Project description:Rheumatoid arthritis (RA) is linked to depression and dementia in later life by inflammatory involvement of the central nervous system (CNS). Regional heterogeneity of brain immunophenotypes was described under homeostasis, but a topographical resolution of CNS immune responses in chronic peripheral inflammatory diseases like RA is missing. We demonstrate regional heterogeneity of CNS susceptibility to chronic peripheral inflammation in the human tumor necrosis factor α transgenic (TNFtg) mouse model of RA. TNFtg mice showed myeloid cell infiltration, microglial activation, and a mutual transcriptomic fingerprint of neuroinflammation in the cortex, striatum, and thalamus. Immune responses were minimal in the hippocampus and cerebellum. We demonstrate regional CNS immune responses to chronic peripheral inflammation, sparing the hippocampus and cerebellum and reversible by peripheral anti-inflammatory treatment. Targeting microenvironmental susceptibility or resilience of brain regions will help to prevent and treat RA-related neuropsychiatric comorbidity. RNA-sequencing was performed from five brain regions (cortex, striatum, thalamus, hippocampus, and cerebellum) from C57Bl6/J wild type mice and TNFtg mice (strain Tg197; kindly provided by George Kollias (Fleming Institute, Vari, Greece).
Project description:Brain glia cells exhibit highly heterogeneity which can modify their genetic landscape and responding sensitivity, thus achieving appropriate responses to environmental changes for maintenance of CNS homeostasis. However, technical restriction has prevented the study on the self-orchestrating activity of CNS resident immune cells. Microglia and astrocytes are predominant responding cells at early stages during CNS viral infection. Their activation not only contributes to the recruitment of peripheral immune cells that aid in viral clearance, but also increases the risk of long-term detrimental inflammatory injury associated with many neurodegenerative diseases. Optimal autophagic activity is vital to maintain brain integrity, yet the autophagy regulation of immune activity in brain glia cells remains poorly understood. Here, we identify the membrane protein SHISA9 as an autophagy cargo receptor that modulates the heterogenic immune responses during CNS infection. By 10x single-cell RNA sequencing, we identify the astrocytes with increased Shisa9 expression followed by decreased expression of inflammatory transcriptional programs. Shisa9 has temporal characteristics in modulating both antiviral and inflammatory responses in microglia and astrocytes at different stages during infection. Shisa9-/- mice are highly susceptible to herpes simplex virus encephalitis, accompanied by higher rates of pathogenic astrocytes which might contribute to neurodegeneration progression and display a more severe neuroinflammation symptoms compared to wild-type mice. Taken together, our study unravels a critical role of selective autophagy in orchestrating immune heterogeneity of different CNS resident cells through SHISA9-IKKi axis.
Project description:RATIONALE: Vaccines made from a person’s cancer proteins may help the body build an effective immune response to kill cancer cells. Colony-stimulating factors, such as GM-CSF, may increase the number of immune cells found in bone marrow or peripheral blood. Giving vaccine therapy together with GM-CSF may make a stronger immune response and kill more cancer cells.
PURPOSE: This phase II trial is studying the side effects and how well giving vaccine therapy together with GM-CSF works in treating patients with CNS lymphoma.
Project description:Stable and commonly bioactive cysteine-rich peptides (CRPs) have are typically discovered via mass shift analysis. However, the accurate assessment of unique CRP species in a given botanical species is often challenged by same mass species, post-translational modifications or modifications derived from sample handling, and incomplete MS2 fragmentation. Mass spectral fingerprint ions can be leveraged to gain additional information about a mass species prior to full sequence characterization and with only poor quality MS2 spectra. Herein we identify sets of mass spectral fingerprint ions characteristic of the CRP cyclotide family, which may indicate a mass belongs to a specific cyclotide subfamily, and “tell-tale” ions that are of importance when discriminating putative cyclotide species, including common oxidation and over-alkylation ions observed experimentally. Cyclotide-containing V. communis material is used as proof-of-principle, where experimental cyclotide fingerprint ions are explored. Fingerprint ions derived from a third type of CRP, the trypsin inhibitors, are assessed in the gourd L. siceraria. Combining mass shift analysis with the identification of prominent MS2 fingerprint ions is then used to identify three novel CRPs. We demonstrate that abundant mass spectral fingerprint ions can be used to quickly discern masses of interest in complex matrices and masses that are already characterized, aiding prioritization of the most promising novel mass species in a natural product sample for characterization.
Project description:Systemic immune dysregulation contributes to the development of neuropsychiatric and neurodegenerative diseases. The precise effect of chronic peripheral immune stimulation on myeloid cells across anatomical brain regions is unclear. We used the human TNF-α transgenic mouse model of RA (TNFtg mice, strain Tg197) (Keffer et al., 1991), which shows increased levels of peripheral cytokines and severe joint pathology at young age and leads to severe disability within 3-4 months after birth (Keffer et al., 1991; Suss et al., 2015) to assess the effect of chronic peripheral inflammation on myeloid cells in the cortex. To examine the response of brain myeloid cells to systemic chronic inflammation, we performed single cell RNA-seq on isolated CD11b+CD45+ cells from the cortex of wt and TNFtg mice.
Project description:Gliogenesis in the Drosophila CNS occurs during embryogenesis and also during the postembryonic larval stages. Several glial subtypes are generated in the postembryonic CNS through the proliferation of differentiated glial cells. The genes and molecular pathways that regulate glial proliferation in the postembryonic CNS are poorly understood. In this study we aimed to use gene expressing profiling of CNS tissue enriched in glia to identify genes expressed in glial cells in the postembryonic CNS. We used microarrays to compare the gene expression profiles from the larval CNS of animals that had increased numbers of glial cells to identify genes that are expressed in glia. RNA was purified from the late third instar larval CNS from control larvae, or larvae expressing an activated form of the FGF receptor (Hlt[ACT]), or overexpressing the insulin receptor (InR) in glial cells using the glial specific driver repoGal4 to increase the number of glial cells and generate CNS tissue enriched in glia.