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Neuroinflammation and Neurodegeneration pp 119–142Cite as

Innate and Adaptive Immune-Mediated Neuroinflammation and Neurodegeneration in Parkinson’s Disease

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Abstract

Innate and adaptive immunity affect the pathogenesis of Parkinson’s disease (PD). In particular, the activation of microglia that feed neuroinflammation and oxidative stress influences the degeneration of dopaminergic neurons along the nigrostriatal axis during disease. Activated microglia that proximate degenerating neurons within the substantia nigra are a hallmark of PD. Other PD hallmarks include neuronal Lewy body inclusions composed primarily of aggregated ubiquitin and neuronal proteins. Under inflammatory conditions, oxidative or nitrative modifications of neuronal proteins, such as ?-synuclein, lead to misfolding and formation of neurotoxic species that accumulate within the neuron. Release of misfolded proteins from injured or dead neurons intensifies neuroinflammation and neuronal injury within the surrounding area. Moreover, once in the peripheral immune compartments, processing and presentation of modified proteins, such as nitrated ?-synuclein by dendritic cells, induce effector T cells to those nitrated epitopes that act as neoantigens. Robust effector T cell immune responses against nitrated or modified self-proteins and migration of those effector T cells to inflammatory sites exacerbate neuroinflammation and dopaminergic neurodegeneration, which lead to accelerated disease progression. The links between T cell immunity and nigrostriatal neurodegeneration are supported by laboratory and animal models as well as human investigations of immune-associated biomarkers in the spinal fluid, peripheral blood, and brain tissue of patients with idiopathic or familial forms of PD. Regulatory T cells modulate both innate and effector T cell-mediated immunity to attenuate neuroinflammation and alleviate neurodegeneration along the nigrostriatal axis. Thus, harnessing proinflammatory and neurotoxic effector immune responses with drugs, vaccination, or immunomodulation affords promising therapeutic strategies either alone as an interdictory therapy or in combination as adjunctive therapy in the context of neuronal replacement. Herein immune-mediated inflammation, oxidative stress, and neurodegeneration as linked to PD pathogenesis are examined as well as the potential benefits of efficacious immune regulatory control over those neurotoxic processes.

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Abbreviations

PD:

Parkinson’s disease

SNpc:

Substantia nigra pars compacta

LB:

Lewy body

α-syn:

α-Synuclein

TNF:

Tumor necrosis factor

LPS:

Lipopolysaccharide

IFN-γ:

Interferon gamma

CD40L:

CD40 ligand

tPA:

Tissue plasminogen activator

MMP-3:

Matrix metalloproteinase-3

β-Amyloid:

Amyloid beta

MHC:

Major histocompatibility complex

ADCC:

Antibody-dependent cell cytotoxicity

LFA-1:

Lymphocyte function-associated antigen-1

ICAM-1:

Intercellular adhesion molecule-1

VCAM-1:

Vascular cell adhesion molecule-1

ROS:

Reactive oxygen species

RNS:

Reactive nitrogen species

iNOS:

Inducible nitric oxide synthase

COX1:

Cyclooxygenase-1

COX 2:

Cyclooxygenase-2

NADPH:

Nicotinamide adenine dinucleotide phosphate

HLA-DR:

Human lymphocyte antigen-DR

MPTP:

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

6-OHDA:

6-Hydroxydopamine

NO:

Nitric oxide

PGE2:

Prostaglandin E2

PRRs:

Pattern recognition receptors

PAMPs:

Pathogen-associated molecular patterns

DAMPs:

Damage-associated molecular patterns

TCR:

T cell receptor

APCs:

Antigen-presenting cells

Th1:

Type 1 T helper

Th2:

Type 2 T helper

Th17:

Type 17 T helper

HSP:

Heat shock protein

GFAP:

Glial fibrillar acidic protein

NGF:

Nerve growth factor

BBB:

Blood-brain barrier

RANTES:

Regulated on activation normal T cell expressed and secreted

Tregs:

Regulatory T cells

N-α-syn:

Nitrated α-syn

Teffs:

Effector T cells

GDNF:

Glial cell-derived neurotrophic factor

nTregs:

Natural Tregs

IPEX:

Immune-dysregulation polyendocrinopathy, enteropathy X-linked

iTregs:

Induced or inducible Tregs

TGF-β:

Transforming growth factor-β

NF-κB:

Nuclear factor-kappa B

NSAIDs:

Nonsteroidal anti-inflammatory drugs

MAP:

Mitogen-activated protein

MCP-1:

Monocyte chemotactic protein-1

BDNF:

Brain-derived neurotrophic factor

VIP:

Vasoactive intestinal peptide

GM-CSF:

Granulocyte/macrophage colony-stimulating factor

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Acknowledgments

Supported by NIH grants 3R01NS070190-03S1 (R.A.W.) and 5R01NS070190-03 (R.L.M.).

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  1. Department of Pharmacology and Experimental Neuroscience, Center for Neurodegenerative Disorders, University of Nebraska Medical Center, 985930 Nebraska Medical Center, Omaha, NE, 68198-5930, USA

    Rebecca A. Wilshusen & R. Lee Mosley Ph.D.

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  1. Rebecca A. Wilshusen
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Correspondence to R. Lee Mosley Ph.D. .

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  1. Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA

    Phillip K. Peterson

  2. Department of Biochemistry Department of Molecular Biology, University of Miami School of Medicine, Miami, Florida, USA

    Michal Toborek

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Wilshusen, R.A., Mosley, R.L. (2014). Innate and Adaptive Immune-Mediated Neuroinflammation and Neurodegeneration in Parkinson’s Disease. In: Peterson, P., Toborek, M. (eds) Neuroinflammation and Neurodegeneration. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1071-7_7

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