Behind the pathology of macrophage-associated demyelination in inflammatory neuropathies: demyelinating Schwann cells

In inflammatory peripheral demyelinating disorders, demyelination represents segmental demyelination in which the myelin sheath of a myelinating Schwann cell (SC) is completely removed by macrophages or a partial myelin degeneration in the paranode occurring due to autoantibodies attacking the node/paranode. For the segmental demyelination from living myelin-forming SCs, macrophages infiltrate within the endoneurium and insinuate between myelin lamellae and the cytoplasm of SCs, and the myelin is then removed via phagocytosis. During the macrophage invasion into the SC cytoplasm from the node of Ranvier and internodal areas, the attacked SCs do not remain quiescent but transdifferentiate into inflammatory demyelinating SCs (iDSCs), which exhibit unique demyelination pathologies, such as myelin uncompaction from Schmidt-Lanterman incisures with myelin lamellae degeneration. The longitudinal extension of this self-myelin clearance process of iDSCs into the nodal region is associated with the degeneration of nodal microvilli and paranodal loops, which provides a potential locus for macrophage infiltration. In addition to the nodal intrusion, macrophages appear to be able to invade fenestrated internodal plasma membrane or the degenerated outer mesaxon of iDSC. These SC demyelination morphologies indicate that the SC reprogramming to iDSCs may be a prerequisite for macrophage-mediated inflammatory demyelination. In contrast, paranodal demyelination caused by autoantibodies to nodal/paranodal antigens does not result in iDSC-dependent macrophage infiltration and subsequent segmental demyelination. In the context of inflammatory demyelination, the novel perspective of iDSCs provides an important viewpoint to understand the pathophysiology of demyelinating peripheral neuropathies and establish diagnostic and therapeutic strategies.

FUNCTIONAL AND MORPHOLOGICAL EFFECTS OF INDIRECT GRADUAL ELONGATION OF PERIPHERAL NERVE: ELECTROPHYSIOLOGICAL AND MORPHOLOGICAL CHANGES AT DIFFERENT ELONGATION RATES

We investigated the neuropathy induced by leg lengthening histological evaluation using teased nerve fiber specimens and electrophysiological evaluation. Indirect elongation of the sciatic nerve associated with leg lengthening was performed at 1 and 3 mm/day over 30 mm in rats. Electrophysiological evaluation was performed immediately and 60 days after the end of elongation, teased nerve fiber specimens were prepared, and the mean axonal diameter was calculated. The electrophysiological results were more wrong, and the recovery was poorer, in the 3-mm than in the 1-mm group. In the 1-mm group, the nerve conduction velocity (NCV) and the duration of the compound nerve action potential (C-NAP) recovered to a level close to the intact side, but the decrease in the amplitude of the C-NAP persisted. In the teased fiber study, while paranodal demyelination was observed in both groups immediately after elongation, demyelination was decreased in the 1-mm group indicationg recovery compared to the 3-mm group. Paranodal demyelination caused by indirect nerve elongation is considered to have induced electrophysiological disorders.Electrophysiological and morphological damages appeared to be more severe according to elongation speed. The nerve disorder were remained even at 1 mm per day in 60 days.

Electrophysiological and morphological studies of a motor nerve in ‘motor endplate disease’ of the mouse

Motor nerves of mice affected with hereditary ‘motor endplate disease’ were examined by means of electrophysiological and morphological techniques. Conduction velocity was slower, the refractory period was prolonged and the temperature sensitivity higher in mutants as compared to controls of the same age. Most of the axons examined in the electron microscope showed signs of paranodal demyelination. The relationship between the morphological and the electrophysiological findings is discussed. We conclude that alterations in the motor axons can account for the failures in neuromuscular transmission described previously in the med mutation.