Neuroinflammation is associated with infiltration of T cells in Lewy body disease and α-synuclein transgenic models

Iba, Michiyo; Kim, Changyoun; Sallin, Michelle; Kwon, Somin; Verma, Anjali; Overk, Cassia R.; Rissman, Robert A.; Sen, Ranjan; Sen, Jyoti Misra; Masliah, Eliezer

doi:10.1186/s12974-020-01888-0

Cited by 70 publications

(80 citation statements)

References 95 publications

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“…The regional distribution of the cells in the brain may account for why T cells were more effective in reducing nigral pathology, but not striatal or cortical pathology. Although we could not determine regional differences in T cell infiltration in the brain, our findings of CD3 + and CD4 + T cells in the brain align well with a growing body of evidence that T cells invade the central nervous system in neurodegenerative conditions [29,63,64].…”

Section: Discussionsupporting

confidence: 83%

“…T lymphocytes are altered and infiltrate the brain in PD [19][20][21][22][23][24][25][26] and it has been reported that autoreactive T lymphocytes directed against α-syn are present in PD patients [27] decades prior to motor PD [28]. Recruitment of CD4+ T cells to the brain occurs in models of a-syn overexpression [29]. In PD models, T cell function has been linked to α-syn pathobiology [30][31][32] and to the death of dopamine neurons [8,33].…”

Section: Introductionmentioning

confidence: 99%

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T cells limit accumulation of aggregate pathology following intrastriatal injection of α-synuclein fibrils

George¹,

Tyson²,

Rey

et al. 2020

Preprint

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α-Synuclein (α-syn) is the predominant protein in Lewy-body inclusions, which are pathological hallmarks of αsynucleinopathies, such as Parkinson's disease (PD) and multiple system atrophy (MSA). Other hallmarks include activation of microglia, elevation of pro-inflammatory cytokines, as well as the activation of T and B cells.These immune changes point towards a dysregulation of both the innate and the adaptive immune system. T cells have been shown to recognize epitopes derived from α-syn and altered populations of T cells have been found in PD and MSA patients, providing evidence that these cells can be key to the pathogenesis of the disease.To study the role of the adaptive immune system with respect to α-syn pathology, we injected human α-syn preformed fibrils (PFFs) into the striatum of immunocompromised mice (NSG) and assessed accumulation of phosphorylated α-syn pathology as well as microgliosis. Compared to wildtype mice, NSG mice had an 8-fold increase in phosphorylated α-syn pathology in the substantia nigra. We also reconstituted T and B cell populations in the NSG mice with cells isolated from a wildtype mouse spleen. Interestingly, reconstituting the T cell population decreased the accumulation of α-syn pathology and resulted in persistent microgliosis when compared to non-transplanted mice; reconstitution of B cells did not alter the nigral neuropathology. Our work provides experimental evidence that T cells play a role in the pathogenesis of α-synucleinopathies.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

T cells limit accumulation of aggregate pathology following intrastriatal injection of α-synuclein fibrils

George¹,

Tyson²,

Rey

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

“…Infiltration of T lymphocytes in the brain parenchyma has also been observed in other synucleinopathies. In particular, CD4 + but not CD8 + or B lymphocytes were found to be increased in the frontal cortex and hippocampus of cases with dementia with Lewy bodies (DLB) compared to controls at postmortem [ 35 ]. A second recent study in DLB cases showed increased T lymphocyte infiltration in both the grey and white matter of the middle temporal gyrus, in the absence of prominent microglial activation [ 2 ].…”

Section: Discussionmentioning

confidence: 99%

Neuroinflammation and protein pathology in Parkinson’s disease dementia

Kouli

Camacho

Allinson

et al. 2020

acta neuropathol commun

106

107

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Parkinson’s disease dementia is neuropathologically characterized by aggregates of α-synuclein (Lewy bodies) in limbic and neocortical areas of the brain with additional involvement of Alzheimer’s disease-type pathology. Whilst immune activation is well-described in Parkinson’s disease (PD), how it links to protein aggregation and its role in PD dementia has not been explored. We hypothesized that neuroinflammatory processes are a critical contributor to the pathology of PDD. To address this hypothesis, we examined 7 brain regions at postmortem from 17 PD patients with no dementia (PDND), 11 patients with PD dementia (PDD), and 14 age and sex-matched neurologically healthy controls. Digital quantification after immunohistochemical staining showed a significant increase in the severity of α-synuclein pathology in the hippocampus, entorhinal and occipitotemporal cortex of PDD compared to PDND cases. In contrast, there was no difference in either tau or amyloid-β pathology between the groups in any of the examined regions. Importantly, we found an increase in activated microglia in the amygdala of demented PD brains compared to controls which correlated significantly with the extent of α-synuclein pathology in this region. Significant infiltration of CD4+ T lymphocytes into the brain parenchyma was commonly observed in PDND and PDD cases compared to controls, in both the substantia nigra and the amygdala. Amongst PDND/PDD cases, CD4+ T cell counts in the amygdala correlated with activated microglia, α-synuclein and tau pathology. Upregulation of the pro-inflammatory cytokine interleukin 1β was also evident in the substantia nigra as well as the frontal cortex in PDND/PDD versus controls with a concomitant upregulation in Toll-like receptor 4 (TLR4) in these regions, as well as the amygdala. The evidence presented in this study show an increased immune response in limbic and cortical brain regions, including increased microglial activation, infiltration of T lymphocytes, upregulation of pro-inflammatory cytokines and TLR gene expression, which has not been previously reported in the postmortem PDD brain.

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“…Although the role of the peripheral immune system in PD-related neuroinflammation has not yet been entirely elucidated, infiltrating CD4 + and CD8 + T lymphocytes have been suggested to contribute to neurodegeneration 65 . CD3 + T cells, which have been found in close proximity to glial cells in brains of DLB patients and α-synuclein transgenic mice, have been suggested to participate in activation of glial cells 66 . In vitro studies suggested that CD4 + /CD25 − effector T cells promote microglial activation and contribute to neurodegeneration while CD4 + / CD25 + Tregs might be inhibiting microgliosis 67 .…”

Section: Discussionmentioning

confidence: 99%

Inflammation and regulatory T cell genes are differentially expressed in peripheral blood mononuclear cells of Parkinson’s disease patients

Karaaslan

Kahraman

Şanlı

et al. 2021

Sci Rep

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Our aim was to identify the differentially expressed genes (DEGs) in peripheral blood mononuclear cells (PBMC) of Parkinson’s disease (PD) patients and healthy controls by microarray technology and analysis of related molecular pathways by functional annotation. Thirty PD patients and 30 controls were enrolled. Agilent Human 8X60 K Oligo Microarray was used for gene level expression identification. Gene ontology and pathway enrichment analyses were used for functional annotation of DEGs. Protein–protein interaction analyses were performed with STRING. Expression levels of randomly selected DEGs were quantified by real time quantitative polymerase chain reaction (RT-PCR) for validation. Flow cytometry was done to determine frequency of regulatory T cells (Tregs) in PBMC. A total of 361 DEGs (143 upregulated and 218 downregulated) were identified after GeneSpring analysis. DEGs were involved in 28 biological processes, 12 cellular components and 26 molecular functions. Pathway analyses demonstrated that upregulated genes mainly enriched in p53 (CASP3, TSC2, ATR, MDM4, CCNG1) and PI3K/Akt (IL2RA, IL4R, TSC2, VEGFA, PKN2, PIK3CA, ITGA4, BCL2L11) signaling pathways. TP53 and PIK3CA were identified as most significant hub proteins. Expression profiles obtained by RT-PCR were consistent with microarray findings. PD patients showed increased proportions of CD49d+ Tregs, which correlated with disability scores. Survival pathway genes were upregulated putatively to compensate neuronal degeneration. Bioinformatics analysis showed an association between survival and inflammation genes. Increased CD49d+ Treg ratios might signify the effort of the immune system to suppress ongoing neuroinflammation.

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Neuroinflammation is associated with infiltration of T cells in Lewy body disease and α-synuclein transgenic models

Cited by 70 publications

References 95 publications

T cells limit accumulation of aggregate pathology following intrastriatal injection of α-synuclein fibrils

T cells limit accumulation of aggregate pathology following intrastriatal injection of α-synuclein fibrils

Neuroinflammation and protein pathology in Parkinson’s disease dementia

Inflammation and regulatory T cell genes are differentially expressed in peripheral blood mononuclear cells of Parkinson’s disease patients

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