Alterations of T-lymphocyte populations in Parkinson disease

https://doi.org/10.1016/j.parkreldis.2005.07.005Get rights and content

Abstract

Immune reaction-related inflammation may be important in the pathogenesis of Parkinson disease (PD). To elucidate peripheral immunologic alterations in PD, we characterized extended peripheral T-lymphocyte populations in 33 patients with PD and 34 normal subjects. Patients with PD had significantly decreased CD4+:CD8+T-cell ratios (P<0.001), fewer CD4+CD25+T cells (P<0.01), and significantly increased ratios of IFN-γ-producing to IL-4-producing T cells (P<0.001). The characteristics of predominant expression of CD8+T cells, depletion of CD4+CD25high cells, and a shift to a TH1-type immune response in the peripheral immune system in PD patients may reflect an immune reaction-associated inflammatory process in the brain.

Introduction

Parkinson disease (PD) is a neurodegenerative disorder characterized by dopamine depletion in the nigrostriatal system. Mitochondrial dysfunction, oxidative stress, environmental toxins, and deficient neurotrophic support have been implicated in the etiopathogenesis of cellular degeneration and death in PD [1]. However, the exact mechanisms leading to this degeneration are unknown. Immune factors have been proposed as one of the possible mechanisms by which cellular death occurs. Indeed, class II major histocompatibility complex (HLA-DR)-positive reactive microglia have been demonstrated in the substantia nigra (SN) of patients with PD [2]. Elevated levels of interleukin (IL)-2 have been reported in the striatum, and elevated levels of inflammatory cytokines, such as IL-1β, IL-2, IL-6, epidermal growth factor, and transforming growth factor (TGF)-α have been reported in the striatal dopaminergic neurons [3], [4]. Parkinsonian features and substantial neuronal loss in the SN that was generated by an antibody against a hybrid cell line of dopaminergic neurons have been demonstrated in an immunized animal model of PD [5]. These observations suggest that an immunologic mechanism may be important in the development of PD [6]. However, it is uncertain whether immunologic changes are primary or secondary to the PD.

Similar immunologic alterations are present in the peripheral blood of PD patients. Specific changes that have been demonstrated include decreases of CD4+CD45RA+ ‘naïve’ T cells and increases of CD4+CD45RO+ ‘memory’ T cells, TCRγδ+ cells [7], [8], CD4 bright+CD8 dull+T cells [9], and IL-2 receptor α (CD25)+T cells [8], [10]. The interpretation of these peripheral immune alterations is uncertain; it has been proposed that they are a reflection of lymphocyte apoptosis [8], previously unrecognized inflammation [11], or postinfectious immune dysfunction [9].

Among immunocompetent cells, CD4 and CD8 are the principal markers of helper and cytotoxic T cells, respectively, and have an important role in immune reactions. Recently, CD4+CD25+T cells have been shown to regulate CD4+ and CD8+ cell proliferation and cytokine production. To further elucidate the immunologic alterations associated with PD, we investigated the characteristics of peripheral T cells, including CD4+, CD8+, and CD4+CD25+T cells and their subpopulations, and evaluated cytokine profile based on the intracellular levels of interferon (IFN)-γ and IL-4 in patients with PD.

Section snippets

Subjects

This study was approved by the Ethics Committee of Fukuoka University School of Medicine. Consecutive patients with PD seen at Fukuoka University who fulfilled the diagnostic criteria of Calne et al. [12] (33 patients, 19 men) were recruited during a 2-year period (2002–2003). Patients with secondary parkinsonism were excluded by clinical examination and by neuroimaging studies. None of the 33 patients had a history of infectious, immune, or any other neurodegenerative disorder. All cases were

Populations of peripheral T lymphocytes

The analysis of leukocyte subsets showed lower total lymphocyte counts in PD patients than in control subjects (1271±312 vs 2107±786 μL, P<0.01). The subpopulations of the peripheral lymphocyte subsets in PD patients and controls are shown in Table 1. The percentage of CD3+T cells was similar for both groups. The percentage of CD4+CD8 lymphocytes was significantly lower (P<0.001) and the percentage of CD4CD8+ lymphocytes was significantly higher in patients with PD than in controls. The

Discussion

Our study is further evidence that immunologic alterations exist in patients with PD. First, PD patients had significantly lower CD4+:CD8+T-cell ratios due to decreased percentages of CD4+CD8 T cells and increased percentages of CD4CD8+T cells in peripheral blood compared with controls. Similar peripheral blood lymphocyte population distributions in patients with PD have been reported [8], [9], [10], [17]. The results of our study provide additional evidence that the ratio of CD8+

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