Home Immune system and new avenues in Parkinson’s disease research and treatment
Article
Licensed
Unlicensed Requires Authentication

Immune system and new avenues in Parkinson’s disease research and treatment

  • Ava Nasrolahi , Fatemeh Safari , Mehdi Farhoudi , Afra Khosravi , Fereshteh Farajdokht , Saiyad Bastaminejad , Siamak Sandoghchian Shotorbani and Javad Mahmoudi EMAIL logo
Published/Copyright: February 23, 2019
Become an author with De Gruyter Brill

Abstract

Parkinson’s disease (PD) is a progressive neurological disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. However, although 200 years have now passed since the primary clinical description of PD by James Parkinson, the etiology and mechanisms of neuronal loss in this disease are still not fully understood. In addition to genetic and environmental factors, activation of immunologic responses seems to have a crucial role in PD pathology. Intraneuronal accumulation of α-synuclein (α-Syn), as the main pathological hallmark of PD, potentially mediates initiation of the autoimmune and inflammatory events through, possibly, auto-reactive T cells. While current therapeutic regimens are mainly used to symptomatically suppress PD signs, application of the disease-modifying therapies including immunomodulatory strategies may slow down the progressive neurodegeneration process of PD. The aim of this review is to summarize knowledge regarding previous studies on the relationships between autoimmune reactions and PD pathology as well as to discuss current opportunities for immunomodulatory therapy.

References

Abou-Sleiman, P.M., Healy, D.G., Quinn, N., Lees, A.J., and Wood, N.W. (2003). The role of pathogenic DJ-1 mutations in Parkinson’s disease. Ann. Neurol. 54, 283–286.10.1002/ana.10675Search in Google Scholar PubMed

Abramsky, O. and Litvin, Y. (1978). Autoimmune response to dopamine-receptor as a possible mechanism in the pathogenesis of Parkinson’s disease and schizophrenia. Perspect. Biol. Med. 22, 104–110.Search in Google Scholar

Agarwal, S., Yadav, A., and Chaturvedi, R.K. (2017). Peroxisome proliferator-activated receptors (PPARs) as therapeutic target in neurodegenerative disorders. Biochem. Biophys. Res. Commun. 483, 1166–1177.10.1016/j.bbrc.2016.08.043Search in Google Scholar PubMed

Ahmed, I., Tamouza, R., Delord, M., Krishnamoorthy, R., Tzourio, C., Mulot, C., Nacfer, M., Lambert, J.C., Beaune, P., and Laurent-Puig, P. (2012). Association between Parkinson’s disease and the HLA-DRB1 locus. Mov. Disord. 27, 1104–1110.10.1002/mds.25035Search in Google Scholar PubMed

Akundi, R.S., Huang, Z., Eason, J., Pandya, J.D., Zhi, L., Cass, W.A., Sullivan, P.G., and Büeler, H. (2011). Increased mitochondrial calcium sensitivity and abnormal expression of innate immunity genes precede dopaminergic defects in Pink1-deficient mice. PLoS One 6, e16038.10.1371/journal.pone.0016038Search in Google Scholar PubMed PubMed Central

Amor, S., Puentes, F., Baker, D., and Van Der Valk, P. (2010). Inflammation in neurodegenerative diseases. Immunology 129, 154–169.10.1111/j.1365-2567.2009.03225.xSearch in Google Scholar PubMed PubMed Central

Antony, P., Diederich, N.J., Krüger, R., and Balling, R. (2013). The hallmarks of Parkinson’s disease. FEBS J. 280, 5981–5993.10.1111/febs.12335Search in Google Scholar PubMed

Bandopadhyay, R., Kingsbury, A.E., Cookson, M.R., Reid, A.R., Evans, I.M., Hope, A.D., Pittman, A.M., Lashley, T., Canet-Aviles, R., and Miller, D.W. (2004). The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson’s disease. Brain 127, 420–430.10.1093/brain/awh054Search in Google Scholar PubMed

Barker, R. and Cahn, A. (1988). Parkinson’s disease: an autoimmune process. Int. J. Neurosci. 43, 1–7.10.3109/00207458808985773Search in Google Scholar PubMed

Barkhuizen, M., Anderson, D.G., and Grobler, A.F. (2016). Advances in GBA-associated Parkinson’s disease – pathology, presentation and therapies. Neurochem. Int. 93, 6–25.10.1016/j.neuint.2015.12.004Search in Google Scholar PubMed

Barrett, P.J. and Greenamyre, J.T. (2015). Post-translational modification of α-synuclein in Parkinson’s disease. Brain Res. 1628, 247–253.10.1016/j.brainres.2015.06.002Search in Google Scholar PubMed

Barrett, J.C., Hansoul, S., Nicolae, D.L., Cho, J.H., Duerr, R.H., Rioux, J.D., Brant, S.R., Silverberg, M.S., Taylor, K.D., and Barmada, M.M. (2008). Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat. Genet. 40, 955–962.10.1038/ng.175Search in Google Scholar PubMed PubMed Central

Bartels, A., Willemsen, A., Doorduin, J., De Vries, E., Dierckx, R., and Leenders, K. (2010). [11 C]-PK11195 PET: quantification of neuroinflammation and a monitor of anti-inflammatory treatment in Parkinson’s disease. Parkinsonism Relat. Disord. 16, 57–59.10.1016/j.parkreldis.2009.05.005Search in Google Scholar PubMed

Batelli, S., Albani, D., Rametta, R., Polito, L., Prato, F., Pesaresi, M., Negro, A., and Forloni, G. (2008). DJ-1 modulates α-synuclein aggregation state in a cellular model of oxidative stress: relevance for Parkinson’s disease and involvement of HSP70. PLoS One 3, e1884.10.1371/journal.pone.0001884Search in Google Scholar PubMed PubMed Central

Beck, S., Geraghty, D., Inoko, H., and Rowen, L. (1999). Complete sequence and gene map of a human major histocompatibility complex. Nature 401, 921–923.10.1038/44853Search in Google Scholar PubMed

Benner, E.J., Banerjee, R., Reynolds, A.D., Sherman, S., Pisarev, V.M., Tsiperson, V., Nemachek, C., Ciborowski, P., Przedborski, S., and Mosley, R.L. (2008). Nitrated α-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One 3, e1376.10.1371/journal.pone.0001376Search in Google Scholar PubMed PubMed Central

Besong-Agbo, D., Wolf, E., Jessen, F., Oechsner, M., Hametner, E., Poewe, W., Reindl, M., Oertel, W.H., Noelker, C., and Bacher, M. (2013). Naturally occurring α-synuclein autoantibody levels are lower in patients with Parkinson disease. Neurology 80, 169–175.10.1212/WNL.0b013e31827b90d1Search in Google Scholar PubMed

Block, M. and Hong, J.-S. (2007). Chronic microglial activation and progressive dopaminergic neurotoxicity. Biochem. Soc. Trans. 35, 1127–1132.10.1042/BST0351127Search in Google Scholar PubMed

Bourgault, S., Vaudry, D., Dejda, A., Doan, N.D., Vaudry, H., and Fournier, A. (2009). Pituitary adenylate cyclase-activating polypeptide: focus on structure-activity relationships of a neuroprotective peptide. Curr. Med. Chem. 16, 4462–4480.10.2174/092986709789712899Search in Google Scholar PubMed

Brochard, V., Combadière, B., Prigent, A., Laouar, Y., Perrin, A., Beray-Berthat, V., Bonduelle, O., Alvarez-Fischer, D., Callebert, J., and Launay, J.-M. (2008). Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J. Clin. Invest. 119, 182–192.10.1172/JCI36470Search in Google Scholar PubMed PubMed Central

Brudek, T., Winge, K., Folke, J., Christensen, S., Fog, K., Pakkenberg, B., and Pedersen, L.Ø. (2017). Autoimmune antibody decline in Parkinson’s disease and multiple system atrophy; a step towards immunotherapeutic strategies. Mol. Neurodegener. 12, 44.10.1186/s13024-017-0187-7Search in Google Scholar PubMed PubMed Central

Brundin, P., Dave, K.D., and Kordower, J.H. (2017). Therapeutic approaches to target alpha-synuclein pathology. Exp. Neurol. 298, 225–235.10.1016/j.expneurol.2017.10.003Search in Google Scholar

Bryan, T., Luo, X., Forsgren, L., Morozova-Roche, L.A., and Davis, J.J. (2012). The robust electrochemical detection of a Parkinson’s disease marker in whole blood sera. Chem. Sci. 3, 3468–3473.10.1039/c2sc21221hSearch in Google Scholar

Caggiu, E., Paulus, K., Galleri, G., Arru, G., Manetti, R., Sechi, G., and Sechi, L. (2017). Homologous HSV1 and alpha-synuclein peptides stimulate a T cell response in Parkinson’s disease. J. Neuroimmunol. 310, 26–31.10.1016/j.jneuroim.2017.06.004Search in Google Scholar

Cai, G., Kastelein, R.A., and Hunter, C.A. (1999). IL-10 enhances NK cell proliferation, cytotoxicity and production of IFN-γ when combined with IL-18. Eur. J. Immunol. 29, 2658–2665.10.1002/(SICI)1521-4141(199909)29:09<2658::AID-IMMU2658>3.0.CO;2-GSearch in Google Scholar

Carta, A., Frau, L., Pisanu, A., Wardas, J., Spiga, S., and Carboni, E. (2011). Rosiglitazone decreases peroxisome proliferator receptor-γ levels in microglia and inhibits TNF-alpha production: new evidences on neuroprotection in a progressive Parkinson’s disease model. Neuroscience 194, 250–261.10.1016/j.neuroscience.2011.07.046Search in Google Scholar

Castano, A., Herrera, A., Cano, J., and Machado, A. (2002). The degenerative effect of a single intranigral injection of LPS on the dopaminergic system is prevented by dexamethasone, and not mimicked by rh-TNF-α, IL-1β and IFN-γ. J. Neurochem. 81, 150–157.10.1046/j.1471-4159.2002.00799.xSearch in Google Scholar

Castelijns, B. (2014). The role of genome-wide association studies in understanding sporadic Parkinson’s disease susceptibility. Master’s thesis.Search in Google Scholar

Cebrián, C., Zucca, F.A., Mauri, P., Steinbeck, J.A., Studer, L., Scherzer, C.R., Kanter, E., Budhu, S., Mandelbaum, J., and Vonsattel, J.P. (2014). MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration. Nat. Commun. 5, 3633.10.1038/ncomms4633Search in Google Scholar

Chandra, G., Roy, A., Rangasamy, S.B., and Pahan, K. (2017). Induction of adaptive immunity leads to nigrostriatal disease progression in MPTP mouse model of Parkinson’s disease. J. Immunol. 2017, 1700149.10.4049/jimmunol.1700149Search in Google Scholar

Chen, H., Zhang, S.M., Hernán, M.A., Schwarzschild, M.A., Willett, W.C., Colditz, G.A., Speizer, F.E., and Ascherio, A. (2003). Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease. Arch. Neurol. 60, 1059–1064.10.1001/archneur.60.8.1059Search in Google Scholar

Chen, L., Cagniard, B., Mathews, T., Jones, S., Koh, H.C., Ding, Y., Carvey, P.M., Ling, Z., Kang, U.J., and Zhuang, X. (2005). Age-dependent motor deficits and dopaminergic dysfunction in DJ-1 null mice. J. Biol. Chem. 280, 21418–21426.10.1074/jbc.M413955200Search in Google Scholar

Chen, Z., Yang, Y., Yang, X., Zhou, C., Li, F., Lei, P., Zhong, L., Jin, X., and Peng, G. (2013). Immune effects of optimized DNA vaccine and protective effects in a MPTP model of Parkinson’s disease. Neurol. Sci. 34, 1559–1570.10.1007/s10072-012-1284-6Search in Google Scholar

Chen, Z., Chen, S., and Liu, J. (2018). The role of T cells in the pathogenesis of Parkinson’s disease. Prog. Neurobiol. 169, 1–23.10.1016/j.pneurobio.2018.08.002Search in Google Scholar

Christine, C.W. (2015). NINDS Exploratory Trials in Parkinson Disease (NET-PD) FS-ZONE Investigators. Pioglitazone in early Parkinson’s disease: a phase 2, multicentre, double-blind, randomised trial. Lancet Neurol. 14, 979–979.10.1016/S1474-4422(15)00144-1Search in Google Scholar

Cicchetti, F., Brownell, A., Williams, K., Chen, Y., Livni, E., and Isacson, O. (2002). Neuroinflammation of the nigrostriatal pathway during progressive 6-OHDA dopamine degeneration in rats monitored by immunohistochemistry and PET imaging. Eur. J. Neurosci. 15, 991–998.10.1046/j.1460-9568.2002.01938.xSearch in Google Scholar

Clements, C.M., McNally, R.S., Conti, B.J., Mak, T.W., and Ting, J.P.Y. (2006). DJ-1, a cancer- and Parkinson’s disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc. Natl. Acad. Sci. USA 103, 15091–15096.10.1073/pnas.0607260103Search in Google Scholar

Codolo, G., Plotegher, N., Pozzobon, T., Brucale, M., Tessari, I., Bubacco, L., and de Bernard, M. (2013). Triggering of inflammasome by aggregated α-synuclein, an inflammatory response in synucleinopathies. PLoS One 8, e55375.10.1371/journal.pone.0055375Search in Google Scholar

Colton, C. and Gilbert, D. (1993). Microglia, an in vivo source of reactive oxygen species in the brain. Adv. Neurol. 59, 321–326.Search in Google Scholar

Coutinho, A., Kazatchkine, M.D., and Avrameas, S. (1995). Natural autoantibodies. Curr. Opin. Immunol. 7, 812–818.10.1016/0952-7915(95)80053-0Search in Google Scholar

Dauer, W. and Przedborski, S. (2003). Parkinson’s disease: mechanisms and models. Neuron 39, 889–909.10.1016/S0896-6273(03)00568-3Search in Google Scholar

De Lella Ezcurra, A.L., Chertoff, M., Ferrari, C., Graciarena, M., and Pitossi, F. (2010). Chronic expression of low levels of tumor necrosis factor-α in the substantia nigra elicits progressive neurodegeneration, delayed motor symptoms and microglia/macrophage activation. Neurobiol. Dis. 37, 630–640.10.1016/j.nbd.2009.11.018Search in Google Scholar PubMed

De Virgilio, A., Greco, A., Fabbrini, G., Inghilleri, M., Rizzo, M.I., Gallo, A., Conte, M., Rosato, C., Appiani, M.C., and de Vincentiis, M. (2016). Parkinson’s disease: autoimmunity and neuroinflammation. Autoimmun. Rev. 15, 1005–1011.10.1016/j.autrev.2016.07.022Search in Google Scholar PubMed

Dehmer, T., Heneka, M.T., Sastre, M., Dichgans, J., and Schulz, J.B. (2004). Protection by pioglitazone in the MPTP model of Parkinson’s disease correlates with IκBα induction and block of NFκB and iNOS activation. J. Neurochem. 88, 494–501.10.1046/j.1471-4159.2003.02210.xSearch in Google Scholar PubMed

Deleidi, M. and Gasser, T. (2013). The role of inflammation in sporadic and familial Parkinson’s disease. Cell. Mol. Life. Sci. 70, 4259–4273.10.1007/s00018-013-1352-ySearch in Google Scholar PubMed

Delgado, M. and Ganea, D. (2013). Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions. Amino Acids 45, 25–39.10.1007/s00726-011-1184-8Search in Google Scholar PubMed PubMed Central

Delgado, M., Chorny, A., Gonzalez-Rey, E., and Ganea, D. (2005). Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo. J. Leukoc. Biol. 78, 1327–1338.10.1189/jlb.0605299Search in Google Scholar PubMed

Dentesano, G., Serratosa, J., Tusell, J.M., Ramón, P., Valente, T., Saura, J., and Solà, C. (2014). CD200R1 and CD200 expression are regulated by PPAR-γ in activated glial cells. Glia 62, 982–998.10.1002/glia.22656Search in Google Scholar PubMed

Dogrukol-Ak, D., Tore, F., and Tuncel, N. (2004). Passage of VIP/PACAP/secretin family across theblood-brain barrier: therapeutic effects. Curr. Pharm. Des. 10, 1325–1340.10.2174/1381612043384934Search in Google Scholar PubMed

Dong, J., Li, S., Mo, J.L., Cai, H.B., and Le, W.D. (2016). Nurr1-based therapies for Parkinson’s disease. CNS Neurosci. Ther. 22, 351–359.10.1111/cns.12536Search in Google Scholar PubMed PubMed Central

Double, K.L., Rowe, D.B., Carew-Jones, F.M., Hayes, M., Chan, D.K.Y., Blackie, J., Corbett, A., Joffe, R., Fung, V., and Morris, J. (2009). Anti-melanin antibodies are increased in sera in Parkinson’s disease. Exp. Neurol. 217, 297–301.10.1016/j.expneurol.2009.03.002Search in Google Scholar PubMed

Duffy, S.S., Keating, B.A., Perera, C.J., and Moalem-Taylor, G. (2018). The role of regulatory T cells in nervous system pathologies. J. Neurosci. Res. 96, 951–968.10.1002/jnr.24073Search in Google Scholar PubMed

Edison, P., Ahmed, I., Fan, Z., Hinz, R., Gelosa, G., Chaudhuri, K.R., Walker, Z., Turkheimer, F.E., and Brooks, D.J. (2013). Microglia, amyloid, and glucose metabolism in Parkinson’s disease with and without dementia. Neuropsychopharmacology 38, 938–949.10.1038/npp.2012.255Search in Google Scholar PubMed PubMed Central

Fan, X., Luo, G., Ming, M., Pu, P., Li, L., Yang, D., and Le, W. (2009). Nurr1 expression and its modulation in microglia. Neuroimmunomodulation 16, 162–170.10.1159/000204229Search in Google Scholar PubMed

Farmer, K., Rudyk, C., Prowse, N.A., and Hayley, S. (2015). Hematopoietic cytokines as therapeutic players in early stages Parkinson’s disease. Front Aging Neurosci. 7, 126.10.3389/fnagi.2015.00126Search in Google Scholar PubMed PubMed Central

Ferger, B., Leng, A., Mura, A., Hengerer, B., and Feldon, J. (2004). Genetic ablation of tumor necrosis factor-alpha (TNF-α) and pharmacological inhibition of TNF-synthesis attenuates MPTP toxicity in mouse striatum. J. Neurochem. 89, 822–833.10.1111/j.1471-4159.2004.02399.xSearch in Google Scholar PubMed

Fernandez-Martin, A., Gonzalez-Rey, E., Chorny, A., Ganea, D., and Delgado, M. (2006). Vasoactive intestinal peptide induces regulatory T cells during experimental autoimmune encephalomyelitis. Eur. J. Immunol. 36, 318–326.10.1002/eji.200535430Search in Google Scholar PubMed

Frank-Cannon, T.C., Tran, T., Ruhn, K.A., Martinez, T.N., Hong, J., Marvin, M., Hartley, M., Treviño, I., O’Brien, D.E., and Casey, B. (2008). Parkin deficiency increases vulnerability to inflammation-related nigral degeneration. J. Neurosci. 28, 10825–10834.10.1523/JNEUROSCI.3001-08.2008Search in Google Scholar PubMed PubMed Central

Gangi, E., Vasu, C., Cheatem, D., and Prabhakar, B.S. (2005). IL-10-producing CD4+CD25+ regulatory T cells play a critical role in granulocyte-macrophage colony-stimulating factor-induced suppression of experimental autoimmune thyroiditis. J. Immunol. 174, 7006–7013.10.4049/jimmunol.174.11.7006Search in Google Scholar PubMed

Gelders, G., Baekelandt, V., and Van der Perren, A. (2018). Linking neuroinflammation and neurodegeneration in Parkinson’s disease. J. Immunol. Res. 2018, 1–12.10.1155/2018/4784268Search in Google Scholar PubMed PubMed Central

Gendelman, H.E., Zhang, Y., Santamaria, P., Olson, K.E., Schutt, C.R., Bhatti, D., Laxmi, B., Shetty, D., Lu, Y., and Estes, K.A. (2017). Evaluation of the safety and immunomodulatory effects of sargramostim in a randomized, double-blind phase 1 clinical Parkinson’s disease trial. NPJ Parkinsons Dis. 3, 1.10.1038/s41531-017-0013-5Search in Google Scholar PubMed PubMed Central

George, S. and Brundin, P. (2015). Immunotherapy in Parkinson’s disease: micromanaging α-synuclein aggregation. J. Parkinsons Dis. 5, 413–424.10.3233/JPD-150630Search in Google Scholar PubMed PubMed Central

Gerhard, A., Pavese, N., Hotton, G., Turkheimer, F., Es, M., Hammers, A., Eggert, K., Oertel, W., Banati, R.B., and Brooks, D.J. (2006). In vivo imaging of microglial activation with [11 C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol Dis. 21, 404–412.10.1016/j.nbd.2005.08.002Search in Google Scholar PubMed

Gold, M., Pul, R., Bach, J.P., Stangel, M., and Dodel, R. (2012). Pathogenic and physiological autoantibodies in the central nervous system. Immunol. Rev. 248, 68–86.10.1111/j.1600-065X.2012.01128.xSearch in Google Scholar PubMed

Gruden, M.A., Yanamandra, K., Kucheryanu, V.G., Bocharova, O.R., Sherstnev, V.V., Morozova-Roche, L.A., and Sewell, R.D. (2012). Correlation between protective immunity to α-synuclein aggregates, oxidative stress and inflammation. Neuroimmunomodulation 19, 334–342.10.1159/000341400Search in Google Scholar PubMed

Guan, L., Ji, Y., Yu, G., Ren, C., Liu, J., Ba, M., Lian, P., and Li, N. (2018). Protective effects of PACAP against lactacystin-induced PC12 cell apoptosis due to prevention of mitochondrial damage and endoplasmic reticulum stress. Biomed. Res. 29, 658–662.10.4066/biomedicalresearch.29-17-3094Search in Google Scholar

Guareschi, S., Cova, E., Cereda, C., Ceroni, M., Donetti, E., Bosco, D.A., Trotti, D., and Pasinelli, P. (2012). An over-oxidized form of superoxide dismutase found in sporadic amyotrophic lateral sclerosis with bulbar onset shares a toxic mechanism with mutant SOD1. Proc. Natl. Acad. Sci. USA 109, 5074–5079.10.1073/pnas.1115402109Search in Google Scholar PubMed PubMed Central

Haddadi, R., Nayebi, A.M., and Brooshghalan, S.E. (2013). Pre-treatment with silymarin reduces brain myeloperoxidase activity and inflammatory cytokines in 6-OHDA hemi-parkinsonian rats. Neurosci. Lett. 555, 106–111.10.1016/j.neulet.2013.09.022Search in Google Scholar PubMed

Hamza, T.H., Zabetian, C.P., Tenesa, A., Laederach, A., Montimurro, J., Yearout, D., Kay, D.M., Doheny, K.F., Paschall, J., and Pugh, E. (2010). Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat. Genet. 42, 781–785.10.1038/ng.642Search in Google Scholar PubMed PubMed Central

Han, S.C., Koo, D.H., Kang, N.J., Yoon, W.J., Kang, G.J., Kang, H.K., and Yoo, E.S. (2015). Docosahexaenoic acid alleviates atopic dermatitis by generating Tregs and IL-10/TGF-β-modified macrophages via a TGF-β-dependent mechanism. J. Invest. Dermatol. 135, 1556–1564.10.1038/jid.2014.488Search in Google Scholar PubMed

Harms, A.S., Barnum, C.J., Ruhn, K.A., Varghese, S., Treviño, I., Blesch, A., and Tansey, M.G. (2011). Delayed dominant-negative TNF gene therapy halts progressive loss of nigral dopaminergic neurons in a rat model of Parkinson’s disease. Mol. Ther. 19, 46–52.10.1038/mt.2010.217Search in Google Scholar PubMed PubMed Central

Harms, A.S., Cao, S., Rowse, A.L., Thome, A.D., Li, X., Mangieri, L.R., Cron, R.Q., Shacka, J.J., Raman, C., and Standaert, D.G. (2013). MHCII is required for α-synuclein-induced activationof microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration. J. Neurosci. 33, 9592–9600.10.1523/JNEUROSCI.5610-12.2013Search in Google Scholar PubMed PubMed Central

Heinzel, S., Gold, M., Deuschle, C., Bernhard, F., Maetzler, W., Berg, D., and Dodel, R. (2014). Naturally occurring α-synuclein autoantibodiesin Parkinson’s disease: sources of (error) variance in biomarker assays. PLoS One 9, e114566.10.1371/journal.pone.0114566Search in Google Scholar PubMed PubMed Central

Hill-Burns, E.M., Factor, S.A., Zabetian, C.P., Thomson, G., and Payami, H. (2011). Evidence for more than one Parkinson’s disease-associated variant within the HLA region. PLoS One 6, e27109.10.1371/journal.pone.0027109Search in Google Scholar PubMed PubMed Central

Hirsch, E.C. and Hunot, S. (2009). Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol. 8, 382–397.10.1016/S1474-4422(09)70062-6Search in Google Scholar

Holmans, P., Moskvina, V., Jones, L., Sharma, M., Consortium, I.P.s.D.G., Vedernikov, A., Buchel, F., Sadd, M., Bras, J.M., and Bettella, F. (2012). A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson’s disease. Hum. Mol. Genet. 22, 1039–1049.10.1093/hmg/dds492Search in Google Scholar PubMed PubMed Central

Hooper, K.M., Kong, W., and Ganea, D. (2016). Immunomodulation by vasoactive intestinal polypeptide (VIP). In: Neuro-Immuno-Gastroenterology (Springer), pp. 75–96.10.1007/978-3-319-28609-9_5Search in Google Scholar

Horvath, I., Iashchishyn, I.A., Forsgren, L., and Morozova-Roche, L.A. (2017). Immunochemical detection of α-synucleinautoantibodies in Parkinson’s disease: correlation between plasma and cerebrospinal fluid levels. ACS Chem. Neurosci. 8, 1170–1176.10.1021/acschemneuro.7b00063Search in Google Scholar PubMed

Jankovic, J. (2018). Immunologic treatment of Parkinson’s disease. Immunotherapy 10, 81–84.10.2217/imt-2017-0146Search in Google Scholar PubMed

Kadkhodaei, B., Ito, T., Joodmardi, E., Mattsson, B., Rouillard, C., Carta, M., Muramatsu, S.-I., Sumi-Ichinose, C., Nomura, T., and Metzger, D. (2009). Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons. J. Neurosci. 29, 15923–15932.10.1523/JNEUROSCI.3910-09.2009Search in Google Scholar PubMed PubMed Central

Kelso, M.L., Elliott, B.R., Haverland, N.A., Mosley, R.L., and Gendelman, H.E. (2015). Granulocyte-macrophage colony stimulating factor exerts protective and immunomodulatory effects in cortical trauma. J. Neuroimmunol. 278, 162–173.10.1016/j.jneuroim.2014.11.002Search in Google Scholar PubMed PubMed Central

Kim, W.-G., Mohney, R.P., Wilson, B., Jeohn, G.-H., Liu, B., and Hong, J.-S. (2000). Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: role of microglia. J. Neurosci. 20, 6309–6316.10.1523/JNEUROSCI.20-16-06309.2000Search in Google Scholar

Kim, J., Byun, J.-W., Choi, I., Kim, B., Jeong, H.-K., Jou, I., and Joe, E. (2013). PINK1 deficiency enhances inflammatory cytokine release from acutely prepared brain slices. Exp. Neurobiol. 22, 38–44.10.5607/en.2013.22.1.38Search in Google Scholar PubMed PubMed Central

Kivisäkk, P., Mahad, D.J., Callahan, M.K., Trebst, C., Tucky, B., Wei, T., Wu, L., Baekkevold, E.S., Lassmann, H., and Staugaitis, S.M. (2003). Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc. Natl. Acad. Sci. USA 100, 8389–8394.10.1073/pnas.1433000100Search in Google Scholar PubMed PubMed Central

Klein, C. and Westenberger, A. (2012). Genetics of Parkinson’s disease. Cold Spring Harb. Perspect Med. 2, a008888.10.1101/cshperspect.a008888Search in Google Scholar PubMed PubMed Central

Koike, H., Ishida, A., Shimamura, M., Mizuno, S., Nakamura, T., Ogihara, T., Kaneda, Y., and Morishita, R. (2006). Prevention of onset of Parkinson’s disease by in vivo gene transfer of human hepatocyte growth factor in rodent model: a model of gene therapy for Parkinson’s disease. Gene Ther. 13, 1639–1644.10.1038/sj.gt.3302810Search in Google Scholar PubMed

Korn, T. and Kallies, A. (2017). T cell responses in the central nervous system. Nat. Rev. Immunol. 17, 179–194.10.1038/nri.2016.144Search in Google Scholar PubMed

Kosloski, L.M., Kosmacek, E.A., Olson, K.E., Mosley, R.L., and Gendelman, H.E. (2013). GM-CSF induces neuroprotective and anti-inflammatory responses in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxicated mice. J. Neuroimmunol. 265, 1–10.10.1016/j.jneuroim.2013.10.009Search in Google Scholar PubMed PubMed Central

Kraft, A.D. and Harry, G.J. (2011). Features of microglia and neuroinflammation relevant to environmental exposure and neurotoxicity. Int. J. Environ. Res. Public Health 8, 2980–3018.10.3390/ijerph8072980Search in Google Scholar PubMed PubMed Central

Kurkowska-Jastrzebska, I., Wrońska, A., Kohutnicka, M., Członkowski, A., and Członkowska, A. (1999). 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, 1–8.10.55782/ane-1999-1289Search in Google Scholar

Lamine-Ajili, A., Fahmy, A.M., Letourneau, M., Chatenet, D., Labonte, P., Vaudry, D., and Fournier, A. (2016). Effect of the pituitary adenylate cyclase-activating polypeptide on the autophagic activation observed in in vitro and in vivo models of Parkinson’s disease. Biochim. Biophys. Acta 1862, 688–695.10.1016/j.bbadis.2016.01.005Search in Google Scholar PubMed

Leal, M.C., Casabona, J.C., Puntel, M., and Pitossi, F.J. (2013). Interleukin-1β and tumor necrosis factor-α: reliable targets for protective therapies in Parkinson’s disease? Front Cell Neurosci. 7, 53.10.3389/fncel.2013.00053Search in Google Scholar PubMed PubMed Central

Lingor, P., Carboni, E., and Koch, J.C. (2017). Alpha-synuclein and iron: two keys unlocking Parkinson’s disease. J. Neural Transm. (Vienna) 124, 973–981.10.1007/s00702-017-1695-xSearch in Google Scholar PubMed

Lipski, D.A., Dewispelaere, R., Foucart, V., Caspers, L.E., Defrance, M., Bruyns, C., and Willermain, F. (2017). MHC class II expression and potential antigen-presenting cells in the retina during experimental autoimmune uveitis. J. Neuroinflamm. 14, 136.10.1186/s12974-017-0915-5Search in Google Scholar PubMed PubMed Central

Liu, J., Halene, S., Yang, M., Iqbal, J., Yang, R., Mehal, W.Z., Chuang, W.-L., Jain, D., Yuen, T., and Sun, L. (2012). Gaucher disease gene GBA functions in immune regulation. Proc. Natl. Acad. Sci. USA 109, 10018–10023.10.1073/pnas.1200941109Search in Google Scholar PubMed PubMed Central

Liu, Y., Holdbrooks, A.T., De Sarno, P., Rowse, A.L., Yanagisawa, L.L., McFarland, B.C., Harrington, L.E., Raman, C., Sabbaj, S., and Benveniste, E.N. (2014). Therapeutic efficacy of suppressing the Jak/STAT pathway in multiple models of experimental autoimmune encephalomyelitis. J. Immunol. 192, 59–72.10.4049/jimmunol.1301513Search in Google Scholar PubMed PubMed Central

Liu, Z., Huang, Y., Cao, B.B., Qiu, Y.H., and Peng, Y.P. (2017). Th17 cells induce dopaminergic neuronal death viaLFA-1/ICAM-1 interaction in a mouse model of Parkinson’s disease. Mol. Neurobiol. 54, 7762–7776.10.1007/s12035-016-0249-9Search in Google Scholar PubMed

Maasz, G., Zrinyi, Z., Reglodi, D., Petrovics, D., Rivnyak, A., Kiss, T., Jungling, A., Tamas, A., and Pirger, Z. (2017). Pituitary adenylate cyclase-activating polypeptide (PACAP) has a neuroprotective function in dopamine-based neurodegeneration in rat and snail parkinsonian models. Dis. Model Mech. 10, 127–139.10.1242/dmm.027185Search in Google Scholar

Maetzler, W., Berg, D., Synofzik, M., Brockmann, K., Godau, J., Melms, A., Gasser, T., Hörnig, S., and Langkamp, M. (2011). Autoantibodies against amyloid and glial-derived antigens are increased in serum and cerebrospinal fluid of Lewy body-associated dementias. J. Alzheimers Dis. 26, 171–179.10.3233/JAD-2011-110221Search in Google Scholar PubMed

Mahmoudi, J., Nayebi, A.M., Reyhani-Rad, S., and Samini, M. (2012). Fluoxetine improves the effect of levodopa on 6-hydroxy dopamine-induced motor impairments in rats. Adv. Pharm. Bull. 2, 149–155.Search in Google Scholar

Mahmoudi, J., Farhoudi, M., Reyhani-Rad, S., and Sadigh-Eteghad, S. (2013). Dampening of serotonergic system through 5HT1A receptors is a promising target for treatment of Levodopa-induced motor problems. Adv. Pharm. Bull. 3, 439–441.Search in Google Scholar

Mahmoudi, J., Mohaddes, G., Erfani, M., Sadigh-Eteghad, S., Karimi, P., Rajabi, M., Reyhani-Rad, S., and Farajdokht, F. (2018). Cerebrolysin attenuates hyperalgesia, photophobia, and neuroinflammation in a nitroglycerin-induced migraine model in rats. Brain Res. Bull. 140, 197–204.10.1016/j.brainresbull.2018.05.008Search in Google Scholar PubMed

Mandler, M., Valera, E., Rockenstein, E., Weninger, H., Patrick, C., Adame, A., Santic, R., Meindl, S., Vigl, B., Smrzka, O., et al. (2014). Next-generation active immunization approach for synucleinopathies: implications for Parkinson’s disease clinical trials. Acta Neuropathol. 127, 861–879.10.1007/s00401-014-1256-4Search in Google Scholar PubMed PubMed Central

Mandler, M., Valera, E., Rockenstein, E., Mante, M., Weninger, H., Patrick, C., Adame, A., Schmidhuber, S., Santic, R., Schneeberger, A., et al. (2015). Active immunization against alpha-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy. Mol. Neurodegener. 10, 10.10.1186/s13024-015-0008-9Search in Google Scholar PubMed PubMed Central

Masliah, E., Rockenstein, E., Adame, A., Alford, M., Crews, L., Hashimoto, M., Seubert, P., Lee, M., Goldstein, J., Chilcote, T., et al. (2005). Effects of alpha-synuclein immunization in a mouse model of Parkinson’s disease. Neuron 46, 857–868.10.1016/j.neuron.2005.05.010Search in Google Scholar PubMed

Matheoud, D., Sugiura, A., Bellemare-Pelletier, A., Laplante, A., Rondeau, C., Chemali, M., Fazel, A., Bergeron, J.J., Trudeau, L.E., Burelle, Y., et al. (2016). Parkinson’s disease-related proteins PINK1 and Parkin repress mitochondrial antigen presentation. Cell 166, 314–327.10.1016/j.cell.2016.05.039Search in Google Scholar PubMed

Matsuo, Y. and Kamitani, T. (2010). Parkinson’s disease-related protein, α-synuclein, in malignant melanoma. PLoS One 5, e10481.10.1371/journal.pone.0010481Search in Google Scholar PubMed PubMed Central

McCoy, M.K., Ruhn, K.A., Martinez, T.N., McAlpine, F.E., Blesch, A., and Tansey, M.G. (2008). Intranigral lentiviral delivery of dominant-negative TNF attenuates neurodegeneration and behavioral deficits inhemiparkinsonian rats. Mol Ther. 16, 1572–1579.10.1038/mt.2008.146Search in Google Scholar PubMed PubMed Central

McGeer, P., Itagaki, S., Boyes, B., and McGeer, E. (1988). Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38, 1285–1285.10.1212/WNL.38.8.1285Search in Google Scholar PubMed

McLelland, G.L., Soubannier, V., Chen, C.X., McBride, H.M., and Fon, E.A. (2014). Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control. EMBO J. 33, 282–295.10.1002/embj.201385902Search in Google Scholar PubMed PubMed Central

Meissner, W.G., Frasier, M., Gasser, T., Goetz, C.G., Lozano, A., Piccini, P., Obeso, J.A., Rascol, O., Schapira, A., Voon, V., et al. (2011). Priorities in Parkinson’s disease research. Nat. Rev. Drug Discov. 10, 377–393.10.1038/nrd3430Search in Google Scholar PubMed

Mira, M.T., Alcais, A., Van Thuc, N., Moraes, M.O., Di Flumeri, C., Thai, V.H., Phuong, M.C., Huong, N.T., Ba, N.N., and Khoa, P.X. (2004). Susceptibility to leprosy is associated with PARK2 and PACRG. Nature 427, 636–640.10.1038/nature02326Search in Google Scholar PubMed

Moehle, M.S. and West, A.B. (2015). M1 and M2 immune activation in Parkinson’s disease: foe and ally? Neuroscience 302, 59–73.10.1016/j.neuroscience.2014.11.018Search in Google Scholar PubMed PubMed Central

Moehle, M.S., Webber, P.J., Tse, T., Sukar, N., Standaert, D.G., DeSilva, T.M., Cowell, R.M., and West, A.B. (2012). LRRK2 inhibition attenuates microglial inflammatory responses. J. Neurosci. 32, 1602–1611.10.1523/JNEUROSCI.5601-11.2012Search in Google Scholar PubMed PubMed Central

Morell, M., Souza-Moreira, L., and González-Rey, E. (2012). VIP in neurological diseases: more than a neuropeptide. Endocr. Metab. Immune Disord. Drug Targets 12, 323–332.10.2174/187153012803832549Search in Google Scholar PubMed

Mosser, D.M. and Zhang, X. (2008). Interleukin-10: new perspectives on an old cytokine. Immunol. Rev. 226, 205–218.10.1111/j.1600-065X.2008.00706.xSearch in Google Scholar PubMed PubMed Central

Nasrolahi, A., Mahmoudi, J., Akbarzadeh, A., Karimipour, M., Sadigh-Eteghad, S., Salehi, R., and Farhoudi, M. (2018). Neurotrophic factors hold promise for the future of Parkinson’s disease treatment: is there a light at the end of the tunnel? Rev. Neurosci. 29, 475–490.10.1515/revneuro-2017-0040Search in Google Scholar PubMed

Oberländer, U., Pletinckx, K., Döhler, A., Müller, N., Lutz, M.B., Arzberger, T., Riederer, P., Gerlach, M., Koutsilieri, E., and Scheller, C. (2011). Neuromelanin is an immune stimulator for dendritic cells in vitro. BMC Neurosci. 12, 116.10.1186/1471-2202-12-116Search in Google Scholar PubMed PubMed Central

Ojeda, V., Fuentealba, J.A., Galleguillos, D., and Andrés, M.E. (2003). Rapid increase of Nurr1 expression in the substantia nigra after 6-hydroxydopamine lesion in the striatum of the rat. J. Neurosci. Res. 73, 686–697.10.1002/jnr.10705Search in Google Scholar

Olson, K.E., Kosloski-Bilek, L.M., Anderson, K.M., Diggs, B.J., Clark, B.E., Gledhill, J.M., Jr., Shandler, S.J., Mosley, R.L., and Gendelman, H.E. (2015). Selective VIP receptor agonists facilitate immune transformation for dopaminergic neuroprotection in MPTP-intoxicated mice. J. Neurosci. 35, 16463–16478.10.1523/JNEUROSCI.2131-15.2015Search in Google Scholar

Onoue, S., Ohshima, K., Endo, K., Yajima, T., and Kashimoto, K. (2002). PACAP protects neuronal PC12 cells from the cytotoxicity of human prion protein fragment 106–126. FEBS Lett. 522, 65–70.10.1016/S0014-5793(02)02886-7Search in Google Scholar

Orihuela, R., McPherson, C.A., and Harry, G.J. (2016). Microglial M1/M2 polarization and metabolic states. Br. J. Pharmacol. 173, 649–665.10.1111/bph.13139Search in Google Scholar PubMed PubMed Central

Ouchi, Y., Yoshikawa, E., Sekine, Y., Futatsubashi, M., Kanno, T., Ogusu, T., and Torizuka, T. (2005). Microglial activation and dopamine terminal loss in early Parkinson’s disease. Ann. Neurol. 57, 168–175.10.1002/ana.20338Search in Google Scholar PubMed

Papachroni, K.K., Ninkina, N., Papapanagiotou, A., Hadjigeorgiou, G.M., Xiromerisiou, G., Papadimitriou, A., Kalofoutis, A., and Buchman, V.L. (2007). Autoantibodies to α-synuclein in inherited Parkinson’s disease. J. Neurochem. 101, 749–756.10.1111/j.1471-4159.2006.04365.xSearch in Google Scholar PubMed PubMed Central

Parkhurst, C.N., Yang, G., Ninan, I., Savas, J.N., Yates, J.R., Lafaille, J.J., Hempstead, B.L., Littman, D.R., and Gan, W.-B. (2013). Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596–1609.10.1016/j.cell.2013.11.030Search in Google Scholar PubMed PubMed Central

Perez, A., Guan, L., Sutherland, K., and Cao, C. (2016). Immune system and Parkinson’s disease. Arch. Med. Jan. 8, 2.Search in Google Scholar

Pickrell, A.M. and Youle, R.J. (2015). The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson’s disease. Neuron 85, 257–273.10.1016/j.neuron.2014.12.007Search in Google Scholar PubMed PubMed Central

Pierce, S. and Coetzee, G.A. (2017). Parkinson’s disease-associated genetic variation is linked to quantitative expression of inflammatory genes. PLoS One 12, e0175882.10.1371/journal.pone.0175882Search in Google Scholar PubMed PubMed Central

Pisanu, A., Lecca, D., Mulas, G., Wardas, J., Simbula, G., Spiga, S., and Carta, A.R. (2014). Dynamic changes in pro-and anti-inflammatory cytokines in microglia after PPAR-γ agonist neuroprotective treatment in the MPTPp mouse model of progressive Parkinson’s disease. Neurobiol. Dis. 71, 280–291.10.1016/j.nbd.2014.08.011Search in Google Scholar PubMed

Price, D.A., Martinez, A.A., Seillier, A., Koek, W., Acosta, Y., Fernandez, E., Strong, R., Lutz, B., Marsicano, G., and Roberts, J.L. (2009). WIN55, 212-2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine mouse model of Parkinson’s disease. Eur. J. Neurosci. 29, 2177–2186.10.1111/j.1460-9568.2009.06764.xSearch in Google Scholar PubMed PubMed Central

Qian, L., Wei, S.-J., Zhang, D., Hu, X., Xu, Z., Wilson, B., El-Benna, J., Hong, J.-S., and Flood, P.M. (2008). Potent anti-inflammatory and neuroprotective effects of TGF-β1 are mediated through the inhibition of ERK and p47phox-Ser345 phosphorylation and translocation in microglia. J. Immunol. 181, 660–668.10.4049/jimmunol.181.1.660Search in Google Scholar PubMed PubMed Central

Ran, C., Willows, T., Sydow, O., Johansson, A., Söderkvist, P., Dizdar, N., Ahmadi, A., Olson, L., and Belin, C. (2013). The HLA-DRA variation rs3129882 is not associated with Parkinsons disease in Sweden. Parkinsonism Relat. Disord. 19, 701–702.10.1016/j.parkreldis.2013.03.001Search in Google Scholar PubMed

Reglodi, D., Kiss, P., Szabadfi, K., Atlasz, T., Gabriel, R., Horvath, G., Szakaly, P., Sandor, B., Lubics, A., Laszlo, E., et al. (2012). PACAP is an endogenous protective factor-insights from PACAP-deficient mice. J. Mol. Neurosci. 48, 482–492.10.1007/s12031-012-9762-0Search in Google Scholar PubMed

Reglodi, D., Renaud, J., Tamas, A., Tizabi, Y., Socias, S.B., Del-Bel, E., and Raisman-Vozari, R. (2017). Novel tactics for neuroprotection in Parkinson’s disease: role of antibiotics, polyphenols and neuropeptides. Prog. Neurobiol. 155, 120–148.10.1016/j.pneurobio.2015.10.004Search in Google Scholar PubMed

Reubi, J.C., Laderach, U., Waser, B., Gebbers, J.O., Robberecht, P., and Laissue, J.A. (2000). Vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide receptor subtypes in human tumors and their tissues of origin. Cancer Res. 60, 3105–3112.Search in Google Scholar

Reyhani-Rad, S. and Mahmoudi, J. (2016). Effect of adenosine A2A receptor antagonists onmotor disorders induced by 6-hydroxydopamine in rat. Acta Cirurgica Brasi. 31, 133–137.10.1590/S0102-865020160020000008Search in Google Scholar PubMed

Reynolds, A.D., Stone, D.K., Mosley, R.L., and Gendelman, H.E. (2009). Nitrated α-synuclein-induced alterations in microglial immunity are regulated by CD4+ Tcell subsets. J. Immunol. 182, 4137–4149.10.4049/jimmunol.0803982Search in Google Scholar PubMed PubMed Central

Rocha, N.P., Assis, F., Scalzo, P.L., Vieira, É.L.M., Barbosa, I.G., de Souza, M.S., Christo, P.P., Reis, H.J., and Teixeira, A.L. (2018). Reduced activated T lymphocytes (CD4+ CD25+) and plasma levels of cytokines in Parkinson’s disease. Mol. Neurobiol. 55, 1488–1497.10.1007/s12035-017-0404-ySearch in Google Scholar PubMed

Rousselet, E., Callebert, J., Parain, K., Joubert, C., Hunot, S., Hartmann, A., Jacque, C., Perez-Diaz, F., Cohen-Salmon, C., and Launay, J.-M. (2002). Role of TNF-α receptors in mice intoxicated with the parkinsonian toxin MPTP. Exp. Neurol. 177, 183–192.10.1006/exnr.2002.7960Search in Google Scholar PubMed

Safari, F., Farajnia, S., Arya, M., Zarredar, H., and Nasrolahi, A. (2018). CRISPR and personalized Treg therapy: new insights into the treatment of rheumatoid arthritis. Immunopharmacol. Immunotoxicol. 40, 201–211.10.1080/08923973.2018.1437625Search in Google Scholar PubMed

Said, S.I. (1976). Evidence for secretion of vasoactive intestinal peptide by tumours of pancreas, adrenal medulla, thyroid and lung: support for the unifying APUD concept. Clin. Endocrinol. (Oxford) 5 (Suppl.), 201s–204s.10.1111/j.1365-2265.1976.tb03828.xSearch in Google Scholar

Saijo, K., Winner, B., Carson, C.T., Collier, J.G., Boyer, L., Rosenfeld, M.G., Gage, F.H., and Glass, C.K. (2009). A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137, 47–59.10.1016/j.cell.2009.01.038Search in Google Scholar

Saura, J., Parés, M., Bové, J., Pezzi, S., Alberch, J., Marin, C., Tolosa, E., and Martí, M.J. (2003). Intranigral infusion of interleukin-1β activates astrocytes and protects from subsequent 6-hydroxydopamine neurotoxicity. J. Neurochem. 85, 651–661.10.1046/j.1471-4159.2003.01676.xSearch in Google Scholar

Schneeberger, A., Mandler, M., Mattner, F., and Schmidt, W. (2012). Vaccination for Parkinson’s disease. Parkinsonism Relat. Disord. 18 (Suppl. 1), S11–S13.10.1016/S1353-8020(11)70006-2Search in Google Scholar

Schutt, C., Gendelman, H.E., and Mosley, R.L. (2017). Immunotherapies for movement disorders: Parkinson’s disease and amyotrophic lateral sclerosis. In: Neuroimmune Pharmacology (Springer), pp. 767–797.10.1007/978-3-319-44022-4_46Search in Google Scholar

Sewal, R.K., Modi, M., Saikia, U.N., Chakrabarti, A., and Medhi, B. (2017). Increase in seizure susceptibility in sepsis like condition explained by spikingcytokines and altered adhesion molecules level with impaired blood brain barrier integrity in experimental model of rats treated with lipopolysaccharides. Epilepsy Res. 135, 176–186.10.1016/j.eplepsyres.2017.05.012Search in Google Scholar

Shavali, S., Combs, C.K., and Ebadi, M. (2006). Reactive macrophages increase oxidative stress and alpha-synuclein nitration during death of dopaminergic neuronal cells in co-culture: relevance to Parkinson’s disease. Neurochem. Res. 31, 85–94.10.1007/s11064-005-9233-xSearch in Google Scholar

Shioda, S., Ohtaki, H., Nakamachi, T., Dohi, K., Watanabe, J., Nakajo, S., Arata, S., Kitamura, S., Okuda, H., Takenoya, F. et al. (2006). Pleiotropic functions of PACAP in the CNS: neuroprotection and neurodevelopment. Ann. NY Acad. Sci. 1070, 550–560.10.1196/annals.1317.080Search in Google Scholar

Shivers, K.Y., Nikolopoulou, A., Machlovi, S.I., Vallabhajosula, S., and Figueiredo-Pereira, M.E. (2014). PACAP27 prevents Parkinson-like neuronal loss and motor deficits but not microglia activation induced by prostaglandin J2. Biochim. Biophys. Acta 1842, 1707–1719.10.1016/j.bbadis.2014.06.020Search in Google Scholar

Sidransky, E. and Lopez, G. (2012). The link between the GBA gene and parkinsonism. Lancet Neurol. 11, 986–998.10.1016/S1474-4422(12)70190-4Search in Google Scholar

Siloşi, I., Siloşi, C.A., Boldeanu, M.V., Cojocaru, M., Biciuşcă, V., Avrămescu, C.S., Cojocaru, I.M., Bogdan, M., and FolcuŢi, R.M. (2016). The role of autoantibodies in health and disease. Rom. J. Morphol. Embryol. 57, 633–638.10.1155/2016/3109135Search in Google Scholar

Smith, L.M., Schiess, M.C., Coffey, M.P., Klaver, A.C., and Loeffler, D.A. (2012). α-Synuclein and anti-α-synuclein antibodies in Parkinson’s disease, atypical Parkinson syndromes, REM sleep behavior disorder, and healthy controls. PLoS One 7, e52285.10.1371/journal.pone.0052285Search in Google Scholar

Sriram, K., Matheson, J.M., Benkovic, S.A., Miller, D.B., Luster, M.I., and O’Callaghan, J.P. (2002). Mice deficient in TNF receptors are protected against dopaminergic neurotoxicity: implications for Parkinson’s disease. FASEB J. 16, 1474–1476.10.1096/fj.02-0216fjeSearch in Google Scholar

Stranger, B.E., Nica, A.C., Forrest, M.S., Dimas, A., Bird, C.P., Beazley, C., Ingle, C.E., Dunning, M., Flicek, P., and Koller, D. (2007). Population genomics of human gene expression. Nat. Genet. 39, 1217.10.1038/ng2142Search in Google Scholar

Su, X., Maguire-Zeiss, K.A., Giuliano, R., Prifti, L., Venkatesh, K., and Federoff, H.J. (2008). Synuclein activates microglia in a model of Parkinson’s disease. Neurobiol. Aging 29, 1690–1701.10.1016/j.neurobiolaging.2007.04.006Search in Google Scholar

Sulzer, D., Alcalay, R.N., Garretti, F., Cote, L., Kanter, E., Agin-Liebes, J., Liong, C., McMurtrey, C., Hildebrand, W.H., and Mao, X. (2017). T cells from patients with Parkinson’s disease recognize α-synuclein peptides. Nature 546, 22815.10.1038/nature22815Search in Google Scholar

Sveinbjornsdottir, S. (2016). The clinical symptoms of Parkinson’s disease. J. Neurochem. 139, 318–324.10.1111/jnc.13691Search in Google Scholar

Svenningsson, A., Andersen, O., Edsbagge, M., and Stemme, S. (1995). Lymphocyte phenotype and subset distribution in normal cerebrospinal fluid. J. Neuroimmunol. 63, 39–46.10.1016/0165-5728(95)00126-3Search in Google Scholar

Szabadfi, K., Szabo, A., Kiss, P., Reglodi, D., Setalo, G., Jr., Kovacs, K., Tamas, A., Toth, G., and Gabriel, R. (2014). PACAP promotes neuron survival in early experimental diabetic retinopathy. Neurochem. Int. 64, 84–91.10.1016/j.neuint.2013.11.005Search in Google Scholar PubMed

Tay, T.L., Savage, J.C., Hui, C.W., Bisht, K., and Tremblay, M.È. (2017). Microglia across the lifespan: from origin to function in brain development, plasticity and cognition. J. Physiol. 595, 1929–1945.10.1113/JP272134Search in Google Scholar PubMed PubMed Central

Teismann, P., Tieu, K., Choi, D.-K., Wu, D.-C., Naini, A., Hunot, S., Vila, M., Jackson-Lewis, V., and Przedborski, S. (2003). Cyclooxygenase-2 is instrumental in Parkinson’s disease neurodegeneration. Proc. Natl. Acad. Sci. USA 100, 5473–5478.10.1073/pnas.0837397100Search in Google Scholar PubMed PubMed Central

Theodore, S., Cao, S., McLean, P.J., and Standaert, D.G. (2008). Targeted overexpression of human α-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease. Neuropathol. Exp. Neurol. 67, 1149–1158.10.1097/NEN.0b013e31818e5e99Search in Google Scholar PubMed PubMed Central

Thorsby, E. and Lie, B.A. (2005). HLA associated genetic predisposition to autoimmune diseases: genes involved and possible mechanisms. Transpl. Immunol. 14, 175–182.10.1016/j.trim.2005.03.021Search in Google Scholar PubMed

Tran, H.T., Chung, C.H.-Y., Iba, M., Zhang, B., Trojanowski, J.Q., Luk, K.C., and Lee, V.M. (2014). α-Synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration. Cell Rep. 7, 2054–2065.10.1016/j.celrep.2014.05.033Search in Google Scholar PubMed PubMed Central

Trudler, D., Weinreb, O., Mandel, S.A., Youdim, M.B., and Frenkel, D. (2014). DJ-1 deficiency triggers microglia sensitivity to dopamine toward a pro-inflammatory phenotype that is attenuated by rasagiline. J. Neurochem. 129, 434–447.10.1111/jnc.12633Search in Google Scholar PubMed

Tzartos, J.S., Craner, M.J., Friese, M.A., Jakobsen, K.B., Newcombe, J., Esiri, M.M., and Fugger, L. (2011). IL-21 and IL-21 receptor expression in lymphocytes and neurons in multiple sclerosis brain. Am. J. Pathol. 178, 794–802.10.1016/j.ajpath.2010.10.043Search in Google Scholar PubMed PubMed Central

Valera, E. and Masliah, E. (2013). Immunotherapy for neurodegenerative diseases: focus on alpha-synucleinopathies. Pharmacol. Ther. 138, 311–322.10.1016/j.pharmthera.2013.01.013Search in Google Scholar PubMed PubMed Central

Van der Perren, A., Macchi, F., Toelen, J., Carlon, M.S., Maris, M., de Loor, H., Kuypers, D.R., Gijsbers, R., Van den Haute, C., and Debyser, Z. (2015). FK506 reduces neuroinflammation and dopaminergic neurodegeneration in an α-synuclein-based rat model for Parkinson’s disease. Neurobiol. Aging 36, 1559–1568.10.1016/j.neurobiolaging.2015.01.014Search in Google Scholar PubMed

Vaudry, D., Falluel-Morel, A., Bourgault, S., Basille, M., Burel, D., Wurtz, O., Fournier, A., Chow, B.K., Hashimoto, H., Galas, L. et al. (2009). Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacol. Rev. 61, 283–357.10.1124/pr.109.001370Search in Google Scholar PubMed

Vivekanantham, S., Shah, S., Dewji, R., Dewji, A., Khatri, C., and Ologunde, R. (2015). Neuroinflammation in Parkinson’s disease: role in neurodegeneration and tissue repair. Int. J. Neurosci. 125, 717–725.10.3109/00207454.2014.982795Search in Google Scholar PubMed

Vogel, D.Y., Vereyken, E.J., Glim, J.E., Heijnen, P.D., Moeton, M., van der Valk, P., Amor, S., Teunissen, C.E., van Horssen, J., and Dijkstra, C.D. (2013). Macrophages in inflammatory multiple sclerosis lesions have an intermediate activation status. J. Neuroinflamm. 10, 35.10.1186/1742-2094-10-35Search in Google Scholar PubMed PubMed Central

von Euler Chelpin, M. and Vorup-Jensen, T. (2017). Targets and mechanisms in prevention of Parkinson’s disease through immunomodulatory treatments. Scand. J. Immunol. 85, 321–330.10.1111/sji.12542Search in Google Scholar PubMed

Waak, J., Weber, S.S., Waldenmaier, A., Görner, K., Alunni-Fabbroni, M., Schell, H., Vogt-Weisenhorn, D., Pham, T.-T., Reumers, V., and Baekelandt, V. (2009). Regulation of astrocyte inflammatory responses by the Parkinson’s disease-associated gene DJ-1. FASEB J. 23, 2478–2489.10.1096/fj.08-125153Search in Google Scholar PubMed

Wakade, C., Giri, B., Malik, A., Khodadadi, H., Morgan, J.C., Chong, R.K., and Baban, B. (2018). Niacin modulates macrophage polarization in Parkinson’s disease. J. Neuroimmunol. 320, 76–79.10.1016/j.jneuroim.2018.05.002Search in Google Scholar PubMed

Wang, J., Bankiewicz, K.S., Plunkett, R.J., and Oldfield, E.H. (1994). Intrastriatal implantation of interleukin-1: reduction of parkinsonism in rats by enhancing neuronal sprouting from residual dopaminergic neurons in the ventral tegmental area of the midbrain. J. Neurosurg. 80, 484–490.10.3171/jns.1994.80.3.0484Search in Google Scholar PubMed

Wang, Q., Liu, Y., and Zhou, J. (2015a). Neuroinflammation in Parkinson’s disease and its potential as therapeutic target. Transl. Neurodegener. 4, 19.10.1186/s40035-015-0042-0Search in Google Scholar PubMed PubMed Central

Wang, S., Chu, C.-H., Stewart, T., Ginghina, C., Wang, Y., Nie, H., Guo, M., Wilson, B., Hong, J.-S., and Zhang, J. (2015b). α-Synuclein, a chemoattractant, directs microglial migration via H2O2-dependent Lyn phosphorylation. Proc. Natl. Acad. Sci. USA 112, E1926–E1935.10.1073/pnas.1417883112Search in Google Scholar PubMed PubMed Central

Watson, M.B., Richter, F., Lee, S.K., Gabby, L., Wu, J., Masliah, E., Effros, R.B., and Chesselet, M.-F. (2012). Regionally-specific microglial activation in young mice over-expressing human wildtype alpha-synuclein. Exp. Neurol. 237, 318–334.10.1016/j.expneurol.2012.06.025Search in Google Scholar PubMed PubMed Central

Wissemann, W.T., Hill-Burns, E.M., Zabetian, C.P., Factor, S.A., Patsopoulos, N., Hoglund, B., Holcomb, C., Donahue, R.J., Thomson, G., and Erlich, H. (2013). Association of Parkinson disease with structural and regulatory variants in the HLA region. Am. J. Hum. Genet. 93, 984–993.10.1016/j.ajhg.2013.10.009Search in Google Scholar PubMed PubMed Central

Witoelar, A., Jansen, I.E., Wang, Y., Desikan, R.S., Gibbs, J.R., Blauwendraat, C., Thompson, W.K., Hernandez, D.G., Djurovic, S., and Schork, A.J. (2017). Genome-wide pleiotropy between Parkinson disease and autoimmune diseases. JAMA Neurol. 74, 780–792.10.1001/jamaneurol.2017.0469Search in Google Scholar PubMed PubMed Central

Witte, M.E., Geurts, J.J., de Vries, H.E., van der Valk, P., and van Horssen, J. (2010). Mitochondrial dysfunction: a potential link between neuroinflammation and neurodegeneration? Mitochondrion 10, 411–418.10.1016/j.mito.2010.05.014Search in Google Scholar PubMed

Woulfe, J., Duke, R., Middeldorp, J., Stevens, S., Vervoort, M., Hashimoto, M., Masliah, E., Chan, P., Di Monte, D., and Langston, J. (2002). Absence of elevated anti-α-synuclein and anti-EBV latent membrane protein antibodies in PD. Neurology 58, 1435–1435.10.1212/WNL.58.9.1435Search in Google Scholar PubMed

Xu, S. and Chan, P. (2015). Interaction between neuromelanin and alpha-synuclein in Parkinson’s disease. Biomolecules 5, 1122–1142.10.3390/biom5021122Search in Google Scholar PubMed PubMed Central

Xu, J., Zhong, N., Wang, H., Elias, J.E., Kim, C.Y., Woldman, I., Pifl, C., Gygi, S.P., Geula, C., and Yankner, B.A. (2005). The Parkinson’s disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis. Hum. Mol. Gen. 14, 1231–1241.10.1093/hmg/ddi134Search in Google Scholar PubMed

Xu, Q., Evetts, S., Hu, M., Talbot, K., Wade-Martins, R., and Davis, J.J. (2014). An impedimetric assay of α-synuclein autoantibodies in early stage Parkinson’s disease. RSC Adv. 4, 58773–58777.10.1039/C4RA10100FSearch in Google Scholar

Xuan, Q., Xu, S.-L., Lu, D.-H., Yu, S., Zhou, M., Uéda, K., Cui, Y.-Q., Zhang, B.-Y., and Chan, P. (2011). Increase expression of α-synuclein in aged human brain associated with neuromelanin accumulation. J. Neural. Transm. 118, 1575–1583.10.1007/s00702-011-0636-3Search in Google Scholar PubMed

Yanamandra, K., Gruden, M.A., Casaite, V., Meskys, R., Forsgren, L., and Morozova-Roche, L.A. (2011). α-Synuclein reactive antibodies as diagnostic biomarkers in blood sera of Parkinson’s disease patients. PLoS One 6, e18513.10.1371/journal.pone.0018513Search in Google Scholar PubMed PubMed Central

Yang, F., Li, B., Li, L., and Zhang, H. (2016). The clinical significance of the imbalance of Th17 and Treg cells and their related cytokines in peripheral blood of Parkinson’s disease patients. Int. J. Clin. Exp. Med. 9, 17946–17951.Search in Google Scholar

Yurek, D.M., Flectcher, A.M., Kowalczyk, T.H., Padegimas, L., and Cooper, M.J. (2009). Compacted DNA nanoparticle gene transfer of GDNF to the rat striatum enhances the survival of grafted fetal dopamine neurons. Cell Transplant. 18, 1183–1196.10.3727/096368909X12483162196881Search in Google Scholar PubMed PubMed Central

Zappia, M., Crescibene, L., Bosco, D., Arabia, G., Nicoletti, G., Bagala, A., Bastone, L., Napoli, I., Caracciolo, M., and Bonavita, S. (2002). Anti-GM1 ganglioside antibodies in Parkinson’s disease. Acta Neurol. Scand. 106, 54–57.10.1034/j.1600-0404.2002.01240.xSearch in Google Scholar PubMed

Zecca, L., Wilms, H., Geick, S., Claasen, J.-H., Brandenburg, L.-O., Holzknecht, C., Panizza, M.L., Zucca, F.A., Deuschl, G., and Sievers, J. (2008). Human neuromelanin induces neuroinflammation and neurodegeneration in the rat substantia nigra: implications for Parkinson’s disease. Acta Neuropathol. 116, 47–55.10.1007/s00401-008-0361-7Search in Google Scholar PubMed

Zhang, W., Wang, T., Pei, Z., Miller, D.S., Wu, X., Block, M.L., Wilson, B., Zhang, W., Zhou, Y., and Hong, J.-S. (2005). Aggregated α-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J. 19, 533–542.10.1096/fj.04-2751comSearch in Google Scholar PubMed

Zhang, W., Phillips, K., Wielgus, A.R., Liu, J., Albertini, A., Zucca, F.A., Faust, R., Qian, S.Y., Miller, D.S., and Chignell, C.F. (2011). Neuromelanin activates microglia and induces degeneration of dopaminergic neurons: implications for progression of Parkinson’s disease. Neurotox. Res. 19, 63–72.10.1007/s12640-009-9140-zSearch in Google Scholar PubMed PubMed Central

Zhang, W., Yan, Z.-F., Gao, J.-H., Sun, L., Huang, X.-Y., Liu, Z., Yu, S.-Y., Cao, C.-J., Zuo, L.-J., and Chen, Z.-J. (2014). Role and mechanism of microglial activation in iron-induced selective and progressive dopaminergic neurodegeneration. Mol. Neurobiol. 49, 1153–1165.10.1007/s12035-013-8586-4Search in Google Scholar PubMed PubMed Central

Zhu, R., Lu, X., Tang, L., Huang, B., Yu, W., Li, S., and Li, L. (2015). Association between HLA rs3129882 polymorphism and Parkinson’s disease: a meta-analysis. Eur. Rev. Med. Pharmacol. Sci. 19, 423–432.Search in Google Scholar

Zucca, F.A., Basso, E., Cupaioli, F.A., Ferrari, E., Sulzer, D., Casella, L., and Zecca, L. (2014). Neuromelanin of the human substantia nigra: an update. Neurotox Res. 25, 13–23.10.1007/s12640-013-9435-ySearch in Google Scholar PubMed

Received: 2018-10-22
Accepted: 2018-12-28
Published Online: 2019-02-23
Published in Print: 2019-10-25

©2019 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 28.10.2025 from https://www.degruyterbrill.com/document/doi/10.1515/revneuro-2018-0105/html
Scroll to top button