Central nervous system (CNS) was considered as an “immunologically privileged site”. However, accumulating evidence supports a role for neuro inflammation in progress in Parkinson’s disease (PD). Not only the activated resident microglia in brains, cytokine levels in CNS and blood, the presence of auto antibodies, and the infiltration of T-cell in CNS also contribute disease progression. The interplay between innate and adaptive immunity in the pathobiology of PD will be focused on this article.

The presence of HLA-DR (human MHC class II cell surface receptor) positive activated microgliain Parkinson’s disease (PD) patients’brain including Substantia Nigras (SNs) has been described [1-3]. In vivo imaging using positron emission tomography (PET) suggests widespread activated microglia in PD patients [4]. Moreover, HLA-DQ as well as HLA-DR, both expressed by monocytes in the CSF and peripheral blood of PD patients are significantly higher compared with controls [5]. More recently, genome-wide association studies (GWASs) of PD patients [6-10], including a meta-analysis of the GWASs, [11] verified an increased relative risk for PD and expression of HLA-DR or HLA-DQ MHC II molecules, leading to the designation of HLA-DRA as PARK18, a genetic marker recently found to be associated with susceptibility to PD [6]. Activated microglia and monocytes in PD brains secrete proinflammatory neurotoxic cytokines. Indeed, levels of IL-1β, IL-6, and TNF-α are elevated in the CFS of PD patients [11,12]. Increased expression of NFκB (nuclear factor κB) in the SN of PD patients is found in CD11b+ microglia and also in affected neurons [13]. These data support the hypothesis that activation of cells of the innate immune system, such as microglia and monocytes, directly contribute to the pathobiology of PD.

It is likely that α-synuclein (αSyn) associated pathology modulates the microglia response as αSyn deposition correlates with the presence of MHC II expressing microglia [14]. Nitrated αSyn within Lewy bodies, released from dying or dead dopaminergic neurons, was reported to induced microglia activation [15]. In addition, αSyninduced microglia activation was mediated through PRRs binding [16]. Although αSynis a typical cytosolic protein, it has also been found not only in CSF but also blood. Changes in the levels and characteristics of extracellular αSyn are associated with the disease and extracellular αSyn has been shown to be taken up by cultured microglia as well as neuron [17]. Moreover, presence of abnormal αSyn expression in cells surrounding neuroinflammatory lesions was reported within the brains of patients with multiple sclerosis [18]. Therefore, neurotoxicity related to accumulation of in PD may occur through an excessive microglia stimulation.

A harmful role of reactive microglia has also found in several PD animal models. Behavial changes or dopaminergic neurodegeneration, which are caused by neurotoxins MPTP and 6-OHDA, are associated with microglial activation and increased production of proinflammatory cytokines in the SNc [19-22]. MPTP treated mice showed behavioral dysfunction, activated microglia, and increased the levels of IL-10, IL-12(p40) IL-13, IFN-γ, and MCP-1 in CSF [22]. Moreover, both peripheral and intranigral administration of lipopolysaccharide (LPS), a potent microglial activator and a ligand of TLR-4, induces a rapid microglial response and increased levels of pro-inflammatory cytokines and free radicals in the brain, which is followed only at a later time by dopaminergic degeneration [23-27]. Finally, several studies have demonstrated a clear relationship between pro-inflammatory cytokines and nigral degeneration; over expression of TNF-a via virus delivery system causes dopaminergic cell death, while deficiency of TNF-a receptor is neuroprotective against MPTP toxicity[28-29] and IL1-b over expression exacerbates LPS or 6-OHDA-induced neurodegeneration [30-31].

Today, accumulating evidence suggested the adaptive immune system also involve PD pathology. Both patients and animal models showed exacerbation of the neurodegenerative process after a peripheral inflammatory stimulus [32]. Increasing inflammation and breakdown of the blood–brain barrier (BBB) forces increased communication between the CNS and peripheral immune systems as evidenced in several neurodegenerative diseases with increased leukocyte migration within the brain parenchyma [33].

Along with activated microglia and astrocytes, T cells may also comprise components of PD pathobiology. More recently, both CD4+ and CD8+ T cells have been discovered within the SN of PD patients and MPTP treated mice [33]. Intercellular adhesion molecule-1 (ICAM-1) is known to play a key role in T-cell mediated host defense mechanisms and ICAM1-positive glia are also increased in the SN of PD brains and MPTP treated monkey brain [34], as well as association with lesioned areas of Alzheimer disease, amyotrophic lateral sclerosis, Pick’s disease and progressive supranuclear palsy [35].

Although several autoantibodies for dopamine neuron antigens are reported in sera and CSF of PD patients [36,37], the role of the adaptive immune system has only recently begun to be investigated in depth. IgG from PD patients (PD-IgG) activated microglia via the Fcgamma receptor (FcR) and induce dopaminergic cell injury, while PD IgG injection in FcR -/- mice resulted in no significant increase of microglia and no loss of TH-positive cells in the SNpc [38]. Accumulating evidence suggested that PD patients showed brain-associated autoantibodies including those directed against, GM1, S100B, glial fibrillar acidic protein (GFAP), NGF, neurofilament, myelin basic protein, tau, Aβ, and neuronal calcium channels, as well as α-syn and its modified and fibriliary forms [38-45]. Immunohistochemical staining of tissues from PD patients show that Lewy bodies were strongly immunolabelled with IgG. [47]In MPTP-intoxicated mice, α-syn drains to cervical lymph nodes where it activates antigen-presenting cells and T cells [48]. Moreover, antibodies to α-syn and catecholamine-derived melanin (neuromelanin) are increased in PD patients with antineuromelanin immunoglobulin binding shown to be more active in early disease [49]. Indeed, these data suggest that endogenous antibodies of unknown specificity have the capacity to cross the BBB and bind cognate antigens expressed by dopaminergic neurons.

I have reviewed here the overwhelming evidence that supports a role for neuroinflammation in PD. The number of activated microglia in brains, cytokine levels in CNS and blood, the presence of autoantibodies, and the infiltration of T-cell in CNS suggest that not only the local immune system but the peripheral immune system involve disease progression. However, more evidence is necessary for immunomodulatory strategies in PD treatment.

1. McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 38(8): 1285-1291.
2. Banati RB, Daniel SE, Blunt SB (1998) Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson's disease.Mov Disord 13(2): 221-227.
3. Hirsch EC, Hunot S (2009) Neuroinflammation in Parkinson's disease: a target for neuroprotection? Lancet Neurol 8(4): 382-397.
4. Gerhard A, Pavese N, Hotton G, Turkheimer F, Es M, et al. (2006) In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson's disease. Neurobiol Dis 21(2): 404-412.
5. Fiszer U, Mix E, Fredrikson S, Kostulas V, Link H (1994) 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(3): 160-166.
6. Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, et al. (2010) Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease. Nat Genet 42(9): 781-785.
7. Saiki M, Baker A, Williams-Gray CH, Foltynie T, Goodman RS, et al. (2010) Association of the human leucocyte antigen region with susceptibility to Parkinson's disease. J Neurol Neurosurg Psychiatry 81: 890-891.
8. Nalls MA, Couper DJ, Tanaka T, van Rooij FJ, Chen MH, et al. (2011) Multiple loci are associated with white blood cell phenotypes. PLoS Genet 7(6): e1002113.
9. Puschmann A, Verbeeck C, Heckman MG, Soto-Ortolaza AI, Lynch T, et al. (2011) Human leukocyte antigen variation and Parkinson's disease. Parkinsonism Relat Disord 17(5): 376-378.
10. Simón-Sánchez J, van Hilten JJ, van de Warrenburg B, Post B, Berendse HW, et al. (2011) Genome-wide association study confirms extant PD risk loci among the Dutch.Eur J Hum Genet 19(6): 655-661.
11. Blum-Degen D, Müller T, Kuhn W, Gerlach M, Przuntek H, et al. (1995) Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer's and de novo Parkinson's disease patients. Neurosci Lett 202(1-2): 17-20.
12. González-Scarano F, Baltuch G (1999) Microglia as mediators of inflammatory and degenerative diseases. Annu Rev Neurosci 22: 219-240.
13. Ghosh A, Roy A, Liu X, Kordower JH, Mufson EJ, et al. (2007) Selective inhibition of NF-kappaB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson's disease. Proc Natl Acad Sci U S A 104(47): 18754-18759.
14. Croisier E, Moran LB, Dexter DT, Pearce RK, Graeber MB (2005) Microglial inflammation in the parkinsonian substantia nigra: relationship to alpha-synuclein deposition. J Neuroinflammation 2: 14.
15. Reynolds AD, Stone DK, Mosley RL, Gendelman HE (2009) Nitrated {alpha}-synuclein-induced alterations in microglial immunity are regulated by CD4+ T cell subsets. J Immunol 182(7): 4137-4149.
16. Béraud D, Twomey M, Bloom B, Mittereder A, Ton V, et al. (2011) α-Synuclein Alters Toll-Like Receptor Expression.Front Neurosci 5: 80.
17. Bae EJ, Lee HJ, Rockenstein E, Ho DH, Park EB, et al. (2012) Antibody-aided clearance of extracellular α-synuclein prevents cell-to-cell aggregate transmission. J Neurosci 32: 13454-13469.
18. Lu JQ, Fan Y, Mitha AP, Bell R, Metz L, et al. (2009) Association of alpha-synuclein immunoreactivity with inflammatory activity in multiple sclerosis lesions. J Neuropathol Exp Neurol 68(2): 179-89.
19. Kohutnicka M, Lewandowska E, Kurkowska-Jastrzebska I, Członkowski A, Członkowska A (1998) Microglial and astrocytic involvement in a murine model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Immunopharmacology 39(3): 167-180.
20. Luchtman DW, Shao D, Song C (2009) Behavior, neurotransmitters and inflammation in three regimens of the MPTP mouse model of Parkinson's disease. Physiol Behav 98(1-2): 130-138.
21. Schintu N, Frau L, Ibba M, Garau A, Carboni E, et al. (2009) Progressive dopaminergic degeneration in the chronic MPTPp mouse model of Parkinson's disease. Neurotox Res 16(2): 127-139.
22. Yasuda Y, Shimoda T, Uno K, Tateishi N, Furuya S, et al. (2008) The effects of MPTP on the activation of microglia/astrocytes and cytokine/chemokine levels in different mice strains. J Neuroimmunol 204(1-2): 43-51.
23. Arai H, Furuya T, Yasuda T, Miura M, Mizuno Y, et al. (2004) Neurotoxic effects of lipopolysaccharide on nigral dopaminergic neurons are mediated by microglial activation, interleukin-1beta, and expression of caspase-11 in mice. J Biol Chem 279(49): 51647-51653.
24. Dutta G, Zhang P, Liu B (2008) The lipopolysaccharide Parkinson's disease animal model: mechanistic studies and drug discovery.Fundam Clin Pharmacol 22(5): 453-464.
25. Herrera AJ, Castaño A, Venero JL, Cano J, Machado A (2000) The single intranigral injection of LPS as a new model for studying the selective effects of inflammatory reactions on dopaminergic system. Neurobiol Dis 7(4): 429-447.
26. Iravani MM, Leung CC, Sadeghian M, Haddon CO, Rose S, et al. (2005) The acute and the long-term effects of nigral lipopolysaccharide administration on dopaminergic dysfunction and glial cell activation. Eur J Neurosci 22(5): 317-330.
27. De Lella Ezcurra AL, Chertoff M, Ferrari C, Graciarena M, Pitossi F (2010) Chronic expression of low levels of tumor necrosis factor-alpha in the substantia nigra elicits progressive neurodegeneration, delayed motor symptoms and microglia/macrophage activation. Neurobiol Dis 37(3): 630-640.
28. Sriram K, Matheson JM, Benkovic SA, Miller DB, Luster MI, et al. (2006) Deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP-induced neurotoxicity: role of TNF-alpha. FASEB J 20: 670-682.
29. Ferrari CC, Pott Godoy MC, Tarelli R, Chertoff M, Depino AM, et al. (2006) Progressive neurodegeneration and motor disabilities induced by chronic expression of IL-1beta in the substantia nigra. Neurobiol Dis 24(1): 183-193.
30. Long-Smith CM, Collins L, Toulouse A, Sullivan AM, Nolan YM (2010) Interleukin-1β contributes to dopaminergic neuronal death induced by lipopolysaccharide-stimulated rat glia in vitro. J Neuroimmunol 226(1-2): 20-26.
31. Pott Godoy MC, Tarelli R, Ferrari CC, Sarchi MI, Pitossi FJ (2008) Central and systemic IL-1 exacerbates neurodegeneration and motor symptoms in a model of Parkinson's disease. Brain 131(Pt 7): 1880-1894.
32. Ferrari CC, Tarelli R (2011) Parkinson's disease and systemic inflammation. Parkinsons Dis 2011: 436813.
33. Brochard V, Combadière B, Prigent A, Laouar Y, Perrin A, et al. (2009) Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest 119(1): 182-192.
34. Miklossy J, Doudet DD, Schwab C, Yu S, Mc Geer EG, et al. (2006) Role of ICAM-1 in persisting inflammation in Parkinson disease and MPTP monkeys. Exp Neurol 197: 275-283.
35. Ikeda K, Akiyama H, Kondo H, Ikeda K (1993) Anti-tau-positive glial fibrillary tangles in the brain of postencephalitic parkinsonism of Economo type. Neurosci Lett 162(1-2): 176-178.
36. McRae-Degueurce A, Rosengren L, Haglid K, Bööj S, Gottfries CG, et al. (1998) Immunocytochemical investigations on the presence of neuron-specific antibodies in the CSF of Parkinson's disease cases. Neurochem Res 13(7): 679-684.
37. Dahlström A, Wigander A, Lundmark K, Gottfries CG, Carvey PM, et al. (1990) Investigations on auto-antibodies in Alzheimer's and Parkinson's diseases, using defined neuronal cultures.J Neural Transm Suppl 29: 195-206.
38. He Y, Le WD, Appel SH (2002) Role of Fcgamma receptors in nigral cell injury induced by Parkinson disease immunoglobulin injection into mouse substantia nigra. Exp Neurol 176(2): 322-327.
39. Elizan TS, Casals J, Yahr MD (1983) Antineurofilament antibodies in postencephalitic and idiopathic Parkinson's disease. J Neurol Sci 59(3): 341-347.
40. Karcher D, Federsppiel BS, Lowenthal FD, Frank F, Lowenthal A (1986) Anti-neurofilament antibodies in blood of patients with neurological diseases. Acta Neuropathol 72(1): 82-85.
41. Appel SH, Smith RG, Alexianu M, Engelhardt J, Mosier D, et al. (1994) Neurodegenerative disease: autoimmunity involving calcium channels. Ann N Y Acad Sci 747: 183-194.
42. Terryberry JW, Thor G, Peter JB (1998) Autoantibodies in neurodegenerative diseases: antigen-specific frequencies and intrathecal analysis. Neurobiol Aging 19(3): 205-216.
43. Poletaev AB, Morozov SG, Gnedenko BB, Zlunikin VM, Korzhenevskey DA (2000) Serum anti-S100b, anti-GFAP and anti-NGF autoantibodies of IgG class in healthy persons and patients with mental and neurological disorders. Autoimmunity 32(1): 33-38.
44. Zappia M, Crescibene L, Bosco D, Arabia G, Nicoletti G, et al. (2002) Anti-GM1 ganglioside antibodies in Parkinson's disease. Acta Neurol Scand 106(1): 54-57.
45. Papachroni KK, Ninkina N, Papapanagiotou A, Hadjigeorgiou GM, Xiromerisiou G, et al. (2007) Autoantibodies to alpha-synuclein in inherited Parkinson's disease. J Neurochem 101(3): 749-756.
46. Yanamandra K, Gruden MA, Casaite V, Meskys R, Forsgren L, et al. (2011) α-synuclein reactive antibodies as diagnostic biomarkers in blood sera of Parkinson's disease patients. PLoS One 6(4): e18513.
47. Orr CF, Rowe DB, Mizuno Y, Mori H, Halliday GM (2005) A possible role for humoral immunity in the pathogenesis of Parkinson's disease. Brain 128(pt 11): 2665-2674.
48. Benner EJ, Banerjee R, Reynolds AD, Sherman S, Pisarev VM, et al. (2008) Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One 3(1): e1376.
49. Double KL, Rowe DB, Carew-Jones FM, Hayes M, Chan DK, et al. (2009) Anti-melanin antibodies are increased in sera in Parkinson's disease. Exp Neurol 217(2): 297-301.