Mechanisms of lesion localization in multiple sclerosis

多发性硬化症(MS)是一种慢性疾病，影响大脑和脊髓的所有区域(中枢神经系统或CNS)，导致各种临床症状和体征，具体取决于中枢神经系统的哪些部分受到影响。多发性硬化症影响全球约200万人，发病年龄通常在20-40岁之间，而此时家庭和工作承诺往往处于高峰期。多发性硬化症是无法治愈的，大多数患有这种疾病的人在一生中会变得越来越残疾。多发性硬化症是一种自身免疫性疾病，即一个人的自身免疫系统开始将中枢神经系统视为需要靶向和消除的外来物质。以前，人们认为多发性硬化症患者在中枢神经系统的特定部位发生病变没有特别的原因，也就是说，这被认为是相当随机的事件。然而，我们最近发现，中枢神经系统某些部位的病变发展与免疫系统靶向的中枢神经系统内的特定分子，以及MS患者携带的一些控制免疫系统的基因之间存在明显的相关性。本研究的目的是找出自身免疫反应性将病变靶向中枢不同部位的机制(S)。我们将专注于一种名为髓鞘蛋白脂蛋白或PLP的靶分子。携带某些免疫相关基因的多发性硬化症患者更有可能有针对PLP的免疫细胞，我们的工作强烈表明，这随后会导致脑干或小脑病变的发展。这项工作对多发性硬化症的疾病发病机制、预测和治疗具有重要意义，因为对导致特定临床结果的自身免疫反应模式的了解将提高我们的能力，使多发性硬化症患者了解他们可能经历的症状，并允许对受益最大的患者给予特定的治疗。

Multiple sclerosis (MS) is a chronic disease that affects all areas of the brain and spinal cord (central nervous system or CNS), leading to a huge variety of clinical symptoms and signs, depending upon which parts of the CNS are affected. MS affects about 2 million people worldwide, with the onset of disease often between 20-40 years of age, at a time when family and work commitments are often at their peak. There is no cure for MS, and most people who develop this disease become more and more disabled over their lifetime. MS is an autoimmune disease, i.e. one's own immune system starts to see the CNS as something foreign that needs to be targetted and eliminated. Previously, it has been considered that there are no particular reasons why people with MS develop lesions in the specific parts of the CNS that they do, i.e. it has been thought to be a fairly random event. However, we have recently shown that there are clear correlations between the development of lesions in some parts of the CNS, the particular molecules within the CNS that are being targetted by the immune system, and some genes that control the immune system that are carried by people with MS. The aim of the current study is to work out the mechanism(s) by which autoimmune reactivity targets lesions to different parts of the CNS. We will focus on one target molecule known as myelin proteolipid protein or PLP. People with MS who carry certain immune-related genes are more likely to have immune cells that target PLP, and our work strongly suggests that this subsequently leads to the development of lesions in the brainstem or cerebellum. This work has implications for disease pathogenesis, prognostication and therapy for MS, as a knowledge of patterns of autoimmune reactivity that lead to particular clinical outcomes will improve our ability to give people with MS an idea of they symptoms they might experience and allow specific therapies to be given to patients who will benefit most from them.