysiologic nerve regeneration

“…Persistent activation of inflammatory pathways is also a common transcriptional correlate of neuropathic pain in higher-order structures (brain 17 , 43 , spinal cord 44 , 45 , and dorsal root ganglia 46 , 47 ) after peripheral nerve injury. Importantly, although the adaptive immune response to nerve injury is incompletely characterized, previous studies suggest the adaptive immune cells have little impact on the kinetics of WD, and suppression may even may facilitate peripheral nerve regeneration 48 , 49 . Conversely, aberrant activation of adaptive immunity is implicated in chronic pain states, potentially governing steady recruitment of inflammatory species thereby influencing axonal sensitization 50 .…”

Machine intelligence for nerve conduit design and production

“…This suggests that the humoral immune system induced phagocytosis also plays a role in nerve regeneration. However, a more recent study showed that adaptive immunodeficiency Rag −/− had an increase in axonal degeneration and increased healing due to increase in macrophages to compensate for the reduced T and B cells [85]. Given the contrasting and possibly conflicting results between humoral immune system and PNS healing, more studies are needed to confirm their relationship.…”