Alterations of T-lymphocyte populations in Parkinson disease

Baba, Yasuhiko; Kuroiwa, Ataru; Uitti, Ryan J.; Wszołek, Zbigniew K.; Yamada, Tatsuo

doi:10.1016/j.parkreldis.2005.07.005

Cited by 293 publications

(248 citation statements)

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“…Importantly, microglial activation occurs first in the striatum (1 month of age) and later in the substantia nigra (5-6 months of age), which correlates with recent imaging studies in PD patients [75]. In addition to innate immune [77,78] and the brain [79,80]. Correspondingly, there were significant increases in the percentages of cytotoxic T cells in the blood of 22-month-old Thy1-aSyn mice compared with age-matched WT mice (Watson et al, in preparation).…”

Section: Thy1-asyn Mice Show Inflammatory Changes In the Innate And Asupporting

confidence: 74%

A Progressive Mouse Model of Parkinson's Disease: The Thy1-aSyn (“Line 61”) Mice

et al. 2012

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Identification of mutations that cause rare familial forms of Parkinson's disease (PD) and subsequent studies of genetic risk factors for sporadic PD have led to an improved understanding of the pathological mechanisms that may cause nonfamilial PD. In particular, genetic and pathological studies strongly suggest that alpha-synuclein, albeit very rarely mutated in PD patients, plays a critical role in the vast majority of individuals with the sporadic form of the disease. We have extensively characterized a mouse model over-expressing full-length, human, wild-type alpha-synuclein under the Thy-1 promoter. We have also shown that this model reproduces many features of sporadic PD, including progressive changes in dopamine release and striatal content, alphasynuclein pathology, deficits in motor and nonmotor functions that are affected in pre-manifest and manifest phases of PD, inflammation, and biochemical and molecular changes similar to those observed in PD. Preclinical studies have already demonstrated improvement with promising new drugs in this model, which provides an opportunity to test novel neuroprotective strategies during different phases of the disorder using endpoint measures with high power to detect drug effects.

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Section: Thy1-asyn Mice Show Inflammatory Changes In the Innate And Asupporting

confidence: 74%

A Progressive Mouse Model of Parkinson's Disease: The Thy1-aSyn (“Line 61”) Mice

et al. 2012

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“…By contrast, although altered cellular and humoral functions have been reported in the peripheral immune system of PD patients, the role of adaptive immunity in the pathogenesis of this disorder has remained much more elusive (5,20). Among these peripheral immune changes, the significant increased ratio of CD8 + Tc to CD4 + Th and of IFN-γ-producing to IL-4-producing T cells suggests the existence of a disease-associated shift to a Tc1/Th1-type immune response, which may reflect and/or contribute to the harmful brain inflammatory reaction (21). Nonetheless, a role for the cellular arm of the adaptive immune system in neurodegeneration is curbed by the fact that no clear demonstration of a prominent involvement of leukocytes at the site of neuronal injury has been provided in PD.…”

Section: Discussionmentioning

confidence: 99%

Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease

Brochard¹,

Combadière²,

Prigent³

et al. 2008

J. Clin. Invest.

799

1,028

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Parkinson disease (PD) is a neurodegenerative disorder characterized by a loss of dopamine-containing neurons. Mounting evidence suggests that dopaminergic cell death is influenced by the innate immune system. However, the pathogenic role of the adaptive immune system in PD remains enigmatic. Here we showed that CD8 + and CD4 + T cells but not B cells had invaded the brain in both postmortem human PD specimens and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD during the course of neuronal degeneration. We further demonstrated that MPTP-induced dopaminergic cell death was markedly attenuated in the absence of mature T lymphocytes in 2 different immunodeficient mouse strains (Rag1 -/-and Tcrb -/-mice). Importantly, similar attenuation of MPTP-induced dopaminergic cell death was seen in mice lacking CD4 as well as in Rag1 -/-mice reconstituted with FasL-deficient splenocytes. However, mice lacking CD8 and Rag1 -/-mice reconstituted with IFN-γ-deficient splenocytes were not protected. These data indicate that T cell-mediated dopaminergic toxicity is almost exclusively arbitrated by CD4 + T cells and requires the expression of FasL but not IFNγ. Further, our data may provide a rationale for targeting the adaptive arm of the immune system as a therapeutic strategy in PD.

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“…A similar pattern of neuroprotection was seen in mice null for the T‐cell receptor or CD4 (Brochard et al, 2009) and as MHC II is important for activation of T‐cells (Dong and Flavell, 2001) these data suggest that an adaptive immune response is involved in MPTP‐induced dopaminergic neuron death. Interestingly, CD4 + T‐helper (T H ) cells, particularly T H 1 cells, are increased in the peripheral blood of PD patients (Baba et al, 2005) and T H 1 cells recruit CD8 + cytotoxic T cells which are the predominant T‐cell infiltrate in the brain in PD patients at post‐mortem and in MPTP‐lesioned animals (Brochard et al, 2009), providing further support for an adaptive CD4 + T H cell mediated immune response in PD. Further evidence is emerging for a possible role of the adaptive immune in the development of Parkinson's disease as toll‐like receptor 4 (TLR4) gene polymorphisms have been linked to sporadic Parkinson's disease (Zhao et al, 2015) and α‐synuclein can induce the up‐regulation of TLRs (Beraud et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

Martin

Santoro

Mustafa

et al. 2015

Glia

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Parkinson's disease (PD) is the second most common neurodegenerative disease and results from the loss of dopaminergic neurons of the nigrostriatal pathway. The pathogenesis of PD is poorly understood, but inflammatory processes have been implicated. Indeed increases in the number of major histocompatibility complex II (MHC II) reactive cells have long been recognised in the brains of PD patients at post‐mortem. However whether cells expressing MHC II play an active role in PD pathogenesis has not been delineated. This was addressed utilising a transgenic mouse null for MHC II and the parkinsonian toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). In wild‐type mice MHC II levels in the ventral midbrain were upregulated 1–2 days after MPTP treatment and MHC II was localized in both astrocytes and microglia. MHC II null mice showed significant reductions in MPTP‐induced dopaminergic neuron loss and a significantly reduced invasion of astrocytes and microglia in MHC II null mice receiving MPTP compared with controls. In addition, MHC II null mice failed to show increases in interferon‐γ or tumour necrosis factor‐α in the brain after MPTP treatment, as was found in wild‐type mice. However, interleukin‐1β was significantly increased in both wild‐type and MHC II null mice. These data indicate that in addition to microglial cell/myeloid cell activation MHC Class II‐mediated T cell activation is required for the full expression of pathology in this model of PD. GLIA 2016;64:386–395

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Alterations of T-lymphocyte populations in Parkinson disease

Cited by 293 publications

References 50 publications

A Progressive Mouse Model of Parkinson's Disease: The Thy1-aSyn (“Line 61”) Mice

A Progressive Mouse Model of Parkinson's Disease: The Thy1-aSyn (“Line 61”) Mice

Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease

Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

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