Pathogenic Autoantibodies in the Lambert-Eaton Myasthenic Syndrome

• Published in: Annals of the New York Academy of Sciences 2003-09, Vol.998 (1), p.187-195
• Main Authors: LANG, BETHAN, PINTO, ASHWIN, GIOVANNINI, FEDERICA, NEWSOM-DAVIS, JOHN, VINCENT, ANGELA
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Animals; Autoantibodies - immunology; Autoantibodies - pharmacology; Calcium Channel Blockers - pharmacology; Calcium Channels - classification; Calcium Channels - genetics; Calcium Channels - immunology; Calcium Channels - physiology; Cells, Cultured; Dose-Response Relationship, Drug; Electrophysiology; Embryo, Mammalian; Evoked Potentials - drug effects; Humans; Immunoglobulin gamma-Chains - pharmacology; Lambert-Eaton myasthenic syndrome (LEMS); Lambert-Eaton Myasthenic Syndrome - immunology; Lambert-Eaton Myasthenic Syndrome - physiopathology; Neuromuscular Junction - immunology; Neuromuscular Junction - physiopathology; P/Q-type VGCC; passive transfer; Precipitin Tests; Purkinje cell neurons; Purkinje Cells - drug effects; Purkinje Cells - physiology; Transfection; voltage-gated calcium channels (VGCCs)
• ISSN: 0077-8923; 1749-6632
• DOI: 10.1196/annals.1254.019

: 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 ω‐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.