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

INSERM, UMR S679, Experimental Neurology and Therapeutics, Hopital de la Salpetriere, Paris, France.
Journal of Clinical Investigation (Impact Factor: 13.22). 01/2009; 119(1):182-92. DOI: 10.1172/JCI36470
Source: PubMed


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-gamma-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 IFNgamma. 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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    • "Both NM and α-syn are found extracellularly in the postmortem brain of PD patients (Double, 2012), a disorder that features high levels of activated microglia in the SN (Foix and Nicolesco, 1925) and high levels of intracellular oxidative stress (Fahn and Sulzer, 2004). Parkinson's disease patient brain features increased IFN-γ (Mogi et al., 2007) and chemokines (Harris et al., 2012), as well as a compromised blood brain barrier (Farkas et al., 2000; German et al., 2012) that may explain why CTLs are substantially higher in PD patients than age-matched controls (Hisanaga et al., 2001; Brochard et al., 2009). CD4+ T helper cells have also been shown to infiltrate the brain in human PD postmortem samples and exert a cytotoxic effect in mouse brain following nigrostriatal injury (Brochard et al., 2009); thus, T cells and antigen presentation, as well as activated microglia could play a role in PD pathogenesis. "
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    ABSTRACT: Neuronal expression of major histocompatibility complex I (MHC-I) has been implicated in developmental synaptic plasticity and axonal regeneration in the central nervous system (CNS), but recent findings demonstrate that constitutive neuronal MHC-I can also be involved in neurodegenerative diseases by playing a neuroinflammtory role. Recent reports demonstrate its expression in vitro and in human postmortem samples and support a role in neurodegeneration involving proinflammatory cytokines, activated microglia and increased cytosolic oxidative stress. Major histocompatibility complex I may be important for both normal development and pathogenesis of some CNS diseases including Parkinson's.
    Frontiers in Neuroanatomy 10/2014; 8:114. DOI:10.3389/fnana.2014.00114 · 3.54 Impact Factor
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    • "Since the invasion of T cells in the brain was first reported [58, 81], numerous studies have confirmed the infiltration of immune cells in the brain in both postmortem PD patients and animal models [82, 83]. These brain-invading lymphocytes consisted of a heterogeneous population of both CD8+ and CD4+ cells. "
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    ABSTRACT: Parkinson’s disease (PD) is a chronic neurodegenerative disease underpinned by both genetic and environmental etiologic factors. Recent findings suggest that inflammation may be a pathogenic factor in the onset and progression of both familial and sporadic PD. Understanding the precise role of inflammatory factors in PD will likely lead to understanding of how the disease arises. In vivo evidence for inflammation in PD includes dysregulated molecular mediators such as cytokines, complement system and its receptors, resident microglial activation, peripheral immune cells invasion, and altered composition and phenotype of peripheral immune cells. The growing awareness of these factors has prompted novel approaches to modulate the immune system, although it remains whether these approaches can be used in humans. Influences of ageing and differential exposure to environmental agents suggest potential host-pathogen specific pathophysiologic factors. There is a clear need for research to further unravel the pathophysiologic role of immunity in PD, with the potential of developing new therapeutic targets for this debilitating condition.
    BioMed Research International 06/2014; 2014(8):308654. DOI:10.1155/2014/308654 · 3.17 Impact Factor
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    • "Previous studies indicated that an adaptive immune system was important in the pathology of PD, and CD4+/CD8+ T cells appeared in postmortem brain samples from PD patients [7,8,9,10]. Moreover, infiltrated T cells in brain could induce the blood vessel change during PD progression [9,11], and the peripheral T-cell pool also can be changed in PD [12,13]; the CD4+ population especially decreased [14]. "
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    ABSTRACT: The adaptive immune system has implications in pathology of Parkinson's disease (PD). Research data demonstrated that the peripheral CD4+ T-cell population decreased in pathogenesis of PD. The effect of damaged dopaminergic neurons on peripheral T cells of PD is still unknown. In this study, we constructed a neuronal and glial cells co-culture model by using human neuroblastoma cells SH-SY5Y and gliomas cells U87. After the co-culture cells were treated with neurotoxin 1-methyl-4-phenylpyridinium (MPP+) for 24 h, the conditioned media was harvested and used to cultivate T-cell leukemia Jurkat cells for another 24 h. We then analyzed the cell proliferation, cell cycle and necrosis effect of Jurkat cells. The results showed that co-culture medium of SH-SY5Y and U87 cells with MPP+ treatment inhibited the proliferation of Jurkat cells compared to control medium without MPP+, even though the same concentration of MPP+ had very little toxicity to the Jurkat cell. Furthermore, co-culture medium with low concentration of MPP+ (100 µM) arrested Jurkat cells cycle in G2/M phase through increasing cell cycle division 2 (CDC2) and CyclinB1 expression level, whereas co-culture medium with high concentration of MPP+ (500 µM) induced Jurkat cell necrosis through cellular swelling and membrane breakage. Our data implies that damaged dopamine neurons with glial cells can lead to the reduced number or inhibited proliferation activity of peripheral T cells.
    International Journal of Molecular Sciences 06/2014; 15(6):10738-10750. DOI:10.3390/ijms150610738 · 2.86 Impact Factor
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