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Regulation of the Neurodegenerative Process Associated to Parkinson’s Disease by CD4+ T-cells

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Abstract

Neuroinflammation constitutes a fundamental process involved in the physiopathology of Parkinson’s disease (PD). Microglial cells play a central role in the outcome of neuroinflammation and consequent neurodegeneration of dopaminergic neurons in the substantia nigra. Current evidence indicates that CD4+ T-cells infiltrate the central nervous system (CNS) in PD, where they play a critical role determining the functional phenotype of microglia, thus regulating the progression of the neurodegenerative process. Here, we first analysed the pathogenic role of inflammatory phenotypes and the beneficial role of anti-inflammatory phenotypes of encephalitogenic CD4+ T-cells involved in the physiopathology of PD. Next, we discussed how alterations of neurotransmitter levels observed in the basal ganglia throughout the time course of PD progression could be strongly affecting the behaviour of encephalitogenic CD4+ T-cells and thereby the outcome of the neuroinflammatory process and the consequent neurodegeneration of dopaminergic neurons. Afterward, we integrated the evidence indicating the involvement of an antigen-specific immune response mediated by T-cells and B-cells against CNS-derived self-constituents in PD. Consistent with the involvement of a relevant autoimmune component in PD, we also reviewed the polymorphisms of both, class I and class II major histocompatibility complexes, associated to the risk of PD. Overall, this study gives an overview of how an autoimmune component involved in PD plays a fundamental role in the progression of the neurodegenerative process.

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Abbreviations

AD:

Alzheimer’s disease

ALS:

Amyotrophic lateral sclerosis

AMPA:

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

APCs:

Antigen-presenting cells

BBB:

Blood–brain barrier

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

DA:

dopamine

DnR:

DA receptor n

EAE:

Experimental autoimmune encephalomyelitis

GABA:

γ-aminobutyric acid

GABAARs:

GABA ionotropic receptors

GABABRs:

GABA metabotropic receptors

glu:

glutamate

GluR:

glu receptors

GM-CSF:

Granulocyte macrophage-colony stimulating factor

HLA:

Human leukocyte antigen

IFN-γ:

interferon γ

IL-n :

interleukin n

L-DOPA:

L-3,4-dihydroxyphenylalanine

LPS:

Lipopolysaccharide

MHC:

Major histocompatibility complex

MPTP:

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MS:

Multiple sclerosis

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NMDA:

N-methyl-D-aspartate

PD:

Parkinson’s disease

RAG1:

recombination-activating gen 1

RAG1KO:

RAG1 knockout

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SN:

Substantia nigra

TCRs:

T-cell receptors

Thn :

T helper n

TLRs:

Toll like receptors

TGF-β:

Transforming growth factor β

TNF-α:

Tumor Necrosis Factor α

TNFR1:

TNF-α receptor 1

6-OHDA:

6-hydroxidopamine.

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Acknowledgments

This work was supported by grants 1130271 from the Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT), PFB-16 from the Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) and 10332 from the Michael J. Fox foundation (MJFF).

Compliance with Ethical Standards

This study was funded by grants from the Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT 1130271, to RP), from the Comisión Nacional de Investigación Científica y Tecnológica (PFB-16, to RP) and from the Michael J. Fox foundation (MJFF 10332, to RP). RP is Associate Investigator at Fundación Ciencia & Vida and Associate Professor at Universidad Andres Bello. HG and FC are postdoctoral trainees supervised by RP at the Laboratory of Neuroimmunology of the Fundación Ciencia & Vida. All authors declare that they have no conflicts of interest. This article does not contain any studies with human participants or animals performed by any of the authors.

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  1. Laboratory of Neuroimmunology, Fundación Ciencia & Vida, Avenida Zañartu #1482, Ñuñoa, 7780272, Santiago, Chile

    Hugo González, Francisco Contreras & Rodrigo Pacheco

  2. Facultad de Ciencias Biológicas, Universidad Andres Bello, 8370146, Santiago, Chile

    Rodrigo Pacheco

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  1. Hugo González
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  3. Rodrigo Pacheco
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Correspondence to Rodrigo Pacheco.

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González, H., Contreras, F. & Pacheco, R. Regulation of the Neurodegenerative Process Associated to Parkinson’s Disease by CD4+ T-cells. J Neuroimmune Pharmacol 10, 561–575 (2015). https://doi.org/10.1007/s11481-015-9618-9

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