Interrogating immune signatures in the thoracic duct of patients with multiple sclerosis

项目摘要 多发性硬化（MS）是一种慢性、免疫介导的脱髓鞘和神经退行性疾病， 中枢神经系统（CNS）。MS的免疫病理生理学仍不完全清楚。中的这一空白 理解可以部分归因于几个免疫区室的相对不可及性 涉及MS免疫病理生理学，即CNS、颈深淋巴结、肠道和其他 淋巴组织在人类中，这些组织的免疫区室至少部分地流入人体， 深传出纤维，最终在胸导管（TD）中合并。为此，我们的实验室 建立了一个研究方案，通过该方案从MS患者和健康供体中获得TD淋巴液， MS，作为一种手段，通过它可以更好地了解与MS相关的免疫过程，在这些上游 隔间有了这个资源，除了现有的脑脊液（CSF）/外周血（PB）单一 细胞基因表达数据库，从患者和没有MS，我假设我将能够确定 TD内存在MS的新的组织特异性免疫特征。 在这个提议中，我将采用高通量蛋白基因组单细胞方法， 表达和表面标志物谱，以确定在单细胞中检测到的免疫特征。 MS患者的TD。将使用组成和基因表达评估免疫特征 并行分析。此外，研究结果将与我们实验室现有的CSF/PB单细胞 基因表达数据库，以更好地确定检测到的TD免疫特征的组织特异性。 总的来说，这项提议将提供对MS（TD）中尚未探索的免疫区室的深入了解， 有助于指导未来的研究，以进一步了解MS免疫病理生理学领域。

PROJECT SUMMARY Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating and neurodegenerative disease of the central nervous system (CNS). The immune pathophysiology of MS is still incompletely understood. This gap in understanding can be partially attributed to the relative inaccessibility of several immune compartments implicated in MS immune pathophysiology, namely, the CNS, deep cervical lymph nodes, gut, and other lymphoid tissues. In humans, the immune compartments of these tissues drain, at least partially, into the human deep efferent lymphatics, which coalesce ultimately in the thoracic duct (TD). To this end, our laboratory has established a research protocol by which to obtain TD lymph from patients with MS and healthy donors without MS, as a means by which to better understand the immune processes associated with MS in these upstream compartments. With this resource, alongside an existing cerebrospinal fluid (CSF)/peripheral blood (PB) single cell gene expression database from patients with and without MS, I hypothesize that I will be able to identify novel, tissue-specific immune signatures of MS present within the TD. In this proposal, I will employ a high throughput proteo-genomic single-cell approach that recovers joint gene expression and surface marker profiles from single cells in order to determine immune signatures detected in the TD of patients with MS. Immune signatures will be assessed using both compositional and gene-expression analyses in parallel. Furthermore, the findings will be integrated with our laboratory’s existing CSF/PB single cell gene expression database to better determine the tissue-specificity of the detected TD immune signatures. Overall, this proposal will provide insight into a still unexplored immune compartment in MS (the TD) and will help guide future studies to further the field’s understanding of MS immune pathophysiology.