This review analyzes immunological impairments in Parkinson’s disease (PD). We present data on neuroinflammation, with which cell degeneration in the substantia nigra of the brain is associated and in which innate and adaptive immune system cells are involved. Brain, cerebrospinal fluid, and peripheral blood cytokine levels are analyzed. The interaction between neuroinflammation and neuron dysfunction is considered. Data on immunological impairments in people with PD and animals with models of this disease are presented. The characteristics of models of PD are discussed. Data on impairments to the blood–brain barrier are presented, along with evidence for the occurrence of autoimmune inflammation in this disease. We discuss the question of preclinical markers of PD, including immunological, i.e., cytokines, HLA-DR and HLA-DQ antigens, autoantibodies, etc. The creation of algorithms for the presymptomatic diagnosis of PD and its prophylaxis and treatment at the presymptomatic stage will lead to the cessation or slowing of neuron death.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
O. S. Levin and N. V. Fedorova, O. S. Parkinson’s Disease, MEDpress-inform, Moscow (2015), 5th ed.
L. V. Kalia and A. E. Lang, “Parkinson’s disease,” Lancet, 386, No. 9996, 896–912 (2015), https://doi.org/10.1016/S0140-6736(14)61393-3.
A. B. Hecht, G. R. Popov, A. A. Gudkova, et al., “Parkinson’s disease: clinical features, diagnosis, and treatment,” in: Human Neurodegenerative Diseases from Genome to the Whole Body, M. V. Ugryumov (ed.), Nauchnyi Mir, Moscow (2014).
C. Papagno and L. Trojano, “Cognitive and behavioral disorders in Parkinson’s disease: an update. I: cognitive impairments,” Neurol. Sci., 39, No. 2, 215–223 (2018), https://doi.org/10.1007/s10072-017-3154-8.
L. Trojano and C. Papagno, “Cognitive and behavioral disorders in Parkinson’s disease: an update. II: behavioral disorders,” Neurol. Sci., 39, No. 1, 53–61 (2018), https://doi.org/10.1007/s10072-017-3155-7.
M. G. Spillantini, R. A. Crowther, R. Jakes, et al., “alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies,” Proc. Natl. Acad. Sci. USA, 95, No. 11, 6469–6473 (1998), https://doi.org/10.1073/pnas.95.11.6469.
K. A. Jellinger, “Morphological substrates of parkinsonism with and without dementia: a retrospective clinico-pathological study,” J. Neural. Transm. Suppl., 72, 91–104 (2007).
S. N. Pchelina and A. K. Emel’yanov, “Alpha-synuclein as a marker for Parkinson’s disease,” in: Human Neurodegenerative Diseases from Genome to the Whole Body, M. V. Ugyumov (ed.), Nauchnyi Mir, Moscow (2014).
R. Cacabelos, “Parkinson’s disease: From pathogenesis to pharmacogenomics,” Int. J. Mol. Sci., 18, No. 3, pii: E551 (2017), https://doi.org/10.3390/ijms18030551.
M. V. Ugryumov, “Translational, personalized, and prophylactic medicine as the basis for the battle with neurodegenerative diseases,” in: Human Neurodegenerative Diseases from Genome to the Whole Body, M. V. Ugyumov (ed.), Nauchnyi Mir, Moscow (2014).
S. N. Illarioshkin, “Current concepts of the etiology of Parkinson’s disease,” Nevrol. Zh., 20, No. 4, 4–13 (2015), https://doi.org/10.18821/1560-9545-2015-20-4-4-13.
V. V. Ponomarev, A. V. Boiko, and O. A. Ionova, V. V. “Laboratory biomarkers for the early diagnosis of Parkinson’s disease,” Mezhdunarod. Bol. Parkinsona, 81, No. 3, 17–22 (2016).
M. R. Cookson, “alpha-Synuclein and neuronal cell death,” Mol. Neurodegener., 4, 9 (2009), https://doi.org/10.1186/1750-1326-4-9.
M. B. Watson, F. Richter, S. K. Lee, M. V. Ugyumov, et al., “Regionally-specifi c microglial activation in young mice over-expressing human wildtype alpha-synuclein,” Exp. Neurol., 237, No. 2, 318–334 (2012), https://doi.org/10.1016/j.expneurol.2012.06.025.
K. L. Emmer, E. A. Waxman, J. P. Covy, and B. I. Giasson, “E46K human alpha-synuclein transgenic mice develop Lewy-like and tau pathology associated with age-dependent, detrimental motor impairment,” J. Biol. Chem., 286, No. 40, 35104–35118 (2011), https://doi.org/10.1074/jbc.M111.247965.
B. I. Giasson, J. E. Duda, I. V. Murray, et al., “Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions,” Science, 290, No. 5493, 985–989 (2000), https://doi.org/10.1126/science.290.5493.985.
H. M. Gao, P. T. Kotzbauer, K. Uryu, et al., “Neuroinfl ammation and oxidation/nitration of alpha-synuclein linked to dopaminergic neurodegeneration,” J. Neurosci., 28, No. 30, 7687–7698 (2008), https://doi.org/10.1523/JNEUROSCI.0143-07.2008.
S. Theodore, S. Cao, P. J. McLean, and D. G. Standaert, “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., 67, No. 12, 1149–1158 (2008), https://doi.org/10.1097/NEN.0b013e31818e5e99.
L. M. Kosloski, D. M. Ha, J. A. Hutter, et al., “Adaptive immune regulation of glial homeostasis as an immunization strategy for neurodegenerative diseases,” J. Neurochem., 114, No. 5, 1261–1276 (2010), https://doi.org/10.1111/j.1471-4159.2010.06834.x.
A. De Virgilio, A. Greco, G. Fabbrini, et al., “Parkinson’s disease: autoimmunity and neuroinfl ammation,” Autoimmun. Rev., 15, No. 10, 1005–1011 (2016), https://doi.org/10.1016/j.autrev.2016.07.022.
M. L. Block and J. S. Hong, “Microglia and infl ammation-mediated neurodegeneration: multiple triggers with a common mechanism,” Prog. Neurobiol., 76, No. 2, 77–98 (2005), https://doi.org/10.1016/j.pneurobio.2005.06.004.
V. Calabrese, A. Santoro, D. Monti, et al., “Aging and Parkinson’s disease: Infl ammaging, neuroinfl ammation and biological remodeling as key factors in pathogenesis,” Free Radic. Biol. Med., 115, 80–91 (2018), https://doi.org/10.1016/j.freeradbiomed.2017.10.379.
L. S. Schneider, F. Mangialasche, N. Andreasen, et al., “Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014,” J. Intern. Med., 275, No. 3, 251–283 (2014), https://doi.org/10.1111/joim.12191.
V. Pizza, A. Agresta, C. W. D’Acunto, et al., “Neuroinfl amm-aging and neurodegenerative diseases: an overview,” CNS Neurol. Disord. Drug Targets, 10, No. 5, 621–634 (2011), https://doi.org/10.2174/187152711796235014.
C. Franceschi, M. Capri, D. Monti, et al., “Infl ammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans,” Mech. Aging Dev., 128, No. 1, 92–105 (2007), https://doi.org/10.1016/j.mad.2006.11.016.
T. C. Frank-Cannon, L. T. Alto, F. E. McAlpine, and M. G. Tansey, “Does neuroinfl ammation fan the fl ame in neurodegenerative diseases?” Mol. Neurodegener., 4, 47 (2009), https://doi.org/10.1186/1750-1326-4-47.
T. Wyss-Coray, “Infl ammation in Alzheimer disease: driving force, bystander or benefi cial response?” Nat. Med., 12, No. 9, 1005–1015 (2006), https://doi.org/10.1038/nm1484.
F. Blandini, A. Mangiagalli, M. Cosentino, et al., “Peripheral markers of apoptosis in Parkinson’s disease: the effect of dopaminergic drugs,” Ann. N. Y. Acad. Sci., 1010, 675–678 (2003), https://doi.org/10.1196/annals.1299.123.
B. Liu and J. S. Hong, “Role of microglia in infl ammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention,” J. Pharmacol. Exp. Ther., 304, No. 1, 1–7 (2003), https://doi.org/10.1124/jpet.102.035048.
M. Mogi, M. Harada, P. Riederer, et al., “Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fl uid from parkinsonian patients,” Neurosci. Lett., 165, No. 1–2, 208–210 (1994), https://doi.org/10.1016/0304-3940(94)90746-3.
M. G. Tansey, M. K. McCoy, and T. C. Frank-Cannon, “Neuroinflammatory mechanisms in Parkinson’s disease: potential environmental triggers, pathways, and targets for early therapeutic intervention,” Exp. Neurol., 208, No. 1, 1–25 (2007), https://doi.org/10.1016/j.expneurol.2007.07.004.
T. Yamada, P. L. McGeer, and E. G. McGeer, “Lewy bodies in Parkinson’s disease are recognized by antibodies to complement proteins,” Acta Neuropathol., 84, No. 1, 100–104 (1992), https://doi.org/10.1007/BF00427222.
M. Mogi, M. Harada, H. Narabayashi, et al., “Interleukin (IL)-1 beta, IL-2, IL-4, IL-6 and transforming growth factor-alpha levels are elevated in ventricular cerebrospinal fl uid in juvenile parkinsonism and Parkinson’s disease,” Neurosci. Lett., 211, No. 1, 13–16 (1996), https://doi.org/10.1016/0304-3940(96)12706-3.
M. N. Karpenko, A. A. Vasilishina, E. A. Gromova, et al., “Interleukin-1β, interleukin-1 receptor antagonist, interleukin-6, interleukin-10, and tumor necrosis factor-α levels in CSF and serum in relation to the clinical diversity of Parkinson’s disease,” Cell. Immunol., 327, 77–82 (2018), https://doi.org/10.1016/j.cellimm.2018.02.011.
D. Koziorowski, R. Tomasiuk, S. Szlufi k, and A. Friedman, “Infl amma tory cytokines and NT-proCNP in Parkinson’s disease patients,” Cytokine, 60, No. 3, 762–766 (2012), https://doi.org/10.1016/j.cyto.2012.07.030.
H. Chen, E. J. O’Reilly, M. A. Schwarzschild, and A. Ascherio, “Peripheral infl ammatory biomarkers and risk of Parkinson’s disease,” Am. J. Epidemiol., 167, 90–95 (2008), https://doi.org/10.1093/aje/kwm260.
I. Stojkovska, B. M. Wagner, and B. E. Morrison, “Parkinson’s disease and enhanced infl ammatory response,” Exp. Biol. Med. (Maywood), 240, No. 11, 1387–1395 (2015), https://doi.org/10.1177/1535370215576313.
A. J. Herrera, A. Castano, J. L. Venero, et al., “The single intranigral injection of LPS as a new model for studying the selective effects of infl ammatory reactions on dopaminergic system,” Neurobiol. Dis., 7, No. 4, 429–447 (2000), https://doi.org/10.1006/nbdi.2000.0289.
I. Kurkowska-Jastrzebska, A. Wronska, M. Kohutnicka, et al., “The infl ammatory reaction following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxication in mouse,” Exp. Neurol., 156, No. 1, 50–61 (1999), https://doi.org/10.1006/exnr.1998.6993.
A. Czlonkowska, M. Kohutnicka, I. Kurkowska-Jastrzebska, and A. Czlonkowski, “Microglial reaction in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced Parkinson’s disease mice model,” Neurodegeneration, 5, No. 2, 137–143 (1996), https://doi.org/10.1006/neur.1996.0020.
M. Mogi, A. Togari, K. Tanaka, et al., “Increase in level of tumor necrosis factor-alpha in 6-hydroxydopamine-lesioned striatum in rats is suppressed by immunosuppressant FK506,” Neurosci. Lett., 289, No. 3, 165–168 (2000), https://doi.org/10.1016/S0304-3940(00)01275-1.
M. K. McCoy, T. N. Martinez, K. A. Ruhn, et al., “Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson’s disease,” J. Neurosci., 26, No. 37, 9365–9375 (2006), https://doi.org/10.1523/JNEUROSCI.1504-06.2006.
E. M. Quintero, L. Willis, R. Singleton, et al., “Behavioral and morphological effects of minocycline in the 6-hydroxydopamine rat model of Parkinson’s disease,” Brain Res., 1093, No. 1, 198–207 (2006), https://doi.org/10.1016/j.brainres.2006.03.104.
P. Klivenyi, G. Gardian, N. Y. Calingasan, et al., “Additive neuroprotective effects of creatine and a cyclooxygenase 2 inhibitor against dopamine depletion in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease,” J. Mol. Neurosci., 21, No. 3, 191–198 (2003), https://doi.org/10.1385/JMN:21:3:191.
A. Castano, A. J. Herrera, J. Cano, and A. Machado, “Lipopolysaccharide intranigral injection induces infl ammatory reaction and damage in nigrostriatal dopaminergic system,” J. Neurochem., 70, 1584–1592 (1998), https://doi.org/10.1046/j.1471-4159.1998.70041584.x.
H. M. Gao, J. Jiang, B. Wilson, et al., “Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: relevance to Parkinson’s disease,” J. Neurochem., 81, No. 6, 1285–1297 (2002), https://doi.org/10.1046/j.1471-4159.2002.00928.x.
K. Saijo, B. Winner, C. T. Carson, et al., “A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death,” Cell, 137, No. 1, 47–59 (2009), https://doi.org/10.1016/j.cell.2009.01.038.
S. O. McGuire, Z. D. Ling, J. W. Lipton, et al., “Tumor necrosis factor alpha is toxic to embryonic mesencephalic dopamine neurons,” Exp. Neurol., 169, No. 2, 219–230 (2001), https://doi.org/10.1006/exnr.2001.7688.
M. P. Mount, A. Lira, D. Grimes, et al., “Involvement of interferon-gamma in microglial-mediated loss of dopaminergic neurons,” J. Neurosci., 27, No. 12, 3328–3337 (2007), https://doi.org/10.1523/JNEUROSCI.5321-06.2007.
D. Kempuraj, G. P. Selvakumar, S. Zaheer, et al., “Cross-talk between glia, neurons and mast cells in neuroinfl ammation associated with Parkinson’s disease,” J. Neuroimmune. Pharmacol., 13, No. 1, 100–112 (2018), https://doi.org/10.1007/s11481-017-9766-1.
D. Kempuraj, R. Thangavel, R. Fattal, et al., “Mast cells release chemokine CCL2 in response to Parkinsonian toxin 1-methyl-4-phenyl-pyridinium (MPP(+)),” Neurochem. Res., 41, No. 5, 1042–1049 (2016), https://doi.org/10.1007/s11064-015-1790-z.
M. G. Tansey and M. S. Goldberg, “Neuroinflammation in Parkinson’s disease: its role in neuronal death and implications for therapeutic intervention,” Neurobiol. Dis., 37, No. 3, 510–518 (2010), https://doi.org/10.1016/j.nbd.2009.11.004.
V. Pisani, A. Stefani, M. Pierantozzi, et al., “Increased transfer of blood-cerebrospinal fluid albumin in advanced Parkinson’s disease,” J. Neuroinflammation, 9, 188 (2012), https://doi.org/10.1186/1742-2094-9-188.
R. Kortekaas, K. L. Leenders, J. C. van Oostrom, et al., “Blood-brain barrier dysfunction in parkinsonian midbrain in vivo,” Ann. Neurol., 57, No. 2, 176–179 (2005), https://doi.org/10.1002/ana.20369.
E. Farkas, G. I. De Jong, R. A. de Vos, et al., “Pathological features of cerebral cortical capillaries are doubled in Alzheimer’s disease and Parkinson’s disease,” Acta Neuropathol., 100, No. 4, 395–402 (2000), https://doi.org/10.1007/s004010000195.
B. A. Faucheux, A. M. Bonnet, Y. Agid, and E. C. Hirsch, “Blood vessels change in the mesencephalon of patients with Parkinson’s disease,” Lancet, 353, No. 9157, 981–982 (1999), https://doi.org/10.1016/S0140-6736(99)00641-8.
V. Brochard, B. Combadiere, A. Prigent, et al., “Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease,” J. Clin. Invest., 119, 182–192 (2009), https://doi.org/10.1172/JCI36470.
J. Miklossy, D. D. Doudet, C. Schwab, et al., “Role of ICAM-1 in persisting inflammation in Parkinson disease and MPTP monkeys,” Exp. Neurol., 197, No. 2, 275–283 (2006), https://doi.org/10.1016/j.expneurol.2005.10.034.
B. S. Desai, A. J. Monahan, P. M. Carvey, and B. Hendey, “Blood–brain barrier pathology in Alzheimer’s and Parkinson’s disease: implications for drug therapy,” Cell Transplant., 16, No. 3, 285–299 (2007), https://doi.org/10.3727/000000007783464731.
P. L. McGeer, S. Itagaki, B. E. Boyes, and E. G. McGeer, “Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains,” Neurology, 38, No. 8, 1285–1291 (1988), https://doi.org/10.1212/WNL.38.8.1285.
U. Fiszer, E. Mix, S. Fredrikson, et al., “Parkinson’s disease and immunological abnormalities: increase of HLA-DR expression on monocytes in cerebrospinal fluid and of CD45RO+ T cells in peripheral blood,” Acta Neurol. Scand., 90, No. 3, 160–166 (1994), https://doi.org/10.1111/j.1600-0404.1994.tb02699.x.
K. Imamura, N. Hishikawa, M. Sawada, et al., “Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson’s disease brains,” Acta Neuropathol., 106, 518–526 (2003), https://doi.org/10.1007/s00401-003-0766-2.
T. H. Hamza, C. P. Zabetian, A. Tenesa, et al., “Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease,” Nat. Genet., 42, No. 9, 781–785 (2010), https://doi.org/10.1038/ng.642.
A. Puschmann, C. Verbeeck, M. G. Heckman, et al., “Human leukocyte antigen variation and Parkinson’s disease,” Parkinsonism Relat. Disord., 17, No. 5, 376–378 (2011), https://doi.org/10.1016/j.parkreldis.2011.03.008.
R. L. Zhu, X. C. Lu, L. J. Tang, et al., “Association between HLA rs3129882 polymorphism and Parkinson’s disease: a meta-analysis,” Eur. Rev. Med. Pharmacol. Sci., 19, No. 3, 423–32 (2015).
K. Saijo and C. K. Glass, “Microglial cell origin and phenotypes in health and disease,” Nat. Rev. Immunol., 11, No. 11, 775–787 (2011), https://doi.org/10.1038/nri3086.
F. Aloisi, “Immune function of microglia,” Glia, 36, 165–179 (2001), https://doi.org/10.1002/glia.1106.
X. Su, K. A. Maguire-Zeiss, R. Giuliano, et al., “Synuclein activates microglia in a model of Parkinson’s disease,” Neurobiol. Aging, 29, No. 11, 1690–1701 (2008), https://doi.org/10.1016/j.neurobiolaging.2007.04.006.
H. Wilms, P. Rosenstiel, M. Romero-Ramos, et al., “Suppression of MAP kinases inhibits microglial activation and attenuates neuronal cell death induced by alpha-synuclein protofibrils,” Int. J. Immunopathol. Pharmacol., 22, No. 4, 897–909 (2009), https://doi.org/10.1177/039463200902200405.
E. J. Lee, M. S. Woo, P. G. Moon, et al., “Alpha-synuclein activates microglia by inducing the expressions of matrix metalloproteinases and the subsequent activation of protease-activated receptor-1,” J. Immunol., 185, No. 1, 615–623 (2010), https://doi.org/10.4049/jimmunol.0903480.
Y. Couch, L. Alvarez-Erviti, N. R. Sibson, et al., “The acute inflammatory response to intranigral alpha-synuclein differs significantly from intranigral lipopolysaccharide and is exacerbated by peripheral inflammation,” J. Neuroinflammation, 8, 166 (2011), https://doi.org/10.1186/1742-2094-8-166.
J. L. Marin-Teva, M. A. Cuadros, D. Martin-Oliva, and J. Navascues, “Microglia and neuronal cell death,” Neuron Glia Biol., 7, No. 1, 25–40 (2011), https://doi.org/10.1017/S1740925X12000014.
A. D. Reynolds, D. K. Stone, J. A. Hutter, et al., “Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson’s disease,” J. Immunol., 184, No. 5, 2261–2271 (2010), https://doi.org/10.4049/jimmunol.0901852.
J. W. Langston, L. S. Forno, J. Tetrud, et al., “Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure,” Ann. Neurol., 46, 598–605 (1999), https://doi.org/10.1002/1531-8249(199910)46:4<598::AID-ANA7>3.0.CO;2-F.
M. Vazquez-Claverie, P. Garrido-Gil, W. San Sebastián, et al., “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., 68, No. 9, 977–984 (2009), https://doi.org/10.1097/NEN.0b013e3181b35e41.
E. Croisier, L. B. Moran, D. T. Dexter, et al., “Microglial inflammation in the parkinsonian substantia nigra: relationship to alpha-synuclein deposition,” J. Neuroinfl ammation, 2, 14 (2005), https://doi.org/10.1186/1742-2094-2-14.
Y. Ouchi, E. Yoshikawa, Y. Sekine, et al., “Microglial activation and dopamine terminal loss in early Parkinson’s disease,” Ann. Neurol., 57, No. 2, 168–175 (2005), https://doi.org/10.1002/ana.20338.
A. S. Harms, S. Cao, A. L. Rowse, et al., “MHCII is required for α-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration,” J. Neurosci., 33, No. 23, 9592–9600 (2013), https://doi.org/10.1523/JNEUROSCI.5610-12.2013.
M. Mogi, M. Harada, T. Kondo, et al., “Brain beta 2-microglobulin levels are elevated in the striatum in Parkinson’s disease,” J. Neural Transm. Park. Dis. Dement. Sect., 9, No. 1, 87–92 (1995), https://doi.org/10.1007/BF02252965.
C. Cebrian, F. A. Zucca, P. Mauri, et al., “MHC-I expression renders catecholaminergic neurons susceptible to Tcell-mediated degeneration,” Nat. Commun., 5, 3633 (2014), https://doi.org/10.1038/ncomms4633.
A. Lira, J. Kulczycki, R. Slack, et al., “Involvement of the Fc gamma receptor in a chronic N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of dopaminergic loss,” J. Biol. Chem., 286, No. 33, 28783–28793 (2011), https://doi.org/10.1074/jbc.M111.244830.
E. J. Benner, R. Banerjee, A. D. Reynolds, et al., “Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons,” PLoS One, 3, No. 1, e1376 (2008), https://doi.org/10.1371/journal.pone.0001376.
A. D. Reynolds, R. Banerjee, J. Liu, et al., “Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson’s disease,” J. Leukoc. Biol., 82, No. 5, 1083–1094 (2007), https://doi.org/10.1189/jlb.0507296.
Y. Huang, Z. Liu, X. Q. Wang, et al., “A dysfunction of CD4+ T lymphocytes in peripheral immune system of Parkinson’s disease model mice,” Zhongguo Ying Yong Sheng Li Xue Za Zhi, 30, No. 6, 567–576 (2014).
S. S. Duffy, B. A. Keating, C. J. Perera, and G. Moalem-Taylor, “The role of regulatory T cells in nervous system pathologies,” J. Neurosci. Res., 96, No. 6, 951–968 (2018), https://doi.org/10.1002/jnr.24073.
Y. Chi, Y. Fan, L. He, et al., “Novel role of aquaporin-4 in CD4+CD25+ T regulatory cell development and severity of Parkinson’s disease,” Aging Cell, 10, No. 3, 368–382 (2011), https://doi.org/10.1111/j.1474-9726.2011.00677.x.
E. S. Chung, G. Lee, C. Lee, et al., “Bee venom phospholipase A2, a novel Foxp3+ regulatory T cell inducer, protects dopaminergic neurons by modulating neuroinflammatory responses in a mouse model of Parkinson’s disease,” J. Immunol., 195, No. 10, 4853–4860 (2015), https://doi.org/10.4049/jimmunol.1500386.
C. A. Colton, “Heterogeneity of microglial activation in the innate immune response in the brain,” J. Neuroimmune. Pharmacol., 4, No. 4, 399–418 (2009), https://doi.org/10.1007/s11481-009-9164-4.
J. Bas, M. Calopa, M. Mestre, et al., “Lymphocyte populations in Parkinson’s disease and in rat models of parkinsonism,” J. Neuroimmunol., 113, 146–152 (2001), https://doi.org/10.1016/S0165-5728(00)00422-7.
C. H. Stevens, D. Rowe, M. C. Morel-Kopp, et al., “Reduced T helper and B lymphocytes in Parkinson’s disease,” J. Neuroimmunol., 252, No. 1–2, 95–99 (2012), https://doi.org/10.1016/j.jneuroim.2012.07.015.
U. Fiszer, E. Mix, S. Fredrikson, et al., “Parkinson’s disease and immunological abnormalities: increase of HLA-DR expression on monocytes in cerebrospinal fluid and of CD45RO+ T cells in peripheral blood,” Acta Neurol. Scand., 90, No. 3, 160–166 (1994), https://doi.org/10.1111/j.1600-0404.1994.tb02699.x.
B. Crucian, P. Dunne, H. Friedman, et al., “Alterations in levels of CD28-/CD8+ suppressor cell precursor and CD45RO+/ CD4+ memory T lymphocytes in the peripheral blood of multiple sclerosis patients,” Clin. Diagn. Lab. Immunol., 2, No. 2, 249–252 (1995).
K. Hisanaga, M. Asagi, Y. Itoyama, and Y. Iwasaki, “Increase in peripheral CD4 bright+ CD8 dull+ T cells in Parkinson disease,” Arch. Neurol., 58, No. 10, 1580–1583 (2001), https://doi.org/10.1001/archneur.58.10.1580.
Y. Baba, A. Kuroiwa, R. J. Uitti, et al., “Alterations of T-lymphocyte populations in Parkinson disease,” Parkinsonism Relat. Disord., 11, 493–498 (2005), https://doi.org/10.1016/j.parkreldis.2005.07.005.
J. A. Saunders, K. A. Estes, L. M. Kosloski, et al., “CD4+ regulatory and effector/memory T cell subsets profile motor dysfunction in Parkinson’s disease,” J. Neuroimmun. Pharmacol., 7, No. 4, 927–938 (2012), https://doi.org/10.1007/s11481-012-9402-z.
M. Rentzos, C. Nikolaou, E. Andreadou, et al., “Circulating interleukin-15 and RANTES chemokine in Parkinson’s disease,” Acta Neurol. Scand., 116, No. 6, 374–379 (2007), https://doi.org/10.1111/j.1600-0404.2007.00894.x.
M. Rentzos, C. Nikolaou, E. Andreadou, et al., “Circulating interleukin-10 and interleukin-12 in Parkinson’s disease,” Acta Neurol. Scand., 119, No. 5, 332–337 (2009), https://doi.org/10.1111/j.1600-0404.2008.01103.x.
U. Fiszer, E. Mix, S. Fredrikson, et al., “Gamma delta+ T cells are increased in patients with Parkinson’s disease,” J. Neurol. Sci., 121, No. 1, 39–45 (1994), https://doi.org/10.1016/0022-510X(94)90154-6.
L. Cen, C. Yang, S. Huang, et al., “Peripheral lymphocyte subsets as a marker of Parkinson’s disease in a Chinese population,” Neurosci. Bull., 33, No. 5, 493–500 (2017), https://doi.org/10.1007/s12264-017-0163-9.
D. Rosenkranz, S. Weyer, E. Tolosa, et al., “Higher frequency of regulatory T cells in the elderly and increased suppressive activity in neurodegeneration,” J. Neuroimmunol., 188, No. 1–2, 117–127 (2007), https://doi.org/10.1016/j.jneuroim.2007.05.011.
Y. Chen, B. Qi, W. Xu, et al., “Clinical correlation of peripheral CD4+ cell subsets, their imbalance and Parkinson’s disease,” Mol. Med. Rep., 12, No. 4, 6105–6111 (2015), https://doi.org/10.3892/mmr.2015.4136.
U. Fiszer, S. Fredrikson, E. Mix, et al., “V region T cell receptor repertoire in Parkinson’s disease,” Acta Neurol. Scand., 93, No. 1, 25–29 (1996), https://doi.org/10.1111/j.1600-0404.1996.tb00165.x.
T. Alberio, A. C. Pippione, M. Zibetti, et al., “Discovery and verification of panels of T-lymphocyte proteins as biomarkers of Parkinson’s disease,” Sci. Rep., 2, 953 (2012), https://doi.org/10.1038/srep00953.
M. Han, E. Nagele, C. DeMarshall, et al., “Diagnosis of Parkinson’s disease based on disease-specific autoantibody profiles in human sera,” PLoS One, 7, e32383 (2012), https://doi.org/10.1371/journal.pone.0032383.
K. L. Double, D. B. Rowe, F. M. Carew-Jones, et al., “Anti-melanin antibodies are increased in sera in Parkinson’s disease,” Exp. Neurol., 217, No. 2, 297–301 (2009), https://doi.org/10.1016/j.expneurol.2009.03.002.
U. Fiszer, S. Fredrikson, and A. Członkowska, “Humoral response to hsp 65 and hsp 70 in cerebrospinal fluid in Parkinson’s disease,” J. Neurol. Sci., 139, No. 1, 66–70 (1996), https://doi.org/10.1016/0022-510X(96)00002-0.
J. W. Terryberry, G. Thor, and J. B. Peter, “Autoantibodies in neurodegenerative diseases: antigen-specific frequencies and intrathecal analysis,” Neurobiol. Aging, 19, No. 3, 205–216 (1998), https://doi.org/10.1016/S0197-4580(98)00049-9.
A. B. Poletaev, S. G. Morozov, B. B. Gnedenko, et al., “Serum anti-S100b, anti-GFAP and anti-NGF autoantibodies of IgG class in healthy persons and patients with mental and neurological disorders,” Autoimmunity, 32, No. 1, 33–38 (2000), https://doi.org/10.3109/08916930008995985.
C. F. Orr, D. B. Rowe, Y. Mizuno, et al., “A possible role for humoral immunity in the pathogenesis of Parkinson’s disease,” Brain, 128, No. 11, 2665–2674 (2005), https://doi.org/10.1093/brain/awh625.
C. Depboylu, M. K. Schafer, O. Arias-Carrion, et al., “Possible involvement of complement factor C1q in the clearance of extracellular neuromelanin from the substantia nigra in Parkinson disease,” J. Neuropathol. Exp. Neurol., 70, No. 2, 125–132 (2011), https://doi.org/10.1097/NEN.0b013e31820805b9.
Y. He, W. D. Le, and S. H. Appel, “Role of Fcgamma receptors in nigral cell injury induced by Parkinson disease immunoglobulin injection into mouse substantia nigra,” Exp. Neurol., 176, No. 2, 322–327 (2002), https://doi.org/10.1006/exnr.2002.7946.
S. Cao, S. Theodore, and D. G. Standaert, “Fcγ receptors are required for NF-κB signaling, microglial activation and dopaminergic neurodegeneration in an AAV-synuclein mouse model of Parkinson’s disease,” Mol. Neurodegener., 5, 42 (2010), https://doi.org/10.1186/1750-1326-5-42.
E. J. Bae, H. J. Lee, E. Rockenstein, et al., “Antibody-aided clearance of extracellular alpha-synuclein prevents cell-to-cell aggregate transmission,” J. Neurosci., 32, No. 39, 13454–13469 (2012), https://doi.org/10.1523/JNEUROSCI.1292-12.2012.
K. K. Papachroni, N. Ninkina, A. Papapanagiotou, et al., “Autoantibodies to alpha-synuclein in inherited Parkinson’s disease,” J. Neurochem., 101, No. 3, 749–756 (2007), https://doi.org/10.1111/j.1471-4159.2006.04365.x.
X. Li, J. Sundquist and K. Sundquist, “Subsequent risks of Parkinson disease in patients with autoimmune and related disorders: a nationwide epidemiological study from Sweden,” Neurodegener. Dis., 10, 277-284 (2012), https://doi.org/10.1159/000333222.
R. H. Walker, H. Spiera, M. F. Brin, and C. W. Olanow, “Parkinsonism associated with Sjogren’s syndrome: three cases and a review of the literature,” Mov. Disord., 14, No. 2, 262–268 (1999), https://doi.org/10.1002/1531-8257(199903)14:2<262::AID-MDS1011>3.0.CO;2-6.
S. M. Langan, R. W. Groves, and J. West, “The relationship between neurological disease and bullous pemphigoid: a population-based case-control study,” J. Invest. Dermatol., 131, No. 3, 631–636 (2011), https://doi.org/10.1038/jid.2010.357.
R. T. Ravenholt and W. H. Foege, “1918 influenza, encephalitis lethargica, parkinsonism,” Lancet, 2, No. 8303, 860–864 (1982), https://doi.org/10.1016/S0140-6736(82)90820-0.
O. Miman, O. Y. Kusbeci, O. C. Aktepe, and Z. Cetinkaya, “The probable relation between Toxoplasma gondii and Parkinson’s disease,” Neurosci. Lett., 475, No. 3, 129–131 (2010), https://doi.org/10.1016/j.neulet.2010.03.057.
J. Woulfe, H. Hoogendoorn, M. Tarnopolsky, and D. G. Musoz, “Monoclonal antibodies against Epstein–Barr virus cross-react with alpha-synuclein in human brain,” Neurology, 55, No. 9, 1398–1401 (2000), https://doi.org/10.1212/WNL.55.9.1398.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Translated from Zhurnal Nevrologii i Psikhiatrii imeni S. S. Korsakova, Vol. 120, No. 2, Iss. 1, pp. 110–119, February, 2020.
Rights and permissions
About this article
Cite this article
Belova, O.V., Arefieva, T.I. & Moskvina, S.N. Immunoinflammatory Aspects of Parkinson’s Disease. Neurosci Behav Physi 50, 1127–1135 (2020). https://doi.org/10.1007/s11055-020-01014-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11055-020-01014-w