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

• 批准号: 10445211
• 负责人: CARLOS A PARDO-VILLAMIZAR
• 金额: $ 67.62万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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/10445211
• 关键词: Acute-Phase Proteins; Address; 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; Immunoprecipitation; Individual; Infection; Inflammation; Inflammatory; Interferons; Interleukin-6; Libraries; Link; Meningitis; Methods; Molecular; Molecular Immunology; Molecular Profiling; Myelitis; Neuroimmune; Neurologic; Neurologic Symptoms; Outcome; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patient Care; Patient Recruitments; Patients; Phage Display; Phase; Phenotype; Play; Precipitation; Process; Prognosis; Readiness; Relapse; Role; Sampling; Sarcoidosis; TNF gene; Techniques; base; 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; phenotypic biomarker; prospective; repository; response; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics; treatment response

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)是一种多系统肉芽肿，是结节病的神经系统表现。 原因不明的炎症性疾病。在5-15%的结节病患者中可能会出现NS， 不成比例地影响北欧血统的非裔美国人和白人的世界性疾病。 我们的初步研究表明，NS具有广泛的临床表型，包括脑膜炎， 脑炎和脊髓炎。我们还发现，NS患者的脑脊液(CSF)显示出一种独特的 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 假设NS的发病机制是由于对下列抗原的神经炎症反应 临床表型由特定基因决定的易感人群的感染性药物暴露 表情签名。这项研究涉及两个中心和现有的NS患者队列，这些患者具有 收集临床数据和生物样本以剖析脑脊液免疫致病途径，确定免疫 并发现可能与NS表型相关的抗原或病原体。我们的具体目标 重点研究临床NS表型与免疫表型和基因表达途径信号的关系 脑脊液以及与宿主或病原体相关抗体的联系。在目标1中，我们将执行严格的表型分析 并使用诸如脑脊液等生物样本来表征先前发现的细胞因子和 急性期反应物及其作为疾病结局生物标志物的有用性。在目标2中，我们将使用主机 确定NS中存在的特定分子特征和途径的脑脊液转录图谱将建立 动态神经炎和疾病的免疫致病机制和因素 进步。在目标3中，我们将使用最先进的阶段展示文库和噬菌体展示 免疫沉淀测序技术以确定宿主和微生物抗体的存在- 可能识别与NS炎症过程相关的触发机制的相关抗原。全 AIMS被很好地整合，因为AIMS 1将提供一个具有良好特征和表型的NS患者队列 这将有助于在脑脊液转录分析中更准确地识别疾病途径 在目标2中概述，以及在目标3中发现与宿主或病原体相关的抗体反应。 将解决我们对NS发病机制理解中的关键空白，并建议未来的新疗法 战略。