Antibodies against GM1 ganglioside affect K+ and NA+ currents in isolated rat myelinated nerve fibers

IgM paraproteins associated with autoimmune peripheral neuropathy and anti-Pr cold agglutinins react with sialic acid epitopes present on disialylated gangliosides including GD1b, GT1b, GQ1b, and GD3. A causal relationship between the paraprotein and the neuropathy has never been proven experimentally. From peripheral blood B cells of an affected patient, we have cloned a human hybridoma secreting an antidisialosyl IgM mAb, termed Ha1, that shows identical structural and functional characteristics to its serum counterpart. Variable region analysis shows Ha1 is encoded by the same V H 1 family heavy chain gene, V1-18, as the only other known anti-Pr antibody sequence and is somatically mutated, suggesting that is arose in vivo in response to antigenic stimulation. In the rodent peripheral nervous system, Ha1 immunolocalizes to dorsal root ganglia, motor nerve terminals, muscle spindles, myelinated axons, and nodes of Ranvier. After intraperitoneal injection of affinity-purified antibody into mice for 10 d, electrophysiological recordings from the phrenic nerve-hemidiaphragm preparation demonstrated impairment of nerve excitability and a reduction in quantal release of neurotransmitter. These data unequivocally establish that an antidisialosyl antibody can exert pathophysiological effects on the peripheral nervous system and strongly support the view that the antibody contributes to the associated human disease. ( J. Clin. Invest. 1996. 97:1155-1164.)

show abstract

“…GM1 antibodies (56). A similar effect of antidiasolysyl antibodies might be responsible for the changes in neuronal excitability described here.…”

Section: Discussionsupporting

confidence: 65%

A somatically mutated human antiganglioside IgM antibody that induces experimental neuropathy in mice is encoded by the variable region heavy chain gene, V1-18.

Willison

O’Hanlon²,

Paterson³

et al. 1996

J. Clin. Invest.

View full text Add to dashboard Cite

show abstract

“…Experimental results of the effect of anti-GM1 antibodies on Na v channel function are conflicting. Anti-GM1 antibodies suppressed Na ϩ currents on isolated single myelinated rat nerve fibers in the presence of complement (Takigawa et al, 1995), although this was not confirmed by other investigators (Hirota et al, 1997). New experimental approaches are required to elucidate the contribution of antiganglioside antibody-mediated Na v channel dysfunction in the pathophysiology of AMAN.…”

Section: Introductionmentioning

confidence: 80%

Anti-GM1 Antibodies Cause Complement-Mediated Disruption of Sodium Channel Clusters in Peripheral Motor Nerve Fibers

Susuki¹,

Rasband²,

Tohyama³

et al. 2007

J. Neurosci.

339

276

View full text Add to dashboard Cite

Voltage-gated Naϩ (Na v ) channels are highly concentrated at nodes of Ranvier in myelinated axons and facilitate rapid action potential conduction. Autoantibodies to gangliosides such as GM1 have been proposed to disrupt nodal Nav channels and lead to Guillain-Barré syndrome, an autoimmune neuropathy characterized by acute limb weakness. To test this hypothesis, we examined the molecular organization of nodes in a disease model caused by immunization with gangliosides. At the acute phase with progressing limb weakness, Na v channel clusters were disrupted or disappeared at abnormally lengthened nodes concomitant with deposition of IgG and complement products. Paranodal axoglial junctions, the nodal cytoskeleton, and Schwann cell microvilli, all of which stabilize Na v channel clusters, were also disrupted. The nodal molecules disappeared in lesions with complement deposition but no localization of macrophages. During recovery, complement deposition at nodes decreased, and Na v channels redistributed on both sides of affected nodes. These results suggest that Na v channel alterations occur as a consequence of complement-mediated disruption of interactions between axons and Schwann cells. Our findings support the idea that acute motor axonal neuropathy is a disease that specifically disrupts the nodes of Ranvier.

show abstract

“…Therefore, it is very likely that anti-GMl antibody per se caused specific effects on the action potential and ionic currents. The effect of anti-GMl antisera obtained from rabbits immunized with GM1ganglioside on single myelinated rat nerve fibers has been reported (6). High concentrations of anti-GMl antibodies with active complement induced a-marked decrease of Na+ current and caused a progressive increase of nonspecific leakage current.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it has been shown that high titers of anti-GM l antisera from rabbits immunized with GM1ganglioside induce impairment of action potential with an accompanying decrease in Na+currents and an increase in K+currents in rat myelinated nerve fibers (6). However, there have been controversial results on the effect of anti-GMl antibody on nerve fibers and neurons (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

The Sera from GM1 Ganglioside Antibody Positive Patients with Guillain-Barre Syndrome or Chronic Inflammatory Demyelinating Polyneuropathy Blocks Na+ Currents in Rat Single Myelinated Nerve Fibers.

et al. 2000

Self Cite

View full text Add to dashboard Cite

Objective To determine the possible role of anti-GMl ganglioside antisera from patients with Gullain-Barre syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP) in the development of nerve dysfunction.Methods The effect of the anti-GMl antibody positive antisera obtained from 4 GBS patients and 1 CIDP patient on membranepotential and ionic currents in rat single myelinated nerve fibers was investigated using the voltage clamp technique and compared with that of the anti-GMl negative antisera obtained from 3 healthy controls and 2GBSpatients. Results In the presence of active complement, anti-GMl positive antisera from 5 patients including 4 GBSpatients and 1 CIDPpatient significantly suppressed Na+current more than anti-GMl negative antisera. Conclusion This study supports the notion that antiGMlantibody is one of the causative factors of conduction abnormality in GBSpatients.

show abstract

Antibodies against GM₁ ganglioside affect K⁺ and NA⁺ currents in isolated rat myelinated nerve fibers

Cited by 242 publications

References 32 publications

A somatically mutated human antiganglioside IgM antibody that induces experimental neuropathy in mice is encoded by the variable region heavy chain gene, V1-18.

A somatically mutated human antiganglioside IgM antibody that induces experimental neuropathy in mice is encoded by the variable region heavy chain gene, V1-18.

Anti-GM1 Antibodies Cause Complement-Mediated Disruption of Sodium Channel Clusters in Peripheral Motor Nerve Fibers

The Sera from GM1 Ganglioside Antibody Positive Patients with Guillain-Barre Syndrome or Chronic Inflammatory Demyelinating Polyneuropathy Blocks Na+ Currents in Rat Single Myelinated Nerve Fibers.

Contact Info

Product

Resources

About