T cell numbers correlate with neuronal loss rather than with seizure activity in medial temporal lobe epilepsy

Tröscher, Anna R.; Sakaraki, Eirini; Mair, Katharina M; Köck, Ulrike; Rácz, A.; Borger, Valeri; Cloppenborg, Thomas; Becker, Albert; Bien, Christian G.; Bauer, Jan

doi:10.1111/epi.16914

Cited by 16 publications

(18 citation statements)

References 36 publications

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“…Increased CD14 + levels in serum and cerebrospinal fluid (CSF) have also been associated with schizophrenia and bipolar disorder risk ( Jakobsson et al, 2015 ; Johansson et al, 2017 ). Similarly, for the other immune cell types implicated in the MSEA analysis of miRNA blood-brain correlates, significant aberrations in cell subpopulation levels have been reported for various neurological and psychiatric conditions, both in brain tissue ( Busse et al, 2012 ; Geng and Huang, 2021 ; Troscher et al, 2021 ) and peripheral blood samples ( Schleifer et al, 2002 ; Richartz-Salzburger et al, 2007 ; Miller et al, 2013 ; Cacabelos et al, 2016 ; Rocha et al, 2018 ; Furlan et al, 2019 ; Pietruczuk et al, 2019 ), including major depression, schizophrenia, epilepsy, bipolar disorder and Parkinson’s disease, among others, further suggesting a broad, pathophysiological role for changes in inflammation profiles.…”

Section: Discussionmentioning

confidence: 75%

Blood-Based miRNA Biomarkers as Correlates of Brain-Based miRNA Expression

Kos

Puppala

Cruz

et al. 2022

Front. Mol. Neurosci.

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The use of easily accessible peripheral samples, such as blood or saliva, to investigate neurological and neuropsychiatric disorders is well-established in genetic and epigenetic research, but the pathological implications of such biomarkers are not easily discerned. To better understand the relationship between peripheral blood- and brain-based epigenetic activity, we conducted a pilot study on captive baboons (Papio hamadryas) to investigate correlations between miRNA expression in peripheral blood mononuclear cells (PBMCs) and 14 different cortical and subcortical brain regions, represented by two study groups comprised of 4 and 6 animals. Using next-generation sequencing, we identified 362 miRNAs expressed at ≥ 10 read counts in 80% or more of the brain samples analyzed. Nominally significant pairwise correlations (one-sided P < 0.05) between peripheral blood and mean brain expression levels of individual miRNAs were observed for 39 and 44 miRNAs in each group. When miRNA expression levels were averaged for tissue type across animals within the groups, Spearman’s rank correlations between PBMCs and the brain regions are all highly significant (rs = 0.47–0.57; P < 2.2 × 10–16), although pairwise correlations among the brain regions are markedly stronger (rs = 0.86–0.99). Principal component analysis revealed differentiation in miRNA expression between peripheral blood and the brain regions for the first component (accounting for ∼75% of variance). Linear mixed effects modeling attributed most of the variance in expression to differences between miRNAs (>70%), with non-significant 7.5% and 13.1% assigned to differences between blood and brain-based samples in the two study groups. Hierarchical UPGMA clustering revealed a major co-expression branch in both study groups, comprised of miRNAs globally upregulated in blood relative to the brain samples, exhibiting an enrichment of miRNAs expressed in immune cells (CD14+, CD15+, CD19+, CD3+, and CD56 + leukocytes) among the top blood-brain correlates, with the gene MYC, encoding a master transcription factor that regulates angiogenesis and neural stem cell activation, representing the most prevalent miRNA target. Although some differentiation was observed between tissue types, these preliminary findings reveal wider correlated patterns between blood- and brain-expressed miRNAs, suggesting the potential utility of blood-based miRNA profiling for investigating by proxy certain miRNA activity in the brain, with implications for neuroinflammatory and c-Myc-mediated processes.

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Section: Discussionmentioning

confidence: 75%

Blood-Based miRNA Biomarkers as Correlates of Brain-Based miRNA Expression

Kos

Puppala

Cruz

et al. 2022

Front. Mol. Neurosci.

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“…These responses produced more cytokines and inflammatory mediators which contribute to the progression of epilepsy. Activation of the adaptive immune system, specifically T and B lymphocytes, is thought to be associated with viral infections and autoimmune diseases, which may lead to neuronal loss [ 39 ]. Thus, the innate and adaptive immune responses were more pronounced in the second group of epilepsy samples with a significant activation of the adipocytokine signaling pathway, which may contribute to the persistence of epilepsy and the progression of clinical symptoms.…”

Section: Discussionmentioning

confidence: 99%

Identification of Adipocytokine Pathway-Related Genes in Epilepsy and Its Effect on the Peripheral Immune Landscape

et al. 2022

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Epilepsy is a multifactorial neurological disorder with recurrent epileptic seizures. Current research stresses both inflammatory and autoimmune conditions as enablers in the pathophysiological process of epilepsy. In view of the growing concern about the role of adipocytokines in antiepileptic and modulating immune responses, we aimed to investigate the relevance of the adipocytokine signaling pathway in the pathological process of epilepsy and its impacts on peripheral immune characteristics. In this study, expression profiles of 142 peripheral blood samples were downloaded from the Gene Expression Omnibus (GEO) database. Adipocytokine pathway-related genes were screened out by feature selection using machine-learning algorithms. A nomogram was then constructed and estimated for the efficacy of diagnosis. Cluster analysis was employed for the recognization of two distinct epilepsy subtypes, followed by an estimation of the immune cell infiltration levels using single-sample gene-set enrichment analysis (ssGSEA). The biological characteristics were analyzed by functional enrichment analysis. The aberrant regulation of adipocytokine signaling pathway was found in the peripheral blood of patients with epilepsy. Twenty-one differently expressed adipocytokine pathway-related genes were identified and five (RELA, PRKAB1, TNFRSF1A, CAMKK2, and CPT1B) were selected to construct a nomogram. Subsequent validations of its forecasting ability revealed that this model has satisfactory predictive value. The immune cell infiltration degrees, such as those of innate immune cells and lymphocytes, were found to significantly correlate to the levels of adipocytokine pathway-related genes. Additionally, 239 differentially expressed genes (DEGs) were identified and their biological functions were mainly enriched in the regulation of the immune response. In conclusion, our results confirmed the predictive value of adipocytokine pathway-related genes for epilepsy and explored their effects on immune infiltration, thereby improving our understanding of the pathogenesis of epilepsy and providing assistance in the diagnosis and treatment of epilepsy.

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“…Moreover, an endothelial upregulation of chemokines can lead to increased leukocyte influx, which has been shown to act pro-convulsively and induce an epileptogenic inflammatory milieu within the brain parenchyma in animals (Fabene et al, 2008 , 2010 ; Cerri et al, 2017 ). In humans, T cell numbers were found to be uncorrelated with seizure frequency, making a direct link between T cells and epileptogenesis less likely (Tröscher et al, 2021 ). The neuronal chemokine fraktalkine (CX3CL1), which mediates neuronal-microglial interaction, has been shown to modulate GABA A currents in human temporal lobe epilepsy (Roseti et al, 2013 ; all inflammatory changes occurring in epilepsy in Figure 1 in bold).…”

Section: Post-stroke Epilepsymentioning

confidence: 99%

“…In addition, T cell and monocyte-attracting chemokines are expressed in the early, intermediate, and late stages after an ischemic infarct and in epilepsy resections (Fabene et al, 2010 ; García-Berrocoso et al, 2014 ; Cerri et al, 2017 ). How these chemokines act pro-epileptogenically is not yet fully understood, but T cells have been shown to infiltrate the brain in both epilepsy and after an ischemic stroke, albeit in low numbers (Zrzavy et al, 2017 ; Tröscher et al, 2021 ). However, a recent study showed that the number of T cells in medial temporal lobe epilepsy does not correlate with the seizure frequency.…”

Section: Post-stroke Epilepsymentioning

confidence: 99%

“…However, a recent study showed that the number of T cells in medial temporal lobe epilepsy does not correlate with the seizure frequency. Therefore, parenchymal T cells are unlikely to be the key driver of post-ischemic epileptogenesis (Tröscher et al, 2021 ). However, so far little is known about the parenchymal inflammatory milieu in PSE brains.…”

Section: Post-stroke Epilepsymentioning

confidence: 99%

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Inflammation Mediated Epileptogenesis as Possible Mechanism Underlying Ischemic Post-stroke Epilepsy

Tröscher

Gruber

Wagner

et al. 2021

Front. Aging Neurosci.

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Post-stroke Epilepsy (PSE) is one of the most common forms of acquired epilepsy, especially in the elderly population. As people get increasingly older, the number of stroke patients is expected to rise and concomitantly the number of people with PSE. Although many patients are affected by post-ischemic epileptogenesis, not much is known about the underlying pathomechanisms resulting in the development of chronic seizures. A common hypothesis is that persistent neuroinflammation and glial scar formation cause aberrant neuronal firing. Here, we summarize the clinical features of PSE and describe in detail the inflammatory changes after an ischemic stroke as well as the chronic changes reported in epilepsy. Moreover, we discuss alterations and disturbances in blood-brain-barrier leakage, astrogliosis, and extracellular matrix changes in both, stroke and epilepsy. In the end, we provide an overview of commonalities of inflammatory reactions and cellular processes in the post-ischemic environment and epileptic brain and discuss how these research questions should be addressed in the future.

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T cell numbers correlate with neuronal loss rather than with seizure activity in medial temporal lobe epilepsy

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 16 publications

References 36 publications

Blood-Based miRNA Biomarkers as Correlates of Brain-Based miRNA Expression

Blood-Based miRNA Biomarkers as Correlates of Brain-Based miRNA Expression

Identification of Adipocytokine Pathway-Related Genes in Epilepsy and Its Effect on the Peripheral Immune Landscape

Inflammation Mediated Epileptogenesis as Possible Mechanism Underlying Ischemic Post-stroke Epilepsy

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