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Nature Jul 2015One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous...
One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.
Topics: Animals; Central Nervous System; Cranial Sinuses; Female; Humans; Immune Tolerance; Immunologic Surveillance; Lymphatic Vessels; Male; Meninges; Mice, Inbred C57BL; T-Lymphocytes
PubMed: 26030524
DOI: 10.1038/nature14432 -
Trends in Molecular Medicine Jun 2018The central nervous system (CNS) is an immunologically specialized tissue protected by a blood-brain barrier. The CNS parenchyma is enveloped by a series of overlapping... (Review)
Review
The central nervous system (CNS) is an immunologically specialized tissue protected by a blood-brain barrier. The CNS parenchyma is enveloped by a series of overlapping membranes that are collectively referred to as the meninges. The meninges provide an additional CNS barrier, harbor a diverse array of resident immune cells, and serve as a crucial interface with the periphery. Recent studies have significantly advanced our understanding of meningeal immunity, demonstrating how a complex immune landscape influences CNS functions under steady-state and inflammatory conditions. The location and activation state of meningeal immune cells can profoundly influence CNS homeostasis and contribute to neurological disorders, but these cells are also well equipped to protect the CNS from pathogens. In this review, we discuss advances in our understanding of the meningeal immune repertoire and provide insights into how this CNS barrier operates immunologically under conditions ranging from neurocognition to inflammatory diseases.
Topics: Animals; Central Nervous System; Disease Susceptibility; Homeostasis; Humans; Immune System; Immunity; Meninges; Meningitis
PubMed: 29731353
DOI: 10.1016/j.molmed.2018.04.003 -
Genesis (New York, N.Y. : 2000) May 2019The meninges are membranous layers surrounding the central nervous system. In the head, the meninges lie between the brain and the skull, and interact closely with both... (Review)
Review
The meninges are membranous layers surrounding the central nervous system. In the head, the meninges lie between the brain and the skull, and interact closely with both during development. The cranial meninges originate from a mesenchymal sheath on the surface of the developing brain, called primary meninx, and undergo differentiation into three layers with distinct histological characteristics: the dura mater, the arachnoid mater, and the pia mater. While genetic regulation of meningeal development is still poorly understood, mouse mutants and other models with meningeal defects have demonstrated the importance of the meninges to normal development of the calvaria and the brain. For the calvaria, the interactions with the meninges are necessary for the progression of calvarial osteogenesis during early development. In later stages, the meninges control the patterning of the skull and the fate of the sutures. For the brain, the meninges regulate diverse processes including cell survival, cell migration, generation of neurons from progenitors, and vascularization. Also, the meninges serve as a stem cell niche for the brain in the postnatal life. Given these important roles of the meninges, further investigation into the molecular mechanisms underlying meningeal development can provide novel insights into the coordinated development of the head.
Topics: Animals; Arachnoid; Brain; Cell Differentiation; Developmental Biology; Dura Mater; Humans; Meninges; Pia Mater; Skull
PubMed: 30801905
DOI: 10.1002/dvg.23288 -
Continuum (Minneapolis, Minn.) Oct 2018This article describes the clinical presentation, diagnostic approach (including the use of novel diagnostic platforms), and treatment of select infectious and... (Review)
Review
PURPOSE OF REVIEW
This article describes the clinical presentation, diagnostic approach (including the use of novel diagnostic platforms), and treatment of select infectious and noninfectious etiologies of chronic meningitis.
RECENT FINDINGS
Identification of the etiology of chronic meningitis remains challenging, with no cause identified in at least one-third of cases. Often, several serologic, CSF, and neuroimaging studies are indicated, although novel diagnostic platforms including metagenomic deep sequencing may hold promise for identifying organisms. Infectious etiologies are more common in those at risk for disseminated disease, specifically those who are immunocompromised because of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), transplantation, or immunosuppressant medications. An important step in identifying the etiology of chronic meningitis is assembling a multidisciplinary team of individuals, including those with specialized expertise in ophthalmology, dermatology, rheumatology, and infectious diseases, to provide guidance regarding diagnostic procedures.
SUMMARY
Chronic meningitis is defined as inflammation involving the meninges that lasts at least 4 weeks and is associated with a CSF pleocytosis. Chronic meningitis has numerous possible infectious and noninfectious etiologies, making it challenging to definitively diagnose patients. Therefore, a multifaceted approach that combines history, physical examination, neuroimaging, and laboratory analysis, including novel diagnostic platforms, is needed. This article focuses on key aspects of the evaluation of and approach to patients with chronic meningitis. Specific infectious etiologies and differential diagnoses of subacute and chronic meningitis, including noninfectious etiologies, are addressed.
Topics: Chronic Disease; Humans; Meningitis
PubMed: 30273241
DOI: 10.1212/CON.0000000000000664 -
Nature Mar 2023The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache. Bacterial meningitis causes life-threatening infections of the...
The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache. Bacterial meningitis causes life-threatening infections of the meninges and central nervous system, affecting more than 2.5 million people a year. How pain and neuroimmune interactions impact meningeal antibacterial host defences are unclear. Here we show that Nav1.8 nociceptors signal to immune cells in the meninges through the neuropeptide calcitonin gene-related peptide (CGRP) during infection. This neuroimmune axis inhibits host defences and exacerbates bacterial meningitis. Nociceptor neuron ablation reduced meningeal and brain invasion by two bacterial pathogens: Streptococcus pneumoniae and Streptococcus agalactiae. S. pneumoniae activated nociceptors through its pore-forming toxin pneumolysin to release CGRP from nerve terminals. CGRP acted through receptor activity modifying protein 1 (RAMP1) on meningeal macrophages to polarize their transcriptional responses, suppressing macrophage chemokine expression, neutrophil recruitment and dural antimicrobial defences. Macrophage-specific RAMP1 deficiency or pharmacological blockade of RAMP1 enhanced immune responses and bacterial clearance in the meninges and brain. Therefore, bacteria hijack CGRP-RAMP1 signalling in meningeal macrophages to facilitate brain invasion. Targeting this neuroimmune axis in the meninges can enhance host defences and potentially produce treatments for bacterial meningitis.
Topics: Humans; Brain; Calcitonin Gene-Related Peptide; Meninges; Neuroimmunomodulation; Pain; NAV1.8 Voltage-Gated Sodium Channel; Meningitis, Bacterial; Streptococcus agalactiae; Streptococcus pneumoniae; Nociceptors; Receptor Activity-Modifying Protein 1; Macrophages
PubMed: 36859544
DOI: 10.1038/s41586-023-05753-x -
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 -
The Journal of Clinical Investigation Sep 2017Recent discoveries of the glymphatic system and of meningeal lymphatic vessels have generated a lot of excitement, along with some degree of skepticism. Here, we... (Review)
Review
Recent discoveries of the glymphatic system and of meningeal lymphatic vessels have generated a lot of excitement, along with some degree of skepticism. Here, we summarize the state of the field and point out the gaps of knowledge that should be filled through further research. We discuss the glymphatic system as a system that allows CNS perfusion by the cerebrospinal fluid (CSF) and interstitial fluid (ISF). We also describe the recently characterized meningeal lymphatic vessels and their role in drainage of the brain ISF, CSF, CNS-derived molecules, and immune cells from the CNS and meninges to the peripheral (CNS-draining) lymph nodes. We speculate on the relationship between the two systems and their malfunction that may underlie some neurological diseases. Although much remains to be investigated, these new discoveries have changed our understanding of mechanisms underlying CNS immune privilege and CNS drainage. Future studies should explore the communications between the glymphatic system and meningeal lymphatics in CNS disorders and develop new therapeutic modalities targeting these systems.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Central Nervous System; Central Nervous System Diseases; Dura Mater; Extracellular Fluid; Humans; Immune System; Lymph Nodes; Lymphatic System; Lymphatic Vessels; Meninges; Neuroglia
PubMed: 28862640
DOI: 10.1172/JCI90603 -
Science (New York, N.Y.) Jul 2021The meninges contain adaptive immune cells that provide immunosurveillance of the central nervous system (CNS). These cells are thought to derive from the systemic...
The meninges contain adaptive immune cells that provide immunosurveillance of the central nervous system (CNS). These cells are thought to derive from the systemic circulation. Through single-cell analyses, confocal imaging, bone marrow chimeras, and parabiosis experiments, we show that meningeal B cells derive locally from the calvaria, which harbors a bone marrow niche for hematopoiesis. B cells reach the meninges from the calvaria through specialized vascular connections. This calvarial-meningeal path of B cell development may provide the CNS with a constant supply of B cells educated by CNS antigens. Conversely, we show that a subset of antigen-experienced B cells that populate the meninges in aging mice are blood-borne. These results identify a private source for meningeal B cells, which may help maintain immune privilege within the CNS.
Topics: Aging; Animals; B-Lymphocyte Subsets; B-Lymphocytes; Bone Marrow Cells; Cell Movement; Central Nervous System; Dura Mater; Fibroblasts; Homeostasis; Immune Privilege; Lymphopoiesis; Meninges; Mice; Plasma Cells; Single-Cell Analysis; Skull
PubMed: 34083450
DOI: 10.1126/science.abf9277 -
Neuron Oct 2018The nature of fluid dynamics within the brain parenchyma is a focus of intensive research. Of particular relevance is its participation in diseases associated with... (Review)
Review
The nature of fluid dynamics within the brain parenchyma is a focus of intensive research. Of particular relevance is its participation in diseases associated with protein accumulation and aggregation in the brain, such as Alzheimer's disease (AD). The meningeal lymphatic vessels have recently been recognized as an important player in the complex circulation and exchange of soluble contents between the cerebrospinal fluid (CSF) and the interstitial fluid (ISF). In aging mammals, for example, impaired functioning of the meningeal lymphatic vessels can lead to accelerated accumulation of toxic amyloid beta protein in the brain parenchyma, thus aggravating AD-related pathology. Given that meningeal lymphatic vessels are functionally linked to paravascular influx/efflux of the CSF/ISF, and in light of recent findings that certain cytokines, classically perceived as immune molecules, exert neuromodulatory effects, it is reasonable to suggest that the activity of meningeal lymphatics could alter the accessibility of CSF-borne immune neuromodulators to the brain parenchyma, thereby altering their effects on the brain. Accordingly, in this Perspective we propose that the meningeal lymphatic system can be viewed as a novel player in neurophysiology.
Topics: Animals; Brain; Glymphatic System; Humans; Meninges; Neurophysiology
PubMed: 30359603
DOI: 10.1016/j.neuron.2018.09.022 -
Biomolecules May 2022There is a growing prevalence of vascular cognitive impairment (VCI) worldwide, and most research has suggested that cerebral small vessel disease (CSVD) is the main... (Review)
Review
There is a growing prevalence of vascular cognitive impairment (VCI) worldwide, and most research has suggested that cerebral small vessel disease (CSVD) is the main contributor to VCI. Several potential physiopathologic mechanisms have been proven to be involved in the process of CSVD, such as blood-brain barrier damage, small vessels stiffening, venous collagenosis, cerebral blood flow reduction, white matter rarefaction, chronic ischaemia, neuroinflammation, myelin damage, and subsequent neurodegeneration. However, there still is a limited overall understanding of the sequence and the relative importance of these mechanisms. The glymphatic system (GS) and meningeal lymphatic vessels (mLVs) are the analogs of the lymphatic system in the central nervous system (CNS). As such, these systems play critical roles in regulating cerebrospinal fluid (CSF) and interstitial fluid (ISF) transport, waste clearance, and, potentially, neuroinflammation. Accumulating evidence has suggested that the glymphatic and meningeal lymphatic vessels played vital roles in animal models of CSVD and patients with CSVD. Given the complexity of CSVD, it was significant to understand the underlying interaction between glymphatic and meningeal lymphatic transport with CSVD. Here, we provide a novel framework based on new advances in main four aspects, including vascular risk factors, potential mechanisms, clinical subtypes, and cognition, which aims to explain how the glymphatic system and meningeal lymphatic vessels contribute to the progression of CSVD and proposes a comprehensive insight into the novel therapeutic strategy of CSVD.
Topics: Animals; Brain; Central Nervous System; Cerebral Small Vessel Diseases; Glymphatic System; Humans; Lymphatic System; Meninges
PubMed: 35740873
DOI: 10.3390/biom12060748