Autoimmunity in Parkinson's Disease: The Role of α-Synuclein-Specific T Cells

Francesca Garretti, Dritan Agalliu, Cecilia S Lindestam Arlehamn, Alessandro Sette, David Sulzer, Francesca Garretti, Dritan Agalliu, Cecilia S Lindestam Arlehamn, Alessandro Sette, David Sulzer

Abstract

Evidence from a variety of studies implicates a role for the adaptive immune system in Parkinson's disease (PD). Similar to multiple sclerosis (MS) patients who display a high number of T cells in the brain attacking oligodendrocytes, PD patients show higher numbers of T cells in the ventral midbrain than healthy, age-matched controls. Mouse models of the disease also show the presence of T cells in the brain. The role of these infiltrating T cells in the propagation of disease is controversial; however, recent studies indicate that they may be autoreactive in nature, recognizing disease-altered self-proteins as foreign antigens. T cells of PD patients can generate an autoimmune response to α-synuclein, a protein that is aggregated in PD. α-Synuclein and other proteins are post-translationally modified in an environment in which protein processing is altered, possibly leading to the generation of neo-epitopes, or self-peptides that have not been identified by the host immune system as non-foreign. Infiltrating T cells may also be responding to such modified proteins. Genome-wide association studies (GWAS) have shown associations of PD with haplotypes of major histocompatibility complex (MHC) class II genes, and a polymorphism in a non-coding region that may increase MHC class II in PD patients. We speculate that the inflammation observed in PD may play both pathogenic and protective roles. Future studies on the adaptive immune system in neurodegenerative disorders may elucidate steps in disease pathogenesis and assist with the development of both biomarkers and treatments.

Keywords: Parkinson's disease; T cells; adaptive immune system; autoimmunity; blood-brain barrier; neuroinflammation; α-synuclein.

Figures

Figure 1
Figure 1
α-Syn T cells infiltrate into the CNS and recognize antigen presented by microglia and dopaminergic neurons. (A) Prior to BBB damage, peripherally primed α-syn T cells circulate throughout the blood in the presence of proinflammatory cytokines. α-Syn aggregates have already formed in dopaminergic neurons and microglia. (B) Increased BBB permeability through either weakened tight junctions or increased transcytosis allows for extravasation of α-syn T cells. Recognition of α-syn presented by MHC-I on neurons and MHC-I and –II on microglia leads to T cell activation and release of granzymes and proinflammatory cytokines. Dopaminergic neurons eventually die in the presence of sustained inflammation and cytotoxic environment.

References

    1. Amor S, Peferoen LA, Vogel DY, Breur M, van der Valk P, Baker D, et al. . Inflammation in neurodegenerative diseases–an update. Immunology (2014) 142:151–66. 10.1111/imm.12233
    1. Dorsey ER, Constantinescu R, Thompson JP, Biglan KM, Holloway RG, Kieburtz K, et al. . Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology (2007) 68:384–6. 10.1212/01.wnl.0000247740.47667.03
    1. Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, et al. . MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord. (2015) 30:1591–601. 10.1002/mds.26424
    1. Billingsley KJ, Bandres-Ciga S, Saez-Atienzar S, Singleton AB. Genetic risk factors in Parkinson's disease. Cell Tissue Res. (2018) 373:9–20. 10.1007/s00441-018-2817-y
    1. Kalia LV, Lang AE. Parkinson's disease. Lancet (2015) 386:896–912. 10.1016/S0140-6736(14)61393-3
    1. Postuma RB, Aarsland D, Barone P, Burn DJ, Hawkes CH, Oertel W, et al. . Identifying prodromal Parkinson's disease: pre-motor disorders in Parkinson's disease. Mov Disord. (2012) 27:617–26. 10.1002/mds.24996
    1. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, et al. . Parkinson disease. Nat Rev Dis Primers (2017) 3:17013. 10.1038/nrdp.2017.13
    1. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging (2003) 24:197–211. 10.1016/S0197-4580(02)00065-9
    1. Abbott RD, Petrovitch H, White LR, Masaki KH, Tanner CM, Curb JD, et al. . Frequency of bowel movements and the future risk of Parkinson's disease. Neurology (2001) 57:456–62. 10.1212/WNL.57.3.456
    1. Pont-Sunyer C, Hotter A, Gaig C, Seppi K, Compta Y, Katzenschlager R, et al. . The onset of nonmotor symptoms in Parkinson's disease (the ONSET PD study). Mov Disord. (2015) 30:229–37. 10.1002/mds.26077
    1. Edwards LL, Pfeiffer RF, Quigley EM, Hofman R, Balluff M. Gastrointestinal symptoms in Parkinson's disease. Mov Disord. (1991) 6:151–6. 10.1002/mds.870060211
    1. Keshavarzian, Green SJ, Engen PA, Voigt RM, Naqib A, Forsyth CB, et al. . Colonic bacterial composition in Parkinson's disease. Mov Disord. (2015) 30:1351–60. 10.1002/mds.26307
    1. Unger MM, Spiegel J, Dillmann KU, Grundmann D, Philippeit H, Burmann J, et al. . Short chain fatty acids and gut microbiota differ between patients with Parkinson's disease and age-matched controls. Parkinsonism Relat Disord. (2016) 32:66–72. 10.1016/j.parkreldis.2016.08.019
    1. Hasegawa S, Goto S, Tsuji H, Okuno T, Asahara T, Nomoto K, et al. . Intestinal dysbiosis and lowered serum lipopolysaccharide-binding protein in Parkinson's disease. PLoS ONE (2015) 10:e0142164. 10.1371/journal.pone.0142164
    1. Scheperjans F, Aho V, Pereira PA, Koskinen K, Paulin L, Pekkonen E, et al. . Gut microbiota are related to Parkinson's disease and clinical phenotype. Mov Disord. (2015) 30:350–8. 10.1002/mds.26069
    1. Davies KN, King D, Billington D, Barrett JA. Intestinal permeability and orocaecal transit time in elderly patients with Parkinson's disease. Postgraduate Med J. (1996) 72:164–7. 10.1136/pgmj.72.845.164
    1. Salat-Foix D, Tran K, Ranawaya R, Meddings J, Suchowersky O. Increased intestinal permeability and Parkinson disease patients: chicken or egg? Can J Neurol Sci. (2012) 39:185–8. 10.1017/S0317167100013202
    1. Forsyth CB, Shannon KM, Kordower JH, Voigt RM, Shaikh M, Jaglin JA, et al. . Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson's disease. PLoS ONE (2011) 6:e28032. 10.1371/journal.pone.0028032
    1. Chen SG, Stribinskis V, Rane MJ, Demuth DR, Gozal E, Roberts AM, et al. . Exposure to the functional bacterial amyloid protein curli enhances alpha-synuclein aggregation in aged fischer 344 rats and Caenorhabditis elegans. Sci Rep. (2016) 6:34477. 10.1038/srep34477
    1. Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, et al. . Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease. Cell (2016) 167:1469–80 e12. 10.1016/j.cell.2016.11.018
    1. Braak H, Rub U, Gai WP, Del Tredici K. Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Trans. (2003) 110:517–36. 10.1007/s00702-002-0808-2
    1. Braak H, de Vos RA, Bohl J, Del Tredici K. Gastric alpha-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology. Neurosci Lett. (2006) 396:67–72. 10.1016/j.neulet.2005.11.012
    1. Shannon KM, Keshavarzian A, Mutlu E, Dodiya HB, Daian D, Jaglin JA, et al. . Alpha-synuclein in colonic submucosa in early untreated Parkinson's disease. Mov Disord. (2012) 27:709–15. 10.1002/mds.23838
    1. Beach TG, Adler CH, Sue LI, Vedders L, Lue L, White Iii CL, et al. Arizona Parkinson's disease, multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol. (2010) 119:689–702. 10.1007/s00401-010-0664-3
    1. Adler CH, Beach TG. Neuropathological basis of nonmotor manifestations of Parkinson's disease. Mov Disord. (2016) 31:1114–9. 10.1002/mds.26605
    1. Heikkila RE, Nicklas WJ, Vyas I, Duvoisin RC. Dopaminergic toxicity of rotenone and the 1-methyl-4-phenylpyridinium ion after their stereotaxic administration to rats: implication for the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity. Neurosci Lett. (1985) 62:389–94. 10.1016/0304-3940(85)90580-4
    1. Spivey A. Rotenone and paraquat linked to Parkinson's disease: human exposure study supports years of animal studies. Environ Health Perspect. (2011) 119:A259. 10.1289/ehp.119-a259a
    1. Pan-Montojo F, Anichtchik O, Dening Y, Knels L, Pursche S, Jung R, et al. . Progression of Parkinson's disease pathology is reproduced by intragastric administration of rotenone in mice. PloS ONE (2010) 5:e8762. 10.1371/journal.pone.0008762
    1. Pan-Montojo F, Schwarz M, Winkler C, Arnhold M, O'Sullivan GA, Pal A, et al. . Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice. Sci Rep. (2012) 2:898. 10.1038/srep00898
    1. Devos D, Lebouvier T, Lardeux B, Biraud M, Rouaud T, Pouclet H, et al. . Colonic inflammation in Parkinson's disease. Neurobiol Dis. (2013) 50:42–8. 10.1016/j.nbd.2012.09.007
    1. Chen Y, Yu M, Liu X, Qu H, Chen Q, Qian W, et al. . Clinical characteristics and peripheral T cell subsets in Parkinson's disease patients with constipation. Int J Clin Exp Pathol. (2015) 8:2495–504.
    1. Mogi M, Harada M, Narabayashi H, Inagaki H, Minami M, Nagatsu T. Interleukin (IL)-1 beta, IL-2, IL-4, IL-6 and transforming growth factor-alpha levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson's disease. Neurosci Lett. (1996) 211:13–6. 10.1016/0304-3940(96)12706-3
    1. Stypula G, Kunert-Radek J, Stepien H, Zylinska K, Pawlikowski M. Evaluation of interleukins, ACTH, cortisol and prolactin concentrations in the blood of patients with parkinson's disease. Neuroimmunomodulation (1996) 3:131–4. 10.1159/000097237
    1. Blum-Degen D, Muller T, Kuhn W, Gerlach M, Przuntek H, Riederer P. Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer's and de novo Parkinson's disease patients. Neurosci Lett. (1995) 202:17–20. 10.1016/0304-3940(95)12192-7
    1. Dobbs RJ, Charlett A, Purkiss AG, Dobbs SM, Weller C, Peterson DW. Association of circulating TNF-alpha and IL-6 with ageing and parkinsonism. Acta Neurol Scand. (1999) 100:34–41. 10.1111/j.1600-0404.1999.tb00721.x
    1. Mogi M, Harada M, Kondo T, Riederer P, Inagaki H, Minami M, et al. . Interleukin-1 beta, interleukin-6, epidermal growth factor and transforming growth factor-alpha are elevated in the brain from parkinsonian patients. Neurosci Lett. (1994) 180:147–50. 10.1016/0304-3940(94)90508-8
    1. Muller T, Blum-Degen D, Przuntek H, Kuhn W. Interleukin-6 levels in cerebrospinal fluid inversely correlate to severity of Parkinson's disease. Acta Neurol Scand. (1998) 98:142–4. 10.1111/j.1600-0404.1998.tb01736.x
    1. Reale M, Iarlori C, Thomas A, Gambi D, Perfetti B, Di Nicola M, et al. . Peripheral cytokines profile in Parkinson's disease. Brain Behav Immun. (2009) 23:55–63. 10.1016/j.bbi.2008.07.003
    1. Rentzos M, Nikolaou C, Andreadou E, Paraskevas GP, Rombos A, Zoga M, et al. . Circulating interleukin-15 and RANTES chemokine in Parkinson's disease. Acta Neurol Scand. (2007) 116:374–9. 10.1111/j.1600-0404.2007.00894.x
    1. Boka G, Anglade P, Wallach D, Javoy-Agid F, Agid Y, Hirsch EC. Immunocytochemical analysis of tumor necrosis factor and its receptors in Parkinson's disease. Neurosci Lett. (1994) 172:151–4. 10.1016/0304-3940(94)90684-X
    1. Hunot S, Boissiere F, Faucheux B, Brugg B, Mouatt-Prigent A, Agid Y, et al. . Nitric oxide synthase and neuronal vulnerability in Parkinson's disease. Neuroscience (1996) 72:355–63. 10.1016/0306-4522(95)00578-1
    1. Kustrimovic N, Comi C, Magistrelli L, Rasini E, Legnaro M, Bombelli R, et al. . Parkinson's disease patients have a complex phenotypic and functional Th1 bias: cross-sectional studies of CD4+ Th1/Th2/T17 and Treg in drug-naive and drug-treated patients. J Neuroinflamm. (2018) 15:205. 10.1186/s12974-018-1248-8
    1. Sommer, Maxreiter F, Krach F, Fadler T, Grosch J, Maroni M, et al. . Th17 lymphocytes induce neuronal cell death in a human iPSC-based model of Parkinson's disease. Cell Stem Cell (2018) 23:123–31 e6. 10.1016/j.stem.2018.06.015
    1. Bas J, Calopa M, Mestre M, Mollevi DG, Cutillas B, Ambrosio S, et al. . Lymphocyte populations in Parkinson's disease and in rat models of parkinsonism. J Neuroimmunol. (2001) 113:146–52. 10.1016/S0165-5728(00)00422-7
    1. Saunders JA, Estes KA, Kosloski LM, Allen HE, Dempsey KM, Torres-Russotto DR, et al. . CD4+ regulatory and effector/memory T cell subsets profile motor dysfunction in Parkinson's disease. J Neuroimmune Pharmacol. (2012) 7:927–38. 10.1007/s11481-012-9402-z
    1. Calopa M, Bas J, Callen A, Mestre M. Apoptosis of peripheral blood lymphocytes in Parkinson patients. Neurobiol Dis. (2010) 38:1–7. 10.1016/j.nbd.2009.12.017
    1. Stevens CH, Rowe D, Morel-Kopp MC, Orr C, Russell T, Ranola M, et al. . Reduced T helper and B lymphocytes in Parkinson's disease. J Neuroimmunol. (2012) 252:95–9. 10.1016/j.jneuroim.2012.07.015
    1. Chiba S, Matsumoto H, Saitoh M, Kasahara M, Matsuya M, Kashiwagi M. A correlation study between serum adenosine deaminase activities and peripheral lymphocyte subsets in Parkinson's disease. J Neurol Sci. (1995) 132:170–3. 10.1016/0022-510X(95)00136-P
    1. Baba Y, Kuroiwa A, Uitti RJ, Wszolek ZK, Yamada T. Alterations of T-lymphocyte populations in Parkinson disease. Parkinsonism Relat Disord. (2005) 11:493–8. 10.1016/j.parkreldis.2005.07.005
    1. Gruden MA, Sewell RD, Yanamandra K, Davidova TV, Kucheryanu VG, Bocharov EV, et al. . Immunoprotection against toxic biomarkers is retained during Parkinson's disease progression. J Neuroimmunol. (2011) 233:221–7. 10.1016/j.jneuroim.2010.12.001
    1. Chen Y, Qi B, Xu W, Ma B, Li L, Chen Q, et al. . Clinical correlation of peripheral CD4+cell subsets, their imbalance and Parkinson's disease. Mol Med Rep. (2015) 12:6105–11. 10.3892/mmr.2015.4136
    1. Rosenkranz D, Weyer S, Tolosa E, Gaenslen A, Berg D, Leyhe T, et al. . Higher frequency of regulatory T cells in the elderly and increased suppressive activity in neurodegeneration. J Neuroimmunol. (2007) 188:117–27. 10.1016/j.jneuroim.2007.05.011
    1. Chen S, Liu Y, Niu Y, Xu Y, Zhou Q, Xu X, et al. . Increased abundance of myeloid-derived suppressor cells and Th17 cells in peripheral blood of newly-diagnosed Parkinson's disease patients. Neurosci Lett. (2017) 648:21–5. 10.1016/j.neulet.2017.03.045
    1. Kondelkova K, Vokurkova D, Krejsek J, Borska L, Fiala Z, Ctirad A. Regulatory T cells (TREG) and their roles in immune system with respect to immunopathological disorders. Acta Med. (2010) 53:73–7. 10.14712/18059694.2016.63
    1. Liebner S, Dijkhuizen RM, Reiss Y, Plate KH, Agalliu D, Constantin G. Functional morphology of the blood-brain barrier in health and disease. Acta Neuropathol. (2018) 135:311–36. 10.1007/s00401-018-1815-1
    1. Daneman R, Prat A. The blood-brain barrier. Cold Spring Harb Perspect Biol. (2015) 7:a020412. 10.1101/cshperspect.a020412
    1. Varatharaj, Galea I. The blood-brain barrier in systemic inflammation. Brain Behav. Immun. (2017) 60:1–12. 10.1016/j.bbi.2016.03.010
    1. Daneman R, Engelhardt B. Brain barriers in health and disease. Neurobiol Dis. (2017) 107:1–3. 10.1016/j.nbd.2017.05.008
    1. Kortekaas R, Leenders KL, van Oostrom JC, Vaalburg W, Bart J, Willemsen AT, et al. . Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann Neurol. (2005) 57:176–9. 10.1002/ana.20369
    1. Ham JH, Yi H, Sunwoo MK, Hong JY, Sohn YH, Lee PH. Cerebral microbleeds in patients with Parkinson's disease. J Neurol. (2014) 261:1628–35. 10.1007/s00415-014-7403-y
    1. Janelidze S, Lindqvist D, Francardo V, Hall S, Zetterberg H, Blennow K, et al. . Increased CSF biomarkers of angiogenesis in Parkinson disease. Neurology (2015) 85:1834–42. 10.1212/WNL.0000000000002151
    1. Gray MT, Woulfe JM. Striatal blood-brain barrier permeability in Parkinson's disease. J Cereb Blood Flow Metab. (2015) 35:747–50. 10.1038/jcbfm.2015.32
    1. Pienaar IS, Lee CH, Elson JL, McGuinness L, Gentleman SM, Kalaria RN, et al. . Deep-brain stimulation associates with improved microvascular integrity in the subthalamic nucleus in Parkinson's disease. Neurobiol Dis. (2015) 74:392–405. 10.1016/j.nbd.2014.12.006
    1. Desai Bradaric B, Patel A, Schneider JA, Carvey PM, Hendey B. Evidence for angiogenesis in Parkinson's disease, incidental Lewy body disease, and progressive supranuclear palsy. J Neural Trans. (2012) 119:59–71. 10.1007/s00702-011-0684-8
    1. McGeer PL, Itagaki S, Akiyama H, McGeer EG. Rate of cell death in parkinsonism indicates active neuropathological process. Ann Neurol. (1988) 24:574–6. 10.1002/ana.410240415
    1. McGeer PL, Itagaki S, McGeer EG. Expression of the histocompatibility glycoprotein HLA-DR in neurological disease. Acta Neuropathol. (1988) 76:550–7. 10.1007/BF00689592
    1. Brochard V, Combadiere B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V, et al. . Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Investig. (2009) 119:182–92. 10.1172/JCI36470
    1. Ungerstedt U. 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur J Pharmacol. (1968) 5:107–10. 10.1016/0014-2999(68)90164-7
    1. Saner, Thoenen H. Model experiments on the molecular mechanism of action of 6-hydroxydopamine. Mol Pharmacol. (1971) 7:147–54.
    1. Graham DG. Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones. Mol Pharmacol. (1978) 14:633–43.
    1. Blum D, Torch S, Lambeng N, Nissou M, Benabid AL, Sadoul R, et al. . Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson's disease. Prog Neurobiol. (2001) 65:135–72. 10.1016/S0301-0082(01)00003-X
    1. Theodore S, Maragos W. 6-Hydroxydopamine as a tool to understand adaptive immune system-induced dopamine neurodegeneration in Parkinson's disease. Immunopharmacol Immunotoxicol. (2015) 37:393–9. 10.3109/08923973.2015.1070172
    1. Ambrosi G, Kustrimovic N, Siani F, Rasini E, Cerri S, Ghezzi C, et al. . Complex changes in the innate and adaptive immunity accompany progressive degeneration of the nigrostriatal pathway induced by intrastriatal injection of 6-hydroxydopamine in the rat. Neurotoxicity Res. (2017) 32:71–81. 10.1007/s12640-017-9712-2
    1. Davis GC, Williams AC, Markey SP, Ebert MH, Caine ED, Reichert CM, et al. . Chronic Parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry Res. (1979) 1:249–54. 10.1016/0165-1781(79)90006-4
    1. Langston JW, Ballard PA, Jr. Parkinson's disease in a chemist working with 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. N Eng J Med. (1983) 309:310.
    1. Cui M, Aras R, Christian WV, Rappold PM, Hatwar M, Panza J, et al. . The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathway. Proc Natl Acad Sci USA. (2009) 106:8043–8. 10.1073/pnas.0900358106
    1. Rappold PM, Tieu K. Astrocytes and therapeutics for Parkinson's disease. Neurotherapeutics (2010) 7:413–23. 10.1016/j.nurt.2010.07.001
    1. Nicklas WJ, Vyas I, Heikkila RE. Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. Life Sci. (1985) 36:2503–8. 10.1016/0024-3205(85)90146-8
    1. Mizuno Y, Sone N, Saitoh T. Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 1-methyl-4-phenylpyridinium ion on activities of the enzymes in the electron transport system in mouse brain. J Neurochem. (1987) 48:1787–93. 10.1111/j.1471-4159.1987.tb05737.x
    1. Choi SJ, Panhelainen A, Schmitz Y, Larsen KE, Kanter E, Wu M, et al. . Changes in neuronal dopamine homeostasis following 1-methyl-4-phenylpyridinium (MPP+) exposure. J Biol Chem. (2015) 290:6799–809. 10.1074/jbc.M114.631556
    1. Lieberman OJ, Choi SJ, Kanter E, Saverchenko A, Frier MD, Fiore GM, et al. . alpha-synuclein-dependent calcium entry underlies differential sensitivity of cultured SN and VTA dopaminergic neurons to a Parkinsonian neurotoxin. eNeuro (2017) 4:ENEURO.0167-17.2017. 10.1523/ENEURO.0167-17.2017
    1. Kurkowska-Jastrzebska, Wronska A, Kohutnicka M, Czlonkowski A, Czlonkowska A. 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. (1999) 59:1–8.
    1. Depboylu C, Stricker S, Ghobril JP, Oertel WH, Priller J, Hoglinger GU. Brain-resident microglia predominate over infiltrating myeloid cells in activation, phagocytosis and interaction with T-lymphocytes in the MPTP mouse model of Parkinson disease. Exp. Neurol. (2012) 238:183–91. 10.1016/j.expneurol.2012.08.020
    1. Benner EJ, Banerjee R, Reynolds AD, Sherman S, Pisarev VM, Tsiperson V, et al. . Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PloS ONE (2008) 3:e1376. 10.1371/journal.pone.0001376
    1. Nagai Y, Ueno S, Saeki Y, Soga F, Hirano M, Yanagihara T. Decrease of the D3 dopamine receptor mRNA expression in lymphocytes from patients with Parkinson's disease. Neurology (1996) 46:791–5. 10.1212/WNL.46.3.791
    1. Gonzalez H, Contreras F, Prado C, Elgueta D, Franz D, Bernales S, et al. . Dopamine receptor D3 expressed on CD4+ T cells favors neurodegeneration of dopaminergic neurons during Parkinson's disease. J Immunol. (2013) 190:5048–56. 10.4049/jimmunol.1203121
    1. Contreras F, Prado C, Gonzalez H, Franz D, Osorio-Barrios F, Osorio F, et al. . Dopamine receptor D3 signaling on CD4+ T cells favors Th1- and Th17-mediated immunity. J Immunol. (2016) 196:4143–9. 10.4049/jimmunol.1502420
    1. Benner EJ, Mosley RL, Destache CJ, Lewis TB, Jackson-Lewis V, Gorantla S, et al. . Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson's disease. Proc Natl Acad Sci USA. (2004) 101:9435–40. 10.1073/pnas.0400569101
    1. Reynolds AD, Banerjee R, Liu J, Gendelman HE, Mosley RL. Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson's disease. J Leukoc Biol. (2007) 82:1083–94. 10.1189/jlb.0507296
    1. Reynolds AD, Stone DK, Mosley RL, Gendelman HE. Nitrated {alpha}-synuclein-induced alterations in microglial immunity are regulated by CD4+ T cell subsets. J Immunol. (2009) 182:4137–49. 10.4049/jimmunol.0803982
    1. Reynolds AD, Stone DK, Hutter JA, Benner EJ, Mosley RL, Gendelman HE. Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson's disease. J Immunol. (2010) 184:2261–71. 10.4049/jimmunol.0901852
    1. Theodore S, Cao S, McLean PJ, Standaert DG. Targeted overexpression of human alpha-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease. J Neuropathol Exp Neurol. (2008) 67:1149–58. 10.1097/NEN.0b013e31818e5e99
    1. Van der Perren, Macchi F, Toelen J, Carlon MS, Maris M, de Loor H, et al. . FK506 reduces neuroinflammation and dopaminergic neurodegeneration in an alpha-synuclein-based rat model for Parkinson's disease. Neurobiol Aging (2015) 36:1559–68. 10.1016/j.neurobiolaging.2015.01.014
    1. Reich DS, Lucchinetti CF, Calabresi PA. Multiple sclerosis. N Eng J Med. (2018) 378:169–80. 10.1056/NEJMra1401483
    1. Hemmer B, Kerschensteiner M, Korn T. Role of the innate and adaptive immune responses in the course of multiple sclerosis. Lancet Neurol. (2015) 14:406–19. 10.1016/S1474-4422(14)70305-9
    1. Li YF, Zhang SX, Ma XW, Xue YL, Gao C, Li XY. Levels of peripheral Th17 cells and serum Th17-related cytokines in patients with multiple sclerosis: a meta-analysis. Multiple Sclerosis Relat Disord. (2017) 18:20–5. 10.1016/j.msard.2017.09.003
    1. Siffrin V, Radbruch H, Glumm R, Niesner R, Paterka M, Herz J, et al. . In vivo imaging of partially reversible th17 cell-induced neuronal dysfunction in the course of encephalomyelitis. Immunity (2010) 33:424–36. 10.1016/j.immuni.2010.08.018
    1. Kang Z, Wang C, Zepp J, Wu L, Sun K, Zhao J, et al. . Act1 mediates IL-17-induced EAE pathogenesis selectively in NG2+ glial cells. Nat Neurosci. (2013) 16:1401–8. 10.1038/nn.3505
    1. Kebir H, Kreymborg K, Ifergan I, Dodelet-Devillers A, Cayrol R, Bernard M, et al. . Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med. (2007) 13:1173–5. 10.1038/nm1651
    1. Codarri L, Gyulveszi G, Tosevski V, Hesske L, Fontana A, Magnenat L, et al. . RORgammat drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol. (2011) 12:560–7. 10.1038/ni.2027
    1. El-Behi M, Ciric B, Dai H, Yan Y, Cullimore M, Safavi F, et al. . The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat Immunol. (2011) 12:568–75. 10.1038/ni.2031
    1. Croxford AL, Lanzinger M, Hartmann FJ, Schreiner B, Mair F, Pelczar P, et al. . The cytokine GM-CSF drives the inflammatory signature of CCR2+ monocytes and licenses autoimmunity. Immunity (2015) 43:502–14. 10.1016/j.immuni.2015.08.010
    1. Ajami B, Bennett JL, Krieger C, McNagny KM, Rossi FM. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci. (2011) 14:1142–9. 10.1038/nn.2887
    1. Cebrian C, Zucca FA, Mauri P, Steinbeck JA, Studer L, Scherzer CR, et al. . MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration. Nat Commun. (2014) 5:3633. 10.1038/ncomms4633
    1. Wissemann WT, Hill-Burns EM, Zabetian CP, Factor SA, Patsopoulos N, Hoglund B, et al. . Association of Parkinson disease with structural and regulatory variants in the HLA region. Am J Hum Genet. (2013) 93:984–93. 10.1016/j.ajhg.2013.10.009
    1. Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, Yearout D, et al. . Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease. Nat Genet. (2010) 42:781–5. 10.1038/ng.642
    1. Greenbaum J, Sidney J, Chung J, Brander C, Peters B, Sette A. Functional classification of class II human leukocyte antigen (HLA) molecules reveals seven different supertypes and a surprising degree of repertoire sharing across supertypes. Immunogenetics (2011) 63:325–35. 10.1007/s00251-011-0513-0
    1. Kannarkat GT, Cook DA, Lee JK, Chang J, Chung J, Sandy E, et al. . Common genetic variant association with altered HLA expression, synergy with pyrethroid exposure, and risk for Parkinson's disease: an Observational and Case-Control Study. NPJ Parkinson's Dis. (2015) 1:15002. 10.1038/npjparkd.2015.2
    1. Hill-Burns EM, Wissemann WT, Hamza TH, Factor SA, Zabetian CP, Payami H. Identification of a novel Parkinson's disease locus via stratified genome-wide association study. BMC Genomics (2014) 15:118. 10.1186/1471-2164-15-118
    1. Imamura K, Hishikawa N, Sawada M, Nagatsu T, Yoshida M, Hashizume Y. Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson's disease brains. Acta Neuropathol. (2003) 106:518–26. 10.1007/s00401-003-0766-2
    1. Harms AS, Cao S, Rowse AL, Thome AD, Li X, Mangieri LR, et al. . MHCII is required for alpha-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration. J Neurosci. (2013) 33:9592–600. 10.1523/JNEUROSCI.5610-12.2013
    1. Martin HL, Santoro M, Mustafa S, Riedel G, Forrester JV, Teismann P. Evidence for a role of adaptive immune response in the disease pathogenesis of the MPTP mouse model of Parkinson's disease. Glia (2016) 64:386–95. 10.1002/glia.22935
    1. Bryant CE, Orr S, Ferguson B, Symmons MF, Boyle JP, Monie TP. International Union of Basic and Clinical Pharmacology. XCVI. Pattern recognition receptors in health and disease. Pharmacol Rev. (2015) 67:462–504. 10.1124/pr.114.009928
    1. Hughes CD, Choi ML, Ryten M, Hopkins L, Drews A, Botia JA, et al. . Correction to: Picomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson's disease pathogenesis. Acta Neuropathol. (2018) 137:121. 10.1007/s00401-018-1919-7
    1. Zhang W, Phillips K, Wielgus AR, Liu J, Albertini A, Zucca FA, et al. . Neuromelanin activates microglia and induces degeneration of dopaminergic neurons: implications for progression of Parkinson's disease. Neurotoxic Res. (2011) 19:63–72. 10.1007/s12640-009-9140-z
    1. Grozdanov V, Bliederhaeuser C, Ruf WP, Roth V, Fundel-Clemens K, Zondler L, et al. . Inflammatory dysregulation of blood monocytes in Parkinson's disease patients. Acta Neuropathol. (2014) 128:651–63. 10.1007/s00401-014-1345-4
    1. Stolzenberg E, Berry D, Yang, Lee EY, Kroemer A, Kaufman S, et al. . A role for neuronal alpha-synuclein in gastrointestinal immunity. J Innate Immun. (2017) 9:456–63. 10.1159/000477990
    1. Ransohoff RM. Microglia and monocytes: ’tis plain the twain meet in the brain. Nat Neurosci. (2011) 14:1098–100. 10.1038/nn.2917
    1. Harms AS, Thome AD, Yan Z, Schonhoff AM, Williams GP, Li X, et al. . Peripheral monocyte entry is required for alpha-Synuclein induced inflammation and Neurodegeneration in a model of Parkinson disease. Exp Neurol. (2018) 300:179–87. 10.1016/j.expneurol.2017.11.010
    1. Shemer, Erny D, Jung S, Prinz M. Microglia plasticity during health and disease: an immunological perspective. Trends Immunol. (2015) 36:614–24. 10.1016/j.it.2015.08.003
    1. Gerhard, Pavese N, Hotton G, Turkheimer F, Es M, Hammers A, Eggert K, et al. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson's disease. Neurobiol. Dis. (2006) 21:404–12. 10.1016/j.nbd.2005.08.002
    1. Ouchi Y, Yoshikawa E, Sekine Y, Futatsubashi M, Kanno T, Ogusu T, et al. . Microglial activation and dopamine terminal loss in early Parkinson's disease. Ann Neurol. (2005) 57:168–75. 10.1002/ana.20338
    1. Roy A, Mondal S, Kordower JH, Pahan K. Attenuation of microglial RANTES by NEMO-binding domain peptide inhibits the infiltration of CD8(+) T cells in the nigra of hemiparkinsonian monkey. Neuroscience (2015) 302:36–46. 10.1016/j.neuroscience.2015.03.011
    1. Chandra G, Rangasamy SB, Roy A, Kordower JH, Pahan K. Neutralization of RANTES and eotaxin prevents the loss of dopaminergic neurons in a mouse model of parkinson disease. J Biol Chem. (2016) 291:15267–81. 10.1074/jbc.M116.714824
    1. Tristao FS, Lazzarini M, Martin S, Amar M, Stuhmer W, Kirchhoff F, et al. . CX3CR1 disruption differentially influences dopaminergic neuron degeneration in Parkinsonian mice depending on the neurotoxin and route of administration. Neurotoxic Res. (2016) 29:364–80. 10.1007/s12640-015-9557-5
    1. Parillaud VR, Lornet G, Monnet Y, Privat AL, Haddad AT, Brochard V, et al. . Analysis of monocyte infiltration in MPTP mice reveals that microglial CX3CR1 protects against neurotoxic over-induction of monocyte-attracting CCL2 by astrocytes. J Neuroinflamm. (2017) 14:60. 10.1186/s12974-017-0830-9
    1. Sadeghian M, Mullali G, Pocock JM, Piers T, Roach A, Smith KJ. Neuroprotection by safinamide in the 6-hydroxydopamine model of Parkinson's disease. Neuropathol Appl Neurobiol. (2016) 42:423–35. 10.1111/nan.12263
    1. Zhang S, Wang XJ, Tian LP, Pan J, Lu GQ, Zhang YJ, et al. . CD200-CD200R dysfunction exacerbates microglial activation and dopaminergic neurodegeneration in a rat model of Parkinson's disease. J Neuroinflamm. (2011) 8:154. 10.1186/1742-2094-8-154
    1. Sanchez-Guajardo V, Barnum CJ, Tansey MG, Romero-Ramos M. Neuroimmunological processes in Parkinson's disease and their relation to alpha-synuclein: microglia as the referee between neuronal processes and peripheral immunity. ASN Neuro (2013) 5:113–39. 10.1042/AN20120066
    1. Przuntek H, Muller T, Riederer P. Diagnostic staging of Parkinson's disease: conceptual aspects. J Neural Trans. (2004) 111:201–16. 10.1007/s00702-003-0102-y
    1. Cuervo AM, Wong ES, Martinez-Vicente M. Protein degradation, aggregation, and misfolding. Mov Disord. (2010) 25 (Suppl. 1) S49–54. 10.1002/mds.22718
    1. Sulzer D, Alcalay RN, Garretti F, Cote L, Kanter E, Agin-Liebes J, et al. . T cells from patients with Parkinson's disease recognize alpha-synuclein peptides. Nature (2017) 546:656–61. 10.1038/nature22815
    1. Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M. alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies. Proc Natl Acad Sci USA. (1998) 95:6469–73. 10.1073/pnas.95.11.6469
    1. Rowin J, Thiruppathi M, Arhebamen E, Sheng J, Prabhakar BS, Meriggioli MN. Granulocyte macrophage colony-stimulating factor treatment of a patient in myasthenic crisis: effects on regulatory T cells. Muscle Nerve (2012) 46:449–53. 10.1002/mus.23488
    1. Gendelman HE, Zhang Y, Santamaria P, Olson KE, Schutt CR, Bhatti D, et al. . Evaluation of the safety and immunomodulatory effects of sargramostim in a randomized, double-blind phase 1 clinical Parkinson's disease trial. NPJ Parkinson's Dis. (2017) 3:10. 10.1038/s41531-017-0013-5
    1. Games D, Valera E, Spencer B, Rockenstein E, Mante M, Adame A, et al. . Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson's disease-like models. J Neurosci. (2014) 34:9441–54. 10.1523/JNEUROSCI.5314-13.2014
    1. Lindstrom V, Fagerqvist T, Nordstrom E, Eriksson F, Lord A, Tucker S, et al. . Immunotherapy targeting alpha-synuclein protofibrils reduced pathology in (Thy-1)-h[A30P] alpha-synuclein mice. Neurobiol. Dis. (2014) 69:134–43. 10.1016/j.nbd.2014.05.009
    1. Jankovic J, Goodman I, Safirstein B, Marmon TK, Schenk DB, Koller M, et al. . Safety and tolerability of multiple ascending doses of PRX002/RG7935, an anti-alpha-synuclein monoclonal antibody, in patients with Parkinson disease: a randomized clinical trial. JAMA Neurol. (2018) 75:1206–14. 10.1001/jamaneurol.2018.1487
    1. Foltynie T, Langston JW. Therapies to slow, stop, or reverse Parkinson's disease. J Parkinson's Dis. (2018) 8:S115–21. 10.3233/JPD-181481
    1. Horvath, Iashchishyn IA, Forsgren L, Morozova-Roche LA. Immunochemical detection of alpha-synuclein autoantibodies in Parkinson's disease: correlation between plasma and cerebrospinal fluid levels. ACS Chem Neurosci. (2017) 8:1170–6. 10.1021/acschemneuro.7b00063
    1. Shalash A, Salama M, Makar M, Roushdy T, Elrassas HH, Mohamed W, et al. . Elevated serum alpha-synuclein autoantibodies in patients with Parkinson's disease relative to Alzheimer's disease and controls. Front Neurol. (2017) 8:720. 10.3389/fneur.2017.00720
    1. Akhtar RS, Licata JP, Luk KC, Shaw LM, Trojanowski JQ, Lee VM. Measurements of auto-antibodies to alpha-synuclein in the serum and cerebral spinal fluids of patients with Parkinson's disease. J Neurochem. (2018) 145:489–503. 10.1111/jnc.14330

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren