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Brain tumors (gliomas) are heterogeneous cellular ecosystems, where non-neoplastic monocytic cells have emerged as key regulators of tumor maintenance and progression. However, relative to macrophages/microglia, comparatively less is known about the roles of neurons and T cells in glioma pathobiology. Herein, we leverage genetically engineered mouse models and human biospecimens to define the axis in which neurons, T cells, and microglia interact to govern Neurofibromatosis-1 (NF1) low-grade glioma (LGG) growth. NF1 -mutant human and mouse brain neurons elaborate midkine to activate naïve CD8 +  T cells to produce Ccl4, which induces microglia to produce a key LGG growth factor (Ccl5) critical for LGG stem cell survival. Importantly, increased CCL5 expression is associated with reduced survival in patients with LGG. The elucidation of the critical intercellular dependencies that constitute the LGG neuroimmune axis provides insights into the role of neurons and immune cells in controlling glioma growth, relevant to future therapeutic targeting. The role of neurons and T cells in glioma progression remains poorly understood. Here the authors show that midkine-dependent activation of a neuron-T cell-microglia axis promotes the growth of optic pathway gliomas.

Individuals with Neurofibromatosis type 1 (NF1) are at increased risk for pediatric brain tumors (PBTs), especially optic gliomas; however, factors influencing their development are largely unknown. Extensive research suggests that allergic conditions protect against brain tumors, particularly gliomas in individuals without NF1. In this large cross-sectional study, we employed two different data sources to evaluate evidence for the hypothesis that allergic conditions (allergies, asthma, and eczema) may protect against PBT development in individuals with NF1. We used self- and parent/legal guardian reported questionnaire data from participants in the NF1 Patient Registry Initiative (NPRI, n = 1660) born from 1933 to 2014 to ascertain allergic condition and PBT diagnosis histories. Medical records (MRs) of 629 NF1 patients at a large medical center born from 1930 to 2012 were also reviewed for PBT and allergic condition diagnoses to evaluate additional evidence for our hypothesis. We used logistic regression to calculate odds ratios (ORs) and 95 % confidence intervals (CIs) for associations between allergic condition diagnoses and PBTs. Both data sources provided limited to no support for a protective effect of allergies or eczema on PBT development. Non-significant inverse associations between asthma and PBTs were observed (NPRI: OR = 0.80, 95 % CI 0.55–1.17; MR: OR = 0.71, 95 % CI 0.40–1.28) with stronger associations for optic gliomas specifically. Additionally, a significant inverse association was observed in an NPRI subgroup analysis where the reported asthma diagnosis age was younger than the reported PBT diagnosis age (OR = 0.57; 95 % CI 0.36–0.89). Our study supports the hypothesis that asthma protects against PBT development in NF1.

To elucidate the mechanisms underlying the reduced incidence of brain tumors in children with Neurofibromatosis type 1 (NF1) and asthma, we leverage Nf1 optic pathway glioma ( Nf1 OPG ) mice, human and mouse RNAseq data, and two different experimental asthma models. Following ovalbumin or house dust mite asthma induction at 4–6 weeks of age (WOA), Nf1 OPG mouse optic nerve volumes and proliferation are decreased at 12 and 24 WOA, indicating no tumor development. This inhibition is accompanied by reduced expression of the microglia-produced optic glioma mitogen, Ccl5. Human and murine T cell transcriptome analyses reveal that inhibition of microglia Ccl5 production results from increased T cell expression of decorin, which blocks Ccl4-mediated microglia Ccl5 expression through reduced microglia NFκB signaling. Decorin or NFκB inhibitor treatment of Nf1 OPG mice at 4–6 WOA inhibits tumor formation at 12 WOA, thus establishing a potential mechanistic etiology for the attenuated glioma incidence observed in children with asthma. Clinical studies have suggested a reduced incidence of brain tumors, including optic gliomas, in children with asthma. Here, in a mouse model of Neurofibromatosis type 1 associated low grade optic glioma, the authors show that experimental asthma induction decreases glioma formation and growth, resulting from T cell-dependent inhibition of microglia-mediated tumor support.

To analyze the clinical manifestations, imaging, electroencephalography, treatment, and prognosis of 35 cases of autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) in children. Children hospitalized in the Department of Neurology, Hunan Children's Hospital, China, between January 2015 and June 2021, owing to autoimmune diseases of the central nervous system were subjected to a cell-based assay (CBA). The assay identified 40 children positive for GFAP-immunoglobulin (Ig)G antibodies in the serum and/or the cerebrospinal fluid. Based on clinical manifestations and imaging characteristics, five children who were only positive for GFAP-IgG antibodies in serum were excluded, and the remaining 35 children were diagnosed with autoimmune GFAP-A. The clinical data derived from the 35 children were retrospectively analyzed. A total of 35 children, including 23 males and 12 females with a mean age of 6.3 ± 0.6 years, manifested clinical symptoms of fever (62.9%), headache (42.9%), convulsions (42.9%), abnormal mental behavior (51.4%), disorders of consciousness (54.3%), visual disturbance (22.9%), ataxia (11.4%), paralysis (40%), and autonomic dysfunction (25.7%). One child exhibited only the clinical symptom of peripheral facial nerve palsy. Eleven out of 35 children were also positive for other antibodies. In addition to the common overlapping autoimmune syndromes, one case of autoimmune GFAP-A also manifested as Bickerstaff's brainstem encephalitis. Linear periventricular enhancement upon MRI was significantly less frequent in children (8.5%) than in adults. In pediatric patients, MRI contrast enhancement was principally seen in the meninges and brain lobes. Although repeated relapse (17.1%) and sequelae symptoms (20%) occurred in some cases, most children showed a favorable prognosis. Spearman's rank correlation showed that the antibody titer was not significantly associated with the severity of the initial disease conditions. The disease diagnosis in children seropositive for GFAP antibodies only should receive a comprehensive diagnosis based on their clinical symptoms, imaging, electroencephalographic characteristics, and treatment responses. Some patients with relapses should receive repeated gamma globulin and corticosteroid therapy or the addition of immunosuppressants to their therapeutic regimen, and slow-dose tapering of corticosteroids and extended treatment are recommended for patients with overlapping autoimmune syndromes.

Inflammatory chemokines are a group of G‐protein receptor ligands characterized by conserved cysteine residues, which can be divided into four main subfamilies: CC, CXC, XC, and CX3C. The C‐X‐C chemokine receptor (CXCR) 3 and its ligands, C‐X‐C chemokine ligands (CXCLs), are widely expressed in both the peripheral nervous system (PNS) and central nervous system (CNS). This comprehensive literature review aims to examine the functions and pathways of CXCR3 and its ligands in nervous system‐related diseases. In summary, while the related pathways and the expression levels of CXCR3 and its ligands are varied among different cells in PNS and CNS, the MPAK pathway is the core via which CXCR3 exerts physiological functions. It is not only the core pathway of CXCR3 after activation but also participates in the expression of CXCR3 ligands in the nervous system. In addition, despite CXCR3 being a common inflammatory chemokine receptor, there is no consensus on its precise roles in various diseases. This uncertainty may be attributable to distinct inflammatory characteristics, that inflammation simultaneously possesses the dual properties of damage induction and repair facilitation.

Glioblastoma cells infiltrate brain tissue and migrate preferentially along white matter fibre tracts, an environment that is highly inhibitory to the migration of astrocytes and the growth of neurites because of the presence of specific inhibitory proteins. In vitro, spreading and migration of rat C6 glioma cells on a CNS (central nervous system) myelin substrate is correlated with and dependent on the presence of a metalloprotease. This membrane-bound metalloendoprotease exhibits a blocker profile different from known proteases. Pretreatment of CNS myelin or of a highly purified CNS myelin component, the inhibitory protein bNI-220, with C6 metalloproteolytic activity converts these non-permissive substrates into permissive environments for astrocytes and fibroblasts, indicating that this C6 cell-derived metalloprotease may inactivate myelin-associated inhibitory proteins. Antibodies were raised in chicken against fractions enriched in metalloproteolytic activity; these antibodies were able to inhibit specifically spreading and migration of C6 glioma cells on a CNS myelin substrate, as well as the invasion of C6 cells into adult rat optic nerve explants in vitro. These results suggest a crucial involvement of a membrane-bound metalloprotease in the mechanisms of C6 glioma migration and infiltration of brain tissue by proteolytic inactivation of the neurite growth inhibitory proteins present in CNS myelin.