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

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.

The dopamine transporter: An unrecognized nexus for dysfunctional peripheral immunity and signaling in Parkinson’s Disease

“…As the current standard in visualizing the degree of cell death in PD, quantifying DAT uptake capacity represents a valuable longitudinal readout in order to better understand the links between symptom severity, L-DOPA efficacy, and overall progression of the disease. Although, peripheral dopamine level is decreased in PD patients (Kustrimovic et al, 2016), whether peripheral DAT uptake capacity and/or its level are changed in PD are unknown. Addressing this important knowledge gap may provide a potential connection, or lack thereof, between changes in the peripheral dopamine and DAT levels and the central nervous system.…”

“…Immune-related side effects have been reported in patients taking antiparkinson’s medications such as L-DOPA, dopamine agonists, and catabolic inhibitors (Table 2) suggesting alterations in peripheral dopamine levels may lead to dysfunctional immune responses. Indeed, plasma dopamine is elevated in patients on dopamine substitution therapy compared to healthy controls (Kustrimovic et al, 2016) and thus this may lead to increased dopamine signaling on immune cells. On a more clinically relevant scale, L-DOPA treatment in a 6-hydroxydopamine rat model of Parkinson’s increases immunogenic response after xenogeneic ventral mesencephalon graft (Breger et al, 2017), implicating over-activation of microglia.…”

“…On a more clinically relevant scale, L-DOPA treatment in a 6-hydroxydopamine rat model of Parkinson’s increases immunogenic response after xenogeneic ventral mesencephalon graft (Breger et al, 2017), implicating over-activation of microglia. Additionally, PD patients on dopaminergic therapies showed increased expression of D1R on CD4+ T-cell when compared to drug-naïve patients (Kustrimovic et al, 2016). This evidence, along with the report by Cordano and colleagues, shows that while dopaminergic therapies are aimed at rescuing CNS dopamine levels, they also have effects on peripheral dopamine tone and, consequently, immunological effects.…”

“…Furthermore, not only are T-cell levels different between healthy and PD samples, but studies have also shown that dopamine receptor expression varies between the two populations, and treatment with α-synuclein resulted in different effects on dopamine receptor expression in healthy vs PD patient T-cells (Kustrimovic et al, 2016). Since dopamine signaling has been shown to regulate T-cell function and DR activation is potentially associated with overall pro-inflammatory immune activation, it is reasonable to postulate that dopamine signaling on peripheral T cells may cause a pro-inflammatory response that may migrate to the CNS and lead to neuroinflammation.…”

cAMP levels in lymphocytes and CD4+ regulatory T‐cell functions are affected by dopamine receptor gene polymorphisms

“…To this end, we collected venous blood samples from healthy volunteers, as part of a project aimed at assessing the expression and role of DR on circulating CD4 + T cells in Parkinson's disease. The study protocol was approved by the Ethics Committee of the Ospedale di Circolo and Fondazione Macchi, Varese (I) . Lymphocytes were isolated by Ficoll‐Paque Plus density gradient centrifugation, resuspended in RPMI‐1640 medium supplemented with 10% heat‐inactivated fetal calf serum and 2 m m glutamine, at a final concentration of 1 × 10 6 cells/ml for subsequent culture at 37° in a moist atmosphere of 5% CO 2 .…”