Dopaminergic Receptors on CD4+ T Naive and Memory Lymphocytes Correlate with Motor Impairment in Patients with Parkinson's Disease.

Natasa Kustrimovic,Marco Mauri,Vanesa Sanchez-Guajardo,Franca Marino,Emanuela Rasini,Fabio Blandini,Giulio Riboldazzi,Massimiliano Legnaro,Marco Cosentino,Cristoforo Comi,Raffaella Bombelli,Brigida Minafra,Iva Aleksic

doi:10.1038/srep33738

Abstract

Parkinson’s disease (PD) is characterized by loss of dopaminergic neurons in substantia nigra pars compacta, α-synuclein (α-syn)-rich intraneuronal inclusions (Lewy bodies), and microglial activation. Emerging evidence suggests that CD4+ T lymphocytes contribute to neuroinflammation in PD. Since the mainstay of PD treatment is dopaminergic substitution therapy and dopamine is an established transmitter connecting nervous and immune systems, we examined CD4+ T naive and memory lymphocytes in PD patients and in healthy subjects (HS), with specific regard to dopaminergic receptor (DR) expression. In addition, the in vitro effects of α-syn were assessed on CD4+ T naive and memory cells. Results showed extensive association between DR expression in T lymphocytes and motor dysfunction, as assessed by UPDRS Part III score. In total and CD4+ T naive cells expression of D1-like DR decrease, while in T memory cells D2-like DR increase with increasing score. In vitro, α-syn increased CD4+ T memory cells, possibly to a different extent in PD patients and in HS, and affected DR expression with cell subset-specific patterns. The present results support the involvement of peripheral adaptive immunity in PD, and may contribute to develop novel immunotherapies for PD, as well as to better use of current dopaminergic antiparkinson drugs.

Highlights

Over the last 15 years, several studies described the occurrence of peculiar modifications of peripheral immunity in Parkinson’s disease (PD), such as decreased CD4+/CD8+T-cell ratios, fewer CD4+CD25+T cells and increased ratios of interferon (IFN)-γ-producing to interleukin (IL)-4-producing T cells[8], as well as decreased CD4+T lymphocytes and CD19+B cells[9,10]
Our results are in line with previous studies showing decreased CD4+T lymphocytes in PD patients[9,10], and in particular with Saunders et al.[12], who recently reported that in PD patients increased effector/memory CD4+T cells correlated with increased motor dysfunction
Possible explanations include that l-DOPA may undergo conversion to dopamine only in the brain, and that dopaminergic receptor agonists are usually D2-like dopaminergic receptors (DR) selective

Summary

Introduction

Over the last 15 years, several studies described the occurrence of peculiar modifications of peripheral immunity in PD, such as decreased CD4+/CD8+T-cell ratios, fewer CD4+CD25+T cells and increased ratios of interferon (IFN)-γ-producing to interleukin (IL)-4-producing T cells[8], as well as decreased CD4+T lymphocytes and CD19+B cells[9,10]. Α-syn is a protein expressed in brain and in peripheral tissues It is the main component of Lewy bodies and it may contribute to the pathogenesis of PD through different concurrent mechanisms, including direct activation of microglial cells as well as possibly by acting as an antigen itself, triggering the adaptive immune response in the periphery[30,31,32]. For these reasons, the effects of α-syn on CD4+T naive and memory cells were compared with those of a common recall antigen like tetanus toxoid (TTd)

Methods

Results

Discussion

Conclusion