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Abstract
Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive loss of dopaminergic neurons, appearance of Lewy bodies and presence of neuroinflammation. No treatments currently exist to prevent PD or delay its progression, and dopaminergic substitution treatments just relieve the consequences of dopaminergic neuron loss. Increasing evidence points to peripheral T lymphocytes as key players in PD, and recently there has been growing interest into the specific role of T helper (Th) 17 lymphocytes. Th17 are a proinflammatory CD4+ T cell lineage named after interleukin (IL)-17, the main cytokine produced by these cells. Th17 are involved in immune-related disease such as psoriasis, rheumatoid arthritis and inflammatory bowel disease, and drugs targeting Th17/IL-17 are currently approved for clinical use in such disease. In the present paper, we first summarized current knowledge about contribution of the peripheral immune system in PD, as well as about the physiopharmacology of Th17 and IL-17 together with its therapeutic relevance. Thereafter, we systematically retrieved and evaluated published evidence about Th17 and IL-17 in PD, to help assessing Th17/IL-17-targeting drugs as potentially novel antiparkinson agents. Critical appraisal of the evidence did not allow to reach definite conclusions: both animal as well as clinical studies are limited, just a few provide mechanistic evidence and none of them investigates the eventual relationship between Th17/IL-17 and clinically relevant endpoints such as disease progression, disability scores, intensity of dopaminergic substitution treatment. Careful assessment of Th17 in PD is anyway a priority, as Th17/IL-17-targeting therapeutics might represent a straightforward opportunity for the unmet needs of PD patients.
Highlights
Reviewed by: Anindya Bhattacharya, Janssen Research and Development, United States Graziella Madeo, National Institutes of Health (NIH), United States Héctor Alberto González-Usigli, Instituto Mexicano del Seguro Social (IMSS), Mexico
In the present review we systematically retrieved and critically evaluated available evidence regarding the contribution of Th17 cells and IL-17 to neuroinflammation and neurodegeneration in Parkinson’s disease (PD), to provide a state-of-the-art compendium which will help identifying the future directions that research in this field may take to assess the possible benefits of targeting Th17/IL-17 to develop novel therapeuticts for PD patients
We identified 3 studies in animals matching the inclusion criteria, two in C57BL/6J mice treated with i.p. injections of 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [86, 87] and one in human leucine-rich repeat kinase 2 (LRRK) G2019S gene transgenic rats [88] (Table 1)
Summary
In the present review we systematically retrieved and critically evaluated available evidence regarding the contribution of Th17 cells and IL-17 to neuroinflammation and neurodegeneration in PD, to provide a state-of-the-art compendium which will help identifying the future directions that research in this field may take to assess the possible benefits of targeting Th17/IL-17 to develop novel therapeuticts for PD patients. Experiments in ventral midbrain cell cultures provided direct evidence and mechanistic explanation of Th17-dependent exacerbation of MPP+-induced dopaminergic cell death [87] As a whole, these two studies provide consistent evidence about the pathogenetic role of Th17 in the MPTP mouse model of PD. Means of surface markers found similar or even reduced Th17 in patients in comparison to HS Another critical issue is that in most of the studies Th17 are quantified just as percentage of a reference cell population and not as absolute number of cells per volume of blood. While the frequency of Th17 identified by means of their established surface markers may not differ between PD patients and controls, increased frequency of IL-17-producing cells has been consistently reported. LRRK2 gene polymorphisms are a risk factor for PD LRRK2 G2019S is the most prevalent LRRK2 mutation found in PD patients
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