Pathogenic autoantibodies in the lambert-eaton myasthenic syndrome.
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.
Neurosciences Group and Department of Clinical Neurology, Oxford University, Oxford, United Kingdom. blang@hammer.imm.ox.ac.uk
Bethan
B
Lang
Ashwin
A
Pinto
Federica
F
Giovannini
John
J
Newsom-Davis
Angela
A
Vincent
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001323:Autoantibodies / Q000276:immunology* / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000145:classification / Q000235:genetics / Q000276:immunology / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D004622:Embryo, Mammalian; D005071:Evoked Potentials / Q000187:drug effects; D006801:Humans; D007142:Immunoglobulin gamma-Chains / Q000494:pharmacology; D015624:Lambert-Eaton Myasthenic Syndrome / Q000276:immunology* / Q000503:physiopathology; D009469:Neuromuscular Junction / Q000276:immunology* / Q000503:physiopathology; D011233:Precipitin Tests; D011689:Purkinje Cells / Q000187:drug effects / Q000502:physiology; D014162:Transfection
D001323:Autoantibodies; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D007142:Immunoglobulin gamma-Chains