Immunoassays Fad to Detect Antibodies Against Neuronal Calcium Channels in Amyotrophic Lateral Sclerosis Serum

Abstract : Recent studies suggested that autoantibodies that bind to voltage-dependent calcium channels and activate calcium entry may play a role in the progressive degeneration of motoneurons in sporadic amyotrophic lateral sclerosis. Immunoassays were performed to assess autoantibody titer in patients with amyotrophic lateral sclerosis or Lambert-Eaton myasthenic syndrome, a disease in which the presence of anti-calcium channel antibodies is well documented. Based on immunopre-cipitation assays for antibodies against N-type calcium channels, only 8% (2 / 2 5) of amyotrophic lateral sclerosis patients had marginally positive titers, whereas 58% (18/31) of patients with Lambert-Eaton myasthenic syndrome had positive titers. Enzyme-linked immunosorbent assays with purified neuronal N-type calcium channels revealed immunoreactivity in 2 of 25 amyotrophic lateral sclerosis sera and 12 of 31 Lambert-Eaton myasthenic syndrome sera, which is not compatible with suggestions that enzyme-linked immunosorbent assay is a more sensitive technique for the detection of autoantibodies in amyotrophic lateral sclerosis. Furthermore, based on immunoprecipitation assays, amyotrophic lateral sclerosis sera were totally negative for antibodies against L-type calcium channels from skeletal muscle or brain. These data do not support the hypothesis that an autoimmune response against calcium channels plays a primary role in amyotrophic lateral sclerosis. Arsac C, Raymond C, Martin-Moutot N, Dargent B, Couraud F, Pouget J, Seagar M. Immunoassays fail to detect antibodies against neuronal calcium channels in amyotrophic lateral sclerosis serum. Ann Neurol 1996;40:695-700 Amyotrophic lateral sclerosis (ALS) is a progressive de-generative disease primarily affecting motor neurons in the spinal cord, brainstem, and cerebral motor cortex. Although the etiology and pathogenesis of sporadic ALS remain unknown, the possibility that autoimmu-nity could play a primary role has been examined for several years [ 11. A series of reports by Appel and colleagues (reviewed in [ 2 ]) provides evidence that autoantibodies that activate voltage-gated calcium channels may be involved in initiating neurotoxicity. Immunoglobulins from ALS patients increase spontaneous quantal acetylcho-line release from mouse motor neuron terminals, suggesting that calcium influx through the voltage-dependent calcium channels coupled to exocytosis may be enhanced [3]. At least five distinct classes of calcium channels are expressed in neurons [4]. P/Q-Type channels are thought to play a major role in controlling transmission at the mammalian neuromuscular junction IS], although N-type channels may also be involved [6]. Voltage clamp recording has shown that ALS IgG can increase channel activity in cerebellar Purkinje neurons where P-type currents predominate [7], in Xenopus oocytes heterologously expressing N-type currents [S], and in a hybrid motor neuron cell line [9]. Results of further experiments in the motor neuron cell line were consistent with the hypothesis that antibody-mediated channel activation triggers neu-rotoxicity. Incubation with ALS IgG reduced cell survival and an evaluation of the protective effects of selective channel antagonists indicated that N-and P/Q-type, but not L-type channels, mediated toxicity [ 101. Immunoassay of an anti-calcium channel specificity in ALS sera would provide crucial support for anti-body-mediated channel activation. Appel and colleagues [ l l ] reported that 75% of patients with sporadic ALS produce antibodies that react with L-type calcium channels purified from rabbit skeletal muscle in enzyme-linked immunosorbent assays (ELISAs). However the observations outlined in the preceding paragraph predict that autoantibodies also react with Nor P/Q-type calcium channels. Calcium channels
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Cécile Raymond, Christine Arsac, Nicole Martin-Moutot, Bénédicte Dargent, Frangois Couraud, et al.. Immunoassays Fad to Detect Antibodies Against Neuronal Calcium Channels in Amyotrophic Lateral Sclerosis Serum. Annals of Neurology, 1996. ⟨inserm-02139111⟩

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