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; 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.

神经性神经病（NS）代表结节病的神经系统表现，这是一种多系统肉芽肿 未知原因的炎症障碍。在5-15％的结节病患者中，可以观察到NS 在全球疾病中影响北欧遗产的非裔美国人和白人。 我们的初步研究表明，NS具有广泛的临床表型，包括脑膜炎， 脑炎和骨髓炎。我们还发现，来自NS患者的脑脊液（CSF）揭示了独特的 免疫介质经常与感染相关的免疫介质的特征（干扰素-γ，肿瘤坏死因子-α和 白介素6）和与分枝杆菌抗原有关的抗体特征。基于这些观察，我们 假设NS的发病机理是由于对源自抗原的神经炎症反应 暴露于特定基因确定的临床表型的易感人群中的感染剂 表达签名。这项研究使两个中心与现有的NS患者同类中心 收集临床数据和生物样品以剖析CSF免疫病途径，定义免疫 profiles, and uncover antigens or pathogens which may be associated with NS phenotypes.我们的具体目标 专注于将临床NS表型与免疫特征和基因表达途径相关联 CSF以及与宿主或病原体相关抗体的链接。 In Aim 1, we will perform rigorous phenotyping NS患者，并使用CSF等生物学样本来表征先前鉴定的细胞因子和 急性相应物及其作为疾病结局的生物标志物的实用性。在AIM 2中，我们将使用主机 CSF转录分析以识别NS中存在的特定分子特征和途径将建立 有助于动态神经炎症和疾病的免疫致病机制和因素 进展。在AIM 3中，我们将使用最先进的相位显示库和噬菌体播放 免疫沉淀测序技术，以确定宿主和微生物的抗体的存在 相关的抗原，可以鉴定与NS炎症过程有关的触发机制。全部 AIM 1的AIMS已很好地整合到AIM 1将提供NS患者的表征和表型的队列 这将促进CSF转录组分析中对疾病途径的更精确识别 在AIM 2中概述了AIM 3中的宿主或病原体相关抗体反应发现。 will address critical voids in our understanding of the pathogenesis of NS and suggest future novel therapy 策略。