Anti-GQ1b ganglioside antibodies mediate complement-dependent destruction of the motor nerve terminal

Abstract

Miller-Fisher syndrome is an autoimmune neuropathy characterized by ataxia, areflexia and ophthalmoplegia, and in the majority of cases the presence of high titres of anti-GQ1b ganglioside antibodies. In an ex vivo model, human and mouse anti-GQ1b antibodies have been shown previously to induce a complement-dependent alpha-latrotoxin-like effect on the murine motor endplate, i.e. they bring about massive quantal release of acetylcholine and eventually block neuromuscular transmission. Using immunofluorescence microscopy with image analysis, we show here that the late stages of this electrophysiological effect temporally coincide with the loss of heavy neurofilament (200 kDa) and type III beta-tubulin immunostaining and structural breakdown of the nerve terminal, as demonstrated by electron microscopy. Ultrastructurally, axon terminals were disorganized, depleted of vesicles, and subdivided by the infiltrating processes of capping Schwann cells. These findings provide clear pathological evidence to support a role for anti-ganglioside antibodies in mediating nerve terminal injury and further advance the view that this site may be of importance as a target in some human neuropathies.

Ganglioside Molecular Mimicry and Its Pathological Roles in Guillain-Barré Syndrome and Related Diseases

“…The neuromuscular junction (NMJ) is rich in gangliosides, lies outside the blood-nerve barrier, and is an important site of antibody-mediated autoimmune diseases (61). In vitro electrophysiological evidence suggests muscle weakness may be affected via the action of antibodies on the NMJ (14).…”

Mannose-Binding Lectin Contributes to the Severity of Guillain-Barré Syndrome

“…2) Deposits of activated complement factors, C3d and C5b-9, are present on the outer membrane of Schwann cells in acute inflammatory demyelinating polyneuropathy (5), and on the axolemma of motor fibers in acute motor axonal neuropathy (6). 3) In the mouse diaphragm-phrenic nerve model, complement activation is crucial for the induction of the Ab-mediated pathophysiological effects and for axonal cytoskeletal breakdown and perisynaptic Schwann cell damage (7)(8)(9). The complement dependency of the pathogenic effect of anti-ganglioside Abs was confirmed in an in vitro assay using neuronal cells expressing gangliosides (10).…”

Neuromuscular synaptic function in mice lacking major subsets of gangliosides

“…Gangliosides can also function as cell surface receptors for microbial toxins (Fishman, 1982;Bullens et al, 2002). Experimental studies in mice by us and others have shown that GBS/MFS-associated anti-ganglioside antibodies can mediate functional and structural damage to neuromuscular junctions (NMJs) (Buchwald et al, 1995;Plomp et al, 1999;Ortiz et al, 2001;O'Hanlon et al, 2001;Halstead et al, 2004;Santafe et al, 2005).…”