Neurosarcoidosis: Clinical Phenotype, Biomarkers and Immunopathogensis

点击翻译按钮获取中文摘要

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.