Macrophages and Autoantibodies in Demyelinating Diseases

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.

Emerging Infection, Vaccination, and Guillain–Barré Syndrome: A Review

“…Antibodies against GM1, GM2, GD1a, and GQ1b have also been reported in patients with GBS associated with COVID-19 [ 69 , 70 ]. As described earlier, anti-ganglioside antibodies reported to be associated with GBS tend to be found in patients with AMAN rather than AIDP [ 12 ]. Further studies of antibodies are needed to verify the molecular mimicry hypothesis in GBS associated with SARS-CoV-2 infection.…”

“…GBS is categorized into a demyelinating subtype known as acute inflammatory demyelinating polyneuropathy (AIDP) and an axonal subtype known as acute motor axonal neuropathy (AMAN) or acute motor sensory axonal neuropathy (AMSAN) based on the absence or presence of sensory involvement [ 11 ]. Although antecedent infection has been reported for both the demyelinating and axonal subtypes, some pathogens are closely associated with a specific form [ 4 , 12 ]. For example, GBS that occurs after Zika virus infection or COVID-19 usually manifests as AIDP, as described later, whereas Campylobacter jejuni is strongly associated with AMAN [ 12 ].…”

“…Although antecedent infection has been reported for both the demyelinating and axonal subtypes, some pathogens are closely associated with a specific form [ 4 , 12 ]. For example, GBS that occurs after Zika virus infection or COVID-19 usually manifests as AIDP, as described later, whereas Campylobacter jejuni is strongly associated with AMAN [ 12 ].…”

“…The hypothesis of molecular mimicry has not been clearly demonstrated in AIDP [ 12 ]. Although phagocytosis of myelin by macrophages has been recognized to be important in AIDP, the mechanisms that drive macrophages to initiate myelin phagocytosis have not been clarified [ 14 ].…”

“…However, anti-ganglioside antibodies are typically associated with AMAN but not with AIDP [ 12 , 14 ]. As most patients with Zika virus-associated GBS have AIDP [ 31 ], the significance of anti-ganglioside antibodies should be interpreted with caution.…”