Comprehensive multimodal analysis of patients with neuroimmunological diseases

中枢神经系统（CNS）的神经免疫性疾病代表了广泛的非常不同的诊断，其中大多数被认为是罕见的疾病。除了多发性硬化（MS）、急性脱髓鞘性脑脊髓炎（ADEM）、横肌萎缩（TM）和CNS狼疮之外，文献中报告的队列很少超过10-20名患者，并且需要数年时间来收集这些数字。此外，除MS外，几乎所有报告都集中在临床结果上，这些患者的鞘内或全身免疫应答特征数据非常缺乏。因此，这些疾病的病理生理学知之甚少，有效的治疗方法非常罕见。 新出现的数据表明，免疫反应不仅由病原体形成，而且还由炎症过程发展的组织形成。从这个角度来看，CNS组织是独特的。优雅的动物数据表明，如果移植到CNS组织中，绕过其抗原的全身呈递，外来移植物可以无限期地存活，而当移植到其他器官中时，它们很容易被排斥。事实上，T细胞与神经元的相互作用可以塑造T细胞效应表型，从致病性到更具调节性。毫无疑问，这些复杂的免疫调节机制的出现是为了保证中枢神经系统组织，这是至关重要的功能和生存的主机，将受到保护，免受无意中的损害免疫系统。因此，临床上表现为CNS自身免疫的免疫系统的明显失效可能起源于控制CNS-免疫系统相互作用的天然免疫调节机制的崩溃。 该项目研究了因神经免疫性CNS疾病诊断而转诊至NIB的患者的鞘内和全身免疫反应。本研究的目的是确定免疫介导的CNS疾病中残疾发展的病理生理机制，并将其与人类免疫系统对CNS损伤的生理（通常是有益的）反应区分开来。我们已经制定了自然历史协议（09-N-0032），根据该标准，所有未接受治疗的疑似免疫介导的CNS疾病患者在NIB接受详细评估，包括收集疾病活动和残疾的临床和临床旁定量测量、标准和新型定量神经影像学标志物以及源自脑脊液（CSF）的免疫学和分子生物标志物，从外周血和CSF收集血清和免疫细胞。此外，患者可以接受皮肤活检以收集成纤维细胞，用于将其转化为诱导多能干细胞（iPS），以开发神经细胞的自体来源，从而研究人类的生理神经-免疫相互作用，这迄今为止还不可能。 对所有患者进行编码，并以无偏（即盲法）方式进行临床旁、神经成像和分子生物标志物的分析，以确定哪些生物标志物与特定神经免疫疾病或表型相关。 该研究的长期目标是获得知识，使我们能够在治疗上抑制免疫介导的CNS疾病的致病机制并增强修复机制，从而最大限度地减少CNS组织损伤的程度并促进恢复。此外，我们预计这些研究将导致生物标志物（成像，免疫学和分子）的发展，反映并发免疫介导的和神经退行性病理生理学机制和那些能够区分不同的诊断实体。 这将导致合理开发和更快地筛选针对具体过程的治疗方法，并将允许查明具有主要疾病机制的患者，这是个性化医疗方法的一个要求。最终，了解疾病过程的机制将影响整个CNS免疫介导疾病的管理。

Neuroimmunological diseases of the central nervous system (CNS) represent a broad spectrum of very diverse diagnoses, most of which are considered rare disorders. With the exception of multiple sclerosis (MS), acute demyelinating encephalomyelitis (ADEM), transverse myelitis (TM) and CNS lupus, reported cohorts in the literature rarely exceed 10-20 patients, and it takes years to collect these numbers. Additionally, with the exception of MS, virtually all reports focus on clinical findings and there is a great paucity of data characterizing intrathecal or systemic immune responses in these patients. As a result, the pathophysiology of these diseases is poorly understood and effective therapies are very rare. Emerging data indicate that the immune response is shaped not only by pathogens, but also by the tissue where the inflammatory process develops. From this standpoint, CNS tissue is unique. Elegant animal data indicate that foreign grafts survive indefinitely if transplanted into CNS tissue, bypassing systemic presentation of its antigens, whereas they are readily rejected when transplanted into other organs. Indeed, interactions of T cells with neurons can shape T cell effector phenotype, from pathogenic to more regulatory. There is little doubt that these complex immunoregulatory mechanisms emerged as an assurance that CNS tissue, which is vital for the function and survival of the host, will be protected from inadvertent damage by the immune system. Therefore, the apparent failure of the immune system that presents clinically as CNS autoimmunity may originate as a breakdown of natural immunoregulatory mechanisms that govern CNS-immune system interactions. This project studies intrathecal and systemic immune responses in patients referred to NIB for diagnostic work-ups of neuroimmunological CNS disorders. The goal of this study is to define the pathophysiological mechanisms underlying the development of disability in immune-mediated disorders of the CNS and to distinguish these from physiological (and often beneficial) responses of the human immune system to CNS injury. We have established natural history protocol (09-N-0032) under which all untreated patients with suspected immune-mediated disorders of the CNS undergo detailed evaluation at NIB, consisting of the collection of clinical and paraclinical quantitative measures of disease activity and disability, standard and novel quantitative neuroimaging markers and immunological and molecular biomarkers originating from cerebrospinal fluid (CSF), serum and immune cells collected both from peripheral blood and CSF. Additionally, patients may undergo skin biopsy for collection of fibroblasts for their transformation into induced pluripotent stem (iPS) cells in order to develop autologous source of neural cells to study physiological neural-immune interactions in humans, which has not been possible thus far. All patients are coded and analysis of paraclinical, neuroimaging and molecular biomarkers are performed in an unbiased (i.e. blinded) fashion in order to define which biomarkers are associated with specific neuroimmunological disease or phenotype. The long-term objective of the study is to acquire knowledge that would allow us to therapeutically inhibit the pathogenic mechanisms and enhance repair mechanisms in immune-mediated CNS diseases, thereby minimizing the extent of CNS tissue damage and promoting recovery. Additionally, we expect that these studies will lead to the development of biomarkers (imaging, immunological and molecular) reflecting concurrent immune-mediated and neurodegenerative pathophysiological mechanisms and those that would able to distinguish among different diagnostic entities. This will lead to rational development and faster screening of process-specific therapies, and will permit the identification of patients with prevailing disease mechanisms, which is a requirement for an individualized approach to medicine. Ultimately, understanding the mechanisms of disease processes will impact the management of immune-mediated diseases of the CNS as a whole.