CD4
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            T cells contribute to neurodegeneration in Lewy body dementia

Gate, David; Tapp, Emma; Leventhal, Olivia; Shahid, Marian; Nonninger, Tim J.; Yang, Andrew C.; Strempfl, Katharina; Unger, Michael S.; Fehlmann, Tobias; Oh, Hamilton; Channappa, Divya; Henderson, Victor W.; Keller, Andreas; Aigner, Ludwig; Galasko, Douglas; Davis, Mark M.; Poston, Kathleen L.; Wyss‐Coray, Tony

doi:10.1126/science.abf7266

Cited by 105 publications

(95 citation statements)

References 40 publications

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“…In this population, there was gene enrichment for pathways regulating homeostasis of cell numbers ( IL7R, IL15, MALT1 ) and regulation of T cell differentiation ( CAMK4, CD28, ZAP70 ). Our results are congruent with recent findings that clonal expansion of α-synuclein reactive T cells have been identified in the brains of PD patients( 11, 12 ) and that CD4 + T cells contribute to neurodegeneration in Lewy body dementia( 37 ). Our findings add to existing data suggesting that T cell mediated immunity plays an important role in PD and α-synucleinopathies.…”

Section: Discussionsupporting

confidence: 93%

“…Our transcriptomic profiling of PD patients highlights a significant role of ApoE in microglia and calls for further investigation on how ApoE promotes neuroinflammation. It also underscores while PD and AD share microglial neuroinflammatory signatures, T cell mediated adaptive immunity may be different between AD, PD and other α-synucleinopathies such as Lewy body dementia( 37 ).…”

Section: Discussionmentioning

confidence: 99%

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Single-cell transcriptomic and proteomic analysis of Parkinson’s disease Brains

Zhu

Park

Coffey

et al. 2022

Preprint

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Parkinson's disease (PD) is a prevalent neurodegenerative disorder where recent evidence suggests pathogenesis may be mediated by inflammatory processes. The molecular architecture of the disease remains to be fully elucidated. We performed single-nucleus transcriptomics and unbiased proteomics using postmortem tissue obtained from the prefrontal cortex of 12 individuals with late-stage PD and age-matched controls. We analyzed ~80,000 nuclei and identified eight major cell types, including brain-resident T cells, each with distinct transcriptional changes in line with the known genetics of PD. By analyzing Lewy body pathology in the same postmortem tissue, we found that a-synuclein pathology is inversely correlated with chaperone expression in excitatory neurons. Examining cell-cell interactions, we found a selective abatement of neuron-astrocyte interactions and enhanced neuroinflammation. Proteomic analyses of the same brains identified synaptic proteins in prefrontal cortex that were preferentially downregulated in PD. Strikingly, comparing this dataset to a regionally similar published analysis for Alzheimer's disease (AD), we found no common differentially expressed genes in neurons, but identified many shared differentially expressed genes in glial cells, suggesting that disease etiology in PD and AD are likely distinct. These data are presented as a resource for interrogating the molecular and cellular basis of PD and other neurodegenerative diseases.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Single-cell transcriptomic and proteomic analysis of Parkinson’s disease Brains

Zhu

Park

Coffey

et al. 2022

Preprint

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“…Our findings suggest that the hyper-inflammatory state reported in PD does not influence antigen-specific T cell responses to common pathogens consistently encountered either through natural exposure or vaccination. This observation is in agreement with the notion that the targets of peripheral T cell inflammation observed in PD are more directed towards autoantigens such as α-synuclein 11-13,28 .…”

Section: Discussionsupporting

confidence: 91%

Unaltered T cell responses to common antigens in individuals with Parkinson’s disease

Williams

Muskat

et al. 2022

Preprint

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Background and ObjectivesParkinson’s disease (PD) is associated with a heightened inflammatory state, including activated T cells. However, it is unclear whether these PD T cell responses are antigen specific or more indicative of generalized hyperresponsiveness. Our objective was to measure and compare antigen-specific T cell responses directed towards antigens derived from commonly encountered human pathogens/vaccines in patients with PD and age-matched healthy controls (HC).MethodsPeripheral blood mononuclear cells (PBMCs) from 20 PD patients and 19 age-matched HCs were screened. Antigen specific T cell responses were measured by flow cytometry using a combination of the activation induced marker (AIM) assay and intracellular cytokine staining.ResultsHere we show that both PD patients and HCs show similar T cell activation levels to several antigens derived from commonly encountered human pathogens/vaccines in the general population. Similarly, we also observed no difference between HC and PD in the levels of CD4 and CD8 T cell derived cytokines produced in response to any of the common antigens tested. These antigens encompassed both viral (coronavirus, rhinovirus, respiratory syncytial virus, influenza, cytomegalovirus) and bacterial (pertussis, tetanus) targets.ConclusionsThese results suggest the T cell dysfunction observed in PD may not extend itself to abnormal responses to commonly encountered or vaccine-target antigens. Our study supports the notion that the targets of inflammatory T cell responses in PD may be more directed towards autoantigens like α-synuclein (α-syn) rather than common foreign antigens.

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“…In addition, immunohistochemical analyses have revealed the increased expression of inducible nitric oxide synthase (iNOS) in glial cells within the SN of PD patients, which hints at the neurotoxic overproduction of NO and other free radicals, especially in the microglia of the parkinsonian brain [62,63]. Moreover, the possible involvement of adaptive immune responses in PD and DLB was demonstrated by T lymphocyte brain infiltration [64][65][66], which might be related to the antigen-presenting properties of microglia [64].…”

Section: Microglia-mediated Neuroinflammation In Pd and Dlbmentioning

confidence: 99%

Leukotriene Signaling as a Target in α-Synucleinopathies

et al. 2022

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Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are two common types of α-synucleinopathies and represent a high unmet medical need. Despite diverging clinical manifestations, both neurodegenerative diseases share several facets of their complex pathophysiology. Apart from α-synuclein aggregation, an impairment of mitochondrial functions, defective protein clearance systems and excessive inflammatory responses are consistently observed in the brains of PD as well as DLB patients. Leukotrienes are lipid mediators of inflammatory signaling traditionally known for their role in asthma. However, recent research advances highlight a possible contribution of leukotrienes, along with their rate-limiting synthesis enzyme 5-lipoxygenase, in the pathogenesis of central nervous system disorders. This review provides an overview of in vitro as well as in vivo studies, in summary suggesting that dysregulated leukotriene signaling is involved in the pathological processes underlying PD and DLB. In addition, we discuss how the leukotriene signaling pathway could serve as a future drug target for the therapy of PD and DLB.

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CD4 ⁺ T cells contribute to neurodegeneration in Lewy body dementia

Cited by 105 publications

References 40 publications

Single-cell transcriptomic and proteomic analysis of Parkinson’s disease Brains

Single-cell transcriptomic and proteomic analysis of Parkinson’s disease Brains

Unaltered T cell responses to common antigens in individuals with Parkinson’s disease

Leukotriene Signaling as a Target in α-Synucleinopathies

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