Project description:To compare the different immunological mechanisms between aquaporin 4 antibody-associated optic neuritis (AQP4-ON) and myelin oligodendrocyte glycoprotein antibody-associated optic neuritis (MOG-ON) based on RNA sequencing (RNA-seq) of whole blood.
Project description:Background: The diagnosis and monitoring of Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis typically rely on clinical manifestations and the detecting of anti-NMDAR antibodies. However, several studies have found that anti-NMDAR IgG in serum is not entirely specific and can be detected in about 3% of healthy individuals. Objective: To identify novel biomarkers that can accurately monitor the severity of anti-NMDAR encephalitis. Methods: We enrolled 9 patients with anti-NMDAR encephalitis and categorized them into an acute-phase group and a stable-phase group based on the duration of illness and disease severity. The clinical severity of the patients was assessed using the modified Rankin Scale (mRS) and the clinical assessment scale for autoimmune encephalitis (CASE). Then, we isolated exosomal miRNAs from plasma samples and analysed the differentially expressed miRNAs through next-generation sequencing. The sequencing results were validated using RT-qPCR. Furthermore, we conducted correlation analyses between miRNAs and clinical severity. Finally, we performed the functional pathways analysis to explore the underlying mechanisms in anti-NMDAR encephalitis. Results: We have found that exosomal miR-432-5p, miR-4433b-5p and miR-599 exhibited significant differences between patients with anti-NMDAR encephalitis and healthy controls, as well as at different stages of the disease. The expressions of miR-432-5p and miR-4433b-5p were negatively correlated with both the mRS and the CASE. We further identified that the pathways involved in rhythmic processes and neuroinflammation, as well as glutamatergic signaling, play significant roles in the pathogenesis of anti-NMDAR encephalitis. Conclusions: Our research indicates that exosomal miR-432-5p, miR-4433b-5p and miR-599 were highly correlated with the severity of anti-NMDAR encephalitis and can serve as potential biomarkers for disease monitoring. We further identified the pathways play significant roles in anti-NMDAR encephalitis. By modulating the functions of these crucial pathways, we can potentially uncover novel therapeutic targets and improve patient outcomes.
Project description:Optic neuritis (ON) is a common manifestation of multiple sclerosis (MS); it appears as the presenting symptom in about 25% of MS patients and occurs in 30–70% of patients with MS during the course of their illness Purpose. To evaluate the molecular pathways that operate in the early phase of acute ON by studying gene expression profiles of peripheral blood mononuclear cells (PBMCs) subpopulations including CD19+ B cells, CD14+ macrophages, CD4+ and CD8+ T cells. High throughput gene expression analysis was performed on periferal mononuclear blood cells (PBMC) samples from 6 patients within 96 hours of the acute onset of the first demyelinating event of optic neuritis and 9 age matched healthy subjects using Affymetrix Inc. technology
Project description:Guillain-Barré syndrome (GBS) is characterized by acute immune-mediated peripheral neuropathy, which may result in rapidly progressive paralysis and fatal respiratory failure. As the underlying pathological mechanisms of GBS are unclear, we surveyed the transcriptome of rats with experimental autoimmune neuritis (EAN), a model of GBS. Briefly, sciatic nerves on both sides were collected from 8–10-week-old Lewis rats during early (10 days post-induction), peak (19 days), and late neuritis (30 days). Total RNA was sequenced to identify differentially expressed genes. Compared to control rats without induced neuritis, 33 genes were differentially expressed in the early phase (14 upregulated and 19 downregulated), with an adjusted P-value < 0.05 and |log2 fold-change| > 1, as were 137 genes in the peak phase (126 upregulated and 11 downregulated) and 60 genes in the late phase (58 upregulated and 2 downregulated). Eleven of these genes were common to all stages, suggesting their crucial roles throughout the disease course. Analysis of protein-protein interactions revealed Fos, Ccl2, Itgax and C3 as node genes at different stages. Functional analysis of differentially expressed genes identified biological processes and pathways that are activated as neuritis progresses. This is the first genome-wide gene expression study of peripheral nerves in experimental autoimmune neuritis model. Dynamic gene expression and significantly altered biological functions were detected in different phases of the disease, increasing our understanding of the molecular mechanisms underlying EAN and highlighting potential targets for its diagnosis and treatment.
Project description:Secondary muscle atrophy due to neuronal denervation is a key determinant of poor functional recovery in immune-mediated neuropathies, even after resolution of inflammation. Activin II receptors (ActIIRs) are central mediators of muscle atrophy, and their inhibition has shown variable efficacy in primary myopathies. We investigated the therapeutic potential of ActIIR inhibition in promoting motor recovery in immune-mediated neuropathies using the experimental autoimmune neuritis (EAN) model in Lewis rats. Motor performance was evaluated through a composite of clinical neuritis scoring, grip strength testing, and balance beam performance combined with kinematic gait analysis. High-dose antibody treatment significantly improved motor outcome. This improvement was not associated with changes in peripheral nerve inflammation or remyelination but correlated with preservation of muscle fiber size. Muscle proteomic analysis revealed modulation of the FoxO signaling pathway and reduced expression of the atrophy-related E3 ligases Atrogin-1 and MuRF1. These findings indicate that ActIIR inhibition prevents secondary muscle atrophy and enhances motor recovery in autoimmune neuritis. Targeting ActIIR signaling may represent a promising therapeutic strategy to improve motor outcomes in patients with immune-mediated neuropathies.
Project description:The aim of this study was to examine retinal transcriptomic changes associated with optic neuritis and identify those that are reversed upon targeted expression of SIRT1 in RGCs. Conceptually, identification of transcriptional differences between SIRT1-treated and non-treated retinas will help identify genes correlating with resilience and resistance to neurodegeneration and/or the molecular pathways affected by SIRT1 overexpression. To achieve this, we used a mouse model of experimental autoimmune encephalomyelitis (EAE)-induced optic neuritis, a commonly used model of multiple sclerosis, in which myelin oligodendrocyte-specific immune responses are induced by injecting myelin oligodendrocyte glycoprotein peptide (MOG35-55) . EAE mice develop an autoimmune demyelinating reaction characteristic of multiple sclerosis and optic neuritis which include optic nerve inflammation, axon demyelination, and loss of RGCs and visual acuity.Using this disease model and bulk RNA sequencing, we identified genes whose expression is affected by constitutive ubiquitous SIRT1 expression in SIRT1 knock-in mice, and in wild-type mice upon either targeted adeno-associated virus (AAV)-mediated SIRT1 expression in RGCs or oral gavage with resverotrol (RSV), a SIRT1 activator.