T cell infiltration in both human multiple system atrophy and a novel mouse model of the disease

Williams, Gregory P.; Marmion, David J.; Schonhoff, Aubrey M; Jurkuvenaite, Asta; Won, Woong-Jai; Standaert, David G.; Kordower, Jeffrey H.; Harms, Ashley S.

doi:10.1007/s00401-020-02126-w

Cited by 74 publications

(97 citation statements)

References 64 publications

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“…Such an increase in the number of infiltrating T cells could mediate the decrease in phosphorylated α-syn pathology in the substantia nigra. This complements several reports associating altered T cell function with PD and MSA [21][22][23][24][25][26]57] and studies demonstrating activation of immune cells by pathogenic αsyn [27,31,58]. One such study measuring nigral neurodegeneration as the readout supports the hypothesis that immune cells can modulate neuroinflammation and neurodegeneration in PD mouse models [59].…”

Section: Discussionsupporting

confidence: 86%

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: 86%

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

“…A recent study in MSA patients also showed increased infiltration in the brain by CD4+ and CD8+ T cells. Similar results were observed in a viral vectormediated oligodendroglial α-syn expression mouse model, where genetic depletion of TCR-β+ or CD4+ T cells attenuated α-syn-induced inflammation and demyelination in vivo [73]. Taken together, these studies suggest that T cells play a key role in the neuroinflammatory process in synucleinopathies such as DLB, PD, and MSA.…”

Section: Discussionsupporting

confidence: 79%

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

Iba

Kim

Sallin

et al. 2020

J Neuroinflammation

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Background: α-Synuclein (α-syn) is a pre-synaptic protein which progressively accumulates in neuronal and nonneuronal 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 α-syn transgenic (tg) mice (e.g., 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 αsyn 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 expression of pro-inflammatory cytokines. In addition, a subset of CD3+ cells co-expressed interferon γ. Flow cytometric analysis of immune cells in the brains of α-syn tg mice revealed that CD1d-tet+ T cells were also increased in the brains of α-syn tg mice suggestive of natural killer T cells. In post-mortem DLB brains, we similarly detected increased numbers of infiltrating CD3+/CD4+ T cells 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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“…A recent study in MSA patients showed increased infiltration in the brain by CD4 + and CD8 + T cells. Similar results were observed in a viral vectormediated oligodendroglial α-syn expression mouse model, where genetic depletion of TCR-β + or CD4 + T cells attenuated α-syn-induced inflammation and demyelination in vivo [72]. Taken together, these studies suggest that T cells play a key role in the neuroinflammatory process in synucleinopathies such as DLB, PD, and MSA.…”

Section: Discussionsupporting

confidence: 79%

“…To better understand the role of NKT cells in synucleinopathies, follow up studies should be conducted where selected subtypes of T cells, such as NKT cells, are inactivated or deleted in animal models exhibiting α-syn accumulation, including transgenic, viral vector, and α-syn pff injection models. One such study was recently published in a model of MSA [72]. We have also previously shown that on the Rag2 −/− background, where the mice are unable to produce mature lymphocytes, our α-syn tg mice displayed considerably decreased α-syn pathology.…”

Section: Discussionmentioning

confidence: 52%

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

Iba

Kim

Sallin

et al. 2020

Preprint

View full text Add to dashboard Cite

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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T cell infiltration in both human multiple system atrophy and a novel mouse model of the disease

Cited by 74 publications

References 64 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 is associated with infiltration of T cells in Lewy body disease and α-synuclein transgenic models

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

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