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1.
J Headache Pain ; 22(1): 138, 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34794382

RESUMO

BACKGROUND: Pain is generally concomitant with an inflammatory reaction at the site where the nociceptive fibers are activated. Rodent studies suggest that a sterile meningeal inflammatory signaling cascade may play a role in migraine headache as well. Experimental studies also suggest that a parenchymal inflammatory signaling cascade may report the non-homeostatic conditions in brain to the meninges to induce headache. However, how these signaling mechanisms function in patients is unclear and debated. Our aim is to discuss the role of inflammatory signaling in migraine pathophysiology in light of recent developments. BODY: Rodent studies suggest that a sterile meningeal inflammatory reaction can be initiated by release of peptides from active trigeminocervical C-fibers and stimulation of resident macrophages and dendritic/mast cells. This inflammatory reaction might be needed for sustained stimulation and sensitization of meningeal nociceptors after initial activation along with ganglionic and central mechanisms. Most migraines likely have cerebral origin as suggested by prodromal neurologic symptoms. Based on rodent studies, a parenchymal inflammatory signaling cascade has been proposed as a potential mechanism linking cortical spreading depolarization (CSD) to meningeal nociception. A recent PET/MRI study using a sensitive inflammation marker showed the presence of meningeal inflammatory activity in migraine with aura patients over the occipital cortex generating the visual aura. These studies also suggest the presence of a parenchymal inflammatory activity, supporting the experimental findings. In rodents, parenchymal inflammatory signaling has also been shown to be activated by migraine triggers such as sleep deprivation without requiring a CSD because of the resultant transcriptional changes, predisposing to inadequate synaptic energy supply during intense excitatory transmission. Thus, it may be hypothesized that neuronal stress created by either CSD or synaptic activity-energy mismatch could both initiate a parenchymal inflammatory signaling cascade, propagating to the meninges, where it is converted to a lasting headache with or without aura. CONCLUSION: Experimental studies in animals and emerging imaging findings from patients warrant further research to gain deeper insight to the complex role of inflammatory signaling in headache generation in migraine.


Assuntos
Depressão Alastrante da Atividade Elétrica Cortical , Transtornos de Enxaqueca , Animais , Humanos , Meninges , Transtornos de Enxaqueca/complicações , Inflamação Neurogênica , Nociceptores
3.
BMJ Case Rep ; 14(11)2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34799389

RESUMO

We discuss an extremely rare case of low-grade Schwann cell leptomeningeal neoplasm with no evident intradural primary, presenting with rapid neurological decline leading to death reflecting the aggressive biological behaviour of this entity despite its low-grade morphology. Notwithstanding extensive investigations, the diagnosis was only established on autopsy as clinical presentation is non-specific making diagnosis challenging. This condition could be considered in patients presenting with leptomeningeal disease if initial workup of more common causes is non-revealing.


Assuntos
Imageamento por Ressonância Magnética , Neoplasias Meníngeas , Autopsia , Humanos , Neoplasias Meníngeas/diagnóstico por imagem , Meninges , Células de Schwann
5.
Int J Mol Sci ; 22(19)2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34638999

RESUMO

Neural precursors (NPs) present in the hippocampus can be modulated by several neurogenic stimuli, including environmental enrichment (EE) acting through BDNF-TrkB signaling. We have recently identified NPs in meninges; however, the meningeal niche response to pro-neurogenic stimuli has never been investigated. To this aim, we analyzed the effects of EE exposure on NP distribution in mouse brain meninges. Following neurogenic stimuli, although we did not detect modification of the meningeal cell number and proliferation, we observed an increased number of neural precursors in the meninges. A lineage tracing experiment suggested that EE-induced ß3-Tubulin+ immature neuronal cells present in the meninges originated, at least in part, from GLAST+ radial glia cells. To investigate the molecular mechanism responsible for meningeal reaction to EE exposure, we studied the BDNF-TrkB interaction. Treatment with ANA-12, a TrkB non-competitive inhibitor, abolished the EE-induced meningeal niche changes. Overall, these data showed, for the first time, that EE exposure induced meningeal niche remodeling through TrkB-mediated signaling. Fluoxetine treatment further confirmed the meningeal niche response, suggesting it may also respond to other pharmacological neurogenic stimuli. A better understanding of the neurogenic stimuli modulation for meninges may be useful to improve the effectiveness of neurodegenerative and neuropsychiatric treatments.


Assuntos
Microambiente Celular , Meio Ambiente , Glicoproteínas de Membrana/metabolismo , Meninges/metabolismo , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais , Animais , Biomarcadores , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Imunofluorescência , Fluoxetina/farmacologia , Meninges/efeitos dos fármacos , Meninges/patologia , Camundongos , Neuroglia/metabolismo , Neurônios/metabolismo
6.
J Headache Pain ; 22(1): 105, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34496764

RESUMO

BACKGROUND: Calcitonin gene-related peptide (CGRP) is released from activated meningeal afferent fibres in the cranial dura mater, which likely accompanies severe headache attacks. Increased CGRP levels have been observed in different extracellular fluid compartments during primary headaches such as migraine but it is not entirely clear how CGRP is drained from the meninges. METHODS: We have used an in vivo preparation of the rat to examine after which time and at which concentration CGRP applied onto the exposed parietal dura mater appears in the jugular venous blood and the cerebrospinal fluid (CSF) collected from the cisterna magna. Recordings of meningeal (dural) and cortical (pial) blood flow were used to monitor the vasodilatory effect of CGRP. In a new ex vivo preparation we examined how much of a defined CGRP concentration applied to the arachnoidal side penetrates the dura. CGRP concentrations were determined with an approved enzyme immunoassay. RESULTS: CGRP levels in the jugular plasma in vivo were slightly elevated compared to baseline values 5-20 min after dural application of CGRP (10 µM), in the CSF a significant three-fold increase was seen after 35 min. Meningeal but not cortical blood flow showed significant increases. The spontaneous CGRP release from the dura mater ex vivo was above the applied low concentration of 1 pM. CGRP at 1 nM did only partly penetrate the dura. CONCLUSIONS: We conclude that only a small fraction of CGRP applied onto the dura mater reaches the jugular blood and, in a delayed manner, also the CSF. The dura mater may constitute a barrier for CGRP and limits diffusion into the CSF of the subarachnoidal space, where the CGRP concentration is too low to cause vasodilatation.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina , Calcitonina , Animais , Dura-Máter , Meninges , Ratos , Ratos Wistar
7.
Neurologist ; 26(5): 189-195, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34491937

RESUMO

INTRODUCTION: Leptomeningeal amyloidosis (LA) represents a rare subtype of familial transthyretin (TTR) amyloidosis, characterized by deposition of amyloid in cranial and spinal leptomeninges. Of >120 TTR mutations identified, few have been associated with LA. CASE REPORT: A 27-year-old male presented with a 2-year history of progressive symptoms including cognitive decline and right-sided weakness and numbness. Cerebrospinal fluid (CSF) analyses demonstrated high protein level. Gadolinium-enhanced magnetic resonance imaging (MRI) revealed extensive leptomeningeal enhancement over the surface of the brain and spinal cord. Pathologic analyses revealed a TTR mutation c.113A>G (p.D38G). REVIEW SUMMARY: Fifteen mutations and genotype-phenotype correlation of 72 LA patients have been summarized to provide an overview of LA associated with transthyretin mutations. The mean age of clinical onset was 44.9 years and the neurological symptoms primarily included cognitive impairment, headache, ataxia seizures and hearing, visual loss. CSF analysis showed elevated high CSF protein level and MRI revealed extensive leptomeningeal enhancement. CONCLUSION: Clinicians should be aware of this rare form of familial transthyretin amyloidosis as well as its typical MRI enhancement and high CSF protein. The important role of biopsy, genetic testing and the potential early diagnosis value of contrast MRI were suggested. Early recognition of these characteristics is important to provide misdiagnosis and shorten the time before correct diagnosis. These findings expand the phenotypic spectrum of TTR gene and have implications for the diagnosis, treatment, and systematic study of LA.


Assuntos
Amiloidose , Pré-Albumina , Adulto , Humanos , Imageamento por Ressonância Magnética , Masculino , Meninges/diagnóstico por imagem , Mutação/genética , Pré-Albumina/genética
8.
Brain Behav Immun ; 97: 226-238, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34371135

RESUMO

There is increasing interest in how immune cells, including those within the meninges at the blood-brain interface, influence brain function and mood disorders, but little data on humoral immunity in this context. Here, we show that in mice exposed to psychosocial stress, there is increased splenic B cell activation and secretion of the immunoregulatory cytokine interleukin (IL)-10. Meningeal B cells were prevalent in homeostasis but substantially decreased following stress, whereas Ly6Chi monocytes increased, and meningeal myeloid cells showed augmented expression of activation markers. Single-cell RNA sequencing of meningeal B cells demonstrated the induction of innate immune transcriptional programmes following stress, including genes encoding antimicrobial peptides that are known to alter myeloid cell activation. Cd19-/- mice, that have reduced B cells, showed baseline meningeal myeloid cell activation and decreased exploratory behaviour. Together, these data suggest that B cells may influence behaviour by regulating meningeal myeloid cell activation.


Assuntos
Linfócitos B , Meninges , Animais , Apresentação do Antígeno , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides , Estresse Psicológico
9.
Pain ; 162(9): 2386-2396, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34448752

RESUMO

ABSTRACT: The genesis of the headache phase in migraine with aura is thought to be mediated by cortical spreading depression (CSD) and the subsequent activation and sensitization of primary afferent neurons that innervate the intracranial meninges and their related large vessels. Yet, the exact mechanisms underlying this peripheral meningeal nociceptive response remain poorly understood. We investigated the relative contribution of cortical astrocytes to CSD-evoked meningeal nociception using extracellular single-unit recording of meningeal afferent activity and 2-photon imaging of cortical astrocyte calcium activity, in combination with 2 pharmacological approaches to inhibit astrocytic function. We found that fluoroacetate and l-α-aminoadipate, which inhibit astrocytes through distinct mechanisms, suppressed CSD-evoked afferent mechanical sensitization, but did not affect afferent activation. Pharmacological inhibition of astrocytic function, which ameliorated meningeal afferents' sensitization, reduced basal astrocyte calcium activity but had a minimal effect on the astrocytic calcium wave during CSD. We propose that calcium-independent signaling in cortical astrocytes plays an important role in driving the sensitization of meningeal afferents and the ensuing intracranial mechanical hypersensitivity in migraine with aura.


Assuntos
Depressão Alastrante da Atividade Elétrica Cortical , Transtornos de Enxaqueca , Animais , Astrócitos , Meninges , Nociceptores , Ratos , Ratos Sprague-Dawley
10.
J Vis Exp ; (173)2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34398161

RESUMO

The cranial meninges, comprised of the dura mater, arachnoid, and pia mater, are thought to primarily serve structural functions for the nervous system. For example, they protect the brain from the skull and anchor/organize the vascular and neuronal supply of the cortex. However, the meninges are also implicated in nervous system disorders such as migraine, where the pain experienced during a migraine is attributed to local sterile inflammation and subsequent activation of local nociceptive afferents. Of the layers in the meninges, the dura mater is of particular interest in the pathophysiology of migraines. It is highly vascularized, harbors local nociceptive neurons, and is home to a diverse array of resident cells such as immune cells. Subtle changes in the local meningeal microenvironment may lead to activation and sensitization of dural perivascular nociceptors, thus leading to migraine pain. Studies have sought to address how dural afferents become activated/sensitized by using either in vivo electrophysiology, imaging techniques, or behavioral models, but these commonly require very invasive surgeries. This protocol presents a method for comparatively non-invasive application of compounds on the dura mater in mice and a suitable method for measuring headache-like tactile sensitivity using periorbital von Frey testing following dural stimulation. This method maintains the integrity of the dura and skull and reduces confounding effects from invasive techniques by injecting substances through a 0.65 mm modified cannula at the junction of unfused sagittal and lambdoid sutures. This preclinical model will allow researchers to investigate a wide range of dural stimuli and their role in the pathological progression of migraine, such as nociceptor activation, immune cell activation, vascular changes, and pain behaviors, all while maintaining injury-free conditions to the skull and meninges.


Assuntos
Cefaleia , Transtornos de Enxaqueca , Animais , Dura-Máter , Meninges , Camundongos , Ratos , Ratos Sprague-Dawley
11.
Zhonghua Bing Li Xue Za Zhi ; 50(8): 876-881, 2021 Aug 08.
Artigo em Chinês | MEDLINE | ID: mdl-34344070

RESUMO

Objective: To investigate the clinicopathological features, diagnosis and prognosis of diffuse leptomeningeal glioneuronal tumor (DLGNT). Methods: Five cases of DLGNT diagnosed from January 2016 to January 2020 were collected from Xuanwu Hospital, Capital Medical University. The clinical features, histopathologic characteristics, immunohistochemical and molecular genetic findings and prognosis were analyzed and the relevant literature was reviewed. Results: The five patients (two males and three females) were aged 2 to 52 years (median 11 years), and had history of increased intracranial pressure (headache and vomiting) or limb weakness. Three of them were younger than 16 years of age. The imaging studies showed diffuse intracranial and intraspinal nodular leptomeningeal thickening and enhancement, with or without parenchymal involvement. At times there were associated small cyst-like lesions. Imaging interpretations were inflammatory lesions in three cases and space occupying lesions in two. Microscopically, in three cases the tumors showed low to moderate cellularity, consisting of relatively monomorphous oligodendrocyte-like cells arranged in small nests or diffusely distribution. No mitosis and necrosis were observed. In two cases there were increased cellularity with a diffuse honeycomb pattern. The tumor showed mild to moderate polymorphism with hyperchromatic nuclei. Mitosis, endothelial vascular proliferation and glomeruloid vessels were seen. Necrosis was absent. The tumor cells in all five cases were positive for synaptophysin,Olig2 and negative for IDH1 and H3 K27M. GFAP was focally positive in four cases and only one case expressed NeuN partly. The Ki-67 labeling index was 1%-35%. BRAF fusion was detected in four cases. Genetic analysis showed solitary 1p deletion in two cases (2/5), while all cases were negative for 1p/19q co-deletion (0/5). The five patients were followed up for 13 to 28 months (median 15 month). One patient died after 27 months. There was no evidence of tumor progression in the remaining four patients. Conclusions: DLGNT is rare and easily confused with other central nervous system tumors and inflammatory lesions. Therefore, the diagnosis of DLGNT should be made based on comprehensive information including imaging, morphologic and corresponding immunohistochemical examinations and molecular genetics to avoid misdiagnosis and delay in management.


Assuntos
Neoplasias do Sistema Nervoso Central , Neoplasias Meníngeas , Oligodendroglioma , Neoplasias do Sistema Nervoso Central/genética , Feminino , Testes Genéticos , Humanos , Masculino , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/genética , Meninges , Oligodendroglioma/genética
12.
Cells ; 10(7)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34359880

RESUMO

An imbalance of TNF signalling in the inflammatory milieu generated by meningeal immune cell infiltrates in the subarachnoid space in multiple sclerosis (MS), and its animal model may lead to increased cortical pathology. In order to explore whether this feature may be present from the early stages of MS and may be associated with the clinical outcome, the protein levels of TNF, sTNF-R1 and sTNF-R2 were assayed in CSF collected from 122 treatment-naïve MS patients and 36 subjects with other neurological conditions at diagnosis. Potential correlations with other CSF cytokines/chemokines and with clinical and imaging parameters at diagnosis (T0) and after 2 years of follow-up (T24) were evaluated. Significantly increased levels of TNF (fold change: 7.739; p < 0.001), sTNF-R1 (fold change: 1.693; p < 0.001) and sTNF-R2 (fold change: 2.189; p < 0.001) were detected in CSF of MS patients compared to the control group at T0. Increased TNF levels in CSF were significantly (p < 0.01) associated with increased EDSS change (r = 0.43), relapses (r = 0.48) and the appearance of white matter lesions (r = 0.49). CSF levels of TNFR1 were associated with cortical lesion volume (r = 0.41) at T0, as well as with new cortical lesions (r = 0.56), whilst no correlation could be found between TNFR2 levels in CSF and clinical or MRI features. Combined correlation and pathway analysis (ingenuity) of the CSF protein pattern associated with TNF expression (encompassing elevated levels of BAFF, IFN-γ, IL-1ß, IL-10, IL-8, IL-16, CCL21, haptoglobin and fibrinogen) showed a particular relationship to the interaction between innate and adaptive immune response. The CSF sTNF-R1-associated pattern (encompassing high levels of CXCL13, TWEAK, LIGHT, IL-35, osteopontin, pentraxin-3, sCD163 and chitinase-3-L1) was mainly related to altered T cell and B cell signalling. Finally, the CSF TNFR2-associated pattern (encompassing high CSF levels of IFN-ß, IFN-λ2, sIL-6Rα) was linked to Th cell differentiation and regulatory cytokine signalling. In conclusion, dysregulation of TNF and TNF-R1/2 pathways associates with specific clinical/MRI profiles and can be identified at a very early stage in MS patients, at the time of diagnosis, contributing to the prediction of the disease outcome.


Assuntos
Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/genética , Receptores Tipo II do Fator de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Fator de Necrose Tumoral alfa/genética , Imunidade Adaptativa , Adulto , Antígenos CD/líquido cefalorraquidiano , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/líquido cefalorraquidiano , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/imunologia , Linfócitos B/imunologia , Linfócitos B/patologia , Proteína C-Reativa/líquido cefalorraquidiano , Proteína C-Reativa/genética , Proteína C-Reativa/imunologia , Estudos de Casos e Controles , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/imunologia , Córtex Cerebral/patologia , Quimiocina CXCL13/líquido cefalorraquidiano , Quimiocina CXCL13/genética , Quimiocina CXCL13/imunologia , Proteína 1 Semelhante à Quitinase-3/líquido cefalorraquidiano , Proteína 1 Semelhante à Quitinase-3/genética , Proteína 1 Semelhante à Quitinase-3/imunologia , Citocina TWEAK/líquido cefalorraquidiano , Citocina TWEAK/genética , Citocina TWEAK/imunologia , Diagnóstico Precoce , Feminino , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Interleucinas/líquido cefalorraquidiano , Interleucinas/genética , Interleucinas/imunologia , Imageamento por Ressonância Magnética , Masculino , Meninges/diagnóstico por imagem , Meninges/imunologia , Meninges/patologia , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/patologia , Osteopontina/líquido cefalorraquidiano , Osteopontina/genética , Osteopontina/imunologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Receptores Tipo I de Fatores de Necrose Tumoral/líquido cefalorraquidiano , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/líquido cefalorraquidiano , Receptores Tipo II do Fator de Necrose Tumoral/imunologia
13.
Nat Neurosci ; 24(9): 1225-1234, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34253922

RESUMO

The CNS is ensheathed by the meninges and cerebrospinal fluid, and recent findings suggest that these CNS-associated border tissues have complex immunological functions. Unlike myeloid lineage cells, lymphocytes in border compartments have yet to be thoroughly characterized. Based on single-cell transcriptomics, we here identified a highly location-specific composition and expression profile of tissue-resident leukocytes in CNS parenchyma, pia-enriched subdural meninges, dura mater, choroid plexus and cerebrospinal fluid. The dura layer of the meninges contained a large population of B cells under homeostatic conditions in mice and rats. Murine dura B cells exhibited slow turnover and long-term tissue residency, and they matured in experimental neuroinflammation. The dura also contained B lineage progenitors at the pro-B cell stage typically not found outside of bone marrow, without direct influx from the periphery or the skull bone marrow. This identified the dura as an unexpected site of B cell residence and potentially of development in both homeostasis and neuroinflammation.


Assuntos
Linfócitos B/imunologia , Meninges/imunologia , Células Precursoras de Linfócitos B/imunologia , Animais , Camundongos , Ratos , Análise de Célula Única
14.
Cell Mol Life Sci ; 78(16): 6033-6049, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34274976

RESUMO

Melanocytes are pigmented cells residing mostly in the skin and hair follicles of vertebrates, where they contribute to colouration and protection against UV-B radiation. However, the spectrum of their functions reaches far beyond that. For instance, these pigment-producing cells are found inside the inner ear, where they contribute to the hearing function, and in the heart, where they are involved in the electrical conductivity and support the stiffness of cardiac valves. The embryonic origin of such extracutaneous melanocytes is not clear. We took advantage of lineage-tracing experiments combined with 3D visualizations and gene knockout strategies to address this long-standing question. We revealed that Schwann cell precursors are recruited from the local innervation during embryonic development and give rise to extracutaneous melanocytes in the heart, brain meninges, inner ear, and other locations. In embryos with a knockout of the EdnrB receptor, a condition imitating Waardenburg syndrome, we observed only nerve-associated melanoblasts, which failed to detach from the nerves and to enter the inner ear. Finally, we looked into the evolutionary aspects of extracutaneous melanocytes and found that pigment cells are associated mainly with nerves and blood vessels in amphibians and fish. This new knowledge of the nerve-dependent origin of extracutaneous pigment cells might be directly relevant to the formation of extracutaneous melanoma in humans.


Assuntos
Encéfalo/fisiologia , Orelha Interna/fisiologia , Coração/fisiologia , Meninges/fisiologia , Sistema Nervoso/fisiopatologia , Células de Schwann/fisiologia , Anfíbios/metabolismo , Anfíbios/fisiologia , Animais , Encéfalo/metabolismo , Linhagem da Célula/fisiologia , Orelha Interna/metabolismo , Desenvolvimento Embrionário/fisiologia , Feminino , Peixes/metabolismo , Peixes/fisiologia , Melanócitos/metabolismo , Melanócitos/fisiologia , Meninges/metabolismo , Camundongos , Sistema Nervoso/metabolismo , Gravidez , Receptor de Endotelina B/metabolismo , Células de Schwann/metabolismo
15.
Immunology ; 164(3): 450-466, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34293193

RESUMO

Ectopic lymphoid follicles (ELFs), resembling germinal centre-like structures, emerge in a variety of infectious and autoimmune and neoplastic diseases. ELFs can be found in the meninges of around 40% of the investigated progressive multiple sclerosis (MS) post-mortem brain tissues and are associated with the severity of cortical degeneration and clinical disease progression. Of predominant importance for progressive neuronal damage during the progressive MS phase appears to be meningeal inflammation, comprising diffuse meningeal infiltrates, B-cell aggregates and compartmentalized ELFs. However, the absence of a uniform definition of ELFs impedes reproducible and comparable neuropathological research in this field. In this review article, we will first highlight historical aspects and milestones around the discovery of ELFs in the meninges of progressive MS patients. In the next step, we discuss how animal models may contribute to an understanding of the mechanisms underlying ELF formation. Finally, we summarize challenges in investigating ELFs and propose potential directions for future research.


Assuntos
Meninges/patologia , Esclerose Múltipla Crônica Progressiva/imunologia , Estruturas Linfoides Terciárias/imunologia , Animais , Linfócitos B/imunologia , Modelos Animais de Doenças , Humanos , Meninges/imunologia , Esclerose Múltipla Crônica Progressiva/patologia , Estruturas Linfoides Terciárias/patologia
16.
Acta Biomater ; 134: 388-400, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34314888

RESUMO

The cranial meninges have been shown to play a pivotal role in traumatic brain injury mechanopathology. However, while the mechanical response of the brain and its many subregions have been studied extensively, the meninges have conventionally been overlooked. This paper presents the first comparative mechanical analysis of human dura mater, falx cerebri and superior sagittal sinus tissues. Biaxial tensile analysis identified that these tissues are mechanically heterogeneous, in contrast to the assumption that the tissues are mechanically homogeneous which is typically employed in FE model design. A thickness of 0.91 ± 0.05 (standard error) mm for the falx cerebri was also identified. This data can aid in improving the biofidelity of the influential falx structure in FE models. Additionally, the use of a collagen hybridizing peptide on the superior sagittal sinus suggests this structure is particularly susceptible to the effects of circumferential stretch, which may have important implications for clinical treatment of dural venous sinus pathologies. Collectively, this research progresses understanding of meningeal mechanical and structural characteristics and may aid in elucidating the behaviour of these tissues in healthy and diseased conditions. STATEMENT OF SIGNIFICANCE: This study presents the first evaluation of human falx cerebri and superior sagittal sinus mechanical, geometrical and structural properties, along with a comparison to cranial dura mater. To mechanically characterise the tissues, biaxial tensile testing is conducted on the tissues. This analysis identifies, for the first time, mechanical stiffness differences between these tissues. Additionally, geometrical analysis identifies that there are thickness differences between the tissues. The evaluation of human meningeal tissues allows for direct implementation of the novel data to finite element head injury models to enable improved biofidelity of these influential structures in traumatic brain injury simulations. This work also identifies that the superior sagittal sinus may be easily damaged during clinical angioplasty procedures, which may inform the treatment of dural sinus pathologies.


Assuntos
Dura-Máter , Seio Sagital Superior , Encéfalo , Cavidades Cranianas , Humanos , Meninges
17.
Front Immunol ; 12: 692051, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34194440

RESUMO

The meningeal lymphatic vessels (mLVs) in central nervous system (CNS) have been validated by rodent and human studies. The mLVs play a vital role in draining soluble molecules and trafficking lymphocytes, antigens and antibodies from CNS into cervical lymph nodes (CLNs). This indicates that mLVs may serve as a link between the CNS and peripheral immune system, perhaps involving in the neuroinflammatory disease. However, the morphology and drainage function of mLVs in patients with neuroinflammatory disease, such as neuromyelitis optica spectrum disorders (NMOSD), remains unexplored. Using the dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), we found that slower flow through mLVs along superior sagittal sinus in NMOSD patients with acute attack instead of NMOSD patients in chronic phase. The reduced flow in mLVs correlated with the disease severity evaluated by expanded disability status scale (EDSS). The receiver operating characteristic curve (ROC) indicated DCE-MRI might provide objective evidence to predict the acute relapse of NMOSD through evaluating the function of mLVs. Promoting or restoring the function of mLVs might be a new target for the treatment of NMOSD relapse.


Assuntos
Vasos Linfáticos/diagnóstico por imagem , Meninges/diagnóstico por imagem , Neuromielite Óptica/diagnóstico por imagem , Doença Aguda , Adulto , Encéfalo/diagnóstico por imagem , Doença Crônica , Feminino , Humanos , Vasos Linfáticos/fisiologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/imunologia , Nervo Óptico/diagnóstico por imagem , Recidiva , Medula Espinal/diagnóstico por imagem
18.
Sci Rep ; 11(1): 13735, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215779

RESUMO

To analyze the frequency and clinical phenotype of neurosarcoidosis (NS) in one of the largest nationwide cohorts of patients with sarcoidosis reported from southern Europe. NS was evaluated according to the Diagnostic Criteria for Central Nervous System and Peripheral Nervous System Sarcoidosis recently proposed by Stern et al. Pathologic confirmation of granulomatous disease was used to subclassify NS into definite (confirmation in neurological tissue), probable (confirmation in extraneurological tissue) and possible (no histopathological confirmation of the disease). Of the 1532 patients included in the cohort, 85 (5.5%) fulfilled the Stern criteria for NS (49 women, mean age at diagnosis of NS of 47.6 years, 91% White). These patients developed 103 neurological conditions involving the brain (38%), cranial nerves (36%), the meninges (3%), the spinal cord (10%) and the peripheral nerves (14%); no patient had concomitant central and peripheral nerve involvements. In 59 (69%) patients, neurological involvement preceded or was present at the time of diagnosis of the disease. According to the classification proposed by Stern et al., 11 (13%) were classified as a definite NS, 61 (72%) as a probable NS and the remaining 13 (15%) as a possible NS. In comparison with the systemic phenotype of patients without NS, patients with CNS involvement presented a lower frequency of thoracic involvement (82% vs 93%, q = 0.018), a higher frequency of ocular (27% vs 10%, q < 0.001) and salivary gland (15% vs 4%, q = 0.002) WASOG involvements. In contrast, patients with PNS involvement showed a higher frequency of liver involvement (36% vs 12%, p = 0.02) in comparison with patients without NS. Neurosarcoidosis was identified in 5.5% of patients. CNS involvement prevails significantly over PNS involvement, and both conditions do not overlap in any patient. The systemic phenotype associated to each involvement was clearly differentiated, and can be helpful not only in the early identification of neurological involvement, but also in the systemic evaluation of patients diagnosed with neurosarcoidosis.


Assuntos
Encéfalo/patologia , Doenças do Sistema Nervoso Central/diagnóstico , Sistema Nervoso Central/patologia , Nervos Periféricos/patologia , Sarcoidose/diagnóstico , Adulto , Idoso , Sistema Nervoso Central/diagnóstico por imagem , Doenças do Sistema Nervoso Central/classificação , Doenças do Sistema Nervoso Central/patologia , Estudos de Coortes , Nervos Cranianos/patologia , Feminino , Humanos , Masculino , Meninges/patologia , Pessoa de Meia-Idade , Sarcoidose/classificação , Sarcoidose/complicações , Sarcoidose/patologia , Medula Espinal/patologia
19.
Science ; 373(6553)2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34083450

RESUMO

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.


Assuntos
Subpopulações de Linfócitos B/fisiologia , Linfócitos B/fisiologia , Células da Medula Óssea/fisiologia , Sistema Nervoso Central/imunologia , Dura-Máter/citologia , Linfopoese , Meninges/citologia , Meninges/imunologia , Crânio/anatomia & histologia , Envelhecimento , Animais , Subpopulações de Linfócitos B/imunologia , Movimento Celular , Sistema Nervoso Central/fisiologia , Dura-Máter/imunologia , Fibroblastos/fisiologia , Homeostase , Privilégio Imunológico , Camundongos , Plasmócitos/fisiologia , Análise de Célula Única
20.
Front Immunol ; 12: 688254, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093593

RESUMO

Several barriers separate the central nervous system (CNS) from the rest of the body. These barriers are essential for regulating the movement of fluid, ions, molecules, and immune cells into and out of the brain parenchyma. Each CNS barrier is unique and highly dynamic. Endothelial cells, epithelial cells, pericytes, astrocytes, and other cellular constituents each have intricate functions that are essential to sustain the brain's health. Along with damaging neurons, a traumatic brain injury (TBI) also directly insults the CNS barrier-forming cells. Disruption to the barriers first occurs by physical damage to the cells, called the primary injury. Subsequently, during the secondary injury cascade, a further array of molecular and biochemical changes occurs at the barriers. These changes are focused on rebuilding and remodeling, as well as movement of immune cells and waste into and out of the brain. Secondary injury cascades further damage the CNS barriers. Inflammation is central to healthy remodeling of CNS barriers. However, inflammation, as a secondary pathology, also plays a role in the chronic disruption of the barriers' functions after TBI. The goal of this paper is to review the different barriers of the brain, including (1) the blood-brain barrier, (2) the blood-cerebrospinal fluid barrier, (3) the meningeal barrier, (4) the blood-retina barrier, and (5) the brain-lesion border. We then detail the changes at these barriers due to both primary and secondary injury following TBI and indicate areas open for future research and discoveries. Finally, we describe the unique function of the pro-inflammatory cytokine interleukin-1 as a central actor in the inflammatory regulation of CNS barrier function and dysfunction after a TBI.


Assuntos
Barreira Hematoencefálica/metabolismo , Barreira Hematorretiniana/metabolismo , Lesões Encefálicas Traumáticas/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , Interleucina-1/metabolismo , Meninges/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/patologia , Barreira Hematorretiniana/efeitos dos fármacos , Barreira Hematorretiniana/imunologia , Barreira Hematorretiniana/patologia , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/imunologia , Lesões Encefálicas Traumáticas/patologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Mediadores da Inflamação/antagonistas & inibidores , Interleucina-1/antagonistas & inibidores , Meninges/efeitos dos fármacos , Meninges/imunologia , Meninges/patologia , Receptores Tipo I de Interleucina-1/metabolismo , Transdução de Sinais
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