Peripherally derived T regulatory and γδ T cells have opposing roles in the pathogenesis of intractable pediatric epilepsy

Xu, Dan; Robinson, Andrew P.; Ishii, Takeaki; Duncan, D’Anne S; Alden, Tord D.; Goings, Gwendolyn E.; Ifergan, Igal; Podojil, Joseph R.; Penaloza-MacMaster, Pablo; Kearney, Jennifer A.; Swanson, Geoffrey T.; Miller, Stephen D.; Koh, Sookyong

doi:10.1084/jem.20171285

Cited by 99 publications

(95 citation statements)

References 81 publications

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“…The gut environment has been found to significantly influence CNS diseases such as MS, EAE, and ischemic brain injury; however, immune cell mechanisms are unclear. In addition, the pathogenesis of intractable epilepsy is related to gd T cells, where proinflammatory gd T cells were concentrated in epileptogenic lesions, and their numbers positively associated with disease severity (125)(126)(127).…”

Section: Other Central Nervous System Diseasesmentioning

confidence: 99%

The Role of Gamma-Delta T Cells in Diseases of the Central Nervous System

Zhang

et al. 2020

Front. Immunol.

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Gamma-delta (gd) T cells are a subset of T cells that promote the inflammatory responses of lymphoid and myeloid lineages, and are especially vital to the initial inflammatory and immune responses. Given the capability to connect crux inflammations of adaptive and innate immunity, gd T cells are responsive to multiple molecular cues and can acquire the capacity to induce various cytokines, such as GM-CSF, IL-4, IL-17, IL-21, IL-22, and IFN-g. Nevertheless, the exact mechanisms responsible for gd T cell proinflammatory functions remain poorly understood, particularly in the context of the central nervous system (CNS) diseases. CNS disease, usually leading to irreversible cognitive and physical disability, is becoming a worldwide public health problem. Here, we offer a review of the neuroinflammatory and immune functions of gd T cells, intending to understand their roles in CNS diseases, which may be crucial for the development of novel clinical applications.

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Section: Other Central Nervous System Diseasesmentioning

confidence: 99%

The Role of Gamma-Delta T Cells in Diseases of the Central Nervous System

Zhang

et al. 2020

Front. Immunol.

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“…TNF-α can also inhibit the astrocytic glutamate uptake by reducing the expression of glutamate transporters [62]. TNF-α and p55 receptors mediate neuronal loss and demyelination probably by inducing penetration of T cells or activating resident microglia in intractable pediatric epilepsy [63]. The anti-TNF-α therapy has demonstrated potential clinical applications in a recent study.…”

Section: Tnf-α With Dual Functionsmentioning

confidence: 99%

“…Most of the infiltrating T cells are cytotoxic to normal neurons, induce hyper-excitation of the neurons, and modify the seizure threshold through releasing TNF-α, IL-17, and granulocyte-macrophage colony-stimulating factor. The number of infiltrating T cells is also closely correlated with the severity of seizures [63,142]. Both infiltrating CD4 + and CD8 + T cells are observed to express high levels of integrins (very late antigen-4 and lymphocyte function-associated antigen-1) in the brains of 33 drugresistant epileptic patients with Rasmussen's encephalitis, or encephalomalacia (EM), or MTLE, or FCD.…”

Section: Adaptive Immune Cells: Infiltrating Playersmentioning

confidence: 99%

“…These integrins are essential for T cell migration across BBB. In drug-resistant epileptic patients with EM or FCD, neurons and mature oligodendrocytes are found to express MHC molecules in resected brain tissues, making them possible targets for T cells, thereby triggering abnormal losses of myelin sheaths and neurons [63].…”

Section: Adaptive Immune Cells: Infiltrating Playersmentioning

confidence: 99%

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The role of inflammation in epileptogenesis

Meng

Yao

2020

Acta Epileptologica

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Epilepsy is a chronic neurological disorder that has an extensive impact on a patient’s life. Accumulating evidence has suggested that inflammation participates in the progression of spontaneous and recurrent seizures. Pro-convulsant incidences can stimulate immune cells, augment the release of pro-inflammatory cytokines, elicit neuronal excitation as well as blood-brain barrier (BBB) dysfunction, and finally trigger the generation or recurrence of seizures. Understanding the pathogenic roles of inflammatory mediators, including inflammatory cytokines, cells, and BBB, in epileptogenesis will be beneficial for the treatment of epilepsy. In this systematic review, we performed a literature search on the PubMed database using the following keywords: “epilepsy” or “seizures” or “epileptogenesis”, and “immunity” or “inflammation” or “neuroinflammation” or “damage-associated molecular patterns” or “cytokines” or “chemokines” or “adhesion molecules” or “microglia” or “astrocyte” or “blood-brain barrier”. We summarized the classic inflammatory mediators and their pathogenic effects in the pathogenesis of epilepsy, based on the most recent findings from both human and animal model studies.

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“…or suppression(47) of neuronal network excitability. Also, it is noteworthy to mention that a recent report identified opposing effects of different T-lymphocyte subpopulations subsequent to leukocyte extravasation, where γδ T-lymphocytes exacerbated seizures, while on the other hand, regulatory T-lymphocytes displayed anti-convulsant effects in an experimental epilepsy model(48). Thus, it will be important in future studies to determine whether either lymphocytic or myeloid cell subtypes isolated from PBMCs can mediate pathological pro-excitation of pyramidal neurons when co-cultured alone with OCHSCs.…”

mentioning

confidence: 99%

Transduction of inflammation from peripheral immune cells to the hippocampus induces neuronal hyperexcitability mediated by Caspase-1 activation

Shaker

Chattopadhyaya

Amilhon

et al. 2020

Preprint

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Background Recent studies report infiltration of peripheral blood mononuclear cells (PBMCs) into the central nervous system (CNS) in epileptic disorders, suggestive of a potential contribution of PBMC extravasation to the generation of seizures. Nevertheless, the underlying mechanisms involved in PBMC infiltrates promoting neuronal predisposition to ictogenesis remain unclear. Therefore, we developed an in vitro model mimicking PBMC infiltration into the brain in order to investigate potential transduction of inflammatory signals from PBMCs to the CNS.MethodsTo establish our model, we first extracted PBMCs from rat spleen, then, we immunologically primed PBMCs with lipopolysaccharide (LPS), followed by immunological activation with Nigericin. Thereafter, we cultured PBMCs on top of organotypic cortico-hippocampal brain slice cultures (OCHSCs) derived from the same rat, and compared PBMC-OCHSC co-cultures to OCHSCs exposed to PBMCs in the culture media. Also, we targeted a potential molecular pathway underlying transduction of peripheral inflammation to OCHSCs by incubating OCHSCs with the Caspase-1 inhibitor VX-765 prior to co-culturing PBMCs with OCHSCs. After 24 hours, we immunohistochemically analyzed inflammation markers in the cortex and the hippocampus. In addition, we performed whole-cell patch-clamp recordings in cortical layer II/III and hippocampal CA1 pyramidal neurons.ResultsIn the cortex, co-culturing immunoreactive PBMCs treated with LPS + Nigericin on top of OCHSCs induced ectopic expression of inflammation markers and enhanced neuronal excitation. In contrast, no excitability changes were detected after adding primed PBMCs, i.e. treated with LPS only, to OCHSCs. Strikingly, in the hippocampus, both immunoreactive and primed PBMCs elicited similar pro-inflammatory and pro-excitatory effects. However, when immunoreactive and primed PBMCs were cultured in the media separately from OCHSCs, only immunoreactive PBMCs gave rise to neuroinflammation and hyperexcitability in the hippocampus, whereas primed PBMCs failed to produce any significant changes. Finally, VX-765 application to OCHSCs, co-cultured with either immunoreactive or primed PBMCs, protected them from neuroinflammation and hippocampal hyperexcitability.ConclusionsOur study shows a higher susceptibility of the hippocampus to peripheral inflammation as compared to the cortex, mediated via Caspase-1-dependent signaling pathways. Thus, our findings suggest that Caspase-1 inhibition may potentially provide therapeutic benefits during hippocampal neuroinflammation and hyperexcitability secondary to peripheral innate immunity.

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Peripherally derived T regulatory and γδ T cells have opposing roles in the pathogenesis of intractable pediatric epilepsy

Cited by 99 publications

References 81 publications

The Role of Gamma-Delta T Cells in Diseases of the Central Nervous System

The Role of Gamma-Delta T Cells in Diseases of the Central Nervous System

The role of inflammation in epileptogenesis

Transduction of inflammation from peripheral immune cells to the hippocampus induces neuronal hyperexcitability mediated by Caspase-1 activation

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