Pathogenic autoantibodies in the lambert-eaton myasthenic syndrome.

Abstract

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of neuromuscular transmission in which antibodies are directed against voltage-gated calcium channels (VGCCs). We studied the action of LEMS immunoglobulin G (IgG) on cloned human VGCCs stably transfected into human embryonic kidney cells (HEK293). All LEMS IgGs tested bound to the surface of the P/Q-type VGCC cell line and caused a significant reduction in whole-cell calcium currents in these cells. By contrast, only 2 out of 6 IgGs bound extracellularly to the N-type VGCC cell line, and none of the LEMS IgGs tested was able to reduce whole-cell calcium currents in these cells. We used this apparent specificity of LEMS IgG for the P/Q-type VGCC to investigate the action of these IgGs on model systems where a number of different VGCC populations exist in equilibrium. LEMS IgG caused a significant downregulation in the omega-agatoxin IVA-sensitive P/Q-type VGCCs of cultured rat cerebellar neurons, but this was accompanied by a concomitant rise in the "resistant" R-type VGCCs. By using the passive transfer model of LEMS, similar results were observed at the mouse neuromuscular junction, where a significant reduction in P/Q-type VGCCs was paralleled by an increase in L- and R-type VGCCs. These results demonstrate an unexpected plasticity in the expression of VGCCs in mammalian neurons and may represent a mechanism by which the pathogenic effects of LEMS IgG are reduced.

• Authors: Bethan Lang, Ashwin Pinto, Federica Giovannini, John Newsom-Davis, Angela Vincent
• Journal: Annals of the New York Academy of Sciences (Ann N Y Acad Sci) Vol. 998 Pg. 187-95 (Sep 2003) ISSN: 0077-8923 [Print] United States
• PMID: 14592874 (Publication Type: Journal Article)

Chemical References

• Autoantibodies
• Calcium Channel Blockers
• Calcium Channels
• Immunoglobulin gamma-Chains

Topics

• Action Potentials (drug effects)
• Animals
• Autoantibodies (immunology, pharmacology)
• Calcium Channel Blockers (pharmacology)
• Calcium Channels (classification, genetics, immunology, physiology)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Electrophysiology
• Embryo, Mammalian
• Evoked Potentials (drug effects)
• Humans
• Immunoglobulin gamma-Chains (pharmacology)
• Lambert-Eaton Myasthenic Syndrome (immunology, physiopathology)
• Neuromuscular Junction (immunology, physiopathology)
• Precipitin Tests
• Purkinje Cells (drug effects, physiology)
• Transfection