Protective and Pathological Immunity during Central Nervous System Infections

Klein, Robyn S.; Hunter, Christopher A.

doi:10.1016/j.immuni.2017.06.012

Cited by 127 publications

(111 citation statements)

References 253 publications

(290 reference statements)

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“…In response to TGF-β, microglia suppress immunological activity and promote normal microglial functions such as synaptic pruning and neuronal growth support [47]. The expression of genes such as HAVCR2 and its ligand LGALS9 and CD274, together with TGFB2 and IL-10, safeguard the normal brain against excessive inflammation [48]. Muller et al demonstrate that infiltrating macrophages rather than resident microglia encode immunosuppressive cytokines within the GBM microenvironment [49].…”

Section: Discussionmentioning

confidence: 99%

Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma

Stead

Nsengimana

et al. 2019

Clinical and Experimental Immunology

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Summary Glioblastoma (GBM) is an aggressive cancer with a very poor prognosis. Generally viewed as weakly immunogenic, GBM responds poorly to current immunotherapies. To understand this problem more clearly we used a combination of natural killer (NK) cell functional assays together with gene and protein expression profiling to define the NK cell response to GBM and explore immunosuppression in the GBM microenvironment. In addition, we used transcriptome data from patient cohorts to classify GBM according to immunological profiles. We show that glioma stem‐like cells, a source of post‐treatment tumour recurrence, express multiple immunomodulatory cell surface molecules and are targeted in preference to normal neural progenitor cells by natural killer (NK) cells ex vivo. In contrast, GBM‐infiltrating NK cells express reduced levels of activation receptors within the tumour microenvironment, with hallmarks of transforming growth factor (TGF)‐β‐mediated inhibition. This NK cell inhibition is accompanied by expression of multiple immune checkpoint molecules on T cells. Single‐cell transcriptomics demonstrated that both tumour and haematopoietic‐derived cells in GBM express multiple, diverse mediators of immune evasion. Despite this, immunome analysis across a patient cohort identifies a spectrum of immunological activity in GBM, with active immunity marked by co‐expression of immune effector molecules and feedback inhibitory mechanisms. Our data show that GBM is recognized by the immune system but that anti‐tumour immunity is restrained by multiple immunosuppressive pathways, some of which operate in the healthy brain. The presence of immune activity in a subset of patients suggests that these patients will more probably benefit from combination immunotherapies directed against multiple immunosuppressive pathways.

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Section: Discussionmentioning

confidence: 99%

Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma

Stead

Nsengimana

et al. 2019

Clinical and Experimental Immunology

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“…Astrocytes therefore control the relationship between intracerebral and systemic physiology and pathology, including neuroimmune communication. Regional heterogeneity of neuroglia defines specificity of the innate immune response, thus underlying differences in pathogen dissemination and immunopathology in different CNS regions [114].…”

Section: Astroglia Protect the Cns Against Invasive And Systemic Infementioning

confidence: 99%

“…Only a limited number of neutrotropic viruses, fungi and parasites can invade the brain parenchyma with relative ease; the majority of pathogens are effectively fenced by the brain barriers [114]. Pathogens are able to cross the BBB using the paracellular route, via transcytotic mechanism, inside entering monocytes (the Trojan horse hypothesis) as well as by other mechanisms such as hijacking of β-adrenergic receptors as shown for N. meningitides [165].…”

Section: Astrocytes and Cerebral Infectionmentioning

confidence: 99%

Astroglia in Sepsis Associated Encephalopathy

Shulyatnikova

Verkhratsky

2019

Neurochem Res

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Cellular pathophysiology of sepsis associated encephalopathy (SAE) remains poorly characterised. Brain pathology in SAE, which is manifested by impaired perception, consciousness and cognition, results from multifactorial events, including high levels of systemic cytokines, microbial components and endotoxins, which all damage the brain barriers, instigate neuroinflammation and cause homeostatic failure. Astrocytes, being the principal homeostatic cells of the central nervous system contribute to the brain defence against infection. Forming multifunctional anatomical barriers, astroglial cells maintain brain-systemic interfaces and restrict the damage to the nervous tissue. Astrocytes detect, produce and integrate inflammatory signals between immune cells and cells of brain parenchyma, thus regulating brain immune response. In SAE astrocytes are present in both reactive and astrogliopathic states; balance between these states define evolution of pathology and neurological outcomes. In humans pathophysiology of SAE is complicated by frequent presence of comorbidities, as well as age-related remodelling of the brain tissue with senescence of astroglia; these confounding factors further impact upon SAE progression and neurological deficits.

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“…The expression of genes such as HAVCR2, its ligand LGALS9 and CD274, along with TGFB2 and IL10 safeguard the normal brain against excessive inflammation (43). Muller et al demonstrate that infiltrating macrophages rather than resident microglia encode immunosuppressive cytokines within the GBM microenvironment (44).…”

Section: Multiple Mechanisms Of Tumour-mediated Downregulation Of Nk mentioning

confidence: 99%

Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma

Nsengimana

Reilly

et al. 2019

Preprint

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Glioblastoma (GBM) is an aggressive cancer with a very poor prognosis. Generally viewed as weakly immunogenic, GBM responds poorly to current immunotherapies. To better understand this problem we used a combination of NK cell functional assays together with gene and protein expression profiling to define the NK cell response to GBM and explore immunosuppression in the GBM microenvironment.In addition, we used transcriptome data from patient cohorts to classify GBM according to immunological profiles. We show that glioma stem-like cells, a source of post-treatment tumour recurrence, express multiple immunomodulatory cell surface molecules and are targeted in preference to normal neural progenitor cells by natural killer (NK) cells ex vivo. In contrast, GBM-infiltrating NK cells express reduced levels of activation receptors within the tumour microenvironment, with hallmarks of TGF-b mediated inhibition. This NK cell inhibition is accompanied by expression of mutiple immune checkpoint molecules on T cells. Single cell transcriptomics demonstrated that both tumour and haematopoietic-derived cells in GBM express multiple, diverse mediators of immune evasion. Despite this, immunome analysis across a patient cohort identifies a spectrum of immunological activity in GBM, with active immunity marked by co-expression of immune effector molecules and feedback inhibitory mechanisms. Our data show that GBM is recognised by the immune system but that anti-tumour immunity is restrained by multiple immunosuppressive pathways, some of which operate in the healthy brain. The presence of immune activity in a subset of patients suggests that these patients will more likely benefit from combination immunotherapies directed against multiple immunosuppressive pathways.

show abstract

Protective and Pathological Immunity during Central Nervous System Infections

Cited by 127 publications

References 253 publications

Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma

Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma

Astroglia in Sepsis Associated Encephalopathy

Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma

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