Previous studies in the hypomyelinating mouse mutant Trembler have suggested that demyelinating axons are smaller in caliber compared to normal axons, and that there are differences in the organization of axonal neurofilaments. In the normal PNS, however, the relationship between neurofilament organization and myelination has not been investigated extensively. In normal axons, only the initial segments, the nodes of Ranvier (approximately 1 micron), and the terminals are not covered by myelin. We took advantage of an unusual feature of the primary sensory neurons in the dorsal root ganglion, the relatively long nonmyelinated stem process (up to several hundred micrometers), to determine if the presence of myelination correlates with differences in cytoskeletal organization and neurofilament phosphorylation. Axonal caliber and neurofilament numbers were substantially greater in the myelinated internodes than in the stem process or nodes of Ranvier. Neurofilament spacing, assessed by measuring the nearest-neighbor neurofilament distance, was 25–50% less in the stem processes and nodes of Ranvier than in the myelinated internodes. In the myelinated internodes, neurofilaments had greater immunoreactivity for phosphorylated epitopes than those in the stem process. These findings indicate that interactions with Schwann cells modulate neurofilament phosphorylation within the ensheathed axonal segments, and that increased phosphorylation within myelinated internodes leads to greater interfilament spacing. Lastly, the myelinated internodes had three fold more neurofilaments, but the same number of microtubules. Both the increased neurofilament spacing and the increase in neurofilament numbers in myelinated internodes contribute to a greater axonal caliber in the myelinated internodes.

Guillain-Barré syndrome (GBS) is traditionally considered to be a large-fibre neuropathy. However, the presence of hypo-aesthesia, dysaesthesia and dysautonomia in GBS patients raises the possibility that small-diameter sensory and autonomic nerves may also be affected. To investigate small-fibre neuropathy in GBS, we performed a skin biopsy from the distal leg of 20 patients with the demyelinating form of GBS. Skin sections were immunohistochemically stained with antiserum against protein gene product 9.5 (PGP 9.5), a ubiquitin C-terminal hydrolase. Cutaneous innervation was evaluated by measuring epidermal nerve density (END), and END was further correlated with various clinical and electrophysiological parameters. In GBS patients, END values were much lower than in age- and gender-matched control subjects (5.03 +/- 1.18 versus 10.16 +/- 0.87 fibres/mm, P < 0.001). Eleven patients (55%) had reduced epidermal innervation with pathological evidence of active nerve degeneration in the dermis: fragmentation of subepidermal nerve plexuses and a beaded appearance of dermal nerves. GBS patients had significantly elevated thermal thresholds with higher warm threshold temperatures (44.54 +/- 1.04 versus 39.00 +/- 0.35 degrees C, P < 0.001) and lower cold threshold temperatures (25.57 +/- 1.11 versus 29.05 +/- 0.21 degrees C, P = 0.032). Reduced END values were associated with an elevated warm threshold (P = 0.027), ventilatory distress (P = 0.037) and dysautonomia (P = 0.001). END values were negatively correlated with disability grade on a scale of 1-6 (slope -0.134 +/- 0.038, P = 0.0018). Patients with reduced END values tended to have a slower recovery than those with normal END values (P = 0.013, median time 12 versus 2 weeks). Patho logically, sudomotor innervation of the skin was reduced in five of 17 (29.4%) GBS patients in whom sweat glands could be recognized. These findings suggest that small-fibre sensory and autonomic neuropathies exist in a significant proportion of GBS patients, and that END values are correlated with functional disabilities. In summary, GBS should be considered a global neuropathy instead of a pure large-fibre neuropathy.

SummarySkin innervation has been considered to subserve sensory perception only, but several lines of evidence suggest that there are 'effector' influences of skin innervation on the immune system and keratotinocytes. In this study, we transected the sciatic nerves of rats and examined the effects of denervation on the epidermis. In normal skin, the epidermis was densely innervated by fine axons that were immunostained with several axonal markers, including neuronal ubiquitin carboxyl terminal hydrolase (protein gene product 9.5). All of the epidermal axons in the regions innervated by sciatic nerve disappeared within 24-48 h after transection of sciatic nerve, and remained absent as long as subsequent reinnervation by regenerating axonal sprouts was prevented. Denervation produced changes in both the keratinocytes and the Langerhans cells, the bone marrowderived antigen-presenting cells of the epidermis. The thickness of epidermis decreased within 7 days. By 48h after transection, the Langerhans cells and their dendritic processes became intensely immunoreactive for protein gene product. Protein gene product 9.5 expression on Langerhans cells remained prominent as long as skin was denervated, but disappeared with reinnervation. By reverse transcription-polymerase chain reaction, we demonstrated the presence of the transcripts for protein gene product 9.5 in epidermis, consistent with the synthesis of the protein by the Langerhans cells. We conclude that epidermal sensory fibres have novel influences on both keratinocytes and Langerhans cells of the epidermis.