Mechanisms of demyelination and neurodegeneration in the cortical grey matter in multiple sclerosis

多发性硬化症（MS）是英国年轻人最常见的神经系统疾病。时间进程和疾病的严重程度是非常多变的，没有办法预测它是否会遵循轻微或严重的过程。目前的治疗方法只成功地减少了发作的次数，但对疾病的进展没有影响。大脑的损伤被认为是由免疫系统攻击覆盖在神经纤维上的绝缘髓鞘引起的。这表现为纤维束的多处炎症。我们实验室最近对死后大脑的研究已经确定了MS病例的一个亚组（目前研究中占40%），其中大脑表层也有广泛的损伤。这些病例的特征是脑膜炎症，脑膜是形成大脑外层的组织。我们发现产生抗体的细胞，b淋巴细胞，正在脑膜中增殖。这表明，对大脑细胞有毒的物质正在扩散到大脑皮层的底层，并在这部分多发性硬化症病例中造成损害。这些病例的病程也更具侵袭性，导致依赖轮椅的时间更短，死亡时间更早。该项目旨在了解神经元损伤的机制，以便为开发新的治疗方法确定药物靶点。我们将使用两组有死后组织的多发性硬化症病例，一组脑膜中有b淋巴细胞，其病程更具侵袭性，另一组没有。首先，我们将研究组织损伤区域神经元数量的变化，然后研究哪些基因被神经元打开和关闭，这可能解释为什么其中一些神经元正在死亡。这将通过使用基因芯片同时研究这些细胞中的所有30,000多个基因来实现。研究人员将分析大脑组织中存在的已知对神经元有毒的蛋白质，这些蛋白质可能是从大脑表面扩散出来的。患者病史将用于将这些信息与疾病发作和复发频率等变量相关联。识别出这一预后不良的高风险MS患者亚群，有助于在发生广泛和不可逆转的损害之前进行早期治疗。

Multiple Sclerosis (MS) is the commonest neurological disorder of young adults in the UK. The time course and severity of the disease is extremely variable and there is no way to predict whether it will follow a mild or aggressive course. Current treatments are only successful at decreasing the number of attacks but have no effect on the progression of the disease. Damage to the brain is thought to be caused by an attack by the immune system on the insulating myelin sheath that covers nerve fibres. This appears as multiple areas of inflammation in the fibre tracts. Recent research in our laboratories on post-mortem brains has identified a subgroup of MS cases (40% in the current study) in which there is also extensive damage to the surface layers of the brain. These cases are characterised by inflammation in the meninges, the tissue that forms the outside lining of the brain. We have found that antibody producing cells, B-lymphocytes, are proliferating in the meninges. This suggests that substances toxic to the cells of the brain are diffusing into the underlying layers of the cerebral cortex and causing the damage in this subset of MS cases. These cases also followed a more aggressive disease course, resulting in a shorter time to wheelchair dependence and earlier death. This project is designed to gain an understanding of the mechanisms of damage to neurons in order to identify drug targets for the development of novel treatments. We will use two groups of MS cases for which post-mortem tissue is available, one group that has B-lymphocytes in the meninges and which followed the more aggressive disease course and a group that does not. Firstly, we will study the changes in the number of neurons in areas of tissue damage and then investigate which genes are being turned on and off by the neurons that might explain why some of them are dying. This will be achieved by studying all 30,000+ genes in these cells simultaneously using gene chips. The presence within the brain tissue of proteins known to be toxic to neurons, which may have diffused from the brain surface, will be analysed. Patient histories will be used to correlate this information with variables such as disease onset and relapse frequency. Identification of this sub-group of MS patients at high risk of a poor outcome could facilitate early treatment before extensive and irreversible damage occurs.