Regulation of the Neurodegenerative Process Associated to Parkinson’s Disease by CD4+ T-cells

González, Hugo; Contreras, Francisco; Pacheco, Rodrigo

doi:10.1007/s11481-015-9618-9

Cited by 59 publications

(58 citation statements)

References 143 publications

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“…The extensive microglial activation, persistent viral infection and inflammation observed in these mice recalls the pathology observed in other persistent CNS infections, such as patients chronically infected with HIV. 64 There is an increasing body of work indicating that chronically activated microglia, regulated by CD4+ T cells, can result in neurodegeneration through the chronic secretion of factors such as TNF, NO and IL-1β 65, 66, 67 Given the absence of the apoptosis observed when only CD4+ T cells are present in the CNS, it is likely that the observed neurodegeneration in CD4+ T-cell recipients is the result of gliosis mediated cytotoxicity. The precise molecules and mechanisms involved in this CD4+ T-cell-mediated neurodegeneration are currently under investigation.…”

Section: Discussionmentioning

confidence: 99%

CD4 and CD8 T cells mediate distinct lethal meningoencephalitis in mice challenged with Tacaribe arenavirus

et al. 2016

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Neonates are at increased risk of viral encephalopathies that can result in neurological dysfunction, seizures, permanent disability and even death. The neurological damage results from the combined effect of the virus and the immune response it elicits, thus finding tools to facilitate viral clearance from central nervous system (CNS) while minimizing neuron damage remains a critical challenge. Neonatal mice inoculated intraperitoneally with Tacaribe virus (TCRV) develop seizures, hindlimb paralysis and death within 15 days of inoculation. TCRV localizes to the CNS within days of challenge, primarily infecting astrocytes in the cerebellum and brain stem. We show that infection leads to inflammation, T cell and monocyte infiltration into the cerebellar parenchyma, apoptosis of astrocytes, neuronal degeneration and loss of Purkinje cells. Infiltrating antigen-specific T cells fail to clear the virus but drive the disease, as T-cell-deficient CD3ɛ KO mice survive TCRV infection with minimal inflammation or clinical manifestations despite no difference in CNS viral loads in comparison with T-cell sufficient mice. CD8+ T cells drive the pathology, which even in the absence of CD4+ T-cell help, infiltrate the parenchyma and mediate the apoptotic loss of cerebellar astrocytes, neurodegeneration and loss of Purkinje cells resulting in loss of balance, paralysis and death. CD4+ T cells are also pathogenic inducing gliosis and inflammation in the cerebellum and cerebrum that are associated with wasting and death several weeks after CD4+ T-cell transfer. These data demonstrate distinct pathogenic effects of CD4+ and CD8+ T cells and identify them as possible therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

CD4 and CD8 T cells mediate distinct lethal meningoencephalitis in mice challenged with Tacaribe arenavirus

et al. 2016

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“…In vivo and in vitro studies have demonstrated that overexpression of α-syn can induce the MHC-II expression by microglia. The MHC-II expression in microglia cells can play an important role in the immune responses (innate and adaptive) in PD (Michelucci et al, 2009; Harms et al, 2013; Gonzalez et al, 2015). …”

Section: Parkinson and Microgliamentioning

confidence: 99%

The Role of Microglia in Retinal Neurodegeneration: Alzheimer's Disease, Parkinson, and Glaucoma

Ramírez

Hoz

Salobrar‐García

et al. 2017

Front. Aging Neurosci.

368

341

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Microglia, the immunocompetent cells of the central nervous system (CNS), act as neuropathology sensors and are neuroprotective under physiological conditions. Microglia react to injury and degeneration with immune-phenotypic and morphological changes, proliferation, migration, and inflammatory cytokine production. An uncontrolled microglial response secondary to sustained CNS damage can put neuronal survival at risk due to excessive inflammation. A neuroinflammatory response is considered among the etiological factors of the major aged-related neurodegenerative diseases of the CNS, and microglial cells are key players in these neurodegenerative lesions. The retina is an extension of the brain and therefore the inflammatory response in the brain can occur in the retina. The brain and retina are affected in several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and glaucoma. AD is an age-related neurodegeneration of the CNS characterized by neuronal and synaptic loss in the cerebral cortex, resulting in cognitive deficit and dementia. The extracellular deposits of beta-amyloid (Aβ) and intraneuronal accumulations of hyperphosphorylated tau protein (pTau) are the hallmarks of this disease. These deposits are also found in the retina and optic nerve. PD is a neurodegenerative locomotor disorder with the progressive loss of dopaminergic neurons in the substantia nigra. This is accompanied by Lewy body inclusion composed of α-synuclein (α-syn) aggregates. PD also involves retinal dopaminergic cell degeneration. Glaucoma is a multifactorial neurodegenerative disease of the optic nerve, characterized by retinal ganglion cell loss. In this pathology, deposition of Aβ, synuclein, and pTau has also been detected in retina. These neurodegenerative diseases share a common pathogenic mechanism, the neuroinflammation, in which microglia play an important role. Microglial activation has been reported in AD, PD, and glaucoma in relation to protein aggregates and degenerated neurons. The activated microglia can release pro-inflammatory cytokines which can aggravate and propagate neuroinflammation, thereby degenerating neurons and impairing brain as well as retinal function. The aim of the present review is to describe the contribution in retina to microglial-mediated neuroinflammation in AD, PD, and glaucomatous neurodegeneration.

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“…While the current study is the first to report alterations in both CD4 + and NKT cells in the brain of DLB patients and animals overexpressing α-syn, several groups have described disturbances in various CD4+/CD8 + T cell subsets and NK cells [40,[60][61][62]. For example, one recent study demonstrated that α-syn oligomers and fibrils changed the ratio of CD8 + to CD4 + T cells in the CNS and reduced the expression of STAT3, CD25, and CD127 in CD3 + CD4 + T cells.…”

Section: Discussionmentioning

confidence: 70%

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

Iba

Kim

Sallin

et al. 2020

Preprint

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Background: ɑ-synuclein (ɑ-syn) is a presynaptic protein which progressively accumulates in neuronal and non-neuronal cells in neurodegenerative diseases such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy. Recent evidence suggests that aberrant immune activation may be involved in neurodegeneration in PD/DLB. While previous studies have often focused on the microglial responses, less is known about the role of the peripheral immune system in these disorders.Methods: To understand the involvement of the peripheral immune system in PD/DLB, we evaluated T cell populations in the brains of ɑ-syn transgenic (tg) mice (eg: Thy1 promoter line 61) and DLB patients.Results: Immunohistochemical analysis showed perivascular and parenchymal infiltration by CD3+/CD4+ helper T cells, but not cytotoxic T cells (CD3+/CD8+) or B cells (CD20+), in the neocortex, hippocampus, and striatum of ɑ-syn tg mice. CD3+ cells were found in close proximity to the processes of activated astroglia, particularly in areas of the brain with significant astrogliosis, microgliosis, and pro-inflammatory cytokines. In addition, a subset of CD3+ cells co-expressed interferon γ. Flow cytometric analysis of immune cells revealed that CD1d+ T cells were also increased in the brains of ɑ-syn tg mice and matched an expression profile consistent with natural killer T cells. In post-mortem DLB brains, we similarly detected CD3+ T cells that expressed CD4+ or CD1d+ in close proximity with blood vessels.Conclusion: These results suggest that infiltrating adaptive immune cells play an important role in neuroinflammation and neurodegeneration in synucleinopathies and that modulating peripheral T cells may be a viable therapeutic strategy for PD/DLB.

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Regulation of the Neurodegenerative Process Associated to Parkinson’s Disease by CD4+ T-cells

Cited by 59 publications

References 143 publications

CD4 and CD8 T cells mediate distinct lethal meningoencephalitis in mice challenged with Tacaribe arenavirus

CD4 and CD8 T cells mediate distinct lethal meningoencephalitis in mice challenged with Tacaribe arenavirus

The Role of Microglia in Retinal Neurodegeneration: Alzheimer's Disease, Parkinson, and Glaucoma

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

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