Parkinson’s disease patients have a complex phenotypic and functional Th1 bias: cross-sectional studies of CD4+ Th1/Th2/T17 and Treg in drug-naïve and drug-treated patients

Abstract

BackgroundParkinson’s disease (PD) affects an estimated 7 to 10 million people worldwide, and only symptomatic treatments are presently available to relieve the consequences of brain dopaminergic neurons loss. Neuronal degeneration in PD is the consequence of neuroinflammation in turn influenced by peripheral adaptive immunity, with CD4+ T lymphocytes playing a key role. CD4+ T cells may however acquire proinflammatory phenotypes, such as T helper (Th) 1 and Th17, as well as anti-inflammatory phenotypes, such as Th2 and the T regulatory (Treg) one, and to what extent the different CD4+ T cell subsets are imbalanced and their functions dysregulated in PD remains largely an unresolved issue.MethodsWe performed two cross-sectional studies in antiparkinson drug-treated and drug-naïve PD patients, and in age- and sex-matched healthy subjects. In the first one, we examined circulating Th1, Th2, Th17, and in the second one circulating Treg. Number and frequency of CD4+ T cell subsets in peripheral blood were assessed by flow cytometry and their functions were studied in ex vivo assays. In both studies, complete clinical assessment, blood count and lineage-specific transcription factors mRNA levels in CD4+ T cells were independently assessed and thereafter compared for their consistency.ResultsPD patients have reduced circulating CD4+ T lymphocytes, due to reduced Th2, Th17, and Treg. Naïve CD4+ T cells from peripheral blood of PD patients preferentially differentiate towards the Th1 lineage. Production of interferon-γ and tumor necrosis factor-α by CD4+ T cells from PD patients is increased and maintained in the presence of homologous Treg. This Th1-biased immune signature occurs in both drug-naïve patients and in patients on dopaminergic drugs, suggesting that current antiparkinson drugs do not affect peripheral adaptive immunity.ConclusionsThe complex phenotypic and functional profile of CD4+ T cell subsets in PD patients strengthen the evidence that peripheral adaptive immunity is involved in PD, and represents a target for the preclinical and clinical assessment of novel immunomodulating therapeutics.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1248-8) contains supplementary material, which is available to authorized users.

Peripheral immune biomarkers and neurodegenerative diseases: A prospective cohort study with 20 years of follow‐up

“…For example, a recent study showed that PD patients had lower levels of helper T cells (Th) 2, Th17, and regulatory T cells in the blood, compared to age-and sex-matched healthy controls. 47 It is therefore tempting to speculate that the lower risk of PD in relation to higher concentration of lymphocytes as shown in our study might be due to the increased levels of these specific T-cell subsets. Furthermore, because the concentrations of leukocytes and haptoglobin observed in our study are within the normal ranges, these measurements are unlikely directly useful as predictive biomarkers in the diagnosis of PD.…”

“…Although we agree that peripheral adaptive immunity is involved in PD, we have relatively little knowledge about the detailed peripheral immune phenotypes in PD. For example, a recent study showed that PD patients had lower levels of helper T cells (Th) 2, Th17, and regulatory T cells in the blood, compared to age‐ and sex‐matched healthy controls . It is therefore tempting to speculate that the lower risk of PD in relation to higher concentration of lymphocytes as shown in our study might be due to the increased levels of these specific T‐cell subsets.…”

Immune system responses in Parkinson's disease: Early and dynamic

“…Moreover, examination of the CD4‐Th subpopulations suggests an abnormal distribution with the effector memory (antigen‐experienced) fraction overrepresented in detriment to the naïve T‐cells (Bas et al., ; Fiszer et al., ; Saunders et al., ; Stevens et al., ). A recent study reported that the reduction in CD4‐Th cells in PD patients is due to a decrease in Th2, Th17, and regulatory T‐cell populations; furthermore the authors reported that CD4‐Th cells from PD patients show a Th1‐biased immune response with increased IFN‐gamma and TNF production, strongly suggesting involvement of CD4 cells in the pathophysiology of the disease (Kustrimovic et al., ).…”

Interferon-γ signaling synergizes with LRRK2 in human neurons and microglia

“…Supporting a possible role of IFN-γ in the disease process, increased levels of IFN-γ in the serum, as well as increased production of IFN-γ by peripheral CD4+ T cells, have been detected in PD patients compared to healthy controls 11,12 . Moreover, a significant co-expression of α -synuclein and IFN-γ has been found within the substantia nigra of PD patients 13 .…”

“…Increased IFN-γ levels have been documented in PD patients 11,12 . The source of IFN-γ in the aged and PD brain still needs to be identified.…”