The Role of Th17 Cells in Immunopathogenesis of Neuroinflammatory Disorders

  • Arash PourgholaminejadEmail author
  • Foozhan Tahmasebinia
Part of the Contemporary Clinical Neuroscience book series (CCNE)


Neuroinflammation, characterized by infiltration of immune cells such as T lymphocyte populations and other immune cells, is a prominent pathological feature of neurodegenerative disorders. However, consequence of neural injury during this inflammation is still unclear. Traditionally, CD4+ T helper (Th) cells have been categorized into various subsets. T helper 17 (Th17) cells are a Th subpopulation that plays an important role in the pathogenesis of neuroinflammatory diseases. The chronic forms of inflammatory milieu induce the Th17 cell polarization from their precursors and then secretion of pro-inflammatory cytokines such as interleukin-17 (IL-17), IL-21, IL-22, IL-23, and IL-6. Both interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) from Th17 cells exacerbate the inflammation. Migrating autoreactive Th17 cells into the nervous system can elicit neuronal apoptosis directly via Fas/FasL interaction. Th17 cells increase migration of other immune cells such as neutrophils into the inflamed CNS through the blood-brain barrier (BBB) and trigger the inflammatory reactions that occasionally lead to irreversible neuronal damages. Therefore, it is not surprising that these cells are implicated in a wide range of neuroinflammatory and autoimmune disorders including multiple sclerosis (MS), Alzheimer disease (AD), Parkinson disease (PD), schizophrenia, and many other neuroimmune disorders. In this chapter, we describe the immunopathogenesis of Th17 cells in neuroinflammations and discuss the neuronal injuries induced by Th17 cells and other Th17-related immune cells.


Th17 cell Neuroinflammation Autoimmune disease Neurodegenerative disorder 


  1. 1.
    Zhu J, Paul WE. CD4 T cells: fates, functions, and faults. Blood. 2008;112(5):1557–69.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Cosmi L, et al. T helper cells plasticity in inflammation. Cytometry A. 2014;85(1):36–42.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Raphael I, et al. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine. 2015;74(1):5–17.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Infante-Duarte C, et al. Microbial lipopeptides induce the production of IL-17 in Th cells. J Immunol. 2000;165(11):6107–15.CrossRefGoogle Scholar
  5. 5.
    Annunziato F, et al. Phenotypic and functional features of human Th17 cells. J Exp Med. 2007;204(8):1849–61.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Rostami A, Ciric B. Role of Th17 cells in the pathogenesis of CNS inflammatory demyelination. J Neurol Sci. 2013;333(1–2):76–87.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Tahmasebinia F, Pourgholaminejad A. The role of Th17 cells in auto-inflammatory neurological disorders. Prog Neuro-Psychopharmacol Biol Psychiatry. 2017;79:408–16.CrossRefGoogle Scholar
  8. 8.
    Moseley T, et al. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev. 2003;14(2):155–74.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Waisman A, Hauptmann J, Regen T. The role of IL-17 in CNS diseases. Acta Neuropathol. 2015;129(5):625–37.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Pourgholaminejad A, et al. Is TGFβ as an anti-inflammatory cytokine required for differentiation of inflammatory TH17 cells? J Immunotoxicol. 2016;13(6):775–83.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Ghoreschi K, et al. Generation of pathogenic T H 17 cells in the absence of TGF-β signalling. Nature. 2010;467(7318):967.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Unutmaz D. RORC2: the master of human Th17 cell programming. Eur J Immunol. 2009;39(6):1452–5.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Boniface K, et al. Human Th17 cells comprise heterogeneous subsets including IFN-γ–producing cells with distinct properties from the Th1 lineage. J Immunol. 2010;185:679–87. p. ji_1000366PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Chen Z, et al. Distinct regulation of interleukin-17 in human T helper lymphocytes. Arthritis Rheum. 2007;56(9):2936–46.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Volpe E, et al. A critical function for transforming growth factor-β, interleukin 23 and proinflammatory cytokines in driving and modulating human T H-17 responses. Nat Immunol. 2008;9(6):650.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Frohman EM, Racke MK, Raine CS. Multiple sclerosis—the plaque and its pathogenesis. N Engl J Med. 2006;354(9):942–55.PubMedCrossRefGoogle Scholar
  17. 17.
    Lucchinetti C, Rodriguez M, Weinshenker B. Multiple sclerosis. N Engl J Med. 2000;343:938–52.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Trapp BD, Nave K-A. Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci. 2008;31:247–69.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Denic A, Wootla B, Rodriguez M. CD8+ T cells in multiple sclerosis. Expert Opin Ther Targets. 2013;17(9):1053–66.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Gandhi R, Laroni A, Weiner HL. Role of the innate immune system in the pathogenesis of multiple sclerosis. J Neuroimmunol. 2010;221(1):7–14.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    El-behi M, Rostami A, Ciric B. Current views on the roles of Th1 and Th17 cells in experimental autoimmune encephalomyelitis. J Neuroimmune Pharmacol. 2010;5(2):189–97.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Smith AW, et al. Regulation of Th1/Th17 cytokines and IDO gene expression by inhibition of calpain in PBMCs from MS patients. J Neuroimmunol. 2011;232(1):179–85.PubMedCrossRefGoogle Scholar
  23. 23.
    Brucklacher-Waldert V, et al. Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis. Brain. 2009;132(12):3329–41.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Reboldi A, et al. CC chemokine receptor 6–regulated entry of T H-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat Immunol. 2009;10(5):514.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Rothhammer V, et al. Th17 lymphocytes traffic to the central nervous system independently of α4 integrin expression during EAE. J Exp Med. 2011;208:2465–76. Scholar
  26. 26.
    Matusevicius D, et al. Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult Scler. 1999;5(2):101–4.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Kebir H, et al. Preferential recruitment of interferon-γ–expressing TH17 cells in multiple sclerosis. Ann Neurol. 2009;66(3):390–402.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Fletcher J, et al. T cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Clin Exp Immunol. 2010;162(1):1–11.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Severson C, Hafler DA. T-cells in multiple sclerosis. Results Probl Cell Differ. 2009;51:75–98.Google Scholar
  30. 30.
    Carbajal KS, et al. Th cell diversity in experimental autoimmune encephalomyelitis and multiple sclerosis. J Immunol. 2015;195(6):2552–9.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Gross CC, et al. Distinct pattern of lesion distribution in multiple sclerosis is associated with different circulating T-helper and helper-like innate lymphoid cell subsets. Mult Scler J. 2017;23:1025–30. p. 1352458516662726CrossRefGoogle Scholar
  32. 32.
    Langrish CL, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201(2):233–40.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Lohoff M, et al. Dysregulated T helper cell differentiation in the absence of interferon regulatory factor 4. Proc Natl Acad Sci. 2002;99(18):11808–12.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Yang C, et al. Inhibition of interferon regulatory factor 4 suppresses Th1 and Th17 cell differentiation and ameliorates experimental autoimmune encephalomyelitis. Scand J Immunol. 2015;82(4):345–51.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Jadidi-Niaragh F, Mirshafiey A. Th17 cell, the new player of neuroinflammatory process in multiple sclerosis. Scand J Immunol. 2011;74(1):1–13.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Hofstetter H, Gold R, Hartung H-P. Th17 cells in MS and experimental autoimmune encephalomyelitis. Int MS J. 2009;16(1):12–9.PubMedPubMedCentralGoogle Scholar
  37. 37.
    McGinley AM, et al. Th17cells, gammadelta T cells and their interplay in EAE and multiple sclerosis. J Autoimmun. 2018;87:97–108.CrossRefGoogle Scholar
  38. 38.
    Cosorich I, et al. High frequency of intestinal TH17 cells correlates with microbiota alterations and disease activity in multiple sclerosis. Sci Adv. 2017;3(7):e1700492.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Hao J, et al. Central nervous system (CNS)–resident natural killer cells suppress Th17 responses and CNS autoimmune pathology. J Exp Med. 2010;207(9):1907–21.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Heremans H, et al. Chronic relapsing experimental autoimmune encephalomyelitis (CREAE) in mice: enhancement by monoclonal antibodies against interferon-γ. Eur J Immunol. 1996;26(10):2393–8.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Ferber IA, et al. Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J Immunol. 1996;156(1):5–7.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Wing AC, et al. Interleukin-17-and interleukin-22-secreting myelin-specific CD4+ T cells resistant to corticoids are related with active brain lesions in multiple sclerosis patients. Immunology. 2016;147(2):212–20.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Acosta-Rodriguez EV, et al. Surface phenotype and antigenic specificity of human interleukin 17–producing T helper memory cells. Nat Immunol. 2007;8(6):639–46.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Lee YK, et al. Developmental plasticity of Th17 and Treg cells. Curr Opin Immunol. 2009;21(3):274–80.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Abromson-Leeman S, Bronson RT, Dorf ME. Encephalitogenic T cells that stably express both T-bet and RORγt consistently produce IFNγ but have a spectrum of IL-17 profiles. J Neuroimmunol. 2009;215(1):10–24.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Lee YK, et al. Late developmental plasticity in the T helper 17 lineage. Immunity. 2009;30(1):92–107.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Fleisher TA, et al. Clinical immunology, principles and practice (Expert Consult-Online and Print), 4: Clinical immunology. Elsevier Health Sciences. Mosby: St. Louis.; 2013.Google Scholar
  48. 48.
    Kroenke MA, et al. IL-12–and IL-23–modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition. J Exp Med. 2008;205(7):1535–41.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Korn T, et al. IL-17 and Th17 Cells. Annu Rev Immunol. 2009;27:485–517.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Park H, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6(11):1133.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Komiyama Y, et al. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol. 2006;177(1):566–73.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Witowski J, et al. IL-17 stimulates intraperitoneal neutrophil infiltration through the release of GROα chemokine from mesothelial cells. J Immunol. 2000;165(10):5814–21.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Huppert J, et al. Cellular mechanisms of IL-17-induced blood-brain barrier disruption. FASEB J. 2010;24(4):1023–34.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Strachan-Whaley M, Rivest S, Yong VW. Interactions between microglia and T cells in multiple sclerosis pathobiology. J Interf Cytokine Res. 2014;34(8):615–22.CrossRefGoogle Scholar
  55. 55.
    Lucchinetti CF, et al. Inflammatory cortical demyelination in early multiple sclerosis. N Engl J Med. 2011;365(23):2188–97.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Mahad DJ, Ransohoff RM. The role of MCP-1 (CCL2) and CCR2 in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Semin Immunol. 2003;15:23–32. ElsevierPubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Almolda B, Gonzalez B, Castellano B. Antigen presentation in EAE: role of microglia, macrophages and dendritic cells. Front Biosci. 2011;16:1157–71.CrossRefGoogle Scholar
  58. 58.
    Kawanokuchi J, et al. Production and functions of IL-17 in microglia. J Neuroimmunol. 2008;194(1–2):54–61.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Medana IM, et al. MHC class I-restricted killing of neurons by virus-specific CD8+ T lymphocytes is effected through the Fas/FasL, but not the perforin pathway. Eur J Immunol. 2000;30(12):3623–33.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Liblau RS, et al. Neurons as targets for T cells in the nervous system. Trends Neurosci. 2013;36(6):315–24.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Yshii L, et al. Neurons and T cells: understanding this interaction for inflammatory neurological diseases. Eur J Immunol. 2015;45(10):2712–20.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Kang Z, et al. Act1 mediates IL-17–induced EAE pathogenesis selectively in NG2+ glial cells. Nat Neurosci. 2013;16(10):1401.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Paintlia MK, et al. Synergistic activity of interleukin-17 and tumor necrosis factor-α enhances oxidative stress-mediated oligodendrocyte apoptosis. J Neurochem. 2011;116(4):508–21.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Poh Loh K, et al. Oxidative stress: apoptosis in neuronal injury. Curr Alzheimer Res. 2006;3(4):327–37.CrossRefGoogle Scholar
  65. 65.
    Dringen R, Pawlowski PG, Hirrlinger J. Peroxide detoxification by brain cells. J Neurosci Res. 2005;79(1–2):157–65.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    van der Goes A, et al. Reactive oxygen species are required for the phagocytosis of myelin by macrophages. J Neuroimmunol. 1998;92(1–2):67–75.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Ortiz GG, et al. Immunology and oxidative stress in multiple sclerosis: clinical and basic approach. Clin Dev Immunol. 2013;2013:1.CrossRefGoogle Scholar
  68. 68.
    Haak S, et al. IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice. J Clin Invest. 2009;119(1):61–9.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Almolda B, et al. Increase in Th17 and T-reg lymphocytes and decrease of IL22 correlate with the recovery phase of acute EAE in rat. PLoS One. 2011;6(11):e27473.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Zhou C, et al. Comment and reply on: emerging role of Th22 and IL-22 in multiple sclerosis, an autoimmune disease in the central nervous system. Expert Opin Ther Targets. 2013;17(11):1381–2.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Zhang N, Pan H-F, Ye D-Q. Th22 in inflammatory and autoimmune disease: prospects for therapeutic intervention. Mol Cell Biochem. 2011;353(1–2):41–6.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Kebir H, et al. Human T H 17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med. 2007;13(10):1173.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Vaknin-Dembinsky A, Balashov K, Weiner HL. IL-23 is increased in dendritic cells in multiple sclerosis and down-regulation of IL-23 by antisense oligos increases dendritic cell IL-10 production. J Immunol. 2006;176(12):7768–74.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Hirota K, et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol. 2011;12(3):255.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    McGeachy MJ, et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17–producing effector T helper cells in vivo. Nat Immunol. 2009;10(3):314.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Chen Y, et al. Anti–IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J Clin Invest. 2006;116(5):1317–26.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    El-Behi M, et al. The encephalitogenicity of T H 17 cells is dependent on IL-1-and IL-23-induced production of the cytokine GM-CSF. Nat Immunol. 2011;12(6):568.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Codarri L, et al. RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol. 2011;12(6):560.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Croxford AL, et al. The cytokine GM-CSF drives the inflammatory signature of CCR2+ monocytes and licenses autoimmunity. Immunity. 2015;43(3):502–14.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Stromnes IM, et al. Differential regulation of central nervous system autoimmunity by TH1 and TH17 cells. Nat Med. 2008;14(3):337–42.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Durelli L, et al. T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-β. Ann Neurol. 2009;65(5):499–509.PubMedCrossRefGoogle Scholar
  82. 82.
    Kreymborg K, et al. IL-22 is expressed by Th17 cells in an IL-23-dependent fashion, but not required for the development of autoimmune encephalomyelitis. J Immunol. 2007;179(12):8098–104.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Sweeney CM, et al. IL-27 mediates the response to IFN-β therapy in multiple sclerosis patients by inhibiting Th17 cells. Brain Behav Immun. 2011;25(6):1170–81.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Ramgolam VS, et al. IFN-β inhibits human Th17 cell differentiation. J Immunol. 2009;183:5418–27. p. jimmunol. 0803227PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Mehling M, et al. Th17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis. Neurology. 2010;75(5):403–10.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Miossec P, Kolls JK. Targeting IL-17 and T H 17 cells in chronic inflammation. Nat Rev Drug Discov. 2012;11(10):763.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Bartlett HS, Million RP. Targeting the IL-17–T H 17 pathway. Nat Rev Drug Discov. 2015;14:11–12.Google Scholar
  88. 88.
    Constantinescu CS, et al. Randomized phase 1b trial of MOR103, a human antibody to GM-CSF, in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2015;2(4):e117.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Segal BM, et al. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol. 2008;7(9):796–804.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Vollmer TL, et al. A phase 2, 24-week, randomized, placebo-controlled, double-blind study examining the efficacy and safety of an anti-interleukin-12 and-23 monoclonal antibody in patients with relapsing–remitting or secondary progressive multiple sclerosis. Mult Scler J. 2011;17(2):181–91.CrossRefGoogle Scholar
  91. 91.
    Volpe E, Battistini L, Borsellino G. Advances in T helper 17 cell biology: pathogenic role and potential therapy in multiple sclerosis. Mediat Inflamm. 2015;2015:475158.CrossRefGoogle Scholar
  92. 92.
    Huh JR, et al. Digoxin and its derivatives suppress T H 17 cell differentiation by antagonizing RORγt activity. Nature. 2011;472(7344):486.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Xu T, et al. Ursolic acid suppresses interleukin-17 (IL-17) production by selectively antagonizing the function of RORγt protein. J Biol Chem. 2011;286(26):22707–10.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Karantzoulis S, J.E. Galvin. Distinguishing Alzheimer’s disease from other major forms of dementia. Expert Rev Neurother. 2014.Google Scholar
  95. 95.
    Wray S, Fox NC. Stem cell therapy for Alzheimer’s disease: hope or hype? Lancet Neurol. 2016;15(2):133–5.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Gouras GK, Olsson TT, Hansson O. β-Amyloid peptides and amyloid plaques in Alzheimer’s disease. Neurotherapeutics. 2015;12(1):3–11.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Lyons B, et al. Amyloid plaque in the human brain can decompose from Aβ (1-40/1-42) by spontaneous nonenzymatic processes. Anal Chem. 2016;88(5):2675–84.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Gu L, et al. A new structural model of Alzheimer’s Aβ42 fibrils based on electron paramagnetic resonance data and Rosetta modeling. J Struct Biol. 2016;194(1):61–7.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Rudinskiy N, et al. Amyloid-beta oligomerization is associated with the generation of a typical peptide fragment fingerprint. Alzheimers Dement. 2016;12:996.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Mujahid M. Alzheimer disease: a review. World J Pharm Pharm Sci. 2016;5(6):649–66.Google Scholar
  101. 101.
    Wang W-Y, et al. Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann Transl Med. 2015;3(10):136.PubMedPubMedCentralGoogle Scholar
  102. 102.
    Tahmasebinia F, Emadi S. Effect of metal chelators on the aggregation of beta-amyloid peptides in the presence of copper and iron. Biometals. 2017;30(2):285–93.PubMedCrossRefGoogle Scholar
  103. 103.
    Czirr E, Wyss-Coray T. The immunology of neurodegeneration. J Clin Invest. 2012;122(4):1156–63.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Fehervari Z. Lymphocytes in Alzheimer’s disease. Nat Immunol. 2016;17(4):355.Google Scholar
  105. 105.
    Xin N, et al. Exploring the role of interleukin-22 in neurological and autoimmune disorders. Int Immunopharmacol. 2015;28(2):1076–83.PubMedCrossRefGoogle Scholar
  106. 106.
    Niranjan R. Molecular basis of etiological implications in Alzheimer’s disease: focus on neuroinflammation. Mol Neurobiol. 2013;48(3):412–28.PubMedCrossRefGoogle Scholar
  107. 107.
    Myhre O, et al. Metal dyshomeostasis and inflammation in Alzheimer’s and Parkinson’s diseases: possible impact of environmental exposures. Oxidative Med Cell Longev. 2013;2013:1.CrossRefGoogle Scholar
  108. 108.
    Perry VH, Nicoll JA, Holmes C. Microglia in neurodegenerative disease. Nat Rev Neurol. 2010;6(4):193–201.PubMedCrossRefGoogle Scholar
  109. 109.
    Agnes PK, Christiane S, Peter DB. T-cells show increased production of cytokines and activation markers in Alzheimer’s disease. Brain Disord Ther. 2013;3(1):3–112.Google Scholar
  110. 110.
    Zhang J, et al. Th17 cell-mediated Neuroinflammation is involved in neurodegeneration of Aβ 1-42-induced Alzheimer’s disease model rats. PLoS One. 2013;8(10):e75786.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    McQuillan K, Lynch MA, Mills KH. Activation of mixed glia by Aβ-specific Th1 and Th17 cells and its regulation by Th2 cells. Brain Behav Immun. 2010;24(4):598–607.PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Tzartos JS, et al. IL-21 and IL-21 receptor expression in lymphocytes and neurons in multiple sclerosis brain. Am J Pathol. 2011;178(2):794–802.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Kebir H, et al. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med. 2007;13(10):1173–5.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Chen J-M, et al. Increased serum levels of interleukin-18,-23 and-17 in chinese patients with Alzheimer’s disease. Dement Geriatr Cogn Disord. 2014;38(5–6):321–9.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Jin J-J, et al. Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer’s disease. J Neuroinflammation. 2008;5(1):1.CrossRefGoogle Scholar
  116. 116.
    Swardfager W, et al. A meta-analysis of cytokines in Alzheimer’s disease. Biol Psychiatry. 2010;68(10):930–41.PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Grammas P, Ovase R. Inflammatory factors are elevated in brain microvessels in Alzheimer’s disease. Neurobiol Aging. 2001;22(6):837–42.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Kothur K, et al. CSF cytokines/chemokines as biomarkers in neuroinflammatory CNS disorders: a systematic review. Cytokine. 2016;77:227–37.PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Zhang Y-Y, et al. Atorvastatin attenuates the production of IL-1β, IL-6, and TNF-α in the hippocampus of an amyloid β1-42-induced rat model of Alzheimer’s disease. Clin Interv Aging. 2013;8:103–10.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Zhang Y, et al. Matrine improves cognitive impairment and modulates the balance of Th17/Treg cytokines in a rat model of Aβ1-42-induced Alzheimer’s disease. Cent Eur J Immunol. 2016;40(4):411.PubMedCentralGoogle Scholar
  121. 121.
    Saresella M, et al. Increased activity of Th-17 and Th-9 lymphocytes and a skewing of the post-thymic differentiation pathway are seen in Alzheimer’s disease. Brain Behav Immun. 2011;25(3):539–47.PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Giuliani F, et al. Vulnerability of human neurons to T cell-mediated cytotoxicity. J Immunol. 2003;171(1):368–79.PubMedCrossRefPubMedCentralGoogle Scholar
  123. 123.
    Marciani DJ. Alzheimer’s disease vaccine development: a new strategy focusing on immune modulation. J Neuroimmunol. 2015;287:54–63.PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Delenclos M, et al. Biomarkers in Parkinson’s disease: advances and strategies. Parkinsonism Relat Disord. 2016;22:S106–10.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Ito H. Symptoms and signs of Parkinson’s disease and other movement disorders. In: Deep brain stimulation for neurological disorders. Cham: Springer; 2015. p. 21–37.Google Scholar
  126. 126.
    Williams-Gray CH, et al. Serum immune markers and disease progression in an incident Parkinson’s disease cohort (ICICLE-PD). Mov Disord. 2016;31:995.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Schlachetzki JC, Winkler J. The innate immune system in Parkinson’s disease: a novel target promoting endogenous neuroregeneration. Neural Regen Res. 2015;10(5):704.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Power JH, Barnes OL, Chegini F. Lewy bodies and the mechanisms of neuronal cell death in Parkinson’s disease and dementia with Lewy bodies. Brain Pathol. 2017;27:3–12.PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Allen Reish HE, Standaert DG. Role of α-synuclein in inducing innate and adaptive immunity in Parkinson disease. J Park Dis. 2015;5(1):1–19.Google Scholar
  130. 130.
    Barrett PJ, Greenamyre JT. Post-translational modification of α-synuclein in Parkinson’s disease. Brain Res. 2015;1628:247–53.PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Harms AS, et al. MHCII is required for α-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration. J Neurosci. 2013;33(23):9592–600.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Perez A, Guan L, Sutherland K. Immune system and Parkinson’s disease. Arch Med. 2016;8:2.Google Scholar
  133. 133.
    Benner EJ, et al. Nitrated α–Synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One. 2008;3(1):e1376.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Brochard V, et al. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest. 2009;119(1):182–92.PubMedPubMedCentralGoogle Scholar
  135. 135.
    Appel SH. CD4+ T cells mediate cytotoxicity in neurodegenerative diseases. J Clin Invest. 2009;119(1):13–5.PubMedPubMedCentralGoogle Scholar
  136. 136.
    Hu W-C. Parkinson disease is a TH17 dominant autoimmune disorder against accumulated alpha-synuclein. arXiv preprint arXiv. 2013;1403:3256.Google Scholar
  137. 137.
    Reynolds AD, et al. Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson’s disease. J Immunol. 2010;184(5):2261–71.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Peng Y-P, et al. Treg/Th17 imbalance-mediated neuroinflammation is involved in pathogenesis of Parkinson’s disease. 2013.Google Scholar
  139. 139.
    Storelli E, et al. Do Th17 lymphocytes and IL-17 contribute to Parkinson’s disease? A systematic review of available evidence. Front Neurol.Google Scholar
  140. 140.
    Appel SH, Beers DR, Henkel JS. T cell-microglial dialogue in Parkinson’s disease and amyotrophic lateral sclerosis: are we listening? Trends Immunol. 2010;31(1):7–17.PubMedCrossRefPubMedCentralGoogle Scholar
  141. 141.
    Niwa F, et al. Effects of peripheral lymphocyte subpopulations and the clinical correlation with Parkinson’s disease. Geriatr Gerontol Int. 2012;12(1):102–7.PubMedCrossRefPubMedCentralGoogle Scholar
  142. 142.
    Wahner AD, et al. Inflammatory cytokine gene polymorphisms and increased risk of Parkinson disease. Arch Neurol. 2007;64(6):836–40.PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Blum-Degena D, et al. Interleukin-1β and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients. Neurosci Lett. 1995;202(1):17–20.CrossRefGoogle Scholar
  144. 144.
    Griffin WST, et al. Interleukin-1 mediates Alzheimer and Lewy body pathologies. J Neuroinflammation. 2006;3(1):1.CrossRefGoogle Scholar
  145. 145.
    Asea A, et al. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med. 2000;6(4):435–42.PubMedCrossRefPubMedCentralGoogle Scholar
  146. 146.
    Mills KH. Induction, function and regulation of IL-17-producing T cells. Eur J Immunol. 2008;38(10):2636–49.PubMedCrossRefPubMedCentralGoogle Scholar
  147. 147.
    Gatto EM, et al. Neutrophil function, nitric oxide, and blood oxidative stress in Parkinson’s disease. Mov Disord. 1996;11(3):261–7.PubMedCrossRefPubMedCentralGoogle Scholar
  148. 148.
    Ripke S, et al. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511(7510):421.PubMedCentralCrossRefGoogle Scholar
  149. 149.
    Nasyrova RF, et al. Role of nitric oxide and related molecules in schizophrenia pathogenesis: biochemical, genetic and clinical aspects. Front Physiol. 2015;6:139.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Debnath M. Adaptive immunity in schizophrenia: functional implications of t cells in the etiology, course and treatment. J Neuroimmune Pharmacol. 2015;10(4):610–9.PubMedCrossRefPubMedCentralGoogle Scholar
  151. 151.
    Andreassen OA, et al. Genetic pleiotropy between multiple sclerosis and schizophrenia but not bipolar disorder: differential involvement of immune-related gene loci. Mol Psychiatry. 2015;20(2):207–14.PubMedCrossRefPubMedCentralGoogle Scholar
  152. 152.
    Hyde TM, Bharadwaj RA. Molecular mechanisms and timing of cortical immune activation in schizophrenia. Am J Psychiatry. 2015;172(11):1052.PubMedCrossRefPubMedCentralGoogle Scholar
  153. 153.
    Patterson PH. Immune involvement in schizophrenia and autism: etiology, pathology and animal models. Behav Brain Res. 2009;204(2):313–21.PubMedCrossRefPubMedCentralGoogle Scholar
  154. 154.
    Avramopoulos D, et al. Infection and inflammation in schizophrenia and bipolar disorder: a genome wide study for interactions with genetic variation. PLoS One. 2015;10(3):e0116696.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Na K-S, Jung H-Y, Kim Y-K. The role of pro-inflammatory cytokines in the neuroinflammation and neurogenesis of schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry. 2014;48:277–86.CrossRefGoogle Scholar
  156. 156.
    Khandaker GM, Dantzer R. Is there a role for immune-to-brain communication in schizophrenia? Psychopharmacology. 2016;233(9):1559–73.PubMedCrossRefPubMedCentralGoogle Scholar
  157. 157.
    Van Kesteren C, et al. Immune involvement in the pathogenesis of schizophrenia: a meta-analysis on postmortem brain studies. Transl Psychiatry. 2017;7(3):e1075.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Meyer U. Developmental immune activation models with relevance to schizophrenia. In: Immunology and psychiatry. Cham: Springer; 2015. p. 15–32.CrossRefGoogle Scholar
  159. 159.
    Najjar S, Pearlman DM. Neuroinflammation and white matter pathology in schizophrenia: systematic review. Schizophr Res. 2015;161(1):102–12.PubMedCrossRefPubMedCentralGoogle Scholar
  160. 160.
    Fillman S, et al. Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia. Mol Psychiatry. 2013;18(2):206–14.PubMedCrossRefPubMedCentralGoogle Scholar
  161. 161.
    Hwang Y, et al. Gene expression profiling by mRNA sequencing reveals increased expression of immune/inflammation-related genes in the hippocampus of individuals with schizophrenia. Transl Psychiatry. 2013;3(10):e321.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Gardiner EJ, et al. Gene expression analysis reveals schizophrenia-associated dysregulation of immune pathways in peripheral blood mononuclear cells. J Psychiatr Res. 2013;47(4):425–37.PubMedCrossRefPubMedCentralGoogle Scholar
  163. 163.
    Busse S, et al. Different distribution patterns of lymphocytes and microglia in the hippocampus of patients with residual versus paranoid schizophrenia: further evidence for disease course-related immune alterations? Brain Behav Immun. 2012;26(8):1273–9.PubMedCrossRefPubMedCentralGoogle Scholar
  164. 164.
    Müller N, et al. The immune system and schizophrenia: an integrative view. Ann N Y Acad Sci. 2000;917(1):456–67.PubMedCrossRefPubMedCentralGoogle Scholar
  165. 165.
    Müller N, et al. Cellular and humoral immune system in schizophrenia: a conceptual re-evaluation. World J Biol Psychiatry. 2000;1(4):173–9.PubMedCrossRefPubMedCentralGoogle Scholar
  166. 166.
    Mayilyan KR, Weinberger DR, Sim RB. The complement system in schizophrenia. Drug News Perspect. 2008;21(4):200.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Khandaker GM, et al. Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. Lancet Psychiatry. 2015;2(3):258–70.PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Fernandez-Egea E, et al. Peripheral immune cell populations associated with cognitive deficits and negative symptoms of treatment-resistant schizophrenia. PLoS One. 2016;11(5):e0155631.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Ding M, et al. Activation of Th17 cells in drug naïve, first episode schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry. 2014;51:78–82.CrossRefGoogle Scholar
  170. 170.
    Debnath M, Berk M. Th17 pathway–mediated immunopathogenesis of schizophrenia: mechanisms and implications. Schizophr Bull. 2014;40:1412–21. p. sbu049PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Drexhage RC, et al. An activated set point of T-cell and monocyte inflammatory networks in recent-onset schizophrenia patients involves both pro-and anti-inflammatory forces. Int J Neuropsychopharmacol. 2011;14(6):746–55.PubMedCrossRefPubMedCentralGoogle Scholar
  172. 172.
    Sallusto F, et al. T-cell trafficking in the central nervous system. Immunol Rev. 2012;248(1):216–27.PubMedCrossRefPubMedCentralGoogle Scholar
  173. 173.
    Gyülvészi G, Haak S, Becher B. IL-23-driven encephalo-tropism and Th17 polarization during CNS-inflammation in vivo. Eur J Immunol. 2009;39(7):1864–9.PubMedCrossRefPubMedCentralGoogle Scholar
  174. 174.
    Borovcanin M, et al. Elevated serum level of type-2 cytokine and low IL-17 in first episode psychosis and schizophrenia in relapse. J Psychiatr Res. 2012;46(11):1421–6.PubMedCrossRefPubMedCentralGoogle Scholar
  175. 175.
    Dimitrov DH, et al. Differential correlations between inflammatory cytokines and psychopathology in veterans with schizophrenia: potential role for IL-17 pathway. Schizophr Res. 2013;151(1):29–35.PubMedCrossRefPubMedCentralGoogle Scholar
  176. 176.
    Lin A, et al. The inflammatory response system in treatment-resistant schizophrenia: increased serum interleukin-6. Schizophr Res. 1998;32(1):9–15.PubMedCrossRefPubMedCentralGoogle Scholar
  177. 177.
    Kowalski J, et al. Neuroleptics normalize increased release of interleukin-1β and tumor necrosis factor-α from monocytes in schizophrenia. Schizophr Res. 2001;50(3):169–75.PubMedCrossRefPubMedCentralGoogle Scholar
  178. 178.
    Spanakos G, et al. Cytokine serum levels, autologous mixed lymphocyte reaction and surface marker analysis in never medicated and chronically medicated schizophrenic patients. Schizophr Res. 2001;47(1):13–25.PubMedCrossRefPubMedCentralGoogle Scholar
  179. 179.
    Pourgholaminejad A, et al. The effect of pro-inflammatory cytokines on immunophenotype, differentiation capacity and immunomodulatory functions of human mesenchymal stem cells. Cytokine. 2016;85:51–60.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of ImmunologySchool of Medicine, Guilan University of Medical SciencesRashtIran
  2. 2.Department of Biological SciencesInstitute in Advanced Studies in Basic Sciences (IASBS)ZanjanIran

Personalised recommendations