Abstract
Myelin phagocytosis by macrophages has been an essential feature of demyelinating diseases in the central and peripheral nervous systems, including Guillain–Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and multiple sclerosis (MS). The discovery of autoantibodies, including anti-ganglioside GM1 antibodies in the axonal form of GBS, anti-neurofascin 155 and anti-contactin 1 antibodies in typical and distal forms of CIDP, and anti-aquaporin 4 antibodies in neuromyelitis optica, contributed to the understanding of the disease process in a subpopulation of patients conventionally diagnosed with demyelinating diseases. However, patients with these antibodies are now considered to have independent disease entities, including acute motor axonal neuropathy, nodopathy or paranodopathy, and neuromyelitis optica spectrum disorder, because primary lesions in these diseases are distinct from those in conventional demyelinating diseases. Therefore, the mechanisms underlying demyelination caused by macrophages remain unclear. Electron microscopy studies revealed that macrophages destroy myelin as if they are the principal players in the demyelination process. Recent studies suggest that macrophages seem to select specific sites of myelinated fibers, including the nodes of Ranvier, paranodes, and internodes, for the initiation of demyelination in individual cases, indicating that specific components localized to these sites play an important role in the behavior of macrophages that initiate myelin phagocytosis. Along with the search for autoantibodies, the ultrastructural characterization of myelin phagocytosis by macrophages is a crucial step in understanding the pathophysiology of demyelinating diseases and for the future development of targeted therapies.
Highlights
Macrophages play an important role, in normal immune system maintenance, and in pathological conditions
A concept that molecular mimicry between gangliosides located at the axolemma and the surface epitopes of exogenous pathogens induces the production of anti-ganglioside antibodies has been established in the axonal form of Guillain–Barré syndrome (GBS) [7]
Ultrastructural studies using nerve biopsy specimens obtained from patients with the demyelinating form of GBS (i.e., acute inflammatory demyelinating polyneuropathy (AIDP)) and those with chronic inflammatory demyelinating polyneuropathy (CIDP) have demonstrated putative chronological sequence in the progression of demyelination resulting from myelin phagocytosis by macrophages [4,5]
Summary
Macrophages play an important role, in normal immune system maintenance, and in pathological conditions. GBS is an acute polyneuropathy, which typically occurs following infection [13] This disease was initially considered to be a demyelinating neuropathy, called acute inflammatory demyelinating polyneuropathy (AIDP), because a previous report demonstrated demyelinating lesions owing to myelin phagocytosis by macrophages [1]. Recent studies demonstrated the presence of autoantibodies against paranodal junction components, including neurofascin 155 and contactin 1, in some patients diagnosed with typical CIDP and DADS [8,30,31,32,33,34]. The mechanisms underlying macrophage-associated demyelination remain to be elucidated
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