Abstract
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.
Highlights
Introduction of demyelinating Schwann cellsAxonal injuries result in the destruction of the myelin sheath and axon in the distal portion of the lesion sites via the process of Wallerian degeneration (WD)
While this Schwann cell (SC) self-destruction progresses for 3–7 days after injury, the infiltrated macrophages invade into the endoneurial tube and engulf the primary or secondary myelin ovoids that were exposed outside the demyelinating SCs” (DSCs)
It has long been suggested that the pathological demyelination in typical acute inflammatory demyelinating polyradiculoneuropathy (AIDP)/chronic form of inflammatory demyelinating polyradiculoneuropathy (CIDP) is caused by cell-mediated immunity, which is provoked by autoantibodies to the SC membrane or myelin proteins, and as a result of this autoimmune reaction, inflammatory cells, such as macrophages, are mobilized to the peripheral nerves and execute demyelination [19,20,21,22,23]
Summary
Axonal injuries result in the destruction of the myelin sheath and axon in the distal portion of the lesion sites via the process of Wallerian degeneration (WD). After the primary myelin ovoid is formed, a small myelinosome or secondary ovoid is generated from the primary ovoid, which is digested by SCs via autophagy or exposed to the outside of the DSCs independently or together with the primary ovoid (Fig. 1b) [1, 10,11,12] While this SC self-destruction progresses for 3–7 days after injury, the infiltrated macrophages invade into the endoneurial tube and engulf the primary or secondary myelin ovoids that were exposed outside the DSCs. Inflammatory peripheral demyelination generally indicates partial or functional demyelination in the nodal/paranodal region due to the autoantibodies against the antigens present in these areas and a complete myelin loss in an internode, called segmental demyelination, via the demyelinating attacks of macrophages [13, 14]. To macrophage-dependent or -independent demyelination in inflammatory demyelinating neuropathies
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