Skip to main content

Advertisement

SpringerLink
Log in

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

  • INVITED REVIEW
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

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.

References

  • Adeosun SO, Hou X, Jiao Y, Zheng B, Henry S, Hill R, He Z, Pani A, Kyle P, Ou X, Mosley T, Farley JM, Stockmeier C, Paul I, Bigler S, Brinton RD, Smeyne R, Wang JM (2012) Allopregnanolone reinstates tyrosine hydroxylase immunoreactive neurons and motor performance in an MPTP-lesioned mouse model of Parkinson’s disease. PLoS One 7:e50040

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Anandasabapathy N, Victora GD, Meredith M, Feder R, Dong B, Kluger C, Yao K, Dustin ML, Nussenzweig MC, Steinman RM, Liu K (2011) Flt3L controls the development of radiosensitive dendritic cells in the meninges and choroid plexus of the steady-state mouse brain. J Exp Med 208:1695–1705

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Anderson KM, Olson KE, Estes KA, Flanagan K, Gendelman HE, Mosley RL (2014) Dual destructive and protective roles of adaptive immunity in neurodegenerative disorders. Transl Neurodegener 3:25

    Article  PubMed Central  PubMed  Google Scholar 

  • Appel SH (2009) CD4+ T cells mediate cytotoxicity in neurodegenerative diseases. J Clin Invest 119:13–15

    PubMed Central  CAS  PubMed  Google Scholar 

  • Arnon R, Aharoni R (2004) Mechanism of action of glatiramer acetate in multiple sclerosis and its potential for the development of new applications. Proc Natl Acad Sci U S A 101(Suppl 2):14593–14598

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Badie B, Bartley B, Schartner J (2002) Differential expression of MHC class II and B7 costimulatory molecules by microglia in rodent gliomas. J Neuroimmunol 133:39–45

    Article  CAS  PubMed  Google Scholar 

  • Barcia C, Ros CM, Annese V, Gomez A, Ros-Bernal F, Aguado-Llera D, Martinez-Pagan ME, de Pablos V, Fernandez-Villalba E, Herrero MT (2012) IFN-gamma signaling, with the synergistic contribution of TNF-alpha, mediates cell specific microglial and astroglial activation in experimental models of Parkinson’s disease. Cell Death Dis 3:e379

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Baruch K, Schwartz M (2013) CNS-specific T cells shape brain function via the choroid plexus. Brain Behav Immun 34:11–16

    Article  CAS  PubMed  Google Scholar 

  • Baruch K, Ron-Harel N, Gal H, Deczkowska A, Shifrut E, Ndifon W, Mirlas-Neisberg N, Cardon M, Vaknin I, Cahalon L, Berkutzki T, Mattson MP, Gomez-Pinilla F, Friedman N, Schwartz M (2013) CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging. Proc Natl Acad Sci U S A 110:2264–2269

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bas J, Calopa M, Mestre M, Mollevi DG, Cutillas B, Ambrosio S, Buendia E (2001) Lymphocyte populations in Parkinson’s disease and in rat models of parkinsonism. J Neuroimmunol 113:146–152

    Article  CAS  PubMed  Google Scholar 

  • Benner EJ, Banerjee R, Reynolds AD, Sherman S, Pisarev VM, Tsiperson V, Nemachek C, Ciborowski P, Przedborski S, Mosley RL, Gendelman HE (2008) Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One 3:e1376

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Bennett SR, Carbone FR, Karamalis F, Flavell RA, Miller JF, Heath WR (1998) Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393:478–480

    Article  CAS  PubMed  Google Scholar 

  • Ben-Nun A, Kaushansky N, Kawakami N, Krishnamoorthy G, Berer K, Liblau R, Hohlfeld R, Wekerle H (2014) From classic to spontaneous and humanized models of multiple sclerosis: impact on understanding pathogenesis and drug development. J Autoimmun 54:33–50

    Article  CAS  PubMed  Google Scholar 

  • Bes C, Altunrende B, Yilmaz Turkoglu S, Yildiz N, Soy M (2014) Parkinsonism in elderly rheumatoid arthritis patients. La Clin Ter 165:19–21

    CAS  Google Scholar 

  • Bettelli E, Sullivan B, Szabo SJ, Sobel RA, Glimcher LH, Kuchroo VK (2004) Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. J Exp Med 200:79–87

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Beurel E, Harrington LE, Buchser W, Lemmon V, Jope RS (2014) Astrocytes modulate the polarization of CD4+ T cells to Th1 cells. PLoS One 9:e86257

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Bhat R, Axtell R, Mitra A, Miranda M, Lock C, Tsien RW, Steinman L (2010) Inhibitory role for GABA in autoimmune inflammation. Proc Natl Acad Sci U S A 107:2580–2585

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bixo M, Andersson A, Winblad B, Purdy RH, Backstrom T (1997) Progesterone, 5alpha-pregnane-3,20-dione and 3alpha-hydroxy-5alpha-pregnane-20-one in specific regions of the human female brain in different endocrine states. Brain Res 764:173–178

    Article  CAS  PubMed  Google Scholar 

  • Bortolanza M, Cavalcanti-Kiwiatkoski R, Padovan-Neto FE, da-Silva CA, Mitkovski M, Raisman-Vozari R, Del-Bel E (2014) Glial activation is associated with l-DOPA induced dyskinesia and blocked by a nitric oxide synthase inhibitor in a rat model of Parkinson’s disease. Neurobiol Dis 73C:377–387

    Google Scholar 

  • Boulet S, Lacombe E, Carcenac C, Feuerstein C, Sgambato-Faure V, Poupard A, Savasta M (2006) Subthalamic stimulation-induced forelimb dyskinesias are linked to an increase in glutamate levels in the substantia nigra pars reticulata. J Neurosci 26:10768–10776

    Article  CAS  PubMed  Google Scholar 

  • Brochard V, Combadiere B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V, Bonduelle O, Alvarez-Fischer D, Callebert J, Launay JM, Duyckaerts C, Flavell RA, Hirsch EC, Hunot S (2009) Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest 119:182–192

    PubMed Central  CAS  PubMed  Google Scholar 

  • Burzyn D, Benoist C, Mathis D (2013) Regulatory T cells in nonlymphoid tissues. Nat Immunol 14:1007–1013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Calabresi P, Mercuri NB, Sancesario G, Bernardi G (1993) Electrophysiology of dopamine-denervated striatal neurons. Implications for Parkinson’s disease. Brain: J Neurol 116(Pt 2):433–452

    Google Scholar 

  • Calabresi P, Picconi B, Tozzi A, Di Filippo M (2007) Dopamine-mediated regulation of corticostriatal synaptic plasticity. Trends Neurosci 30:211–219

    Article  CAS  PubMed  Google Scholar 

  • Carrillo-Mora P, Silva-Adaya D, Villaseñor-Aguayo K (2013) Glutamate in Parkinson’s disease: role of antiglutamatergic drugs. Basal Ganglia 3:147–157

    Article  Google Scholar 

  • Chen S, Le WD, Xie WJ, Alexianu ME, Engelhardt JI, Siklos L, Appel SH (1998) Experimental destruction of substantia nigra initiated by Parkinson disease immunoglobulins. Arch Neurol 55:1075–1080

    Article  CAS  PubMed  Google Scholar 

  • Cheramy A, Leviel V, Glowinski J (1981) Dendritic release of dopamine in the substantia nigra. Nature 289:537–542

    Article  CAS  PubMed  Google Scholar 

  • Codarri L, Gyulveszi G, Tosevski V, Hesske L, Fontana A, Magnenat L, Suter T, Becher B (2011) RORgammat drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol 12:560–567

    Article  CAS  PubMed  Google Scholar 

  • Constant SL, Bottomly K (1997) Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. Annu Rev Immunol 15:297–322

    Article  CAS  PubMed  Google Scholar 

  • Cosentino M, Fietta AM, Ferrari M, Rasini E, Bombelli R, Carcano E, Saporiti F, Meloni F, Marino F, Lecchini S (2007) Human CD4 + CD25+ regulatory T cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop. Blood 109:632–642

    Article  CAS  PubMed  Google Scholar 

  • Dardalhon V, Korn T, Kuchroo VK, Anderson AC (2008) Role of Th1 and Th17 cells in organ-specific autoimmunity. J Autoimmun 31:252–256

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • de la Concha EG, Cavanillas ML, Cenit MC, Urcelay E, Arroyo R, Fernandez O, Alvarez-Cermeno JC, Leyva L, Villar LM, Nunez C (2012) DRB1*03:01 haplotypes: differential contribution to multiple sclerosis risk and specific association with the presence of intrathecal IgM bands. PLoS One 7:e31018

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Derecki NC, Cardani AN, Yang CH, Quinnies KM, Crihfield A, Lynch KR, Kipnis J (2010) Regulation of learning and memory by meningeal immunity: a key role for IL-4. J Exp Med 207:1067–1080

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • di Michele F, Luchetti S, Bernardi G, Romeo E, Longone P (2013) Neurosteroid and neurotransmitter alterations in Parkinson’s disease. Front Neuroendocrinol 34:132–142

    Article  PubMed  CAS  Google Scholar 

  • Ehringer H, Hornykiewicz O (1960) Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system. Klin Wochenschr 38:1236–1239

    Article  CAS  PubMed  Google Scholar 

  • Emir UE, Tuite PJ, Oz G (2012) Elevated pontine and putamenal GABA levels in mild-moderate Parkinson disease detected by 7 tesla proton MRS. PLoS One 7:e30918

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Farber K, Pannasch U, Kettenmann H (2005) Dopamine and noradrenaline control distinct functions in rodent microglial cells. Mol Cell Neurosci 29:128–138

    Article  PubMed  CAS  Google Scholar 

  • Fern R, Waxman SG, Ransom BR (1995) Endogenous GABA attenuates CNS white matter dysfunction following anoxia. J Neurosci 15:699–708

    CAS  PubMed  Google Scholar 

  • Fernandez-Suarez D, Celorrio M, Riezu-Boj JI, Ugarte A, Pacheco R, Gonzalez H, Oyarzabal J, Hillard CJ, Franco R, Aymerich MS (2014) The monoacylglycerol lipase inhibitor JZL184 is neuroprotective and alters glial cell phenotype in the chronic MPTP mouse model. Neurobiol Aging 35:2603–2616

    Article  CAS  PubMed  Google Scholar 

  • Fiszer U, Mix E, Fredrikson S, Kostulas V, Olsson T, Link H (1994) gamma delta + T cells are increased in patients with Parkinson’s disease. J Neurol Sci 121:39–45

    Article  CAS  PubMed  Google Scholar 

  • Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4 + CD25+ regulatory T cells. Nat Immunol 4:330–336

    Article  CAS  PubMed  Google Scholar 

  • Frakes AE, Ferraiuolo L, Haidet-Phillips AM, Schmelzer L, Braun L, Miranda CJ, Ladner KJ, Bevan AK, Foust KD, Godbout JP, Popovich PG, Guttridge DC, Kaspar BK (2014) Microglia induce motor neuron death via the classical NF-kappaB pathway in amyotrophic lateral sclerosis. Neuron 81:1009–1023

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS, Shen J, Takio K, Iwatsubo T (2002) alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4:160–164

    Article  CAS  PubMed  Google Scholar 

  • Gauba V, Grunewald J, Gorney V, Deaton LM, Kang M, Bursulaya B, Ou W, Lerner RA, Schmedt C, Geierstanger BH, Schultz PG, Ramirez-Montagut T (2011) Loss of CD4 T-cell-dependent tolerance to proteins with modified amino acids. Proc Natl Acad Sci U S A 108:12821–12826

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Giasson BI, Duda JE, Murray IV, Chen Q, Souza JM, Hurtig HI, Ischiropoulos H, Trojanowski JQ, Lee VM (2000) Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 290:985–989

    Article  CAS  PubMed  Google Scholar 

  • Goeb V, Thomas-L’Otellier M, Daveau R, Charlionet R, Fardellone P, Le Loet X, Tron F, Gilbert D, Vittecoq O (2009) Candidate autoantigens identified by mass spectrometry in early rheumatoid arthritis are chaperones and citrullinated glycolytic enzymes. Arthritis Res Ther 11:R38

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Gonzalez H, Pacheco R (2014) T-cell-mediated regulation of neuroinflammation involved in neurodegenerative diseases. J Neuroinflammation 11:201

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Gonzalez H, Contreras F, Prado C, Elgueta D, Franz D, Bernales S, Pacheco R (2013) Dopamine receptor D3 expressed on CD4+ T cells favors neurodegeneration of dopaminergic neurons during Parkinson’s disease. J Immunol 190:5048–5056

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez H, Elgueta D, Montoya A, Pacheco R (2014) Neuroimmune regulation of microglial activity involved in neuroinflammation and neurodegenerative diseases. J Neuroimmunol 274:1–13

    Article  CAS  PubMed  Google Scholar 

  • Gruden MA, Sewell RD, Yanamandra K, Davidova TV, Kucheryanu VG, Bocharov EV, Bocharova OA, Polyschuk VV, Sherstnev VV, Morozova-Roche LA (2011) Immunoprotection against toxic biomarkers is retained during Parkinson’s disease progression. J Neuroimmunol 233:221–227

    Article  CAS  PubMed  Google Scholar 

  • Guzman JN, Sanchez-Padilla J, Wokosin D, Kondapalli J, Ilijic E, Schumacker PT, Surmeier DJ (2010) Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature 468:696–700

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hagino Y, Kariura Y, Manago Y, Amano T, Wang B, Sekiguchi M, Nishikawa K, Aoki S, Wada K, Noda M (2004) Heterogeneity and potentiation of AMPA type of glutamate receptors in rat cultured microglia. Glia 47:68–77

    Article  PubMed  Google Scholar 

  • Harms AS, Cao S, Rowse AL, Thome AD, Li X, Mangieri LR, Cron RQ, Shacka JJ, Raman C, Standaert DG (2013) MHCII is required for alpha-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration. J Neurosci 33:9592–9600

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hatterer E, Touret M, Belin MF, Honnorat J, Nataf S (2008) Cerebrospinal fluid dendritic cells infiltrate the brain parenchyma and target the cervical lymph nodes under neuroinflammatory conditions. PLoS One 3:e3321

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Hikosaka O (2007) GABAergic output of the basal ganglia. Prog Brain Res 160:209–226

    Article  CAS  PubMed  Google Scholar 

  • Huang ZJ (2006) GABAB receptor isoforms caught in action at the scene. Neuron 50:521–524

    Article  PubMed  Google Scholar 

  • Hutchinson PJ, O’Connell MT, Al-Rawi PG, Kett-White CR, Gupta AK, Maskell LB, Pickard JD, Kirkpatrick PJ (2002) Increases in GABA concentrations during cerebral ischaemia: a microdialysis study of extracellular amino acids. J Neurol Neurosurg Psychiatry 72:99–105

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ilani T, Strous RD, Fuchs S (2004) Dopaminergic regulation of immune cells via D3 dopamine receptor: a pathway mediated by activated T cells. FASEB J 18:1600–1602

    CAS  PubMed  Google Scholar 

  • Kang Z, Altuntas CZ, Gulen MF, Liu C, Giltiay N, Qin H, Liu L, Qian W, Ransohoff RM, Bergmann C, Stohlman S, Tuohy VK, Li X (2010) Astrocyte-restricted ablation of interleukin-17-induced Act1-mediated signaling ameliorates autoimmune encephalomyelitis. Immunity 32:414–425

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Karle AC, Oostingh GJ, Mutschlechner S, Ferreira F, Lackner P, Bohle B, Fischer GF, Vogt AB, Duschl A (2012) Nitration of the pollen allergen bet v 1.0101 enhances the presentation of bet v 1-derived peptides by HLA-DR on human dendritic cells. PLoS One 7:e31483

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kaufman JF, Auffray C, Korman AJ, Shackelford DA, Strominger J (1984) The class II molecules of the human and murine major histocompatibility complex. Cell 36:1–13

    Article  CAS  PubMed  Google Scholar 

  • Kaushal V, Schlichter LC (2008) Mechanisms of microglia-mediated neurotoxicity in a new model of the stroke penumbra. J Neurosci 28:2221–2230

    Article  CAS  PubMed  Google Scholar 

  • Kebir H, Kreymborg K, Ifergan I, Dodelet-Devillers A, Cayrol R, Bernard M, Giuliani F, Arbour N, Becher B, Prat A (2007) Human TH17 lymphocytes promote blood–brain barrier disruption and central nervous system inflammation. Nat Med 13:1173–1175

    Article  CAS  PubMed  Google Scholar 

  • Khan F, Ali R (2006) Antibodies against nitric oxide damaged poly L-tyrosine and 3-nitrotyrosine levels in systemic lupus erythematosus. J Biochem Mol Biol 39:189–196

    Article  CAS  PubMed  Google Scholar 

  • Khan F, Siddiqui AA (2006) Prevalence of anti-3-nitrotyrosine antibodies in the joint synovial fluid of patients with rheumatoid arthritis, osteoarthritis and systemic lupus erythematosus. Clin Chim Acta: Int J Clin Chem 370:100–107

    Article  CAS  Google Scholar 

  • Kim C, Ho DH, Suk JE, You S, Michael S, Kang J, Joong Lee S, Masliah E, Hwang D, Lee HJ, Lee SJ (2013) Neuron-released oligomeric alpha-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat Commun 4:1562

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Kish SJ, Rajput A, Gilbert J, Rozdilsky B, Chang LJ, Shannak K, Hornykiewicz O (1986) Elevated gamma-aminobutyric acid level in striatal but not extrastriatal brain regions in Parkinson’s disease: correlation with striatal dopamine loss. Ann Neurol 20:26–31

    Article  CAS  PubMed  Google Scholar 

  • Klareskog L, Stolt P, Lundberg K, Kallberg H, Bengtsson C, Grunewald J, Ronnelid J, Harris HE, Ulfgren AK, Rantapaa-Dahlqvist S, Eklund A, Padyukov L, Alfredsson L (2006) A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 54:38–46

    Article  CAS  PubMed  Google Scholar 

  • Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker RA, Muller DN, Hafler DA (2013) Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 496:518–522

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kosloski LM, Ha DM, Hutter JA, Stone DK, Pichler MR, Reynolds AD, Gendelman HE, Mosley RL (2010) Adaptive immune regulation of glial homeostasis as an immunization strategy for neurodegenerative diseases. J Neurochem 114:1261–1276

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kuhn SA, van Landeghem FK, Zacharias R, Farber K, Rappert A, Pavlovic S, Hoffmann A, Nolte C, Kettenmann H (2004) Microglia express GABA(B) receptors to modulate interleukin release. Mol Cell Neurosci 25:312–322

    Article  CAS  PubMed  Google Scholar 

  • Kurkowska-Jastrzebska I, Wronska A, Kohutnicka M, Czlonkowski A, Czlonkowska A (1999a) MHC class II positive microglia and lymphocytic infiltration are present in the substantia nigra and striatum in mouse model of Parkinson’s disease. Acta Neurobiol Exp 59:1–8

    CAS  Google Scholar 

  • Kurkowska-Jastrzebska I, Wronska A, Kohutnicka M, Czlonkowski A, Czlonkowska A (1999b) The inflammatory reaction following 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine intoxication in mouse. Exp Neurol 156:50–61

    Article  CAS  PubMed  Google Scholar 

  • Lacan G, Dang H, Middleton B, Horwitz MA, Tian J, Melega WP, Kaufman DL (2013) Bacillus Calmette-Guerin vaccine-mediated neuroprotection is associated with regulatory T-cell induction in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. J Neurosci Res 91:1292–1302

    Article  CAS  PubMed  Google Scholar 

  • Laman JD, Weller RO (2013) Drainage of cells and soluble antigen from the CNS to regional lymph nodes. J Neuroimmune Pharmacol: Off J Soc NeuroImmune Pharmacol 8:840–856

    Article  Google Scholar 

  • Lampe JB, Gossrau G, Herting B, Kempe A, Sommer U, Fussel M, Weber M, Koch R, Reichmann H (2003) HLA typing and Parkinson’s disease. Eur Neurol 50:64–68

    Article  CAS  PubMed  Google Scholar 

  • Langan SM, Groves RW, West J (2011) The relationship between neurological disease and bullous pemphigoid: a population-based case–control study. J Investig Dermatol 131:631–636

    Article  CAS  PubMed  Google Scholar 

  • Laurie C, Reynolds A, Coskun O, Bowman E, Gendelman HE, Mosley RL (2007) CD4+ T cells from Copolymer-1 immunized mice protect dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. J Neuroimmunol 183:60–68

    Article  CAS  PubMed  Google Scholar 

  • Lee M, Schwab C, McGeer PL (2011) Astrocytes are GABAergic cells that modulate microglial activity. Glia 59:152–165

    Article  PubMed  Google Scholar 

  • Letiembre M, Liu Y, Walter S, Hao W, Pfander T, Wrede A, Schulz-Schaeffer W, Fassbender K (2009) Screening of innate immune receptors in neurodegenerative diseases: a similar pattern. Neurobiol Aging 30:759–768

    Article  CAS  PubMed  Google Scholar 

  • Lewitus GM, Schwartz M (2009) Behavioral immunization: immunity to self-antigens contributes to psychological stress resilience. Mol Psychiatry 14:532–536

    Article  CAS  PubMed  Google Scholar 

  • Li X, Sundquist J, Sundquist K (2012) Subsequent risks of Parkinson disease in patients with autoimmune and related disorders: a nationwide epidemiological study from Sweden. Neurodegener Dis 10:277–284

    Article  CAS  PubMed  Google Scholar 

  • Lombardi G, Dianzani C, Miglio G, Canonico PL, Fantozzi R (2001) Characterization of ionotropic glutamate receptors in human lymphocytes. Br J Pharmacol 133:936–944

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Luchetti S, Bossers K, Frajese GV, Swaab DF (2010) Neurosteroid biosynthetic pathway changes in substantia nigra and caudate nucleus in Parkinson’s disease. Brain Pathol 20:945–951

    PubMed  Google Scholar 

  • Manan H, Angham AM, Sitelbanat A (2010) Genetic and diabetic auto-antibody markers in Saudi children with type 1 diabetes. Hum Immunol 71:1238–1242

    Article  CAS  PubMed  Google Scholar 

  • Mangano EN, Litteljohn D, So R, Nelson E, Peters S, Bethune C, Bobyn J, Hayley S (2012) Interferon-gamma plays a role in paraquat-induced neurodegeneration involving oxidative and proinflammatory pathways. Neurobiol Aging 33:1411–1426

    Article  CAS  PubMed  Google Scholar 

  • Mastroeni D, Grover A, Leonard B, Joyce JN, Coleman PD, Kozik B, Bellinger DL, Rogers J (2009) Microglial responses to dopamine in a cell culture model of Parkinson’s disease. Neurobiol Aging 30:1805–1817

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Matsuo K, Xiang Y, Nakamura H, Masuko K, Yudoh K, Noyori K, Nishioka K, Saito T, Kato T (2006) Identification of novel citrullinated autoantigens of synovium in rheumatoid arthritis using a proteomic approach. Arthritis Res Ther 8:R175

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • McCoy MK, Martinez TN, Ruhn KA, Szymkowski DE, Smith CG, Botterman BR, Tansey KE, Tansey MG (2006) Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson’s disease. J Neurosci 26:9365–9375

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • McGeer PL, Itagaki S, Akiyama H, McGeer EG (1988) Rate of cell death in parkinsonism indicates active neuropathological process. Ann Neurol 24:574–576

    Article  CAS  PubMed  Google Scholar 

  • Melcangi RC, Caruso D, Levandis G, Abbiati F, Armentero MT, Blandini F (2012) Modifications of neuroactive steroid levels in an experimental model of nigrostriatal degeneration: potential relevance to the pathophysiology of Parkinson’s disease. J Mol Neurosci : MN 46:177–183

    Article  CAS  PubMed  Google Scholar 

  • Mendu SK, Bhandage A, Jin Z, Birnir B (2012) Different subtypes of GABA-A receptors are expressed in human, mouse and rat T lymphocytes. PLoS One 7:e42959

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, van Wijngaarden P, Wagers AJ, Williams A, Franklin RJ, ffrench-Constant C (2013) M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 16:1211–1218

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mount MP, Lira A, Grimes D, Smith PD, Faucher S, Slack R, Anisman H, Hayley S, Park DS (2007) Involvement of interferon-gamma in microglial-mediated loss of dopaminergic neurons. J Neurosci 27:3328–3337

    Article  CAS  PubMed  Google Scholar 

  • Noda M, Nakanishi H, Nabekura J, Akaike N (2000) AMPA-kainate subtypes of glutamate receptor in rat cerebral microglia. J Neurosci 20:251–258

    CAS  PubMed  Google Scholar 

  • Obeso JA, Marin C, Rodriguez-Oroz C, Blesa J, Benitez-Temino B, Mena-Segovia J, Rodriguez M, Olanow CW (2008) The basal ganglia in Parkinson’s disease: current concepts and unexplained observations. Ann Neurol 64(Suppl 2):S30–S46

    PubMed  Google Scholar 

  • Olsen RW, Sieghart W (2009) GABA A receptors: subtypes provide diversity of function and pharmacology. Neuropharmacology 56:141–148

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Orr CF, Rowe DB, Mizuno Y, Mori H, Halliday GM (2005) A possible role for humoral immunity in the pathogenesis of Parkinson’s disease. Brain: J Neurol 128:2665–2674

    Article  Google Scholar 

  • Pacheco R, Oliva H, Martinez-Navio JM, Climent N, Ciruela F, Gatell JM, Gallart T, Mallol J, Lluis C, Franco R (2006) Glutamate released by dendritic cells as a novel modulator of T cell activation. J Immunol 177:6695–6704

    Article  CAS  PubMed  Google Scholar 

  • Pacheco R, Gallart T, Lluis C, Franco R (2007) Role of glutamate on T-cell mediated immunity. J Neuroimmunol 185:9–19

    Article  CAS  PubMed  Google Scholar 

  • Pacheco R, Riquelme E, Kalergis AM (2010) Emerging evidence for the role of neurotransmitters in the modulation of T cell responses to cognate ligands. Cent Nerv Syst Agents Med Chem 10:65–83

    Article  CAS  PubMed  Google Scholar 

  • Pacheco R, Contreras F, Prado C (2012) Cells, Molecules and Mechanisms Involved in the Neuro-Immune Interaction. In: Gowder S (ed) Cell Interaction. InTech. Europe, Croatia, pp 139–166

    Google Scholar 

  • Papachroni KK, Ninkina N, Papapanagiotou A, Hadjigeorgiou GM, Xiromerisiou G, Papadimitriou A, Kalofoutis A, Buchman VL (2007) Autoantibodies to alpha-synuclein in inherited Parkinson’s disease. J Neurochem 101:749–756

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Parker DC (1993) T cell-dependent B cell activation. Annu Rev Immunol 11:331–360

    Article  CAS  PubMed  Google Scholar 

  • Radjavi A, Smirnov I, Kipnis J (2013) Brain antigen-reactive CD4 T cells are sufficient to support learning behavior in mice with limited T cell repertoire. Brain Behav Immun

  • Rangel-Barajas C, Silva I, Garcia-Ramirez M, Sanchez-Lemus E, Floran L, Aceves J, Erlij D, Floran B (2008) 6-OHDA-induced hemiparkinsonism and chronic L-DOPA treatment increase dopamine D1-stimulated [(3)H]-GABA release and [(3)H]-cAMP production in substantia nigra pars reticulata of the rat. Neuropharmacology 55:704–711

    Article  CAS  PubMed  Google Scholar 

  • Rangel-Barajas C, Silva I, Lopez-Santiago LM, Aceves J, Erlij D, Floran B (2011) L-DOPA-induced dyskinesia in hemiparkinsonian rats is associated with up-regulation of adenylyl cyclase type V/VI and increased GABA release in the substantia nigra reticulata. Neurobiol Dis 41:51–61

    Article  CAS  PubMed  Google Scholar 

  • Reynolds AD, Banerjee R, Liu J, Gendelman HE, Mosley RL (2007) Neuroprotective activities of CD4 + CD25+ regulatory T cells in an animal model of Parkinson’s disease. J Leukoc Biol 82:1083–1094

    Article  CAS  PubMed  Google Scholar 

  • Reynolds AD, Stone DK, Mosley RL, Gendelman HE (2009) Nitrated {alpha}-synuclein-induced alterations in microglial immunity are regulated by CD4+ T cell subsets. J Immunol 182:4137–4149

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Reynolds AD, Stone DK, Hutter JA, Benner EJ, Mosley RL, Gendelman HE (2010) Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson’s disease. J Immunol 184:2261–2271

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ridge JP, Di Rosa F, Matzinger P (1998) A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393:474–478

    Article  CAS  PubMed  Google Scholar 

  • Romero-Ramos M, von Euler CM, Sanchez-Guajardo V (2014) Vaccination strategies for Parkinson disease: induction of a swift attack or raising tolerance? Hum Vaccine immunother 10:852–867

    Article  Google Scholar 

  • Sanchez-Guajardo V, Febbraro F, Kirik D, Romero-Ramos M (2010) Microglia acquire distinct activation profiles depending on the degree of alpha-synuclein neuropathology in a rAAV based model of Parkinson’s disease. PLoS One 5:e8784

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Sanchez-Guajardo V, Annibali A, Jensen PH, Romero-Ramos M (2013) alpha-Synuclein vaccination prevents the accumulation of parkinson disease-like pathologic inclusions in striatum in association with regulatory T cell recruitment in a rat model. J Neuropathol Exp Neurol 72:624–645

    Article  CAS  PubMed  Google Scholar 

  • Schoenberger SP, Toes RE, van der Voort EI, Offringa R, Melief CJ (1998) T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393:480–483

    Article  CAS  PubMed  Google Scholar 

  • Shechter R, Miller O, Yovel G, Rosenzweig N, London A, Ruckh J, Kim KW, Klein E, Kalchenko V, Bendel P, Lira SA, Jung S, Schwartz M (2013) Recruitment of beneficial M2 macrophages to injured spinal cord is orchestrated by remote brain choroid plexus. Immunity 38:555–569

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Shimura H, Schlossmacher MG, Hattori N, Frosch MP, Trockenbacher A, Schneider R, Mizuno Y, Kosik KS, Selkoe DJ (2001) Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson’s disease. Science 293:263–269

    Article  CAS  PubMed  Google Scholar 

  • Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122:787–795

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Soltani N, Qiu H, Aleksic M, Glinka Y, Zhao F, Liu R, Li Y, Zhang N, Chakrabarti R, Ng T, Jin T, Zhang H, Lu WY, Feng ZP, Prud’homme GJ, Wang Q (2011) GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes. Proc Natl Acad Sci U S A 108:11692–11697

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840

    Article  CAS  PubMed  Google Scholar 

  • Sriram K, Matheson JM, Benkovic SA, Miller DB, Luster MI, O’Callaghan JP (2002) Mice deficient in TNF receptors are protected against dopaminergic neurotoxicity: implications for Parkinson’s disease. FASEB J 16:1474–1476

    CAS  PubMed  Google Scholar 

  • Sun C, Wei L, Luo F, Li Y, Li J, Zhu F, Kang P, Xu R, Xiao L, Liu Z, Xu P (2012) HLA-DRB1 alleles are associated with the susceptibility to sporadic Parkinson’s disease in Chinese Han population. PLoS One 7:e48594

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Takeuchi H, Mizuno T, Zhang G, Wang J, Kawanokuchi J, Kuno R, Suzumura A (2005) Neuritic beading induced by activated microglia is an early feature of neuronal dysfunction toward neuronal death by inhibition of mitochondrial respiration and axonal transport. J Biol Chem 280:10444–10454

    Article  CAS  PubMed  Google Scholar 

  • Takeuchi H, Jin S, Wang J, Zhang G, Kawanokuchi J, Kuno R, Sonobe Y, Mizuno T, Suzumura A (2006) Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J Biol Chem 281:21362–21368

    Article  CAS  PubMed  Google Scholar 

  • Tepper JM, Abercrombie ED, Bolam JP (2007) Basal ganglia macrocircuits. Prog Brain Res 160:3–7

    Article  CAS  PubMed  Google Scholar 

  • Tieu K, Ischiropoulos H, Przedborski S (2003) Nitric oxide and reactive oxygen species in Parkinson’s disease. IUBMB Life 55:329–335

    Article  CAS  PubMed  Google Scholar 

  • Walker RH, Spiera H, Brin MF, Olanow CW (1999) Parkinsonism associated with Sjogren’s syndrome: three cases and a review of the literature. Mov Disord : Off J Mov Disord Soc 14:262–268

    Article  CAS  Google Scholar 

  • Watabe-Uchida M, Zhu L, Ogawa SK, Vamanrao A, Uchida N (2012) Whole-brain mapping of direct inputs to midbrain dopamine neurons. Neuron 74:858–873

    Article  CAS  PubMed  Google Scholar 

  • Wing K, Yamaguchi T, Sakaguchi S (2011) Cell-autonomous and -non-autonomous roles of CTLA-4 in immune regulation. Trends Immunol 32:428–433

    Article  CAS  PubMed  Google Scholar 

  • Winner B, Jappelli R, Maji SK, Desplats PA, Boyer L, Aigner S, Hetzer C, Loher T, Vilar M, Campioni S, Tzitzilonis C, Soragni A, Jessberger S, Mira H, Consiglio A, Pham E, Masliah E, Gage FH, Riek R (2011) In vivo demonstration that alpha-synuclein oligomers are toxic. Proc Natl Acad Sci U S A 108:4194–4199

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yirmiya R, Goshen I (2011) Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 25:181–213

    Article  CAS  PubMed  Google Scholar 

  • Yoshida Y, Yoshimi R, Yoshii H, Kim D, Dey A, Xiong H, Munasinghe J, Yazawa I, O’Donovan MJ, Maximova OA, Sharma S, Zhu J, Wang H, Morse HC 3rd, Ozato K (2014) The transcription factor IRF8 activates integrin-mediated TGF-beta signaling and promotes neuroinflammation. Immunity 40:187–198

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, Maeda J, Suhara T, Trojanowski JQ, Lee VM (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53:337–351

    Article  CAS  PubMed  Google Scholar 

  • Yu Z, Xu X, Xiang Z, Zhou J, Zhang Z, Hu C, He C (2010) Nitrated alpha-synuclein induces the loss of dopaminergic neurons in the substantia nigra of rats. PLoS One 5:e9956

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N, Cohen H, Kipnis J, Schwartz M (2006) Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci 9:268–275

    Article  CAS  PubMed  Google Scholar 

  • Zou JY, Crews FT (2005) TNF alpha potentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures: neuroprotection by NF kappa B inhibition. Brain Res 1034:11–24

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  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

Authors
  1. Hugo González
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francisco Contreras
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rodrigo Pacheco
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rodrigo Pacheco.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-015-9618-9

Keywords

Search

Navigation