Pagani Mario R, Reisin Ricardo C, Uchitel Osvaldo D
Laboratorio de Fisiología y Biología Molecular, Instituto de Fisiología Biología Molecular y Neurociencias UBA-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, C1428EHA Buenos Aires, Argentina.
J Neurosci. 2006 Mar 8;26(10):2661-72. doi: 10.1523/JNEUROSCI.4394-05.2006.
Sporadic amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects particularly motoneurons. Several pieces of evidence suggested the involvement of autoimmune mechanisms mediated by antibodies in ALS. However, the significance of those antibodies in the disease and the underlying mechanisms are unknown. Here we showed that IgG purified from a group of sporadic ALS patients, but not familial ALS patients, specifically interact with the presynaptic membrane of motoneurons through an antigen-antibody interaction and modulated synaptic transmission. Immunoreactivity against nerve terminals showed strong correlation with synaptic modulation ability. In addition, several controls have ruled out the possibility for this synaptic modulation to be mediated through proteases or nonspecific effects. Effective IgG potentiated both spontaneous and asynchronous transmitter release. Application of pharmacological inhibitors suggested that activation of this increased release required a nonconstitutive Ca2+ influx through N-type (Cav2.2) channels and phospholipase C activity and that activation of IP3 and ryanodine receptors were necessary to both activate and sustain the increased release. Consistent with the notion that ALS is heterogeneous disorder, our results reveal that, in approximately 50% of ALS patients, motor nerve terminals constitutes a target for autoimmune response.
散发性肌萎缩侧索硬化症（ALS）是一种主要影响运动神经元的神经退行性疾病。多项证据表明，抗体介导的自身免疫机制参与了ALS的发病过程。然而，这些抗体在该疾病中的意义以及潜在机制尚不清楚。在此，我们发现从一组散发性ALS患者而非家族性ALS患者中纯化的IgG，通过抗原-抗体相互作用与运动神经元的突触前膜特异性相互作用，并调节突触传递。对神经末梢的免疫反应性与突触调节能力密切相关。此外，多项对照实验排除了这种突触调节由蛋白酶或非特异性效应介导的可能性。有效的IgG增强了自发和异步递质释放。药理学抑制剂的应用表明，这种增加的释放激活需要通过N型（Cav2.2）通道的非组成性Ca2+内流和磷脂酶C活性，并且IP3和兰尼碱受体的激活对于激活和维持增加的释放都是必需的。与ALS是一种异质性疾病的观点一致，我们的结果表明，在大约50%的ALS患者中，运动神经末梢构成了自身免疫反应的靶点。
