The enteric nervous system is a potential autoimmune target in multiple sclerosis
The enteric nervous system is a potential autoimmune target in multiple sclerosis
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DOI：
10.1007/s00401-017-1742-6
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发表时间：
2017-06
影响因子：
12.7
通讯作者：
Marie Wunsch;S. Jabari;B. Voussen;Michael Enders;S. Srinivasan;F. Cossais;T. Wedel;M. Boettner
中科院分区：
文献类型：
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作者：
Marie Wunsch;S. Jabari;B. Voussen;Michael Enders;S. Srinivasan;F. Cossais;T. Wedel;M. Boettner
多发性硬化症（MS）是一种慢性自身免疫性疾病的中枢神经系统（CNS）的年轻人，有严重的负面社会经济影响。除了CNS病理引起的症状外，大多数MS患者经常表现出胃肠道功能障碍，这在以前被解释为存在脊髓病变或与疾病的自身免疫病因学没有直接联系。在这里，我们研究了肠神经系统（ENS）在B细胞和抗体依赖性小鼠模型MS免疫组化和电子显微镜在不同阶段的疾病。ENS变性在CNS病变发展和小鼠神经功能缺损发作之前是明显的。病理学是抗体介导的，并导致胃肠动力显著下降，这与ENS胶质增生和神经元丢失有关。我们通过免疫沉淀和质谱鉴定了针对来自肠神经胶质细胞和/或神经元的四种潜在靶抗原的自身抗体。针对三种靶抗原的抗体也存在于MS患者的血浆中，如通过ELISA证实的。对人类结肠切除物的分析提供了与非MS对照相比MS患者中神经胶质增生和ENS变性的证据。这项研究首次建立了MS中CNS和ENS病理学的成熟自身免疫攻击之间的病理机制联系，这可能为我们目前对该疾病免疫发病机制的理解提供了一个范式转变，具有广泛的诊断和治疗意义。
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) in young adults that has serious negative socioeconomic effects. In addition to symptoms caused by CNS pathology, the majority of MS patients frequently exhibit gastrointestinal dysfunction, which was previously either explained by the presence of spinal cord lesions or not directly linked to the autoimmune etiology of the disease. Here, we studied the enteric nervous system (ENS) in a B cell- and antibody-dependent mouse model of MS by immunohistochemistry and electron microscopy at different stages of the disease. ENS degeneration was evident prior to the development of CNS lesions and the onset of neurological deficits in mice. The pathology was antibody mediated and caused a significant decrease in gastrointestinal motility, which was associated with ENS gliosis and neuronal loss. We identified autoantibodies against four potential target antigens derived from enteric glia and/or neurons by immunoprecipitation and mass spectrometry. Antibodies against three of the target antigens were also present in the plasma of MS patients as confirmed by ELISA. The analysis of human colon resectates provided evidence of gliosis and ENS degeneration in MS patients compared to non-MS controls. For the first time, this study establishes a pathomechanistic link between the well-established autoimmune attack on the CNS and ENS pathology in MS, which might provide a paradigm shift in our current understanding of the immunopathogenesis of the disease with broad diagnostic and therapeutic implications.