Peripheral Immunity, Immunoaging and Neuroinflammation in Parkinson’s Disease

doi:10.2174/0929867325666181009161048
摘要

帕金森氏病（PD）是老年人口中第二常见的神经退行性疾病，其特征是中脑中的多巴胺能神经元逐渐退化。迄今为止，确切原因仍然未知，神经元死亡的机制尚不确定。它通常被认为是中枢神经系统疾病（CNS）。然而，在过去的几年中，已经积累了许多证据，毫无疑问地证明了神经炎症在PD进展中的主要作用。神经炎症主要与大脑中存在激活的小胶质细胞和中枢神经系统中细胞因子水平升高有关。然而，也已经注意到免疫系统的积极参与，例如血液中细胞因子水平的升高，自身抗体的存在以及CNS中T细胞的浸润。而且，那些T细胞的浸润和再激活可能使神经炎症加剧至更高的神经毒性水平。因此，外周炎症能够引发小胶质细胞进入促炎表型，这可以触发中枢神经系统更强的反应，从而进一步使正在进行的神经退行性过程持续下去。在本综述中，将探讨PD病理生物学中神经炎症与周围免疫反应之间的相互作用。首先，总结并讨论了小胶质细胞激活和神经炎症调节的概述。此后，我们尝试共同分析PD患者外周免疫系统中发生的变化，表明这些外周免疫挑战会加剧神经炎症的进程，从而加剧疾病的症状。最后，我们总结了一些用于治疗PD的免疫疗法。
关键词: 帕金森氏病，神经炎症，外周免疫，α-突触核蛋白，免疫衰老，免疫调节。
« Previous Next »
[1] 
Yoshiyama, Y.; Higuchi, M.; Zhang, B.; Huang, S.M.; Iwata, N.; Saido, T.C.; Maeda, J.; Suhara, T.; Trojanowski, J.Q.; Lee, V.M. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron,  2007, 53(3), 337-351.
[http://dx.doi.org/10.1016/j.neuron.2007.01.010] [PMID: 17270732] 
[2] 
Barcia, C.; Ros, C.M.; Annese, V.; Gómez, A.; Ros-Bernal, F.; Aguado-Llera, D.; Martínez-Pagán, M.E.; de Pablos, V.; Fernandez-Villalba, E.; Herrero, M.T. IFN-γ signaling, with the synergistic contribution of TNF-α, mediates cell specific microglial and astroglial activation in experimental models of Parkinson’s disease. Cell Death Dis.,  2012, 3, e379.
[http://dx.doi.org/10.1038/cddis.2012.123] [PMID: 22914327] 
[3] 
Frakes, A.E.; Ferraiuolo, L.; Haidet-Phillips, A.M.; Schmelzer, L.; Braun, L.; Miranda, C.J.; Ladner, K.J.; Bevan, A.K.; Foust, K.D.; Godbout, J.P.; Popovich, P.G.; Guttridge, D.C.; Kaspar, B.K. Microglia induce motor neuron death via the classical NF-κB pathway in amyotrophic lateral sclerosis. Neuron,  2014, 81(5), 1009-1023.
[http://dx.doi.org/10.1016/j.neuron.2014.01.013] [PMID:  24607225] 
[4] 
Yoshida, Y.; Yoshimi, R.; Yoshii, H.; Kim, D.; Dey, A.; Xiong, H.; Munasinghe, J.; Yazawa, I.; O’Donovan, M.J.; Maximova, O.A.; Sharma, S.; Zhu, J.; Wang, H.; Morse, H.C., III; Ozato, K. The transcription factor IRF8 activates integrin-mediated TGF-β signaling and promotes neuroinflammation. Immunity,  2014, 40(2), 187-198.
[http://dx.doi.org/10.1016/j.immuni.2013.11.022] [PMID:  24485804] 
[5] 
Beal, M.F. Aging, energy, and oxidative stress in neurodegenerative diseases. Ann. Neurol.,  1995, 38(3), 357-366.
[http://dx.doi.org/10.1002/ana.410380304] [PMID:  7668820] 
[6] 
Pringsheim, T.; Jette, N.; Frolkis, A.; Steeves, T.D. The prevalence of Parkinson’s disease: a systematic review and meta-analysis. Mov. Disord.,  2014, 29(13), 1583-1590.
[http://dx.doi.org/10.1002/mds.25945] [PMID:  24976103] 
[7] 
de Lau, L.M.; Breteler, M.M. Epidemiology of Parkinson’s disease. Lancet Neurol.,  2006, 5(6), 525-535.
[http://dx.doi.org/10.1016/S1474-4422(06)70471-9] [PMID:  16713924] 
[8] 
Samii, A.; Nutt, J.G.; Ransom, B.R. Parkinson’s disease. Lancet,  2004, 363(9423), 1783-1793.
[http://dx.doi.org/10.1016/S0140-6736(04)16305-8] [PMID:  15172778] 
[9] 
Gelb, D.J.; Oliver, E.; Gilman, S. Diagnostic criteria for Parkinson disease. Arch. Neurol.,  1999, 56(1), 33-39.
[http://dx.doi.org/10.1001/archneur.56.1.33] [PMID:  9923759] 
[10] 
Jellinger, K.A. Recent developments in the pathology of Parkinson’s disease. J. Neural Transm. Suppl.,  2002, (62), 347-376.
[http://dx.doi.org/10.1007/978-3-7091-6139-5_33] [PMID:  12456078] 
[11] 
Koller, W.C.; Minagan, A. Treatment strategies for the management of Parkinson’s disease In: Parkinson’s disease
management guide; Ed.; Medical economics Company Inc:
Montvale NJ,. , 2001; pp. 347-101	.
[12] 
Brooks, D.J. The early diagnosis of Parkinson’s disease. Ann. Neurol.,  1998, 44(3)(Suppl. 1), S10-S18.
[http://dx.doi.org/10.1002/ana.410440704] [PMID:  9749569] 
[13] 
Ross, O.A. A prognostic view on the application of individualized genomics in Parkinson’s disease. Curr. Genet. Med. Rep.,  2013, 1(1), 52-57.
[http://dx.doi.org/10.1007/s40142-012-0003-1] [PMID:  23504498] 
[14] 
de Rijk, M.C.; Tzourio, C.; Breteler, M.M.; Dartigues, J.F.; Amaducci, L.; Lopez-Pousa, S.; Manubens-Bertran, J.M.; Alpérovitch, A.; Rocca, W.A. Prevalence of parkinsonism and Parkinson’s disease in Europe: the EUROPARKINSON Collaborative Study. European Community Concerted Action on the Epidemiology of Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry,  1997, 62(1), 10-15.
[http://dx.doi.org/10.1136/jnnp.62.1.10] [PMID:  9010393] 
[15] 
Wirdefeldt, K.; Adami, H.O.; Cole, P.; Trichopoulos, D.; Mandel, J. Epidemiology and etiology of Parkinson’s disease: a review of the evidence. Eur. J. Epidemiol.,  2011, 26(Suppl. 1), S1-S58.
[http://dx.doi.org/10.1007/s10654-011-9581-6] [PMID:  21626386] 
[16] 
Connolly, B.S.; Lang, A.E. Pharmacological treatment of Parkinson disease: a review. JAMA,  2014, 311(16), 1670-1683.
[http://dx.doi.org/10.1001/jama.2014.3654] [PMID:  24756517] 
[17] 
Poewe, W.; Antonini, A.; Zijlmans, J.C.; Burkhard, P.R.; Vingerhoets, F. Levodopa in the treatment of Parkinson’s disease: an old drug still going strong. Clin. Interv. Aging,  2010, 5, 229-238.
[PMID:  20852670] 
[18] 
Fox, S.H. Non-dopaminergic treatments for motor control in Parkinson’s disease. Drugs,  2013, 73(13), 1405-1415.
[http://dx.doi.org/10.1007/s40265-013-0105-4] [PMID:  23917951] 
[19] 
Nonnekes, J.; Timmer, M.H.; de Vries, N.M.; Rascol, O.; Helmich, R.C.; Bloem, B.R. Unmasking levodopa resistance in Parkinson’s disease. Mov. Disord.,  2016, 31(11), 1602-1609.
[http://dx.doi.org/10.1002/mds.26712] [PMID:  27430479] 
[20] 
Vivekanantham, S.; Shah, S.; Dewji, R.; Dewji, A.; Khatri, C.; Ologunde, R. Neuroinflammation in Parkinson’s disease: role in neurodegeneration and tissue repair. Int. J. Neurosci.,  2015, 125(10), 717-725.
[http://dx.doi.org/10.3109/00207454.2014.982795] [PMID:  25364880] 
[21] 
Nagatsu, T.; Mogi, M.; Ichinose, H.; Togari, A. Changes in cytokines and neurotrophins in Parkinson’s disease. J. Neural Transm. Suppl.,  2000, 60(60), 277-290.
[http://dx.doi.org/10.1007/978-3-7091-6301-6_19] [PMID:  11205147] 
[22] 
Boka, G.; Anglade, P.; Wallach, D.; Javoy-Agid, F.; Agid, Y.; Hirsch, E.C. Immunocytochemical analysis of tumor necrosis factor and its receptors in Parkinson’s disease. Neurosci. Lett.,  1994, 172(1-2), 151-154.
[http://dx.doi.org/10.1016/0304-3940(94)90684-X] [PMID:  8084523] 
[23] 
Hunot, S.; Dugas, N.; Faucheux, B.; Hartmann, A.; Tardieu, M.; Debré, P.; Agid, Y.; Dugas, B.; Hirsch, E.C. FcepsilonRII/CD23 is expressed in Parkinson’s disease and induces, in vitro, production of nitric oxide and tumor necrosis factor-alpha in glial cells. J. Neurosci.,  1999, 19(9), 3440-3447.
[http://dx.doi.org/10.1523/JNEUROSCI.19-09-03440.1999] [PMID:  10212304] 
[24] 
Tang, Y.; Le, W. Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases. Mol. Neurobiol.,  2016, 53(2), 1181-1194.
[http://dx.doi.org/10.1007/s12035-014-9070-5] [PMID:  25598354] 
[25] 
McGeer, P.L.; Itagaki, S.; Boyes, B.E.; McGeer, E.G. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology,  1988, 38(8), 1285-1291.
[http://dx.doi.org/10.1212/WNL.38.8.1285] [PMID:  3399080] 
[26] 
Mogi, M.; Harada, M.; Kondo, T.; Riederer, P.; Nagatsu, T. Brain beta 2-microglobulin levels are elevated in the striatum in Parkinson’s disease. J. Neural Transm. Park. Dis. Dement. Sect.,  1995, 9(1), 87-92.
[http://dx.doi.org/10.1007/BF02252965] [PMID:  7605592] 
[27] 
Marinova-Mutafchieva, L.; Sadeghian, M.; Broom, L.; Davis, J.B.; Medhurst, A.D.; Dexter, D.T. Relationship between microglial activation and dopaminergic neuronal loss in the substantia nigra: a time course study in a 6-hydroxydopamine model of Parkinson’s disease. J. Neurochem.,  2009, 110(3), 966-975.
[http://dx.doi.org/10.1111/j.1471-4159.2009.06189.x] [PMID:  19549006] 
[28] 
Vázquez-Claverie, M.; Garrido-Gil, P.; San Sebastián, W.; Izal-Azcárate, A.; Belzunegui, S.; Marcilla, I.; López, B.; Luquin, M.R. Acute and chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administrations elicit similar microglial activation in the substantia nigra of monkeys. J. Neuropathol. Exp. Neurol.,  2009, 68(9), 977-984.
[http://dx.doi.org/10.1097/NEN.0b013e3181b35e41] [PMID:  19680145] 
[29] 
Sanchez-Guajardo, V.; Febbraro, F.; Kirik, D.; Romero-Ramos, M. Microglia acquire distinct activation profiles depending on the degree of alpha-synuclein neuropathology in a rAAV based model of Parkinson’s disease. PLoS One,  2010, 5(1), e8784.
[http://dx.doi.org/10.1371/journal.pone.0008784] [PMID:  20098715] 
[30] 
Sanchez-Guajardo, V.; Annibali, A.; Jensen, P.H.; Romero-Ramos, M. α-Synuclein vaccination prevents the accumulation of parkinson disease-like pathologic inclusions in striatum in association with regulatory T cell recruitment in a rat model. J. Neuropathol. Exp. Neurol.,  2013, 72(7), 624-645.
[http://dx.doi.org/10.1097/NEN.0b013e31829768d2] [PMID:  23771222] 
[31] 
Glass, C.K.; Saijo, K.; Winner, B.; Marchetto, M.C.; Gage, F.H. Mechanisms underlying inflammation in neurodegeneration. Cell,  2010, 140(6), 918-934.
[http://dx.doi.org/10.1016/j.cell.2010.02.016] [PMID:  20303880] 
[32] 
Polazzi, E.; Monti, B. Microglia and neuroprotection: from in vitro studies to therapeutic applications. Prog. Neurobiol.,  2010, 92(3), 293-315.
[http://dx.doi.org/10.1016/j.pneurobio.2010.06.009] [PMID:  20609379] 
[33] 
Saijo, K.; Glass, C.K. Microglial cell origin and phenotypes in health and disease. Nat. Rev. Immunol.,  2011, 11(11), 775-787.
[http://dx.doi.org/10.1038/nri3086] [PMID:  22025055] 
[34] 
Jack, C.S.; Arbour, N.; Manusow, J.; Montgrain, V.; Blain, M.; McCrea, E.; Shapiro, A.; Antel, J.P. TLR signaling tailors innate immune responses in human microglia and astrocytes. J. Immunol.,  2005, 175(7), 4320-4330.
[http://dx.doi.org/10.4049/jimmunol.175.7.4320] [PMID:  16177072] 
[35] 
Lehnardt, S. Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia,  2010, 58(3), 253-263.
[PMID:  19705460] 
[36] 
Olson, J.K.; Miller, S.D. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J. Immunol.,  2004, 173(6), 3916-3924.
[http://dx.doi.org/10.4049/jimmunol.173.6.3916] [PMID:  15356140] 
[37] 
Zhang, W.; Dallas, S.; Zhang, D.; Guo, J.P.; Pang, H.; Wilson, B.; Miller, D.S.; Chen, B.; Zhang, W.; McGeer, P.L.; Hong, J.S.; Zhang, J. Microglial PHOX and Mac-1 are essential to the enhanced dopaminergic neurodegeneration elicited by A30P and A53T mutant alpha-synuclein. Glia,  2007, 55(11), 1178-1188.
[http://dx.doi.org/10.1002/glia.20532] [PMID:  17600340] 
[38] 
Kalkonde, Y.V.; Morgan, W.W.; Sigala, J.; Maffi, S.K.; Condello, C.; Kuziel, W.; Ahuja, S.S.; Ahuja, S.K. Chemokines in the MPTP model of Parkinson’s disease: absence of CCL2 and its receptor CCR2 does not protect against striatal neurodegeneration. Brain Res.,  2007, 1128(1), 1-11.
[http://dx.doi.org/10.1016/j.brainres.2006.08.041] [PMID:  17126305] 
[39] 
Ciesielski-Treska, J.; Ulrich, G.; Taupenot, L.; Chasserot-Golaz, S.; Corti, A.; Aunis, D.; Bader, M.F. Chromogranin A induces a neurotoxic phenotype in brain microglial cells. J. Biol. Chem.,  1998, 273(23), 14339-14346.
[http://dx.doi.org/10.1074/jbc.273.23.14339] [PMID:  9603942] 
[40] 
Zhang, W.; Wang, T.; Pei, Z.; Miller, D.S.; Wu, X.; Block, M.L.; Wilson, B.; Zhang, W.; Zhou, Y.; Hong, J.S.; Zhang, J. Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J.,  2005, 19(6), 533-542.
[http://dx.doi.org/10.1096/fj.04-2751com] [PMID:  15791003] 
[41] 
Giasson, B.I.; Duda, J.E.; Murray, I.V.; Chen, Q.; Souza, J.M.; Hurtig, H.I.; Ischiropoulos, H.; Trojanowski, J.Q.; Lee, V.M. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science,  2000, 290(5493), 985-989.
[http://dx.doi.org/10.1126/science.290.5493.985] [PMID:  11062131] 
[42] 
Uversky, V.N.; Yamin, G.; Munishkina, L.A.; Karymov, M.A.; Millett, I.S.; Doniach, S.; Lyubchenko, Y.L.; Fink, A.L. Effects of nitration on the structure and aggregation of alpha-synuclein. Brain Res. Mol. Brain Res.,  2005, 134(1), 84-102.
[http://dx.doi.org/10.1016/j.molbrainres.2004.11.014] [PMID:  15790533] 
[43] 
Gao, H.M.; Kotzbauer, P.T.; Uryu, K.; Leight, S.; Trojanowski, J.Q.; Lee, V.M. Neuroinflammation and oxidation/nitration of alpha-synuclein linked to dopaminergic neurodegeneration. J. Neurosci.,  2008, 28(30), 7687-7698.
[http://dx.doi.org/10.1523/JNEUROSCI.0143-07.2008] [PMID:  18650345] 
[44] 
Mirza, B.; Hadberg, H.; Thomsen, P.; Moos, T. The absence of reactive astrocytosis is indicative of a unique inflammatory process in Parkinson’s disease. Neuroscience,  2000, 95(2), 425-432.
[http://dx.doi.org/10.1016/S0306-4522(99)00455-8] [PMID:  10658622] 
[45] 
Banati, R.B.; Daniel, S.E.; Blunt, S.B. Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson’s disease. Mov. Disord.,  1998, 13(2), 221-227.
[http://dx.doi.org/10.1002/mds.870130205] [PMID:  9539333] 
[46] 
Mogi, M.; Kondo, T.; Mizuno, Y.; Nagatsu, T. p53 protein, interferon-gamma, and NF-kappaB levels are elevated in the parkinsonian brain. Neurosci. Lett.,  2007, 414(1), 94-97.
[http://dx.doi.org/10.1016/j.neulet.2006.12.003] [PMID:  17196747] 
[47] 
Hunot, S.; Boissière, F.; Faucheux, B.; Brugg, B.; Mouatt-Prigent, A.; Agid, Y.; Hirsch, E.C. Nitric oxide synthase and neuronal vulnerability in Parkinson’s disease. Neuroscience,  1996, 72(2), 355-363.
[http://dx.doi.org/10.1016/0306-4522(95)00578-1] [PMID:  8737406] 
[48] 
Knott, C.; Stern, G.; Wilkin, G.P. Inflammatory regulators in Parkinson’s disease: iNOS, lipocortin-1, and cyclooxygenases-1 and -2. Mol. Cell. Neurosci.,  2000, 16(6), 724-739.
[http://dx.doi.org/10.1006/mcne.2000.0914] [PMID:  11124893] 
[49] 
Mogi, M.; Harada, M.; Riederer, P.; Narabayashi, H.; Fujita, K.; Nagatsu, T. Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neurosci. Lett.,  1994, 165(1-2), 208-210.
[http://dx.doi.org/10.1016/0304-3940(94)90746-3] [PMID:  8015728] 
[50] 
Mogi, M.; Harada, M.; Kondo, T.; Riederer, P.; Inagaki, H.; Minami, M.; Nagatsu, T. 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(2), 147-150.
[http://dx.doi.org/10.1016/0304-3940(94)90508-8] [PMID:  7700568] 
[51] 
Mogi, M.; Harada, M.; Kondo, T.; Narabayashi, H.; Riederer, P.; Nagatsu, T. Transforming growth factor-beta 1 levels are elevated in the striatum and in ventricular cerebrospinal fluid in Parkinson’s disease. Neurosci. Lett.,  1995, 193(2), 129-132.
[http://dx.doi.org/10.1016/0304-3940(95)11686-Q] [PMID:  7478158] 
[52] 
Stypuła, G.; Kunert-Radek, J.; Stepień, H.; Zylińska, K.; Pawlikowski, M. Evaluation of interleukins, ACTH, cortisol and prolactin concentrations in the blood of patients with parkinson’s disease. Neuroimmunomodulation,  1996, 3(2-3), 131-134.
[http://dx.doi.org/10.1159/000097237] [PMID:  8945728] 
[53] 
Dobbs, R.J.; Charlett, A.; Purkiss, A.G.; Dobbs, S.M.; Weller, C.; Peterson, D.W. Association of circulating TNF-alpha and IL-6 with ageing and parkinsonism. Acta Neurol. Scand.,  1999, 100(1), 34-41.
[http://dx.doi.org/10.1111/j.1600-0404.1999.tb00721.x] [PMID:  10416510] 
[54] 
Rentzos, M.; Nikolaou, C.; Andreadou, E.; Paraskevas, G.P.; Rombos, A.; Zoga, M.; Tsoutsou, A.; Boufidou, F.; Kapaki, E.; Vassilopoulos, D. Circulating interleukin-15 and RANTES chemokine in Parkinson’s disease. Acta Neurol. Scand.,  2007, 116(6), 374-379.
[http://dx.doi.org/10.1111/j.1600-0404.2007.00894.x] [PMID:  17986095] 
[55] 
Rowe, D.B.; Le, W.; Smith, R.G.; Appel, S.H. Antibodies from patients with Parkinson’s disease react with protein modified by dopamine oxidation. J. Neurosci. Res.,  1998, 53(5), 551-558.
[http://dx.doi.org/10.1002/(SICI)1097-4547(19980901)53:5<551:AID-JNR5>3.0.CO;2-8] [PMID:  9726426] 
[56] 
Müller, 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(2), 142-144.
[http://dx.doi.org/10.1111/j.1600-0404.1998.tb01736.x] [PMID:  9724016] 
[57] 
Hirsch, E.C.; Hunot, S. Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol.,  2009, 8(4), 382-397.
[http://dx.doi.org/10.1016/S1474-4422(09)70062-6] [PMID:  19296921] 
[58] 
Liberatore, G.T.; Jackson-Lewis, V.; Vukosavic, S.; Mandir, A.S.; Vila, M.; McAuliffe, W.G.; Dawson, V.L.; Dawson, T.M.; Przedborski, S. Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat. Med.,  1999, 5(12), 1403-1409.
[http://dx.doi.org/10.1038/70978] [PMID:  10581083] 
[59] 
Wu, D.C.; Teismann, P.; Tieu, K.; Vila, M.; Jackson-Lewis, V.; Ischiropoulos, H.; Przedborski, S. NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. Proc. Natl. Acad. Sci. USA,  2003, 100(10), 6145-6150.
[http://dx.doi.org/10.1073/pnas.0937239100] [PMID:  12721370] 
[60] 
Ara, J.; Przedborski, S.; Naini, A.B.; Jackson-Lewis, V.; Trifiletti, R.R.; Horwitz, J.; Ischiropoulos, H. Inactivation of tyrosine hydroxylase by nitration following exposure to peroxynitrite and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Proc. Natl. Acad. Sci. USA,  1998, 95(13), 7659-7663.
[http://dx.doi.org/10.1073/pnas.95.13.7659] [PMID:  9636206] 
[61] 
Przedborski, S.; Chen, Q.; Vila, M.; Giasson, B.I.; Djaldatti, R.; Vukosavic, S.; Souza, J.M.; Jackson-Lewis, V.; Lee, V.M.; Ischiropoulos, H. Oxidative post-translational modifications of alpha-synuclein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease. J. Neurochem.,  2001, 76(2), 637-640.
[http://dx.doi.org/10.1046/j.1471-4159.2001.00174.x] [PMID:  11208927] 
[62] 
Esposito, E.; Di Matteo, V.; Benigno, A.; Pierucci, M.; Crescimanno, G.; Di Giovanni, G. Non-steroidal anti-inflammatory drugs in Parkinson’s disease. Exp. Neurol.,  2007, 205(2), 295-312.
[http://dx.doi.org/10.1016/j.expneurol.2007.02.008] [PMID:  17433296] 
[63] 
Bassani, T.B.; Vital, M.A.; Rauh, L.K. Neuroinflammation in the pathophysiology of Parkinson’s disease and therapeutic evidence of anti-inflammatory drugs. Arq. Neuropsiquiatr.,  2015, 73(7), 616-623.
[http://dx.doi.org/10.1590/0004-282X20150057] [PMID:  26200058] 
[64] 
Teismann, P.; Tieu, K.; Choi, D.K.; Wu, D.C.; Naini, A.; Hunot, S.; Vila, M.; Jackson-Lewis, V.; Przedborski, S. Cyclooxygenase-2 is instrumental in Parkinson’s disease neurodegeneration. Proc. Natl. Acad. Sci. USA,  2003, 100(9), 5473-5478.
[http://dx.doi.org/10.1073/pnas.0837397100] [PMID:  12702778] 
[65] 
Mogi, M.; Togari, A.; Kondo, T.; Mizuno, Y.; Komure, O.; Kuno, S.; Ichinose, H.; Nagatsu, T. Caspase activities and tumor necrosis factor receptor R1 (p55) level are elevated in the substantia nigra from parkinsonian brain. J. Neural Transm. (Vienna),  2000, 107(3), 335-341.
[http://dx.doi.org/10.1007/s007020050028] [PMID:  10821442] 
[66] 
Hengartner, M.O. The biochemistry of apoptosis. Nature,  2000, 407(6805), 770-776.
[http://dx.doi.org/10.1038/35037710] [PMID:  11048727] 
[67] 
Choi, C.; Benveniste, E.N. Fas ligand/Fas system in the brain: regulator of immune and apoptotic responses. Brain Res. Brain Res. Rev.,  2004, 44(1), 65-81.
[http://dx.doi.org/10.1016/j.brainresrev.2003.08.007] [PMID:  14739003] 
[68] 
Janabi, N.; Chabrier, S.; Tardieu, M. Endogenous nitric oxide activates prostaglandin F2 alpha production in human microglial cells but not in astrocytes: a study of interactions between eicosanoids, nitric oxide, and superoxide anion (O2-) regulatory pathways. J. Immunol.,  1996, 157(5), 2129-2135.
[PMID:  8757337] 
[69] 
Chen, H.; Zhang, S.M.; Hernán, M.A.; Schwarzschild, M.A.; Willett, W.C.; Colditz, G.A.; Speizer, F.E.; Ascherio, A. Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease. Arch. Neurol.,  2003, 60(8), 1059-1064.
[http://dx.doi.org/10.1001/archneur.60.8.1059] [PMID:  12925360] 
[70] 
Mosley, R.L.; Hutter-Saunders, J.A.; Stone, D.K.; Gendelman, H.E. Inflammation and adaptive immunity in Parkinson’s disease. Cold Spring Harb. Perspect. Med.,  2012, 2(1), a009381.
[http://dx.doi.org/10.1101/cshperspect.a009381] [PMID:  22315722] 
[71] 
Cappellano, G.; Carecchio, M.; Fleetwood, T.; Magistrelli, L.; Cantello, R.; Dianzani, U.; Comi, C. Immunity and inflammation in neurodegenerative diseases. Am. J. Neurodegener. Dis.,  2013, 2(2), 89-107.
[PMID:  23844334] 
[72] 
González, H.; Elgueta, D.; Montoya, A.; Pacheco, R. Neuroimmune regulation of microglial activity involved in neuroinflammation and neurodegenerative diseases. J. Neuroimmunol.,  2014, 274(1-2), 1-13.
[http://dx.doi.org/10.1016/j.jneuroim.2014.07.012] [PMID:  25091432] 
[73] 
Ferrari, C.C.; Tarelli, R. Parkinson’s disease and systemic inflammation. Parkinsons Dis.,  2011, 2011436813.
[http://dx.doi.org/10.4061/2011/436813] [PMID:  21403862] 
[74] 
Sanchez-Guajardo, V.; Barnum, C.J.; Tansey, M.G.; Romero-Ramos, M. Neuroimmunological processes in Parkinson’s disease and their relation to α-synuclein: microglia as the referee between neuronal processes and peripheral immunity. ASN Neuro,  2013, 5(2), 113-139.
[http://dx.doi.org/10.1042/AN20120066] [PMID:  23506036] 
[75] 
Fülöp, T.; Dupuis, G.; Witkowski, J.M.; Larbi, A. The role of immunosenescence in the development of age-related diseases. Rev. Invest. Clin.,  2016, 68(2), 84-91.
[PMID:  27103044] 
[76] 
Ciaramella, A.; Bizzoni, F.; Salani, F.; Vanni, D.; Spalletta, G.; Sanarico, N.; Vendetti, S.; Caltagirone, C.; Bossù, P. Increased pro-inflammatory response by dendritic cells from patients with Alzheimer’s disease. J. Alzheimers Dis.,  2010, 19(2), 559-572.
[http://dx.doi.org/10.3233/JAD-2010-1257] [PMID:  20110602] 
[77] 
Greter, M.; Heppner, F.L.; Lemos, M.P.; Odermatt, B.M.; Goebels, N.; Laufer, T.; Noelle, R.J.; Becher, B. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat. Med.,  2005, 11(3), 328-334.
[http://dx.doi.org/10.1038/nm1197] [PMID:  15735653] 
[78] 
Ciaramella, A.; Salani, F.; Bizzoni, F.; Pontieri, F.E.; Stefani, A.; Pierantozzi, M.; Assogna, F.; Caltagirone, C.; Spalletta, G.; Bossù, P. Blood dendritic cell frequency declines in idiopathic Parkinson’s disease and is associated with motor symptom severity. PLoS One,  2013, 8(6), e65352.
[http://dx.doi.org/10.1371/journal.pone.0065352] [PMID:  23776473] 
[79] 
Olweus, J. BitMansour, A.; Warnke, R.; Thompson, P.A.; Carballido, J.; Picker, L.J.; Lund-Johansen, F. Dendritic cell ontogeny: a human dendritic cell lineage of myeloid origin. Proc. Natl. Acad. Sci. USA,  1997, 94(23), 12551-12556.
[http://dx.doi.org/10.1073/pnas.94.23.12551] [PMID:  9356487] 
[80] 
Pawelec, G.; Derhovanessian, E.; Larbi, A.; Strindhall, J.; Wikby, A. Cytomegalovirus and human immunosenescence. Rev. Med. Virol.,  2009, 19(1), 47-56.
[http://dx.doi.org/10.1002/rmv.598] [PMID:  19035529] 
[81] 
Goldeck, D.; Maetzler, W.; Berg, D.; Oettinger, L.; Pawelec, G. Altered dendritic cell subset distribution in patients with Parkinson’s disease: Impact of CMV serostatus. J. Neuroimmunol.,  2016, 290, 60-65.
[http://dx.doi.org/10.1016/j.jneuroim.2015.11.008] [PMID:  26711571] 
[82] 
Mohammad, M.G.; Tsai, V.W.; Ruitenberg, M.J.; Hassanpour, M.; Li, H.; Hart, P.H.; Breit, S.N.; Sawchenko, P.E.; Brown, D.A. Immune cell trafficking from the brain maintains CNS immune tolerance. J. Clin. Invest.,  2014, 124(3), 1228-1241.
[http://dx.doi.org/10.1172/JCI71544] [PMID:  24569378] 
[83] 
Bossù, P.; Spalletta, G.; Caltagirone, C.; Ciaramella, A. Myeloid dendritic cells are potential players in human neurodegenerative diseases. Front. Immunol.,  2015, 6, 632.
[http://dx.doi.org/10.3389/fimmu.2015.00632] [PMID:  26734003] 
[84] 
Della Bella, S.; Bierti, L.; Presicce, P.; Arienti, R.; Valenti, M.; Saresella, M.; Vergani, C.; Villa, M.L. Peripheral blood dendritic cells and monocytes are differently regulated in the elderly. Clin. Immunol.,  2007, 122(2), 220-228.
[http://dx.doi.org/10.1016/j.clim.2006.09.012] [PMID:  17101294] 
[85] 
Adema, G.J. Dendritic cells from bench to bedside and back. Immunol. Lett.,  2009, 122(2), 128-130.
[http://dx.doi.org/10.1016/j.imlet.2008.11.017] [PMID:  19121337] 
[86] 
Gupta, S. Role of dendritic cells in innate and adaptive immune response in human aging. Exp. Gerontol.,  2014, 54, 47-52.
[http://dx.doi.org/10.1016/j.exger.2013.12.009] [PMID:  24370374] 
[87] 
Kim, H.J. Alpha-Synuclein Expression in Patients with Parkinson’s Disease: A Clinician’s Perspective. Exp. Neurobiol.,  2013, 22(2), 77-83.
[http://dx.doi.org/10.5607/en.2013.22.2.77] [PMID:  23833556] 
[88] 
Codolo, G.; Plotegher, N.; Pozzobon, T.; Brucale, M.; Tessari, I.; Bubacco, L.; de Bernard, M. Triggering of inflammasome by aggregated α-synuclein, an inflammatory response in synucleinopathies. PLoS One,  2013, 8(1), e55375.
[http://dx.doi.org/10.1371/journal.pone.0055375] [PMID:  23383169] 
[89] 
Grozdanov, V.; Bliederhaeuser, C.; Ruf, W.P.; Roth, V.; Fundel-Clemens, K.; Zondler, L.; Brenner, D.; Martin-Villalba, A.; Hengerer, B.; Kassubek, J.; Ludolph, A.C.; Weishaupt, J.H.; Danzer, K.M. Inflammatory dysregulation of blood monocytes in Parkinson’s disease patients. Acta Neuropathol.,  2014, 128(5), 651-663.
[http://dx.doi.org/10.1007/s00401-014-1345-4] [PMID:  25284487] 
[90] 
Serbina, N.V.; Pamer, E.G. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat. Immunol.,  2006, 7(3), 311-317.
[http://dx.doi.org/10.1038/ni1309] [PMID:  16462739] 
[91] 
Funk, N.; Wieghofer, P.; Grimm, S.; Schaefer, R.; Bühring, H.J.; Gasser, T.; Biskup, S. Characterization of peripheral hematopoietic stem cells and monocytes in Parkinson’s disease. Mov. Disord.,  2013, 28(3), 392-395.
[http://dx.doi.org/10.1002/mds.25300] [PMID:  23401086] 
[92] 
da Silva, D.J.; Borges, A.F.; Souza, P.O.; de Souza, P.R.; Cardoso, C.R.; Dorta, M.L.; de Oliveira, M.A.; Teixeira, A.L.; Ribeiro-Dias, F. Decreased Toll-like receptor 2 and Toll-like receptor 7/8-induced cytokines in Parkinson’s Disease patients. Neuroimmunomodulation,  2016, 23(1), 58-66.
[http://dx.doi.org/10.1159/000443238] [PMID:  26886382] 
[93] 
Djukic, M.; Mildner, A.; Schmidt, H.; Czesnik, D.; Brück, W.; Priller, J.; Nau, R.; Prinz, M. Circulating monocytes engraft in the brain, differentiate into microglia and contribute to the pathology following meningitis in mice. Brain,  2006, 129(Pt 9), 2394-2403.
[http://dx.doi.org/10.1093/brain/awl206] [PMID:  16891321] 
[94] 
Delpedro, A.D.; Barjavel, M.J.; Mamdouh, Z.; Bakouche, O. Activation of human monocytes by LPS and DHEA. J. Interferon Cytokine Res.,  1998, 18(2), 125-135.
[http://dx.doi.org/10.1089/jir.1998.18.125] [PMID:  9506463] 
[95] 
Mariani, E.; Pulsatelli, L.; Neri, S.; Dolzani, P.; Meneghetti, A.; Silvestri, T.; Ravaglia, G.; Forti, P.; Cattini, L.; Facchini, A. RANTES and MIP-1alpha production by T lymphocytes, monocytes and NK cells from nonagenarian subjects. Exp. Gerontol.,  2002, 37(2-3), 219-226.
[http://dx.doi.org/10.1016/S0531-5565(01)00187-5] [PMID:  11772507] 
[96] 
van Duin, D.; Mohanty, S.; Thomas, V.; Ginter, S.; Montgomery, R.R.; Fikrig, E.; Allore, H.G.; Medzhitov, R.; Shaw, A.C. Age-associated defect in human TLR-1/2 function. J. Immunol.,  2007, 178(2), 970-975.
[http://dx.doi.org/10.4049/jimmunol.178.2.970] [PMID:  17202359] 
[97] 
De La Fuente, M. Changes in the macrophage function with aging. Comp. Biochem. Physiol. A Comp. Physiol.,  1985, 81(4), 935-938.
[http://dx.doi.org/10.1016/0300-9629(85)90933-8] [PMID:  2863082] 
[98] 
Hendriks, J.J.; Teunissen, C.E.; de Vries, H.E.; Dijkstra, C.D. Macrophages and neurodegeneration. Brain Res. Brain Res. Rev.,  2005, 48(2), 185-195.
[http://dx.doi.org/10.1016/j.brainresrev.2004.12.008] [PMID:  15850657] 
[99] 
Kigerl, K.A.; Gensel, J.C.; Ankeny, D.P.; Alexander, J.K.; Donnelly, D.J.; Popovich, P.G. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J. Neurosci.,  2009, 29(43), 13435-13444.
[http://dx.doi.org/10.1523/JNEUROSCI.3257-09.2009] [PMID:  19864556] 
[100] 
Haney, M.J.; Zhao, Y.; Li, S.; Higginbotham, S.M.; Booth, S.L.; Han, H.Y.; Vetro, J.A.; Mosley, R.L.; Kabanov, A.V.; Gendelman, H.E.; Batrakova, E.V. Cell-mediated transfer of catalase nanoparticles from macrophages to brain endothelial, glial and neuronal cells. Nanomedicine (Lond.),  2011, 6(7), 1215-1230.
[http://dx.doi.org/10.2217/nnm.11.32] [PMID:  21449849] 
[101] 
Biju, K.; Zhou, Q.; Li, G.; Imam, S.Z.; Roberts, J.L.; Morgan, W.W.; Clark, R.A.; Li, S. Macrophage-mediated GDNF delivery protects against dopaminergic neurodegeneration: a therapeutic strategy for Parkinson’s disease. Mol. Ther.,  2010, 18(8), 1536-1544.
[http://dx.doi.org/10.1038/mt.2010.107] [PMID:  20531393] 
[102] 
Haney, M.J.; Zhao, Y.; Harrison, E.B.; Mahajan, V.; Ahmed, S.; He, Z.; Suresh, P.; Hingtgen, S.D.; Klyachko, N.L.; Mosley, R.L.; Gendelman, H.E.; Kabanov, A.V.; Batrakova, E.V. Specific transfection of inflamed brain by macrophages: a new therapeutic strategy for neurodegenerative diseases. PLoS One,  2013, 8(4), e61852.
[http://dx.doi.org/10.1371/journal.pone.0061852] [PMID:  23620794] 
[103] 
Biju, K.C.; Santacruz, R.A.; Chen, C.; Zhou, Q.; Yao, J.; Rohrabaugh, S.L.; Clark, R.A.; Roberts, J.L.; Phillips, K.A.; Imam, S.Z.; Li, S. Bone marrow-derived microglia-based neurturin delivery protects against dopaminergic neurodegeneration in a mouse model of Parkinson’s disease. Neurosci. Lett.,  2013, 535, 24-29.
[http://dx.doi.org/10.1016/j.neulet.2012.12.034] [PMID:  23295906] 
[104] 
Harris, S.G.; Padilla, J.; Koumas, L.; Ray, D.; Phipps, R.P. Prostaglandins as modulators of immunity. Trends Immunol.,  2002, 23(3), 144-150.
[http://dx.doi.org/10.1016/S1471-4906(01)02154-8] [PMID:  11864843] 
[105] 
Wu, D.; Meydani, S.N. Mechanism of age-associated up-regulation in macrophage PGE2 synthesis. Brain Behav. Immun.,  2004, 18(6), 487-494.
[http://dx.doi.org/10.1016/j.bbi.2004.05.003] [PMID:  15331118] 
[106] 
Mihara, T.; Nakashima, M.; Kuroiwa, A.; Akitake, Y.; Ono, K.; Hosokawa, M.; Yamada, T.; Takahashi, M. Natural killer cells of Parkinson’s disease patients are set up for activation: a possible role for innate immunity in the pathogenesis of this disease. Parkinsonism Relat. Disord.,  2008, 14(1), 46-51.
[http://dx.doi.org/10.1016/j.parkreldis.2007.05.013] [PMID:  17702627] 
[107] 
Niwa, F.; Kuriyama, N.; Nakagawa, M.; Imanishi, J. Effects of peripheral lymphocyte subpopulations and the clinical correlation with Parkinson’s disease. Geriatr. Gerontol. Int.,  2012, 12(1), 102-107.
[http://dx.doi.org/10.1111/j.1447-0594.2011.00740.x] [PMID:  21929737] 
[108] 
Ogata, K.; Yokose, N.; Tamura, H.; An, E.; Nakamura, K.; Dan, K.; Nomura, T. Natural killer cells in the late decades of human life. Clin. Immunol. Immunopathol.,  1997, 84(3), 269-275.
[http://dx.doi.org/10.1006/clin.1997.4401] [PMID:  9281385] 
[109] 
Borrego, F.; Alonso, M.C.; Galiani, M.D.; Carracedo, J.; Ramirez, R.; Ostos, B.; Peña, J.; Solana, R. NK phenotypic markers and IL2 response in NK cells from elderly people. Exp. Gerontol.,  1999, 34(2), 253-265.
[http://dx.doi.org/10.1016/S0531-5565(98)00076-X] [PMID:  10363791] 
[110] 
Myśliwska, J.; Bryl, E.; Bigda, J.; Kmieć, Z.; Foerster, J.; Myśliwski, A. [Activity of NK in elderly people Acta Haematol. Pol.,  1992, 23(4), 245-251.
[PMID:  1293905] 
[111] 
Greenberg, S.S.; Ouyang, J.; Zhao, X.; Giles, T.D. Human and rat neutrophils constitutively express neural nitric oxide synthase mRNA. Nitric Oxide,  1998, 2(3), 203-212.
[http://dx.doi.org/10.1006/niox.1998.0176] [PMID:  9731638] 
[112] 
Gatto, E.M.; Carreras, M.C.; Pargament, G.A.; Riobo´, N.A.; Reides, C.; Repetto, M.; Fernandez Pardal, M.M.; Llesuy, S.; Poderoso, J.J. Neutrophil function, nitric oxide, and blood oxidative stress in Parkinson’s disease. Mov. Disord.,  1996, 11(3), 261-267.
[http://dx.doi.org/10.1002/mds.870110308] [PMID:  8723142] 
[113] 
Gatto, E.M.; Riobó, N.A.; Carreras, M.C.; Schöpfer, F.J.; Pargament, G.A.; Poderoso, J.J. Circulating plasma factors in Parkinson’s disease enhance nitric oxide release of normal human neutrophils. J. Neurol. Sci.,  1999, 165(1), 66-70.
[http://dx.doi.org/10.1016/S0022-510X(99)00079-9] [PMID:  10426150] 
[114] 
Barthwal, M.K.; Srivastava, N.; Shukla, R.; Nag, D.; Seth, P.K.; Srimal, R.C.; Dikshit, M. Polymorphonuclear leukocyte nitrite content and antioxidant enzymes in Parkinson’s disease patients. Acta Neurol. Scand.,  1999, 100(5), 300-304.
[http://dx.doi.org/10.1111/j.1600-0404.1999.tb00400.x] [PMID:  10536916] 
[115] 
Gatto, E.M.; Riobó, N.A.; Carreras, M.C.; Cherñavsky, A.; Rubio, A.; Satz, M.L.; Poderoso, J.J. Overexpression of neutrophil neuronal nitric oxide synthase in Parkinson’s disease. Nitric Oxide,  2000, 4(5), 534-539.
[http://dx.doi.org/10.1006/niox.2000.0288] [PMID:  11020342] 
[116] 
Salman, H.; Bergman, M.; Djaldetti, R.; Bessler, H.; Djaldetti, M. Decreased phagocytic function in patients with Parkinson’s disease. Biomed. Pharmacother.,  1999, 53(3), 146-148.
[http://dx.doi.org/10.1016/S0753-3322(99)80080-8] [PMID:  10349503] 
[117] 
Fulop, T.; Larbi, A.; Douziech, N.; Fortin, C.; Guérard, K.P.; Lesur, O.; Khalil, A.; Dupuis, G. Signal transduction and functional changes in neutrophils with aging. Aging Cell,  2004, 3(4), 217-226.
[http://dx.doi.org/10.1111/j.1474-9728.2004.00110.x] [PMID:  15268755] 
[118] 
Lord, J.M.; Butcher, S.; Killampali, V.; Lascelles, D.; Salmon, M. Neutrophil ageing and immunesenescence. Mech. Ageing Dev.,  2001, 122(14), 1521-1535.
[http://dx.doi.org/10.1016/S0047-6374(01)00285-8] [PMID:  11511394] 
[119] 
Wenisch, C.; Patruta, S.; Daxböck, F.; Krause, R.; Hörl, W. Effect of age on human neutrophil function. J. Leukoc. Biol.,  2000, 67(1), 40-45.
[http://dx.doi.org/10.1002/jlb.67.1.40] [PMID:  10647996] 
[120] 
Tortorella, C.; Piazzolla, G.; Napoli, N.; Antonaci, S. Neutrophil apoptotic cell death: does it contribute to the increased infectious risk in aging? Microbios,  2001, 106(414), 129-136.
[PMID:  11506063] 
[121] 
Bas, J.; Calopa, M.; Mestre, M.; Molleví, D.G.; Cutillas, B.; Ambrosio, S.; Buendia, E. Lymphocyte populations in Parkinson’s disease and in rat models of parkinsonism. J. Neuroimmunol.,  2001, 113(1), 146-152.
[http://dx.doi.org/10.1016/S0165-5728(00)00422-7] [PMID:  11137586] 
[122] 
Stevens, C.H.; Rowe, D.; Morel-Kopp, M.C.; Orr, C.; Russell, T.; Ranola, M.; Ward, C.; Halliday, G.M. Reduced T helper and B lymphocytes in Parkinson’s disease. J. Neuroimmunol.,  2012, 252(1-2), 95-99.
[http://dx.doi.org/10.1016/j.jneuroim.2012.07.015] [PMID:  22910543] 
[123] 
Bulati, M.; Buffa, S.; Candore, G.; Caruso, C.; Dunn-Walters, D.K.; Pellicanò, M.; Wu, Y.C.; Colonna Romano, G. B cells and immunosenescence: a focus on IgG+IgD-CD27- (DN) B cells in aged humans. Ageing Res. Rev.,  2011, 10(2), 274-284.
[http://dx.doi.org/10.1016/j.arr.2010.12.002] [PMID:  21185406] 
[124] 
Kedmi, M.; Bar-Shira, A.; Gurevich, T.; Giladi, N.; Orr-Urtreger, A. Decreased expression of B cell related genes in leukocytes of women with Parkinson’s disease. Mol. Neurodegener.,  2011, 6, 66.
[http://dx.doi.org/10.1186/1750-1326-6-66] [PMID:  21943286] 
[125] 
Kobo, H.; Bar-Shira, A.; Dahary, D.; Gan-Or, Z.; Mirelman, A.; Goldstein, O.; Giladi, N.; Orr-Urtreger, A. Down-regulation of B cell-related genes in peripheral blood leukocytes of Parkinson’s disease patients with and without GBA mutations. Mol. Genet. Metab.,  2016, 117(2), 179-185.
[http://dx.doi.org/10.1016/j.ymgme.2015.09.005] [PMID:  26410072] 
[126] 
Geginat, J.; Paroni, M.; Maglie, S.; Alfen, J.S.; Kastirr, I.; Gruarin, P.; De Simone, M.; Pagani, M.; Abrignani, S. Plasticity of human CD4 T cell subsets. Front. Immunol.,  2014, 5, 630.
[http://dx.doi.org/10.3389/fimmu.2014.00630] [PMID:  25566245] 
[127] 
González, H.; Pacheco, R. T-cell-mediated regulation of neuroinflammation involved in neurodegenerative diseases. J. Neuroinflammation,  2014, 11, 201.
[http://dx.doi.org/10.1186/s12974-014-0201-8] [PMID:  25441979] 
[128] 
Kebir, H.; Kreymborg, K.; Ifergan, I.; Dodelet-Devillers, A.; Cayrol, R.; Bernard, M.; Giuliani, F.; Arbour, N.; Becher, B.; Prat, A. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat. Med.,  2007, 13(10), 1173-1175.
[http://dx.doi.org/10.1038/nm1651] [PMID:  17828272] 
[129] 
Appel, S.H. CD4+ T cells mediate cytotoxicity in neurodegenerative diseases. J. Clin. Invest.,  2009, 119(1), 13-15.
[PMID:  19104142] 
[130] 
Hisanaga, K.; Asagi, M.; Itoyama, Y.; Iwasaki, Y. Increase in peripheral CD4 bright+ CD8 dull+ T cells in Parkinson disease. Arch. Neurol.,  2001, 58(10), 1580-1583.
[http://dx.doi.org/10.1001/archneur.58.10.1580] [PMID:  11594915] 
[131] 
Baba, Y.; Kuroiwa, A.; Uitti, R.J.; Wszolek, Z.K.; Yamada, T. Alterations of T-lymphocyte populations in Parkinson disease. Parkinsonism Relat. Disord.,  2005, 11(8), 493-498.
[http://dx.doi.org/10.1016/j.parkreldis.2005.07.005] [PMID:  16154792] 
[132] 
Stone, D.K.; Reynolds, A.D.; Mosley, R.L.; Gendelman, H.E. Innate and adaptive immunity for the pathobiology of Parkinson’s disease. Antioxid. Redox Signal.,  2009, 11(9), 2151-2166.
[http://dx.doi.org/10.1089/ars.2009.2460] [PMID:  19243239] 
[133] 
Saunders, J.A.; Estes, K.A.; Kosloski, L.M.; Allen, H.E.; Dempsey, K.M.; Torres-Russotto, D.R.; Meza, J.L.; Santamaria, P.M.; Bertoni, J.M.; Murman, D.L.; Ali, H.H.; Standaert, D.G.; Mosley, R.L.; Gendelman, H.E. CD4+ regulatory and effector/memory T cell subsets profile motor dysfunction in Parkinson’s disease. J. Neuroimmune Pharmacol.,  2012, 7(4), 927-938.
[http://dx.doi.org/10.1007/s11481-012-9402-z] [PMID:  23054369] 
[134] 
Kustrimovic, N.; Rasini, E.; Legnaro, M.; Bombelli, R.; Aleksic, I.; Blandini, F.; Comi, C.; Mauri, M.; Minafra, B.; Riboldazzi, G.; Sanchez-Guajardo, V.; Marino, F.; Cosentino, M. Dopaminergic receptors on CD4+ T naive and memory lymphocytes correlate with motor impairment in patients with Parkinson’s disease. Sci. Rep.,  2016, 6, 33738.
[http://dx.doi.org/10.1038/srep33738] [PMID:  27652978] 
[135] 
Ponomarev, E.D.; Dittel, B.N. Gamma delta T cells regulate the extent and duration of inflammation in the central nervous system by a Fas ligand-dependent mechanism. J. Immunol.,  2005, 174(8), 4678-4687.
[http://dx.doi.org/10.4049/jimmunol.174.8.4678] [PMID:  15814692] 
[136] 
Fiszer, U.; Mix, E.; Fredrikson, S.; Kostulas, V.; Olsson, T.; Link, H. gamma delta+ T cells are increased in patients with Parkinson’s disease. J. Neurol. Sci.,  1994, 121(1), 39-45.
[http://dx.doi.org/10.1016/0022-510X(94)90154-6] [PMID:  8133310] 
[137] 
Calopa, M.; Bas, J.; Callén, A.; Mestre, M. Apoptosis of peripheral blood lymphocytes in Parkinson patients. Neurobiol. Dis.,  2010, 38(1), 1-7.
[http://dx.doi.org/10.1016/j.nbd.2009.12.017] [PMID:  20044003] 
[138] 
Lebouvier, T.; Neunlist, M.; Bruley des Varannes, S.; Coron, E.; Drouard, A.; N’Guyen, J.M.; Chaumette, T.; Tasselli, M.; Paillusson, S.; Flamand, M.; Galmiche, J.P.; Damier, P.; Derkinderen, P. Colonic biopsies to assess the neuropathology of Parkinson’s disease and its relationship with symptoms. PLoS One,  2010, 5(9), e12728.
[http://dx.doi.org/10.1371/journal.pone.0012728] [PMID:  20856865] 
[139] 
Ross, E.A.; Coughlan, R.E.; Flores-Langarica, A.; Bobat, S.; Marshall, J.L.; Hussain, K.; Charlesworth, J.; Abhyankar, N.; Hitchcock, J.; Gil, C.; López-Macías, C.; Henderson, I.R.; Khan, M.; Watson, S.P.; MacLennan, I.C.; Buckley, C.D.; Cunningham, A.F. CD31 is required on CD4+ T cells to promote T cell survival during Salmonella infection. J. Immunol.,  2011, 187(4), 1553-1565.
[http://dx.doi.org/10.4049/jimmunol.1000502] [PMID:  21734076] 
[140] 
Oyaizu, N.; McCloskey, T.W.; Than, S.; Hu, R.; Kalyanaraman, V.S.; Pahwa, S. Cross-linking of CD4 molecules upregulates Fas antigen expression in lymphocytes by inducing interferon-gamma and tumor necrosis factor-alpha secretion. Blood,  1994, 84(8), 2622-2631.
[PMID:  7522637] 
[141] 
Demeure, C.E.; Byun, D.G.; Yang, L.P.; Vezzio, N.; Delespesse, G. CD31 (PECAM-1) is a differentiation antigen lost during human CD4 T-cell maturation into Th1 or Th2 effector cells. Immunology,  1996, 88(1), 110-115.
[http://dx.doi.org/10.1046/j.1365-2567.1996.d01-652.x] [PMID:  8707335] 
[142] 
Kustrimovic, N.; Rasini, E.; Legnaro, M.; Marino, F.; Cosentino, M. Expression of dopaminergic receptors on human CD4+ T lymphocytes: flow cytometric analysis of naive and memory subsets and relevance for the neuroimmunology of neurodegenerative disease. J. Neuroimmune Pharmacol.,  2014, 9(3), 302-312.
[http://dx.doi.org/10.1007/s11481-014-9541-5] [PMID:  24682738] 
[143] 
Sallusto, F.; Geginat, J.; Lanzavecchia, A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu. Rev. Immunol.,  2004, 22, 745-763.
[http://dx.doi.org/10.1146/annurev.immunol.22.012703.104702] [PMID:  15032595] 
[144] 
Lazuardi, L.; Jenewein, B.; Wolf, A.M.; Pfister, G.; Tzankov, A.; Grubeck-Loebenstein, B. Age-related loss of naïve T cells and dysregulation of T-cell/B-cell interactions in human lymph nodes. Immunology,  2005, 114(1), 37-43.
[http://dx.doi.org/10.1111/j.1365-2567.2004.02006.x] [PMID:  15606793] 
[145] 
Agace, W.W. Tissue-tropic effector T cells: generation and targeting opportunities. Nat. Rev. Immunol.,  2006, 6(9), 682-692.
[http://dx.doi.org/10.1038/nri1869] [PMID:  16932753] 
[146] 
Engelhardt, B.; Ransohoff, R.M. The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends Immunol.,  2005, 26(9), 485-495.
[http://dx.doi.org/10.1016/j.it.2005.07.004] [PMID:  16039904] 
[147] 
Forsyth, C.B.; Shannon, K.M.; Kordower, J.H.; Voigt, R.M.; Shaikh, M.; Jaglin, J.A.; Estes, J.D.; Dodiya, H.B.; Keshavarzian, A. Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson’s disease. PLoS One,  2011, 6(12), e28032.
[http://dx.doi.org/10.1371/journal.pone.0028032] [PMID:  22145021] 
[148] 
Di Sabatino, A.; Rovedatti, L.; Rosado, M.M.; Carsetti, R.; Corazza, G.R.; MacDonald, T.T. Increased expression of mucosal addressin cell adhesion molecule 1 in the duodenum of patients with active celiac disease is associated with depletion of integrin alpha4beta7-positive T cells in blood. Hum. Pathol.,  2009, 40(5), 699-704.
[http://dx.doi.org/10.1016/j.humpath.2008.10.014] [PMID:  19157500] 
[149] 
Hawkes, C.H.; Del Tredici, K.; Braak, H. A timeline for Parkinson’s disease. Parkinsonism Relat. Disord.,  2010, 16(2), 79-84.
[http://dx.doi.org/10.1016/j.parkreldis.2009.08.007] [PMID:  19846332] 
[150] 
Baecher-Allan, C.; Brown, J.A.; Freeman, G.J.; Hafler, D.A. CD4+CD25high regulatory cells in human peripheral blood. J. Immunol.,  2001, 167(3), 1245-1253.
[http://dx.doi.org/10.4049/jimmunol.167.3.1245] [PMID:  11466340] 
[151] 
Kipnis, J.; Mizrahi, T.; Hauben, E.; Shaked, I.; Shevach, E.; Schwartz, M. Neuroprotective autoimmunity: naturally occurring CD4+CD25+ regulatory T cells suppress the ability to withstand injury to the central nervous system. Proc. Natl. Acad. Sci. USA,  2002, 99(24), 15620-15625.
[http://dx.doi.org/10.1073/pnas.232565399] [PMID:  12429857] 
[152] 
Sakaguchi, S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol.,  2004, 22, 531-562.
[http://dx.doi.org/10.1146/annurev.immunol.21.120601.141122] [PMID:  15032588] 
[153] 
Thornton, A.M.; Shevach, E.M. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med.,  1998, 188(2), 287-296.
[http://dx.doi.org/10.1084/jem.188.2.287] [PMID:  9670041] 
[154] 
Reynolds, A.D.; Banerjee, R.; Liu, J.; Gendelman, H.E.; Mosley, R.L. Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson’s disease. J. Leukoc. Biol.,  2007, 82(5), 1083-1094.
[http://dx.doi.org/10.1189/jlb.0507296] [PMID:  17675560] 
[155] 
Reynolds, A.D.; Stone, D.K.; Mosley, R.L.; Gendelman, H.E. Proteomic studies of nitrated alpha-synuclein microglia regulation by CD4+CD25+ T cells. J. Proteome Res.,  2009, 8(7), 3497-3511.
[http://dx.doi.org/10.1021/pr9001614] [PMID:  19432400] 
[156] 
Reynolds, A.D.; Stone, D.K.; Hutter, J.A.; Benner, E.J.; Mosley, R.L.; Gendelman, H.E. Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson’s disease. J. Immunol.,  2010, 184(5), 2261-2271.
[http://dx.doi.org/10.4049/jimmunol.0901852] [PMID:  20118279] 
[157] 
Klüter, H.; Vieregge, P.; Stolze, H.; Kirchner, H. Defective production of interleukin-2 in patients with idiopathic Parkinson’s disease. J. Neurol. Sci.,  1995, 133(1-2), 134-139.
[http://dx.doi.org/10.1016/0022-510X(95)00180-A] [PMID:  8583216] 
[158] 
Bessler, H.; Djaldetti, R.; Salman, H.; Bergman, M.; Djaldetti, M. IL-1 beta, IL-2, IL-6 and TNF-alpha production by peripheral blood mononuclear cells from patients with Parkinson’s disease. Biomed. Pharmacother.,  1999, 53(3), 141-145.
[http://dx.doi.org/10.1016/S0753-3322(99)80079-1] [PMID:  10349502] 
[159] 
Reale, M.; Iarlori, C.; Thomas, A.; Gambi, D.; Perfetti, B.; Di Nicola, M.; Onofrj, M. Peripheral cytokines profile in Parkinson’s disease. Brain Behav. Immun.,  2009, 23(1), 55-63.
[http://dx.doi.org/10.1016/j.bbi.2008.07.003] [PMID:  18678243] 
[160] 
Hasegawa, Y.; Inagaki, T.; Sawada, M.; Suzumura, A. Impaired cytokine production by peripheral blood mononuclear cells and monocytes/macrophages in Parkinson’s disease. Acta Neurol. Scand.,  2000, 101(3), 159-164.
[http://dx.doi.org/10.1034/j.1600-0404.2000.101003159.x] [PMID:  10705937] 
[161] 
Rentzos, M.; Nikolaou, C.; Andreadou, E.; Paraskevas, G.P.; Rombos, A.; Zoga, M.; Tsoutsou, A.; Boufidou, F.; Kapaki, E.; Vassilopoulos, D. Circulating interleukin-10 and interleukin-12 in Parkinson’s disease. Acta Neurol. Scand.,  2009, 119(5), 332-337.
[http://dx.doi.org/10.1111/j.1600-0404.2008.01103.x] [PMID:  18976327] 
[162] 
Elias, R.; Karantanos, T.; Sira, E.; Hartshorn, K.L. Immunotherapy comes of age: immune aging & checkpoint inhibitors. J. Geriatr. Oncol.,  2017, 8(3), 229-235.
[http://dx.doi.org/10.1016/j.jgo.2017.02.001] [PMID:  28223073] 
[163] 
Haynes, L.; Eaton, S.M.; Burns, E.M.; Rincon, M.; Swain, S.L. Inflammatory cytokines overcome age-related defects in CD4 T cell responses in vivo. J. Immunol.,  2004, 172(9), 5194-5199.
[http://dx.doi.org/10.4049/jimmunol.172.9.5194] [PMID:  15100256] 
[164] 
Schwab, R.; Szabo, P.; Manavalan, J.S.; Weksler, M.E.; Posnett, D.N.; Pannetier, C.; Kourilsky, P.; Even, J. Expanded CD4+ and CD8+ T cell clones in elderly humans. J. Immunol.,  1997, 158(9), 4493-4499.
[PMID:  9127016] 
[165] 
Huang, M.C.; Liao, J.J.; Bonasera, S.; Longo, D.L.; Goetzl, E.J. Nuclear factor-kappaB-dependent reversal of aging-induced alterations in T cell cytokines. FASEB J.,  2008, 22(7), 2142-2150.
[http://dx.doi.org/10.1096/fj.07-103721] [PMID:  18267981] 
[166] 
Weiskopf, D.; Weinberger, B.; Grubeck-Loebenstein, B. The aging of the immune system. Transpl. Int.,  2009, 22(11), 1041-1050.
[http://dx.doi.org/10.1111/j.1432-2277.2009.00927.x] [PMID:  19624493] 
[167] 
Czesnikiewicz-Guzik, M.; Lee, W.W.; Cui, D.; Hiruma, Y.; Lamar, D.L.; Yang, Z.Z.; Ouslander, J.G.; Weyand, C.M.; Goronzy, J.J. T cell subset-specific susceptibility to aging. Clin. Immunol.,  2008, 127(1), 107-118.
[http://dx.doi.org/10.1016/j.clim.2007.12.002] [PMID:  18222733] 
[168] 
van der Geest, K.S.; Abdulahad, W.H.; Tete, S.M.; Lorencetti, P.G.; Horst, G.; Bos, N.A.; Kroesen, B.J.; Brouwer, E.; Boots, A.M. Aging disturbs the balance between effector and regulatory CD4+ T cells. Exp. Gerontol.,  2014, 60, 190-196.
[http://dx.doi.org/10.1016/j.exger.2014.11.005] [PMID:  25449852] 
[169] 
Raynor, J.; Lages, C.S.; Shehata, H.; Hildeman, D.A.; Chougnet, C.A. Homeostasis and function of regulatory T cells in aging. Curr. Opin. Immunol.,  2012, 24(4), 482-487.
[http://dx.doi.org/10.1016/j.coi.2012.04.005] [PMID:  22560294] 
[170] 
Gregg, R.; Smith, C.M.; Clark, F.J.; Dunnion, D.; Khan, N.; Chakraverty, R.; Nayak, L.; Moss, P.A. The number of human peripheral blood CD4+ CD25high regulatory T cells increases with age. Clin. Exp. Immunol.,  2005, 140(3), 540-546.
[http://dx.doi.org/10.1111/j.1365-2249.2005.02798.x] [PMID:  15932517] 
[171] 
Ransohoff, R.M.; Engelhardt, B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat. Rev. Immunol.,  2012, 12(9), 623-635.
[http://dx.doi.org/10.1038/nri3265] [PMID:  22903150] 
[172] 
Louveau, A.; Smirnov, I.; Keyes, T.J.; Eccles, J.D.; Rouhani, S.J.; Peske, J.D.; Derecki, N.C.; Castle, D.; Mandell, J.W.; Lee, K.S.; Harris, T.H.; Kipnis, J. Structural and functional features of central nervous system lymphatic vessels. Nature,  2015, 523(7560), 337-341.
[http://dx.doi.org/10.1038/nature14432] [PMID:  26030524] 
[173] 
Stolp, H.B.; Dziegielewska, K.M. Review: Role of developmental inflammation and blood-brain barrier dysfunction in neurodevelopmental and neurodegenerative diseases. Neuropathol. Appl. Neurobiol.,  2009, 35(2), 132-146.
[http://dx.doi.org/10.1111/j.1365-2990.2008.01005.x] [PMID:  19077110] 
[174] 
Brochard, V.; Combadière, B.; Prigent, A.; Laouar, Y.; Perrin, A.; Beray-Berthat, V.; Bonduelle, O.; Alvarez-Fischer, D.; Callebert, J.; Launay, J.M.; Duyckaerts, C.; Flavell, R.A.; Hirsch, E.C.; Hunot, S. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J. Clin. Invest.,  2009, 119(1), 182-192.
[PMID:  19104149] 
[175] 
Kortekaas, R.; Leenders, K.L.; van Oostrom, J.C.; Vaalburg, W.; Bart, J.; Willemsen, A.T.; Hendrikse, N.H. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann. Neurol.,  2005, 57(2), 176-179.
[http://dx.doi.org/10.1002/ana.20369] [PMID:  15668963] 
[176] 
Pisani, V.; Stefani, A.; Pierantozzi, M.; Natoli, S.; Stanzione, P.; Franciotta, D.; Pisani, A. Increased blood-cerebrospinal fluid transfer of albumin in advanced Parkinson’s disease. J. Neuroinflammation,  2012, 9, 188.
[http://dx.doi.org/10.1186/1742-2094-9-188] [PMID:  22870899] 
[177] 
Gray, M.T.; Woulfe, J.M. Striatal blood-brain barrier permeability in Parkinson’s disease. J. Cereb. Blood Flow Metab.,  2015, 35(5), 747-750.
[http://dx.doi.org/10.1038/jcbfm.2015.32] [PMID:  25757748] 
[178] 
Hickey, W.F. Leukocyte traffic in the central nervous system: the participants and their roles. Semin. Immunol.,  1999, 11(2), 125-137.
[http://dx.doi.org/10.1006/smim.1999.0168] [PMID:  10329499] 
[179] 
Togo, T.; Akiyama, H.; Iseki, E.; Kondo, H.; Ikeda, K.; Kato, M.; Oda, T.; Tsuchiya, K.; Kosaka, K. Occurrence of T cells in the brain of Alzheimer’s disease and other neurological diseases. J. Neuroimmunol.,  2002, 124(1-2), 83-92.
[http://dx.doi.org/10.1016/S0165-5728(01)00496-9] [PMID:  11958825] 
[180] 
Lucin, K.M.; Wyss-Coray, T. Immune activation in brain aging and neurodegeneration: too much or too little? Neuron,  2009, 64(1), 110-122.
[http://dx.doi.org/10.1016/j.neuron.2009.08.039] [PMID:  19840553] 
[181] 
Miklossy, J.; Doudet, D.D.; Schwab, C.; Yu, S.; McGeer, E.G.; McGeer, P.L. Role of ICAM-1 in persisting inflammation in Parkinson disease and MPTP monkeys. Exp. Neurol.,  2006, 197(2), 275-283.
[http://dx.doi.org/10.1016/j.expneurol.2005.10.034] [PMID:  16336966] 
[182] 
Cserr, H.F.; Knopf, P.M. Cervical lymphatics, the blood-brain barrier and the immunoreactivity of the brain: a new view. Immunol. Today,  1992, 13(12), 507-512.
[http://dx.doi.org/10.1016/0167-5699(92)90027-5] [PMID:  1463583] 
[183] 
Baruch, K.; Schwartz, M. CNS-specific T cells shape brain function via the choroid plexus. Brain Behav. Immun.,  2013, 34, 11-16.
[http://dx.doi.org/10.1016/j.bbi.2013.04.002] [PMID:  23597431] 
[184] 
Carson, M.J.; Sutcliffe, J.G.; Campbell, I.L. Microglia stimulate naive T-cell differentiation without stimulating T-cell proliferation. J. Neurosci. Res.,  1999, 55(1), 127-134.
[http://dx.doi.org/10.1002/(SICI)1097-4547(19990101)55:1<127:AID-JNR14>3.0.CO;2-2] [PMID:  9890441] 
[185] 
Barcia, C.; Ros, C.M.; Annese, V.; Gómez, A.; Ros-Bernal, F.; Aguado-Yera, D.; Martínez-Pagán, M.E.; de Pablos, V.; Fernandez-Villalba, E.; Herrero, M.T. IFN-γ signaling, with the synergistic contribution of TNF-α, mediates cell specific microglial and astroglial activation in experimental models of Parkinson’s disease. Cell Death Dis.,  2011, 2(2), e142.
[http://dx.doi.org/10.1038/cddis.2011.17] [PMID:  21472005] 
[186] 
Shechter, R.; London, A.; Schwartz, M. Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates. Nat. Rev. Immunol.,  2013, 13(3), 206-218.
[http://dx.doi.org/10.1038/nri3391] [PMID:  23435332] 
[187] 
Kurkowska-Jastrzebska, I.; Wrońska, A.; Kohutnicka, M.; Członkowski, A.; Członkowska, A. The inflammatory reaction following 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine intoxication in mouse. Exp. Neurol.,  1999, 156(1), 50-61.
[http://dx.doi.org/10.1006/exnr.1998.6993] [PMID:  10192776] 
[188] 
Benner, E.J.; Banerjee, R.; Reynolds, A.D.; Sherman, S.; Pisarev, V.M.; Tsiperson, V.; Nemachek, C.; Ciborowski, P.; Przedborski, S.; Mosley, R.L.; Gendelman, H.E. Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One,  2008, 3(1), e1376.
[http://dx.doi.org/10.1371/journal.pone.0001376] [PMID:  18167537] 
[189] 
Członkowska, A.; Kohutnicka, M.; Kurkowska-Jastrzebska, I.; Członkowski, A. Microglial reaction in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced Parkinson’s disease mice model. Neurodegeneration,  1996, 5(2), 137-143.
[http://dx.doi.org/10.1006/neur.1996.0020] [PMID:  8819134] 
[190] 
Reynolds, A.D.; Glanzer, J.G.; Kadiu, I.; Ricardo-Dukelow, M.; Chaudhuri, A.; Ciborowski, P.; Cerny, R.; Gelman, B.; Thomas, M.P.; Mosley, R.L.; Gendelman, H.E. Nitrated alpha-synuclein-activated microglial profiling for Parkinson’s disease. J. Neurochem.,  2008, 104(6), 1504-1525.
[http://dx.doi.org/10.1111/j.1471-4159.2007.05087.x] [PMID:  18036154] 
[191] 
Beach, T.G.; Adler, C.H.; Sue, L.I.; Vedders, L.; Lue, L. White, Iii, C.L.; Akiyama, H.; Caviness, J.N.; Shill, H.A.; Sabbagh, M.N.; Walker, D.G. Multi-organ distribution of phosphorylated alphasynuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol.,  2010, 119, 689-702.
[http://dx.doi.org/10.1007/s00401-010-0664-3] [PMID:  20306269] 
[192] 
Yanamandra, K.; Gruden, M.A.; Casaite, V.; Meskys, R.; Forsgren, L.; Morozova-Roche, L.A. α-synuclein reactive antibodies as diagnostic biomarkers in blood sera of Parkinson’s disease patients. PLoS One,  2011, 6(4), e18513.
[http://dx.doi.org/10.1371/journal.pone.0018513] [PMID:  21541339] 
[193] 
Besong-Agbo, D.; Wolf, E.; Jessen, F.; Oechsner, M.; Hametner, E.; Poewe, W.; Reindl, M.; Oertel, W.H.; Noelker, C.; Bacher, M.; Dodel, R. Naturally occurring α-synuclein autoantibody levels are lower in patients with Parkinson disease. Neurology,  2013, 80(2), 169-175.
[http://dx.doi.org/10.1212/WNL.0b013e31827b90d1] [PMID:  23255825] 
[194] 
Sulzer, D.; Alcalay, R.N.; Garretti, F.; Cote, L.; Kanter, E.; Agin-Liebes, J.; Liong, C.; McMurtrey, C.; Hildebrand, W.H.; Mao, X.; Dawson, V.L.; Dawson, T.M.; Oseroff, C.; Pham, J.; Sidney, J.; Dillon, M.B.; Carpenter, C.; Weiskopf, D.; Phillips, E.; Mallal, S.; Peters, B.; Frazier, A.; Arlehamn, C.S.L.; Sette, A. Erratum: T cells from patients with Parkinson’s disease recognize α-synuclein peptides. Nature,  2017, 549(7671), 292.
[http://dx.doi.org/10.1038/nature23896] [PMID:  28905919] 
[195] 
Harms, A.S.; Cao, S.; Rowse, A.L.; Thome, A.D.; Li, X.; Mangieri, L.R.; Cron, R.Q.; Shacka, J.J.; Raman, C.; Standaert, D.G. MHCII is required for α-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration. J. Neurosci.,  2013, 33(23), 9592-9600.
[http://dx.doi.org/10.1523/JNEUROSCI.5610-12.2013] [PMID:  23739956] 
[196] 
Yang, J.Y.; Sarwal, M.M. Transplant genetics and genomics. Nat. Rev. Genet.,  2017, 18(5), 309-326.
[http://dx.doi.org/10.1038/nrg.2017.12] [PMID:  28286337] 
[197] 
Kaufman, J.F.; Auffray, C.; Korman, A.J.; Shackelford, D.A.; Strominger, J. The class II molecules of the human and murine major histocompatibility complex. Cell,  1984, 36(1), 1-13.
[http://dx.doi.org/10.1016/0092-8674(84)90068-0] [PMID:  6198089] 
[198] 
Lampe, J.B.; Gossrau, G.; Herting, B.; Kempe, A.; Sommer, U.; Füssel, M.; Weber, M.; Koch, R.; Reichmann, H. HLA typing and Parkinson’s disease. Eur. Neurol.,  2003, 50(2), 64-68.
[http://dx.doi.org/10.1159/000072500] [PMID:  12944708] 
[199] 
Sun, C.; Wei, L.; Luo, F.; Li, Y.; Li, J.; Zhu, F.; Kang, P.; Xu, R.; Xiao, L.; Liu, Z.; Xu, P. HLA-DRB1 alleles are associated with the susceptibility to sporadic Parkinson’s disease in Chinese Han population. PLoS One,  2012, 7(11), e48594.
[http://dx.doi.org/10.1371/journal.pone.0048594] [PMID:  23139797] 
[200] 
Manan, H.; Angham, A.M.; Sitelbanat, A. Genetic and diabetic auto-antibody markers in Saudi children with type 1 diabetes. Hum. Immunol.,  2010, 71(12), 1238-1242.
[http://dx.doi.org/10.1016/j.humimm.2010.09.008] [PMID:  20858521] 
[201] 
de la Concha, E.G.; Cavanillas, M.L.; Cénit, M.C.; Urcelay, E.; Arroyo, R.; Fernández, Ó.; Álvarez-Cermeño, J.C.; Leyva, L.; Villar, L.M.; Núñez, C. DRB1*03:01 haplotypes: differential contribution to multiple sclerosis risk and specific association with the presence of intrathecal IgM bands. PLoS One,  2012, 7(2), e31018.
[http://dx.doi.org/10.1371/journal.pone.0031018] [PMID:  22363536] 
[202] 
Rugbjerg, K.; Friis, S.; Ritz, B.; Schernhammer, E.S.; Korbo, L.; Olsen, J.H. Autoimmune disease and risk for Parkinson disease: a population-based case-control study. Neurology,  2009, 73(18), 1462-1468.
[http://dx.doi.org/10.1212/WNL.0b013e3181c06635] [PMID:  19776374] 
[203] 
Chemaly, R.E.; Moussalli, A.S. Parkinsonian syndrome as a complication of systemic lupus erythematosus. Report of a case and review of the literature. J. Med. Liban.,  2012, 60(2), 103-105.
[PMID:  22919866] 
[204] 
Li, X.; Sundquist, J.; Sundquist, K. Subsequent risks of Parkinson disease in patients with autoimmune and related disorders: a nationwide epidemiological study from Sweden. Neurodegener. Dis.,  2012, 10(1-4), 277-284.
[http://dx.doi.org/10.1159/000333222] [PMID:  22205172] 
[205] 
Aziz, Q.; Thompson, D.G. Brain-gut axis in health and disease. Gastroenterology,  1998, 114(3), 559-578.
[http://dx.doi.org/10.1016/S0016-5085(98)70540-2] [PMID:  9496948] 
[206] 
Mulak, A.; Bonaz, B. Irritable bowel syndrome: a model of the brain-gut interactions. Med. Sci. Monit.,  2004, 10(4), RA55-RA62.
[PMID:  15260348] 
[207] 
Mulak, A.; Bonaz, B. Brain-gut-microbiota axis in Parkinson’s disease. World J. Gastroenterol.,  2015, 21(37), 10609-10620.
[http://dx.doi.org/10.3748/wjg.v21.i37.10609] [PMID:  26457021] 
[208] 
Vizcarra, J.A.; Wilson-Perez, H.E.; Espay, A.J. The power in numbers: gut microbiota in Parkinson’s disease. Mov. Disord.,  2015, 30(3), 296-298.
[http://dx.doi.org/10.1002/mds.26116] [PMID:  25545262] 
[209] 
Hollister, E.B.; Gao, C.; Versalovic, J. Compositional and functional features of the gastrointestinal microbiome and their effects on human health. Gastroenterology,  2014, 146(6), 1449-1458.
[http://dx.doi.org/10.1053/j.gastro.2014.01.052] [PMID:  24486050] 
[210] 
Lebouvier, T.; Chaumette, T.; Paillusson, S.; Duyckaerts, C.; Bruley des Varannes, S.; Neunlist, M.; Derkinderen, P. The second brain and Parkinson’s disease. Eur. J. Neurosci.,  2009, 30(5), 735-741.
[http://dx.doi.org/10.1111/j.1460-9568.2009.06873.x] [PMID:  19712093] 
[211] 
Braak, H.; de Vos, R.A.; 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(1), 67-72.
[http://dx.doi.org/10.1016/j.neulet.2005.11.012] [PMID:  16330147] 
[212] 
Hawkes, C.H.; Del Tredici, K.; Braak, H. Parkinson’s disease: a dual-hit hypothesis. Neuropathol. Appl. Neurobiol.,  2007, 33(6), 599-614.
[http://dx.doi.org/10.1111/j.1365-2990.2007.00874.x] [PMID:  17961138] 
[213] 
Cosentino, M.; Marino, F. Adrenergic and dopaminergic modulation of immunity in multiple sclerosis: teaching old drugs new tricks? J. Neuroimmune Pharmacol.,  2013, 8(1), 163-179.
[http://dx.doi.org/10.1007/s11481-012-9410-z] [PMID:  23074017] 
[214] 
Cosentino, M.; Bombelli, R.; Ferrari, M.; Marino, F.; Rasini, E.; Maestroni, G.J.M.; Conti, A.; Boveri, M.; Lecchini, S.; Frigo, G. HPLC-ED measurement of endogenous catecholamines in human immune cells and hematopoietic cell lines. Life Sci.,  2000, 68(3), 283-295.
[http://dx.doi.org/10.1016/S0024-3205(00)00937-1] [PMID: 11191644] 
[215] 
Cosentino, M.; Marino, F.; Bombelli, R.; Ferrari, M.; Rasini, E.; Lecchini, S.; Frigo, G. Stimulation with phytohaemagglutinin induces the synthesis of catecholamines in human peripheral blood mononuclear cells: role of protein kinase C and contribution of intracellular calcium. J. Neuroimmunol.,  2002, 125(1-2), 125-133. a
[http://dx.doi.org/10.1016/S0165-5728(02)00019-X] [PMID: 11960648] 
[216] 
Cosentino, M.; Zaffaroni, M.; Marino, F.; Bombelli, R.; Ferrari, M.; Rasini, E.; Lecchini, S.; Ghezzi, A.; Frigo, G. Catecholamine production and tyrosine hydroxylase expression in peripheral blood mononuclear cells from multiple sclerosis patients: effect of cell stimulation and possible relevance for activation-induced apoptosis. J. Neuroimmunol.,  2002, 133(1-2), 233-240. b
[http://dx.doi.org/10.1016/S0165-5728(02)00372-7] [PMID: 12446028] 
[217] 
Cosentino, M.; Martignoni, E.; Michielotto, D.; Calandrella, D.; Riboldazzi, G.; Pacchetti, C.; Frigo, G.; Nappi, G.; Lecchini, S. Medical healthcare use in Parkinson’s disease: survey in a cohort of ambulatory patients in Italy. BMC Health Serv. Res.,  2005, 5(1), 26.
[http://dx.doi.org/10.1186/1472-6963-5-26] [PMID:  15790401] 
[218] 
Cosentino, M.; Fietta, A.M.; Ferrari, M.; Rasini, E.; Bombelli, R.; Carcano, E.; Saporiti, F.; Meloni, F.; Marino, F.; Lecchini, S. Human CD4+CD25+ regulatory T cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop. Blood,  2007, 109(2), 632-642.
[http://dx.doi.org/10.1182/blood-2006-01-028423] [PMID:  16985181] 
[219] 
Levite, M. Dopamine and T cells: dopamine receptors and potent effects on T cells, dopamine production in T cells, and abnormalities in the dopaminergic system in T cells in autoimmune, neurological and psychiatric diseases. Acta Physiol. (Oxf.),  2016, 216(1), 42-89.
[http://dx.doi.org/10.1111/apha.12476] [PMID:  25728499] 
[220] 
Zaffaroni, M.; Marino, F.; Bombelli, R.; Rasini, E.; Monti, M.; Ferrari, M.; Ghezzi, A.; Comi, G.; Lecchini, S.; Cosentino, M. Therapy with interferon-beta modulates endogenous catecholamines in lymphocytes of patients with multiple sclerosis. Exp. Neurol.,  2008, 214(2), 315-321.
[http://dx.doi.org/10.1016/j.expneurol.2008.08.015] [PMID:  18824168] 
[221] 
Cosentino, M.; Zaffaroni, M.; Trojano, M.; Giorelli, M.; Pica, C.; Rasini, E.; Bombelli, R.; Ferrari, M.; Ghezzi, A.; Comi, G.; Livrea, P.; Lecchini, S.; Marino, F. Dopaminergic modulation of CD4+CD25(high) regulatory T lymphocytes in multiple sclerosis patients during interferon-β therapy. Neuroimmunomodulation,  2012, 19(5), 283-292.
[http://dx.doi.org/10.1159/000336981] [PMID:  22472872] 
[222] 
Capellino, S.; Cosentino, M.; Wolff, C.; Schmidt, M.; Grifka, J.; Straub, R.H. Catecholamine-producing cells in the synovial tissue during arthritis: modulation of sympathetic neurotransmitters as new therapeutic target. Ann. Rheum. Dis.,  2010, 69(10), 1853-1860.
[http://dx.doi.org/10.1136/ard.2009.119701] [PMID:  20498218] 
[223] 
Nakano, K.; Yamaoka, K.; Hanami, K.; Saito, K.; Sasaguri, Y.; Yanagihara, N.; Tanaka, S.; Katsuki, I.; Matsushita, S.; Tanaka, Y. Dopamine induces IL-6-dependent IL-17 production via D1-like receptor on CD4 naive T cells and D1-like receptor antagonist SCH-23390 inhibits cartilage destruction in a human rheumatoid arthritis/SCID mouse chimera model. J. Immunol.,  2011, 186(6), 3745-3752.
[http://dx.doi.org/10.4049/jimmunol.1002475] [PMID:  21307293] 
[224] 
González, H.; Contreras, F.; Prado, C.; Elgueta, D.; Franz, D.; Bernales, S.; Pacheco, R. Dopamine receptor D3 expressed on CD4+ T cells favors neurodegeneration of dopaminergic neurons during Parkinson’s disease. J. Immunol.,  2013, 190(10), 5048-5056.
[http://dx.doi.org/10.4049/jimmunol.1203121] [PMID:  23589621] 
[225] 
McCoy, M.K.; Ruhn, K.A.; Martinez, T.N.; McAlpine, F.E.; Blesch, A.; Tansey, M.G. Intranigral lentiviral delivery of dominant-negative TNF attenuates neurodegeneration and behavioral deficits in hemiparkinsonian rats. Mol. Ther.,  2008, 16(9), 1572-1579.
[http://dx.doi.org/10.1038/mt.2008.146] [PMID:  18628756] 
[226] 
Harms, A.S.; Barnum, C.J.; Ruhn, K.A.; Varghese, S.; Treviño, I.; Blesch, A.; Tansey, M.G. Delayed dominant-negative TNF gene therapy halts progressive loss of nigral dopaminergic neurons in a rat model of Parkinson’s disease. Mol. Ther.,  2011, 19(1), 46-52.
[http://dx.doi.org/10.1038/mt.2010.217] [PMID:  20959812] 
[227] 
Lindvall, O.; Wahlberg, L.U. Encapsulated cell biodelivery of GDNF: a novel clinical strategy for neuroprotection and neuroregeneration in Parkinson’s disease? Exp. Neurol.,  2008, 209(1), 82-88.
[http://dx.doi.org/10.1016/j.expneurol.2007.08.019] [PMID:  17963752] 
[228] 
Decressac, M.; Ulusoy, A.; Mattsson, B.; Georgievska, B.; Romero-Ramos, M.; Kirik, D.; Björklund, A. GDNF fails to exert neuroprotection in a rat α-synuclein model of Parkinson’s disease. Brain,  2011, 134(Pt 8), 2302-2311.
[http://dx.doi.org/10.1093/brain/awr149] [PMID:  21712347] 
[229] 
Lo Bianco, C.; Déglon, N.; Pralong, W.; Aebischer, P. Lentiviral nigral delivery of GDNF does not prevent neurodegeneration in a genetic rat model of Parkinson’s disease. Neurobiol. Dis.,  2004, 17(2), 283-289.
[http://dx.doi.org/10.1016/j.nbd.2004.06.008] [PMID:  15474365] 
[230] 
Sánchez-Pernaute, R.; Ferree, A.; Cooper, O.; Yu, M.; Brownell, A.L.; Isacson, O. Selective COX-2 inhibition prevents progressive dopamine neuron degeneration in a rat model of Parkinson’s disease. J. Neuroinflammation,  2004, 1(1), 6.
[http://dx.doi.org/10.1186/1742-2094-1-6] [PMID:  15285796] 
[231] 
Lee, M.; Tazzari, V.; Giustarini, D.; Rossi, R.; Sparatore, A.; Del Soldato, P.; McGeer, E.; McGeer, P.L. Effects of hydrogen sulfide-releasing L-DOPA derivatives on glial activation: potential for treating Parkinson disease. J. Biol. Chem.,  2010, 285(23), 17318-17328.
[http://dx.doi.org/10.1074/jbc.M110.115261] [PMID:  20368333] 
[232] 
Wu, D.C.; Jackson-Lewis, V.; Vila, M.; Tieu, K.; Teismann, P.; Vadseth, C.; Choi, D.K.; Ischiropoulos, H.; Przedborski, S. Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J. Neurosci.,  2002, 22(5), 1763-1771.
[http://dx.doi.org/10.1523/JNEUROSCI.22-05-01763.2002] [PMID:  11880505] 
[233] 
Tikka, T.; Fiebich, B.L.; Goldsteins, G.; Keinanen, R.; Koistinaho, J. Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J. Neurosci.,  2001, 21(8), 2580-2588.
[http://dx.doi.org/10.1523/JNEUROSCI.21-08-02580.2001] [PMID:  11306611] 
[234] 
Yang, L.; Sugama, S.; Chirichigno, J.W.; Gregorio, J.; Lorenzl, S.; Shin, D.H.; Browne, S.E.; Shimizu, Y.; Joh, T.H.; Beal, M.F.; Albers, D.S. Minocycline enhances MPTP toxicity to dopaminergic neurons. J. Neurosci. Res.,  2003, 74(2), 278-285.
[http://dx.doi.org/10.1002/jnr.10709] [PMID:  14515357] 
[235] 
Lu, X.; Bing, G.; Hagg, T. Naloxone prevents microglia-induced degeneration of dopaminergic substantia nigra neurons in adult rats. Neuroscience,  2000, 97(2), 285-291.
[http://dx.doi.org/10.1016/S0306-4522(00)00033-6] [PMID: 10799760] 
[236] 
Liu, B.; Du, L.; Hong, J.S. Naloxone protects rat dopaminergic neurons against inflammatory damage through inhibition of microglia activation and superoxide generation. J. Pharmacol. Exp. Ther.,  2000, 293(2), 607-617.
[PMID:  10773035] 
[237] 
Castaño, A.; Herrera, A.J.; Cano, J.; Machado, A. The degenerative effect of a single intranigral injection of LPS on the dopaminergic system is prevented by dexamethasone, and not mimicked by rh-TNF-alpha, IL-1beta and IFN-gamma. J. Neurochem.,  2002, 81(1), 150-157.
[http://dx.doi.org/10.1046/j.1471-4159.2002.00799.x] [PMID:  12067227] 
[238] 
Benner, E.J.; Mosley, R.L.; Destache, C.J.; Lewis, T.B.; Jackson-Lewis, V.; Gorantla, S.; Nemachek, C.; Green, S.R.; Przedborski, S.; Gendelman, H.E. Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson’s disease. Proc. Natl. Acad. Sci. USA,  2004, 101(25), 9435-9440.
[http://dx.doi.org/10.1073/pnas.0400569101] [PMID:  15197276] 
[239] 
Laurie, C.; Reynolds, A.; Coskun, O.; Bowman, E.; Gendelman, H.E.; Mosley, R.L. CD4+ T cells from Copolymer-1 immunized mice protect dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. J. Neuroimmunol.,  2007, 183(1-2), 60-68.
[http://dx.doi.org/10.1016/j.jneuroim.2006.11.009] [PMID:  17196666] 
[240] 
Kurkowska-Jastrzebska, I.; Bałkowiec-Iskra, E.; Joniec, I.; Litwin, T.; Członkowski, A.; Członkowska, A. Immunization with myelin oligodendrocyte glycoprotein and complete Freund adjuvant partially protects dopaminergic neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced damage in mouse model of Parkinson’s disease. Neuroscience,  2005, 131(1), 247-254.
[http://dx.doi.org/10.1016/j.neuroscience.2004.10.027] [PMID:  15680707] 
[241] 
Armentero, M.T.; Levandis, G.; Nappi, G.; Bazzini, E.; Blandini, F. Peripheral inflammation and neuroprotection: systemic pretreatment with complete Freund’s adjuvant reduces 6-hydroxydopamine toxicity in a rodent model of Parkinson’s disease. Neurobiol. Dis.,  2006, 24(3), 492-505.
[http://dx.doi.org/10.1016/j.nbd.2006.08.016] [PMID:  17023164] 
[242] 
Yong, J.; Lacan, G.; Dang, H.; Hsieh, T.; Middleton, B.; Wasserfall, C.; Tian, J.; Melega, W.P.; Kaufman, D.L. BCG vaccine-induced neuroprotection in a mouse model of Parkinson’s disease. PLoS One,  2011, 6(1), e16610.
[http://dx.doi.org/10.1371/journal.pone.0016610] [PMID:  21304945] 
[243] 
Kosloski, L.M.; Kosmacek, E.A.; Olson, K.E.; Mosley, R.L.; Gendelman, H.E. GM-CSF induces neuroprotective and anti-inflammatory responses in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxicated mice. J. Neuroimmunol.,  2013, 265(1-2), 1-10.
[http://dx.doi.org/10.1016/j.jneuroim.2013.10.009] [PMID:  24210793] 
[244] 
Ugen, K.E.; Lin, X.; Bai, G.; Liang, Z.; Cai, J.; Li, K.; Song, S.; Cao, C.; Sanchez-Ramos, J. Evaluation of an α synuclein sensitized dendritic cell based vaccine in a transgenic mouse model of Parkinson disease. Hum. Vaccin. Immunother.,  2015, 11(4), 922-930.
[http://dx.doi.org/10.1080/21645515.2015.1012033] [PMID:  25714663] 
[245] 
Masliah, E.; Rockenstein, E.; Adame, A.; Alford, M.; Crews, L.; Hashimoto, M.; Seubert, P.; Lee, M.; Goldstein, J.; Chilcote, T.; Games, D.; Schenk, D. Effects of alpha-synuclein immunization in a mouse model of Parkinson’s disease. Neuron,  2005, 46(6), 857-868.
[http://dx.doi.org/10.1016/j.neuron.2005.05.010] [PMID:  15953415] 
[246] 
Masliah, E.; Rockenstein, E.; Mante, M.; Crews, L.; Spencer, B.; Adame, A.; Patrick, C.; Trejo, M.; Ubhi, K.; Rohn, T.T.; Mueller-Steiner, S.; Seubert, P.; Barbour, R.; McConlogue, L.; Buttini, M.; Games, D.; Schenk, D. Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease. PLoS One,  2011, 6(4), e19338.
[http://dx.doi.org/10.1371/journal.pone.0019338] [PMID:  21559417] 
[247] 
Chen, Z.; Yang, Y.; Yang, X.; Zhou, C.; Li, F.; Lei, P.; Zhong, L.; Jin, X.; Peng, G. Immune effects of optimized DNA vaccine and protective effects in a MPTP model of Parkinson’s disease. Neurol. Sci.,  2013, 34(9), 1559-1570.
[http://dx.doi.org/10.1007/s10072-012-1284-6] [PMID:  23354599] 
[248] 
Mandler, M.; Valera, E.; Rockenstein, E.; Weninger, H.; Patrick, C.; Adame, A.; Santic, R.; Meindl, S.; Vigl, B.; Smrzka, O.; Schneeberger, A.; Mattner, F.; Masliah, E. Next-generation active immunization approach for synucleinopathies: implications for Parkinson’s disease clinical trials. Acta Neuropathol.,  2014, 127(6), 861-879.
[http://dx.doi.org/10.1007/s00401-014-1256-4] [PMID:  24525765] 
[249] 
Ghochikyan, A.; Petrushina, I.; Davtyan, H.; Hovakimyan, A.; Saing, T.; Davtyan, A.; Cribbs, D.H.; Agadjanyan, M.G. Immunogenicity of epitope vaccines targeting different B cell antigenic determinants of human α-synuclein: feasibility study. Neurosci. Lett.,  2014, 560, 86-91.
[http://dx.doi.org/10.1016/j.neulet.2013.12.028] [PMID:  24361548] 
[250] 
Etminan, M.; Carleton, B.C.; Samii, A. Non-steroidal anti-inflammatory drug use and the risk of Parkinson disease: a retrospective cohort study. J. Clin. Neurosci.,  2008, 15(5), 576-577.
[http://dx.doi.org/10.1016/j.jocn.2007.02.095] [PMID:  18343119] 
[251] 
Samii, A.; Nutt, J.G.; Ransom, B.R. Parkinson’s disease. Lancet,  2004, 363(9423), 1783-1793.
[http://dx.doi.org/10.1016/S0140-6736(04)16305-8] [PMID: 15172778] 
[252] 
Giuliani, F.; Hader, W.; Yong, V.W. Minocycline attenuates T cell and microglia activity to impair cytokine production in T cell-microglia interaction. J. Leukoc. Biol.,  2005, 78(1), 135-143.
[http://dx.doi.org/10.1189/jlb.0804477] [PMID:  15817702] 
[253] 
Aharoni, R.; Teitelbaum, D.; Leitner, O.; Meshorer, A.; Sela, M.; Arnon, R. Specific Th2 cells accumulate in the central nervous system of mice protected against experimental autoimmune encephalomyelitis by copolymer 1. Proc. Natl. Acad. Sci. USA,  2000, 97(21), 11472-11477.
[http://dx.doi.org/10.1073/pnas.97.21.11472] [PMID:  11027347] 
[254] 
Haas, J.; Korporal, M.; Balint, B.; Fritzsching, B.; Schwarz, A.; Wildemann, B. Glatiramer acetate improves regulatory T-cell function by expansion of naive CD4(+)CD25(+)FOXP3(+)CD31(+) T-cells in patients with multiple sclerosis. J. Neuroimmunol.,  2009, 216(1-2), 113-117.
[http://dx.doi.org/10.1016/j.jneuroim.2009.06.011] [PMID:  19646767] 
[255] 
Simpson, D.; Noble, S.; Perry, C. Glatiramer acetate: a review of its use in relapsing-remitting multiple sclerosis. CNS Drugs,  2002, 16(12), 825-850.
[http://dx.doi.org/10.2165/00023210-200216120-00004] [PMID:  12421116] 
[256] 
Aharoni, R.; Kayhan, B.; Eilam, R.; Sela, M.; Arnon, R. Glatiramer acetate-specific T cells in the brain express T helper 2/3 cytokines and brain-derived neurotrophic factor in situ. Proc. Natl. Acad. Sci. USA,  2003, 100(24), 14157-14162.
[http://dx.doi.org/10.1073/pnas.2336171100] [PMID:  14614135] 
[257] 
Arnon, R.; Aharoni, R. Mechanism of action of glatiramer acetate in multiple sclerosis and its potential for the development of new applications. Proc. Natl. Acad. Sci. USA,  2004, 101(Suppl. 2), 14593-14598.
[http://dx.doi.org/10.1073/pnas.0404887101] [PMID:  15371592] 
[258] 
Zhao, P.; Yang, X.; Yang, L.; Li, M.; Wood, K.; Liu, Q.; Zhu, X. Neuroprotective effects of fingolimod in mouse models of Parkinson’s disease. FASEB J.,  2017, 31(1), 172-179.
[http://dx.doi.org/10.1096/fj.201600751R] [PMID:  27671228] 
[259] 
Schneeberger, A.; Mandler, M.; Mattner, F.; Schmidt, W. AFFITOME® technology in neurodegenerative diseases: the doubling advantage. Hum. Vaccin.,  2010, 6(11), 948-952.
[http://dx.doi.org/10.4161/hv.6.11.13217] [PMID:  20980801] 
[260] 
Schneeberger, A.; Mandler, M.; Mattner, F.; Schmidt, W. Vaccination for Parkinson’s disease. Parkinsonism Relat. Disord.,  2012, 18(Suppl. 1), S11-S13.
[http://dx.doi.org/10.1016/S1353-8020(11)70006-2] [PMID: 22166404] 
[261] 
Oertel, W.; Schulz, J.B. Current and experimental treatments of Parkinson disease: A guide for neuroscientists. J. Neurochem.,  2016, 139(Suppl. 1), 325-337.
[http://dx.doi.org/10.1111/jnc.13750] [PMID:  27577098] 
[262] 
Kalia, L.V.; Kalia, S.K.; Lang, A.E. Disease-modifying strategies for Parkinson’s disease. Mov. Disord.,  2015, 30(11), 1442-1450.
[http://dx.doi.org/10.1002/mds.26354] [PMID:  26208210] 
[263] 
Szoke, B.; Wrasidlo, W.; Stocking, E.; Tsigelny, I.; Schwartz, T.C.; Konrat, R.; Paulino, A.D.; Price, D.L.; Winter, S.; Masliah, E.; Bonhaus, D.; Meier, D. Biophysical
characterization of the interaction of NPT200-11 with alpha-
synuclein, Program No 411.04/L11. Neuroscience
Meeting Planner. Washington, DC: Society for Neuroscience, Congress Washington DC., USA – poster 2014.Online source:. http://www.abstractsonline.com/plan/ViewAbstract.aspx?cKey=46575e37-a6d9-40b6-b6e1-0efd39c7e5ec&mID=3527&mKey=54c85d94-6d69-4b09-afaa-502c0e680ca7&sKey=07411a22-9ccf-4b11-b7ee-5faebb10864a
[264] 
Wagner, J.; Ryazanov, S.; Leonov, A.; Levin, J.; Shi, S.; Schmidt, F.; Prix, C.; Pan-Montojo, F.; Bertsch, U.; Mitteregger-Kretzschmar, G.; Geissen, M.; Eiden, M.; Leidel, F.; Hirschberger, T.; Deeg, A.A.; Krauth, J.J.; Zinth, W.; Tavan, P.; Pilger, J.; Zweckstetter, M.; Frank, T.; Bähr, M.; Weishaupt, J.H.; Uhr, M.; Urlaub, H.; Teichmann, U.; Samwer, M.; Bötzel, K.; Groschup, M.; Kretzschmar, H.; Griesinger, C.; Giese, A. Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson’s disease. Acta Neuropathol.,  2013, 125(6), 795-813.
[http://dx.doi.org/10.1007/s00401-013-1114-9] [PMID:  23604588] 
[265] 
Lee, Y.K.; Mukasa, R.; Hatton, R.D.; Weaver, C.T. Developmental plasticity of Th17 and Treg cells. Curr. Opin. Immunol.,  2009, 21(3), 274-280.
[http://dx.doi.org/10.1016/j.coi.2009.05.021] [PMID:  19524429] 
[266] 
Delgado, M.; Chorny, A.; Gonzalez-Rey, E.; Ganea, D. Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo. J. Leukoc. Biol.,  2005, 78(6), 1327-1338.
[http://dx.doi.org/10.1189/jlb.0605299] [PMID:  16204628] 
[267] 
Rowin, J.; Thiruppathi, M.; Arhebamen, E.; Sheng, J.; Prabhakar, B.S.; Meriggioli, M.N. Granulocyte macrophage colony-stimulating factor treatment of a patient in myasthenic crisis: effects on regulatory T cells. Muscle Nerve,  2012, 46(3), 449-453.
[http://dx.doi.org/10.1002/mus.23488] [PMID:  22907239] 
[268] 
Gendelman, H.E.; Zhang, Y.; Santamaria, P.; Olson, K.E.; Schutt, C.R.; Bhatti, D.; Shetty, B.L.D.; Lu, Y.; Estes, K.A.; Standaert, D.G.; Heinrichs-Graham, E.; Larson, L.; Meza, J.L.; Follett, M.; Forsberg, E.; Siuzdak, G.; Wilson, T.W.; Peterson, C.; Mosley, R.L. Evaluation of the safety and immunomodulatory effects of sargramostim in a randomized, double-blind phase 1 clinical Parkinson’s disease trial. NPJ Parkinsons Dis.,  2017, 3, 10.
[http://dx.doi.org/10.1038/s41531-017-0013-5] [PMID:  28649610] 
[269] 
Schenk, D.; Barbour, R.; Dunn, W.; Gordon, G.; Grajeda, H.; Guido, T.; Hu, K.; Huang, J.; Johnson-Wood, K.; Khan, K.; Kholodenko, D.; Lee, M.; Liao, Z.; Lieberburg, I.; Motter, R.; Mutter, L.; Soriano, F.; Shopp, G.; Vasquez, N.; Vandevert, C.; Walker, S.; Wogulis, M.; Yednock, T.; Games, D.; Seubert, P. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature,  1999, 400(6740), 173-177.
[http://dx.doi.org/10.1038/22124] [PMID:  10408445] 
[270] 
Weiner, H.L.; Lemere, C.A.; Maron, R.; Spooner, E.T.; Grenfell, T.J.; Mori, C.; Issazadeh, S.; Hancock, W.W.; Selkoe, D.J. Nasal administration of amyloid-β peptide decreases cerebral amyloid burden in a mouse model of Alzheimer’s disease. Ann. Neurol.,  2000, 48(4), 567-579.
[http://dx.doi.org/10.1002/1531-8249(200010)48:4<567:AID-ANA3>3.0.CO;2-W] [PMID: 11026440] 
[271] 
Janus, C.; Pearson, J.; McLaurin, J.; Mathews, P.M.; Jiang, Y.; Schmidt, S.D.; Chishti, M.A.; Horne, P.; Heslin, D.; French, J.; Mount, H.T.; Nixon, R.A.; Mercken, M.; Bergeron, C.; Fraser, P.E.; St George-Hyslop, P.; Westaway, D. A β peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature,  2000, 408(6815), 979-982.
[http://dx.doi.org/10.1038/35050110] [PMID:  11140685] 
[272] 
Morgan, D.; Diamond, D.M.; Gottschall, P.E.; Ugen, K.E.; Dickey, C.; Hardy, J.; Duff, K.; Jantzen, P.; DiCarlo, G.; Wilcock, D.; Connor, K.; Hatcher, J.; Hope, C.; Gordon, M.; Arendash, G.W. A β peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature,  2000, 408(6815), 982-985.
[http://dx.doi.org/10.1038/35050116] [PMID:  11140686] 
[273] 
Bard, F.; Cannon, C.; Barbour, R.; Burke, R.L.; Games, D.; Grajeda, H.; Guido, T.; Hu, K.; Huang, J.; Johnson-Wood, K.; Khan, K.; Kholodenko, D.; Lee, M.; Lieberburg, I.; Motter, R.; Nguyen, M.; Soriano, F.; Vasquez, N.; Weiss, K.; Welch, B.; Seubert, P.; Schenk, D.; Yednock, T. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med.,  2000, 6(8), 916-919.
[http://dx.doi.org/10.1038/78682] [PMID:  10932230] 
[274] 
Pride, M.; Seubert, P.; Grundman, M.; Hagen, M.; Eldridge, J.; Black, R.S. Progress in the active immunotherapeutic approach to Alzheimer’s disease: clinical investigations into AN1792-associated meningoencephalitis. Neurodegener. Dis.,  2008, 5(3-4), 194-196.
[http://dx.doi.org/10.1159/000113700] [PMID:  18322388] 
[275] 
Senior, K. Dosing in phase II trial of Alzheimer’s vaccine suspended. Lancet Neurol.,  2002, 1(1), 3.
[http://dx.doi.org/10.1016/S1474-4422(02)00023-6] [PMID: 12849527] 
Rights & Permissions Print Cite
Article Metrics
96
16
2
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/0929867325666181009161048	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X
当代药物化学

帕金森氏病的外周免疫，免疫和神经炎症

摘要

当代药物化学

帕金森氏病的外周免疫，免疫和神经炎症

摘要 Play Pause

Related Journals

Related Books

Related Articles

摘要
