Neurosarcoidosis: Clinical Phenotype, Biomarkers and Immunopathogensis

神经结节病：临床表型、生物标志物和免疫发病机制

基本信息

批准号：
10689680
负责人：
CARLOS A PARDO-VILLAMIZAR
金额：
$ 66.11万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10689680
关键词：
Acute-Phase Proteins African American population Antibodies Antibody Response Antigen Targeting Antigens Autoantigens Autoimmune Responses Automobile Driving Bacteriophages Biological Biological Markers Biological Response Modifiers Blood Cerebrospinal Fluid Chronic Clinical Clinical Data Collaborations Collection Complication Comprehensive Health Care Critical Pathways Data Development Diagnosis Disease Disease Outcome Disease Pathway Disease Progression Encephalitis Etiology European Exposure to Future Gene Expression Gene Expression Profile Gene Expression Profiling Genes Genetic Genomics Genus Mycobacterium Goals Granuloma Granulomatous Immune Immune response Immunologic Markers Immunologics Immunology Immunoprecipitation Individual Infection Inflammation Inflammatory Interferon Type II Interleukin-6 Libraries Link Meningitis Methods Molecular Molecular Profiling Myelitis Neuroimmune Neurologic Neurologic Symptoms Outcome Pathogenesis Pathogenicity Pathology Pathway interactions Patient Care Patient Recruitments Patients Phage Display Phase Phenotype Play Precipitation Predisposition Process Prognosis Readiness Relapse Role Sampling Sarcoidosis System TNF gene Techniques biomarker discovery clinical center clinical phenotype cohort cytokine design disorder control insight microbial mycobacterial neuroimaging neuroinflammation neurosarcoidosis novel novel strategies novel therapeutic intervention novel therapeutics pathogen pathogenic microbe prospective repository response therapeutic target transcriptome transcriptome sequencing transcriptomics treatment response

项目摘要

Neurosarcoidosis (NS) represents the neurologic manifestations of sarcoidosis, a multisystemic granulomatous inflammatory disorder of unknown cause. NS may be observed in 5-15% of patients with sarcoidosis, a worldwide disease that disproportionally impacts African Americans and whites of northern European heritage. Our preliminary studies showed NS has a wide spectrum of clinical phenotypes that includes meningitis, encephalitis, and myelitis. We also found that cerebrospinal fluid (CSF) from patients with NS reveal a unique profile of immune mediators frequently associated with infections (interferon-γ, tumor necrosis factor-α and interleukin-6) and antibody signatures linked to Mycobacteria antigens. Based upon these observations, we hypothesize that the pathogenesis of NS is due to a neuro-inflammatory response to antigens derived from exposure to infective agents in susceptible individuals with the clinical phenotype determined by specific gene expression signatures. This study engages two centers with existing cohorts of NS patients with prospective collection of clinical data and biological samples to dissect CSF immunopathogenic pathways, define immune profiles, and uncover antigens or pathogens which may be associated with NS phenotypes. Our specific aims focus on associating clinical NS phenotypes with immune profiles and gene expression pathway signatures in CSF and the link with host or pathogen-associated antibodies. In Aim 1, we will perform rigorous phenotyping of NS patients, and use biological samples such as CSF to characterize previously identified cytokine and acute phase reactants and their usefulness as biomarkers of disease outcome. In Aim 2, we will use host CSF transcriptional profiling to identify specific molecular signatures and pathways present in NS will establish immunopathogenic mechanisms and factors that contribute to dynamic neuroinflammation and disease progression. In Aim 3, we will use state of the art phase display libraries and phage-displayed immunoprecipitation sequencing techniques to determine the presence of antibodies to host and microbial- associated antigens which may identify triggering mechanisms related to the NS inflammatory process. All aims are well integrated as Aim 1 will provide a well characterized and phenotyped cohort of patients with NS which would facilitate a more precise identification of disease pathways in the CSF transcriptomic analysis outlined in aim 2, and host- or pathogen-related antibody response discovery in Aim 3. The studies proposed will address critical voids in our understanding of the pathogenesis of NS and suggest future novel therapeutic strategies.

神经结节病 (NS) 代表结节病的神经系统表现，是一种多系统肉芽肿病 5-15% 的结节病患者可能会出现不明原因的炎症性疾病。世界范围内的疾病对非裔美国人和北欧血统的白人造成了不成比例的影响。我们的初步研究表明 NS 具有广泛的临床表型，包括脑膜炎、我们还发现 NS 患者的脑脊液 (CSF) 揭示了一种独特的特征。经常与感染相关的免疫介质（干扰素-γ、肿瘤坏死因子-α 和白细胞介素-6）和与分枝杆菌抗原相关的抗体特征基于这些观察，我们。 NS 的发病机制是由于对抗原产生的神经炎症反应具有由特定基因决定的临床表型的易感个体暴露于感染剂这项研究涉及两个中心的现有 NS 患者队列。收集临床数据和生物样本来剖析脑脊液免疫致病途径，定义免疫谱，并揭示可能与 NS 表型相关的抗原或病原体。专注于将临床 NS 表型与免疫谱和基因表达途径特征联系起来 CSF 以及与宿主或病原体相关抗体的联系在目标 1 中，我们将进行严格的表型分析。 NS 患者，并使用生物样本（如脑脊液）来表征先前识别的细胞因子和急性期反应物及其作为疾病结果生物标志物的用途在目标 2 中，我们将使用宿主。用于识别 NS 中存在的特定分子特征和途径的 CSF 转录谱分析将建立导致动态神经炎症和疾病的免疫致病机制和因素在目标 3 中，我们将使用最先进的阶段展示库和噬菌体展示。免疫沉淀测序技术确定宿主和微生物抗体的存在相关抗原可识别与 NS 炎症过程相关的触发机制。目标得到了很好的整合，因为目标 1 将提供一组具有良好特征和表型的 NS 患者这将有助于在脑脊液转录组分析中更精确地识别疾病途径目标 2 中概述，目标 3 中宿主或病原体相关抗体反应发现。拟议的研究将解决我们对 NS 发病机制理解中的关键空白，并提出未来的治疗新方案策略。