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

Williams, Gregory P.; Muskat, Kaylin; Xu, Yaqian; Mateus, José; Grifoni, Alba; Antunes, Ricardo da Silva; Weiskopf, Daniela; Amara, Amy W.; Standaert, David G.; Goldman, Jennifer G.; Litvan, Irene; Alcalay, Roy N.; Sulzer, David; Arlehamn, Cecilia S. Lindestam; Sette, Alessandro

doi:10.1016/j.jns.2022.120510

Cited by 10 publications

(6 citation statements)

References 52 publications

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“…However, an increasing amount of evidence suggests that inflammation and immune mechanisms may be involved. A growing series of studies focusing on gene products linked to familial, genetic forms of PD, suggest that multiple PD- related proteins including Parkin, PINK1 and LRRK2 act as regulators of innate and adaptive immune responses in APCs and that loss of function of some of these proteins can amplify immune responses [1, 13–15, 20–23, 30, 31]. Recent work showed that, in inflammatory conditions, PINK1 and Parkin play a role in restricting the presentation on MHC class I molecules of antigens derived from proteins present in the matrix of mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Adoptive transfer of mitochondrial antigen-specific CD8⁺T-cells in mice causes parkinsonism and compromises the dopamine system

Elemeery,

Tchung,

Boulet

et al. 2024

Preprint

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The progressive dysfunction and degeneration of dopamine (DA) neurons of the ventral midbrain is linked to the development of motor symptoms in Parkinson's disease (PD). Multiple lines of evidence suggest the implication of neuroinflammation and mitochondrial dysfunction as key drivers of neurodegenerative mechanisms in PD. Recent work has revealed that loss of the mitochondrial kinase PINK1 leads to enhanced mitochondrial antigen presentation (MitAP) by antigen-presenting cells (APCs), the amplification of mitochondrial antigen-specific CD8+ T cells and the loss of DA neuron terminals markers in the brain in response to gut infection. However, whether mitochondrial antigen-specific T cells are involved in and/or sufficient to cause DA system dysfunction remains unclear. Here, we investigated the effect of mitochondrial autoimmunity by adoptively transferring mitochondrial peptide-specific CD8+ T cells into wild-type (WT) and PINK1 KO mice. We find that this leads to L-DOPA-reversible motor impairment and to robust loss of DA neurons and axonal markers in the striatum in both PINK1 WT and KO mice. Our findings provide direct evidence of the pivotal role played by mitochondrial-specific CD8+ T cell infiltration in the brain in driving PD-like pathology and the development of parkinsonism. Altogether, our data strongly support the hypothesis that MitAP and autoimmune mechanisms play a key role in the pathophysiological processes leading to PD.

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Section: Discussionmentioning

confidence: 99%

Adoptive transfer of mitochondrial antigen-specific CD8⁺T-cells in mice causes parkinsonism and compromises the dopamine system

Elemeery,

Tchung,

Boulet

et al. 2024

Preprint

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“…Several epidemiological studies have suggested that pertussis may increase the risk of PD ( de Pedro-Cuesta et al, 1996 ; Vlajinac et al, 2013 ). Further research has indicated that there is no direct relationship between PD and pertussis vaccination or immunoglobulin against pertussis, suggesting that the association is not simply a result of immunological responses to the bacteria ( Fiszer et al, 2004 ; Williams et al, 2023 ). On the other hand, studies on atherosclerosis have shown that oxLDL can inhibit the endothelium-dependent relaxation of arteries via pertussis toxin-sensitive G proteins ( Shimokawa et al, 1991 ; Jing et al, 1999 ).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of potential common pathogenic mechanism for carotid atherosclerosis and Parkinson’s disease

Wang

Xue

2023

Front. Aging Neurosci.

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BackgroundCerebrovascular disease (CVD) related to atherosclerosis and Parkinson’s disease (PD) are two prevalent neurological disorders. They share common risk factors and frequently occur together. The aim of this study is to investigate the association between atherosclerosis and PD using genetic databases to gain a comprehensive understanding of underlying biological mechanisms.MethodsThe gene expression profiles of atherosclerosis (GSE28829 and GSE100927) and PD (GSE7621 and GSE49036) were downloaded from the Gene Expression Omnibus (GEO) database. After identifying the common differentially expressed genes (DEGs) for these two disorders, we constructed protein-protein interaction (PPI) networks and functional modules, and further identified hub genes using Least Absolute Shrinkage and Selection Operator (LASSO) regression. The diagnostic effectiveness of these hub genes was evaluated using Receiver Operator Characteristic Curve (ROC) analysis. Furthermore, we used single sample gene set enrichment analysis (ssGSEA) to analyze immune cell infiltration and explored the association of the identified hub genes with infiltrating immune cells through Spearman’s rank correlation analysis in R software.ResultsA total of 50 shared DEGs, with 36 up-regulated and 14 down-regulated genes, were identified through the intersection of DEGs of atherosclerosis and PD. Using LASSO regression, we identified six hub genes, namely C1QB, CD53, LY96, P2RX7, C3, and TNFSF13B, in the lambda.min model, and CD14, C1QB, CD53, P2RX7, C3, and TNFSF13B in the lambda.1se model. ROC analysis confirmed that both models had good diagnostic efficiency for atherosclerosis datasets GSE28829 (lambda.min AUC = 0.99, lambda.1se AUC = 0.986) and GSE100927 (lambda.min AUC = 0.922, lambda.1se AUC = 0.933), as well as for PD datasets GSE7621 (lambda.min AUC = 0.924, lambda.1se AUC = 0.944) and GSE49036 (lambda.min AUC = 0.894, lambda.1se AUC = 0.881). Furthermore, we found that activated B cells, effector memory CD8 + T cells, and macrophages were the shared correlated types of immune cells in both atherosclerosis and PD.ConclusionThis study provided new sights into shared molecular mechanisms between these two disorders. These common hub genes and infiltrating immune cells offer promising clues for further experimental studies to explore the common pathogenesis of these disorders.

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“…Currently, it is not fully understood if the mentioned phenomena are caused by a dysregulation of the immune system due to aging or by disease-related processes. It has recently become known that α-syn aggregates are detectable in the peripheral blood of patients with PD and can activate Toll-like receptors, thereby causing an inflammatory response [54] and the induction of α-syn-specific T cells [127,128] A recent study further investigated antigen-specific T cell responses directed towards commonly encountered human pathogens and vaccines (viral and bacterial, e.g., influenza, rhinovirus, tetanus) in patients with PD and agematched healthy controls [129] . It was found that PD patients and healthy controls showed similar T cell activation levels and levels of cytokines produced upon presentation of these common pathogen-derived antigens.…”

Section: Inflammagingmentioning

confidence: 99%

Aging and Parkinson’s disease: a complex interplay of vulnerable neurons, the immune system and the blood-brain barrier

Bendig,

Frank,

Reichmann

2024

Ageing Neur Dis

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Aging is the biggest risk factor for Parkinson’s disease (PD) and a particular vulnerability of dopaminergic neurons in the substantia nigra to aging-associated effects has been firmly established. More recent work has revealed an important role of non-neuronal systems such as the blood-brain barrier (BBB) or the immune system in the pathogenesis of PD. Effects of aging on the immune system include a chronic inflammatory state termed inflammaging and immunosenescence. Both processes are connected to a higher pro-inflammatory potency and negatively affect the maintenance of self-tolerance. The BBB gets increasingly dysfunctional with advancing age and its endothelial cells display a more pro-inflammatory phenotype while the transport of important plasma proteins to the brain is impaired. The immune system and the BBB are heavily interdependent and are both essential for the homeostasis of especially vulnerable dopaminergic neurons. The degeneration of dopaminergic neurons can, in turn, influence the BBB or the immune system, potentially creating a vicious cycle. In this review, we aim to develop a multisystem perspective on aging and PD by incorporating the aging immune system and aging BBB into the pathophysiological processes. Given the current evidence, it seems likely that a combination of multimodal effects of aging on the levels of SN pars compacta (SNc) dopaminergic neurons, the immune system, and the BBB increase the risk of developing PD.

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

Cited by 10 publications

References 52 publications

Adoptive transfer of mitochondrial antigen-specific CD8⁺T-cells in mice causes parkinsonism and compromises the dopamine system

Adoptive transfer of mitochondrial antigen-specific CD8⁺T-cells in mice causes parkinsonism and compromises the dopamine system

Bioinformatics analysis of potential common pathogenic mechanism for carotid atherosclerosis and Parkinson’s disease

Aging and Parkinson’s disease: a complex interplay of vulnerable neurons, the immune system and the blood-brain barrier

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

Cited by 10 publications

References 52 publications

Adoptive transfer of mitochondrial antigen-specific CD8+T-cells in mice causes parkinsonism and compromises the dopamine system

Adoptive transfer of mitochondrial antigen-specific CD8+T-cells in mice causes parkinsonism and compromises the dopamine system

Bioinformatics analysis of potential common pathogenic mechanism for carotid atherosclerosis and Parkinson’s disease

Aging and Parkinson’s disease: a complex interplay of vulnerable neurons, the immune system and the blood-brain barrier

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Adoptive transfer of mitochondrial antigen-specific CD8⁺T-cells in mice causes parkinsonism and compromises the dopamine system

Adoptive transfer of mitochondrial antigen-specific CD8⁺T-cells in mice causes parkinsonism and compromises the dopamine system