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Nature Nov 2020The central nervous system has historically been viewed as an immune-privileged site, but recent data have shown that the meninges-the membranes that surround the brain...
The central nervous system has historically been viewed as an immune-privileged site, but recent data have shown that the meninges-the membranes that surround the brain and spinal cord-contain a diverse population of immune cells. So far, studies have focused on macrophages and T cells, but have not included a detailed analysis of meningeal humoral immunity. Here we show that, during homeostasis, the mouse and human meninges contain IgA-secreting plasma cells. These cells are positioned adjacent to dural venous sinuses: regions of slow blood flow with fenestrations that can potentially permit blood-borne pathogens to access the brain. Peri-sinus IgA plasma cells increased with age and following a breach of the intestinal barrier. Conversely, they were scarce in germ-free mice, but their presence was restored by gut re-colonization. B cell receptor sequencing confirmed that meningeal IgA cells originated in the intestine. Specific depletion of meningeal plasma cells or IgA deficiency resulted in reduced fungal entrapment in the peri-sinus region and increased spread into the brain following intravenous challenge, showing that meningeal IgA is essential for defending the central nervous system at this vulnerable venous barrier surface.
Topics: Aged; Aging; Animals; Blood-Brain Barrier; Cranial Sinuses; Female; Fungi; Gastrointestinal Microbiome; Germ-Free Life; Humans; Immunoglobulin A, Secretory; Intestines; Male; Meninges; Mice; Mice, Inbred C57BL; Plasma Cells
PubMed: 33149302
DOI: 10.1038/s41586-020-2886-4 -
Nature Neuroscience Dec 2023Decades of research have characterized diverse immune cells surveilling the CNS. More recently, the discovery of osseous channels (so-called 'skull channels') connecting... (Review)
Review
Decades of research have characterized diverse immune cells surveilling the CNS. More recently, the discovery of osseous channels (so-called 'skull channels') connecting the meninges with the skull and vertebral bone marrow has revealed a new layer of complexity in our understanding of neuroimmune interactions. Here we discuss our current understanding of skull and vertebral bone marrow anatomy, its contribution of leukocytes to the meninges, and its surveillance of the CNS. We explore the role of this hematopoietic output on CNS health, focusing on the supply of immune cells during health and disease.
Topics: Bone Marrow; Central Nervous System; Meninges; Skull; Head
PubMed: 37996526
DOI: 10.1038/s41593-023-01487-1 -
The Indian Journal of Medical Research Aug 2019Although the occurrence of tuberculous meningitis (TBM) in children is relatively rare, but it is associated with higher rates of mortality and severe morbidity. The... (Review)
Review
Although the occurrence of tuberculous meningitis (TBM) in children is relatively rare, but it is associated with higher rates of mortality and severe morbidity. The peak incidence of TBM occurs in younger children who are less than five years of age, and most children present with late-stage disease. Confirmation of diagnosis is often difficult, and other infectious causes such as bacterial, viral and fungal causes must be ruled out. Bacteriological confirmation of diagnosis is ideal but is often difficult because of its paucibacillary nature as well as decreased sensitivity and specificity of diagnostic tests. Early diagnosis and management of the disease, though difficult, is essential to avoid death or neurologic disability. Hence, a high degree of suspicion and a combined battery of tests including clinical, bacteriological and neuroimaging help in diagnosis of TBM. Children diagnosed with TBM should be managed with antituberculosis therapy (ATT) and steroids. There are studies reporting low concentrations of ATT, especially of rifampicin and ethambutol in cerebrospinal fluid (CSF), and very young children are at higher risk of low ATT drug concentrations. Further studies are needed to identify appropriate regimens with adequate dosing of ATT for the management of paediatric TBM to improve treatment outcomes. This review describes the clinical presentation, investigations, management and outcome of TBM in children and also discusses various studies conducted among children with TBM.
Topics: Antitubercular Agents; Child; Child, Preschool; Ethambutol; Humans; Mycobacterium tuberculosis; Rifampin; Steroids; Treatment Outcome; Tuberculosis, Meningeal
PubMed: 31670267
DOI: 10.4103/ijmr.IJMR_786_17 -
Arquivos de Neuro-psiquiatria Dec 2020Hypertrophic pachymeningitis (HP) is a non-usual manifestation of rheumatologic, infectious, and neoplastic diseases. Etiological diagnosis is a challenge, but when made...
IMPORTANCE
Hypertrophic pachymeningitis (HP) is a non-usual manifestation of rheumatologic, infectious, and neoplastic diseases. Etiological diagnosis is a challenge, but when made promptly it creates a window of opportunity for treatment, with the possibility of a total reversal of symptoms.
OBSERVATIONS
HP is an inflammatory process of the dura mater that can occur as a manifestation of sarcoidosis, granulomatosis with polyangiitis, and IgG4-related disease. The HP case evaluation is extensive and includes central nervous system imaging, cerebrospinal fluid analysis, serology, rheumatologic tests, and systemic survey for other manifestations sites. After systemic investigation, meningeal biopsy might be necessary. Etiology guides HP treatment, and autoimmune disorders are treated with corticosteroids alone or associated with an immunosuppressor.
CONCLUSION
HP is a manifestation of several diseases, and a precise etiological diagnosis is crucial because of the difference among treatments. An extensive investigation of patients with HP helps early diagnosis and correct treatment.
Topics: Adrenal Cortex Hormones; Dura Mater; Humans; Hypertrophy; Magnetic Resonance Imaging; Meningitis
PubMed: 33295420
DOI: 10.1590/0004-282X20200073 -
Cellular & Molecular Immunology Nov 2023Brain macrophages include microglia in the parenchyma, border-associated macrophages in the meningeal-choroid plexus-perivascular space, and monocyte-derived macrophages... (Review)
Review
Brain macrophages include microglia in the parenchyma, border-associated macrophages in the meningeal-choroid plexus-perivascular space, and monocyte-derived macrophages that infiltrate the brain under various disease conditions. The vast heterogeneity of these cells has been elucidated over the last decade using revolutionary multiomics technologies. As such, we can now start to define these various macrophage populations according to their ontogeny and their diverse functional programs during brain development, homeostasis and disease pathogenesis. In this review, we first outline the critical roles played by brain macrophages during development and healthy aging. We then discuss how brain macrophages might undergo reprogramming and contribute to neurodegenerative disorders, autoimmune diseases, and glioma. Finally, we speculate about the most recent and ongoing discoveries that are prompting translational attempts to leverage brain macrophages as prognostic markers or therapeutic targets for diseases that affect the brain.
Topics: Humans; Macrophages; Microglia; Brain; Meninges; Autoimmune Diseases
PubMed: 37365324
DOI: 10.1038/s41423-023-01053-6 -
Neuron Dec 2023Leptomeninges, consisting of the pia mater and arachnoid, form a connective tissue investment and barrier enclosure of the brain. The exact nature of leptomeningeal...
Leptomeninges, consisting of the pia mater and arachnoid, form a connective tissue investment and barrier enclosure of the brain. The exact nature of leptomeningeal cells has long been debated. In this study, we identify five molecularly distinct fibroblast-like transcriptomes in cerebral leptomeninges; link them to anatomically distinct cell types of the pia, inner arachnoid, outer arachnoid barrier, and dural border layer; and contrast them to a sixth fibroblast-like transcriptome present in the choroid plexus and median eminence. Newly identified transcriptional markers enabled molecular characterization of cell types responsible for adherence of arachnoid layers to one another and for the arachnoid barrier. These markers also proved useful in identifying the molecular features of leptomeningeal development, injury, and repair that were preserved or changed after traumatic brain injury. Together, the findings highlight the value of identifying fibroblast transcriptional subsets and their cellular locations toward advancing the understanding of leptomeningeal physiology and pathology.
Topics: Mice; Animals; Meninges; Arachnoid; Pia Mater; Choroid Plexus; Brain
PubMed: 37776854
DOI: 10.1016/j.neuron.2023.09.002 -
Molecular Neurodegeneration Aug 2023Alzheimer's disease (AD) is an aging-related form of dementia associated with the accumulation of pathological aggregates of amyloid beta and neurofibrillary tangles in... (Review)
Review
Alzheimer's disease (AD) is an aging-related form of dementia associated with the accumulation of pathological aggregates of amyloid beta and neurofibrillary tangles in the brain. These phenomena are accompanied by exacerbated inflammation and marked neuronal loss, which altogether contribute to accelerated cognitive decline. The multifactorial nature of AD, allied to our still limited knowledge of its etiology and pathophysiology, have lessened our capacity to develop effective treatments for AD patients. Over the last few decades, genome wide association studies and biomarker development, alongside mechanistic experiments involving animal models, have identified different immune components that play key roles in the modulation of brain pathology in AD, affecting its progression and severity. As we will relay in this review, much of the recent efforts have been directed to better understanding the role of brain innate immunity, and particularly of microglia. However, and despite the lack of diversity within brain resident immune cells, the brain border tissues, especially the meninges, harbour a considerable number of different types and subtypes of adaptive and innate immune cells. Alongside microglia, which have taken the centre stage as important players in AD research, there is new and exciting evidence pointing to adaptive immune cells, namely T and B cells found in the brain and its meninges, as important modulators of neuroinflammation and neuronal (dys)function in AD. Importantly, a genuine and functional lymphatic vascular network is present around the brain in the outermost meningeal layer, the dura. The meningeal lymphatics are directly connected to the peripheral lymphatic system in different mammalian species, including humans, and play a crucial role in preserving a "healthy" immune surveillance of the CNS, by shaping immune responses, not only locally at the meninges, but also at the level of the brain tissue. In this review, we will provide a comprehensive view on our current knowledge about the meningeal lymphatic vasculature, emphasizing its described roles in modulating CNS fluid and macromolecule drainage, meningeal and brain immunity, as well as glial and neuronal function in aging and in AD.
Topics: Animals; Humans; Alzheimer Disease; Amyloid beta-Peptides; Genome-Wide Association Study; Meninges; Lymphatic System; Brain; Mammals
PubMed: 37580702
DOI: 10.1186/s13024-023-00645-0 -
Nature Immunology Nov 2020Interleukin (IL)-17a has been highly conserved during evolution of the vertebrate immune system and widely studied in contexts of infection and autoimmunity. Studies...
Interleukin (IL)-17a has been highly conserved during evolution of the vertebrate immune system and widely studied in contexts of infection and autoimmunity. Studies suggest that IL-17a promotes behavioral changes in experimental models of autism and aggregation behavior in worms. Here, through a cellular and molecular characterization of meningeal γδ17 T cells, we defined the nearest central nervous system-associated source of IL-17a under homeostasis. Meningeal γδ T cells express high levels of the chemokine receptor CXCR6 and seed meninges shortly after birth. Physiological release of IL-17a by these cells was correlated with anxiety-like behavior in mice and was partially dependent on T cell receptor engagement and commensal-derived signals. IL-17a receptor was expressed in cortical glutamatergic neurons under steady state and its genetic deletion decreased anxiety-like behavior in mice. Our findings suggest that IL-17a production by meningeal γδ17 T cells represents an evolutionary bridge between this conserved anti-pathogen molecule and survival behavioral traits in vertebrates.
Topics: Animals; Anxiety; Behavior, Animal; Cell Proliferation; Cerebral Cortex; Disease Models, Animal; Dura Mater; Gene Expression Profiling; Gene Expression Regulation; Interleukin-17; Meninges; Mice; Mice, Knockout; Neurons; Receptors, Antigen, T-Cell, gamma-delta; Signal Transduction; T-Lymphocyte Subsets; Transcriptome
PubMed: 32929273
DOI: 10.1038/s41590-020-0776-4 -
The Journal of Experimental Medicine Aug 2022Meningeal lymphatic vessels (MLVs) were identified in the dorsal and caudobasal regions of the dura mater, where they ensure waste product elimination and immune...
Meningeal lymphatic vessels (MLVs) were identified in the dorsal and caudobasal regions of the dura mater, where they ensure waste product elimination and immune surveillance of brain tissues. Whether MLVs exist in the anterior part of the murine and human skull and how they connect with the glymphatic system and extracranial lymphatics remained unclear. Here, we used light-sheet fluorescence microscopy (LSFM) imaging of mouse whole-head preparations after OVA-A555 tracer injection into the cerebrospinal fluid (CSF) and performed real-time vessel-wall (VW) magnetic resonance imaging (VW-MRI) after systemic injection of gadobutrol in patients with neurological pathologies. We observed a conserved three-dimensional anatomy of MLVs in mice and humans that aligned with dural venous sinuses but not with nasal CSF outflow, and we discovered an extended anterior MLV network around the cavernous sinus, with exit routes through the foramina of emissary veins. VW-MRI may provide a diagnostic tool for patients with CSF drainage defects and neurological diseases.
Topics: Animals; Glymphatic System; Humans; Lymphatic System; Lymphatic Vessels; Magnetic Resonance Imaging; Meninges; Mice
PubMed: 35776089
DOI: 10.1084/jem.20220035 -
ELife Jan 2023Emerging evidence suggests that the meningeal compartment plays instrumental roles in various neurological disorders, however, we still lack fundamental knowledge about...
Emerging evidence suggests that the meningeal compartment plays instrumental roles in various neurological disorders, however, we still lack fundamental knowledge about meningeal biology. Here, we utilized high-throughput RNA sequencing (RNA-seq) techniques to investigate the transcriptional response of the meninges to traumatic brain injury (TBI) and aging in the sub-acute and chronic time frames. Using single-cell RNA sequencing (scRNA-seq), we first explored how mild TBI affects the cellular and transcriptional landscape in the meninges in young mice at one-week post-injury. Then, using bulk RNA-seq, we assessed the differential long-term outcomes between young and aged mice following TBI. In our scRNA-seq studies, we highlight injury-related changes in differential gene expression seen in major meningeal cell populations including macrophages, fibroblasts, and adaptive immune cells. We found that TBI leads to an upregulation of type I interferon (IFN) signature genes in macrophages and a controlled upregulation of inflammatory-related genes in the fibroblast and adaptive immune cell populations. For reasons that remain poorly understood, even mild injuries in the elderly can lead to cognitive decline and devastating neuropathology. To better understand the differential outcomes between the young and the elderly following brain injury, we performed bulk RNA-seq on young and aged meninges 1.5 months after TBI. Notably, we found that aging alone induced upregulation of meningeal genes involved in antibody production by B cells and type I IFN signaling. Following injury, the meningeal transcriptome had largely returned to its pre-injury signature in young mice. In stark contrast, aged TBI mice still exhibited upregulation of immune-related genes and downregulation of genes involved in extracellular matrix remodeling. Overall, these findings illustrate the dynamic transcriptional response of the meninges to mild head trauma in youth and aging.
Topics: Mice; Animals; Brain Injuries, Traumatic; Brain Concussion; Brain Injuries; Aging; Meninges; Mice, Inbred C57BL; Microglia; Brain; Disease Models, Animal
PubMed: 36594818
DOI: 10.7554/eLife.81154