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: 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
• 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

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， 不明原因的炎症性疾病。5-15%的结节病患者可观察到NS， 对非裔美国人和北方欧洲血统的白人造成严重影响的世界性疾病。 我们的初步研究表明NS具有广泛的临床表型，包括脑膜炎， 脑炎和脑炎。我们还发现NS患者的脑脊液（CSF）显示出独特的 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）和与分枝杆菌抗原连接的抗体特征。根据这些观察，我们 假设NS的发病机制是由于对来源于 临床表型由特定基因决定的易感个体暴露于感染因子 表情签名这项研究让两个中心参与了现有的NS患者队列，具有前瞻性 收集临床数据和生物样本，以剖析CSF免疫致病途径， 谱，并揭示可能与NS表型相关的抗原或病原体。我们的具体目标 重点是将临床NS表型与免疫特征和基因表达途径特征相关联， CSF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 并使用生物样品如CSF来表征先前鉴定的细胞因子， 急性期反应物及其作为疾病结果的生物标志物的用途。在目标2中，我们将使用host CSF转录谱分析，以确定特定的分子签名和途径存在于NS将建立 免疫病理机制和因素，有助于动态神经炎症和疾病 进展在目标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，以确定宿主和微生物抗体的存在， 相关抗原，其可以识别与NS炎症过程相关的触发机制。所有 目标整合良好，因为目标1将提供一个良好表征和表型分析的NS患者队列 这将有助于在CSF转录组学分析中更精确地鉴定疾病途径 目标2中概述的抗体应答，以及目标3中的宿主或病原体相关抗体应答发现。建议的研究 将解决我们对NS发病机制的理解中的关键空白，并提出未来新的治疗方法。 战略布局