Immunization against GAD induces antibody binding to GAD-independent antigens and brainstem GABAergic neuronal loss.
Immunization against GAD induces antibody binding to GAD-independent antigens and brainstem GABAergic neuronal loss.
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DOI：
10.1371/journal.pone.0072921
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Vincent A
中科院分区：
文献类型：
--
作者：
Chang T;Alexopoulos H;Pettingill P;McMenamin M;Deacon R;Erdelyi F;Szabó G;Buckley CJ;Vincent A
僵直人综合征（SPS）是一种以进行性肌肉僵硬和痉挛为特征的中枢神经系统高度致残性神经系统疾病。在大约60-80%的患者中存在谷氨酸脱羧酶（GAD）的自身抗体，这种酶合成γ -氨基丁酸（GABA），这是中枢神经系统主要的抑制性神经递质。虽然GAD是细胞内的，但人们认为对GAD65的自身免疫可能在SPS的发展中起作用。为了验证这一假设，我们用GAD65 （n = 13）或磷酸盐缓冲盐水（n = 13）免疫GAD65启动子下表达增强绿色荧光蛋白（EGFP）的小鼠。GAD65免疫产生自身抗体，免疫沉淀GAD，以高度特征性的模式结合到中枢神经系统组织，令人惊讶的是，不仅在细胞内结合GAD，而且在培养中也结合到小脑神经元表面。此外，免疫导致免疫球蛋白向脑干扩散，脑干中表达GAD-EGFP的细胞部分丧失。虽然GAD65免疫不会在小鼠中产生任何行为异常，但神经元表面抗体的诱导和脑干中gaba能神经元的丧失趋势支持了体液自身免疫在SPS发病机制中的作用，并表明其机制可能涉及传播到这些神经元表面表达的抗原。
Stiff person syndrome (SPS) is a highly-disabling neurological disorder of the CNS characterized by progressive muscular rigidity and spasms. In approximately 60–80% of patients there are autoantibodies to glutamic acid decarboxylase (GAD), the enzyme that synthesizes gamma-amino butyric acid (GABA), the predominant inhibitory neurotransmitter of the CNS. Although GAD is intracellular, it is thought that autoimmunity to GAD65 may play a role in the development of SPS. To test this hypothesis, we immunized mice, that expressed enhanced green fluorescent protein (EGFP) under the GAD65 promoter, with either GAD65 (n = 13) or phosphate buffered saline (PBS) (n = 13). Immunization with GAD65 resulted in autoantibodies that immunoprecipitated GAD, bound to CNS tissue in a highly characteristic pattern, and surprisingly bound not only to GAD intracellularly but also to the surface of cerebellar neurons in culture. Moreover, immunization resulted in immunoglobulin diffusion into the brainstem, and a partial loss of GAD-EGFP expressing cells in the brainstem. Although immunization with GAD65 did not produce any behavioral abnormality in the mice, the induction of neuronal-surface antibodies and the trend towards loss of GABAergic neurons in the brainstem, supports a role for humoral autoimmunity in the pathogenesis of SPS and suggests that the mechanisms may involve spread to antigens expressed on the surface of these neurons.
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影响因子：
14.5
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