Increased levels of regulatory T cells and IL-10-producing regulatory B cells are linked to improved clinical outcome in Parkinson's disease: a 1-year observational study.

Whilst the contribution of peripheral and central inflammation to neurodegeneration in Parkinson's disease and the role of the immune response in this disorder are well known, the effects of the anti-inflammatory response on the disease have not been described in depth. This study is aimed to assess the changes in the regulatory/inflammatory immune response in recently diagnosed, untreated PD patients and a year after. Twenty-one PD patients and 19 healthy controls were included and followed-up for 1 year. The levels of immunoregulatory cells (CD4+ Tregs, Bregs, and CD8+ Tregs); classical, nonclassical, and intermediate monocytes, and proinflammatory cells (Th1, Th2, and Th17) were measured by flow cytometry. Cytokine levels were determined by ELISA. Clinical follow-up was based on the Hoehn & Yahr and UDPRS scales. Our results indicate that the regulatory response in PD patients on follow-up was characterized by increased levels of active Tregs, functional Tregs, TR1, IL-10-producing functional Bregs, and IL-10-producing classical monocytes, along with decreased counts of Bregs and plasma cells. With respect to the proinflammatory immune response, peripheral levels of Th1 IFN-γ+ cells were decreased in treated PD patients, whilst the levels of CD4+ TBET+ cells, HLA-DR+ intermediate monocytes, IL-6, and IL-4 were increased after a 1-year follow-up. Our main finding was an increased regulatory T cell response after a 1-year follow-up and its link with clinical improvement in PD patients. In conclusion, after a 1-year follow-up, PD patients exhibited increased levels of regulatory populations, which correlated with clinical improvement. However, a persistent inflammatory environment and active immune response were observed.

Expression of Dopamine Receptors in Immune Regulatory Cells.

OBJECTIVE: Parkinson's disease (PD) patients are usually treated with L-dopa and/or dopaminergic agonists, which act by binding five types of dopaminergic receptors (DRD1-DRD5). Peripheral immune cells are known to express dopamine receptors on their membrane surface, and therefore they could be directly affected by the treatment. Regulatory cells are the main modulators of inflammation, but it is not clear whether dopaminergic treatment could affect their functions. While only regulatory T cells (Tregs) have been proved to express dopamine receptors, it is not known whether other regulatory cells such as CD8regs, regulatory B cells (Bregs), tolerogenic dendritic cells, and intermediate monocytes also express them. METHODS: The expression of dopamine receptors in Tregs, CD8regs, Bregs, tolerogenic dendritic cells, and intermediate monocytes was herein evaluated. cDNA from 11 PD patients and 9 control subjects was obtained and analyzed. RESULTS: All regulatory cell populations expressed the genes coding for dopamine receptors, and this expression was further corroborated by flow cytometry. These findings may allow us to propose regulatory populations as possible targets for PD treatment. CONCLUSIONS: This study opens new paths to deepen our understanding on the effect of PD treatment on the cells of the regulatory immune response.

Treating activated regulatory T cells with pramipexole protects human dopaminergic neurons from 6-OHDA-induced degeneration.

BACKGROUND: Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, which promotes a sustained inflammatory environment in the central nervous system. Regulatory T cells (Tregs) play an important role in the control of inflammation and might play a neuroprotective role. Indeed, a decrease in Treg number and function has been reported in PD. In this context, pramipexole, a dopaminergic receptor agonist used to treat PD symptoms, has been shown to increase peripheral levels of Treg cells and improve their suppressive function. The aim of this work was to determine the effect of pramipexole on immunoregulatory Treg cells and its possible neuroprotective effect on human dopaminergic neurons differentiated from human embryonic stem cells. METHODS: Treg cells were sorted from white blood cells of healthy human donors. Assays were performed with CD3/CD28-activated and non-activated Treg cells treated with pramipexole at concentrations of 2 or 200 ng/mL. These regulatory cells were co-cultured with in vitro-differentiated human dopaminergic neurons in a cytotoxicity assay with 6-hydroxydopamine (6-OHDA). The role of interleukin-10 (IL-10) was investigated by co-culturing activated IL-10-producing Treg cells with neurons. To further investigate the effect of treatment on Tregs, gene expression in pramipexole-treated, CD3/CD28-activated Treg cells was determined by Fluidigm analysis. RESULTS: Pramipexole-treated CD3/CD28-activated Treg cells showed significant protective effects on dopaminergic neurons when challenged with 6-OHDA. Pramipexole-treated activated Treg cells showed neuroprotective capacity through mechanisms involving IL-10 release and the activation of genes associated with regulation and neuroprotection. CONCLUSION: Anti-CD3/CD28-activated Treg cells protect dopaminergic neurons against 6-OHDA-induced damage. In addition, activated, IL-10-producing, pramipexole-treated Tregs also induced a neuroprotective effect, and the supernatants of these co-cultures promoted axonal growth. Pramipexole-treated, activated Tregs altered their gene expression in a concentration-dependent manner, and enhanced TGFß-related dopamine receptor regulation and immune-related pathways. These findings open new perspectives for the development of immunomodulatory therapies for the treatment of PD.

Pro- and anti-inflammatory response in neurological disorders associated to anti-glutamate decarboxylase antibodies.

Rare conditions showing psychiatric symptoms and movement disorders have been linked with the presence of anti-glutamate decarboxylase antibodies. Proinflammatory and antiinflammatory immune responses were assessed in patients with neurological disorders associated to anti-glutamic acid decarboxylase antibodies (NDGAD). Immunoregulatory and proinflammatory cell populations were quantified by flow cytometry. No polarization toward Th1, Th2, or Th17 phenotypes was observed in NDGAD patients. Immunoregulatory responses were significantly reduced for Breg, activated Treg, Tr1, and Th3 cells, suggesting a deficient regulatory response, while intermediate monocyte levels were increased. The reduced levels of regulatory T and B cells suggest an impairment in regulatory immune response, while intermediate monocytes could be playing a role in the increased proinflammatory response.

Regulatory T Cells: Molecular Actions on Effector Cells in Immune Regulation.

T regulatory cells play a key role in the control of the immune response, both in health and during illness. While the mechanisms through which T regulatory cells exert their function have been extensively described, their molecular effects on effector cells have received little attention. Thus, this revision is aimed at summarizing our current knowledge on those regulation mechanisms on the target cells from a molecular perspective.