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）是一种多系统肉芽肿性结节病的神经系统表现