Journal of Neuroimmune Pharmacology

, Volume 10, Issue 4, pp 645–650 | Cite as

A Perspective on Roles Played by Innate and Adaptive Immunity in the Pathobiology of Neurodegenerative Disorders

PERSPECTIVE

Abstract

Aberrant innate and adaptive immune responses are neurodegenerative disease effectors. Disease is heralded by a generalized, but subtle immune activation orchestrated by the release of extracellular prion-like aggregated and oxidized or otherwise modified proteins. These are responsible for an inflammatory neurotoxic cascade. The perpetrators of such events include effector T cells and activated microglia. What ensues are Alzheimer’s and Parkinson’s disease, amyotrophic lateral sclerosis and stroke with changed frequencies of effector T cell and reduced numbers or function of regulatory lymphocytes. The control of such immune responses could lead to new therapeutic strategies and the means to effectively combat a composite of diseases that have quite limited therapeutic options.

Keywords

Alzheimer’s disease Parkinson’s disease Amyotrophic lateral sclerosis Stroke Adaptive immunity Regulatory T cells Effector T cells Innate immunity Neuroprotection Neurodestruction Neurodegenerative diseases 

Notes

Acknowledgments

This work was supported, in part, by the University of Nebraska Foundation which includes individual donations from Carol Swarts and Frances and Louie Blumkin, the Department of Defense grant W81XWH11-1-0700 and National Institutes of Health grants R01 NS070190, P01 DA028555, R01 NS36126, P01 NS31492, 2R01 NS034239, P01 MH64570, P01 NS43985, P30 MH062261 and R01 AG043540.

References

  1. Allen Reish HE, Standaert DG (2015) Role of alpha-synuclein in inducing innate and adaptive immunity in Parkinson disease. J Park Dis 5:1–19Google Scholar
  2. Anderson KM, Olson KE, Estes KA, Flanagan K, Gendelman HE, Mosley RL (2014) Dual destructive and protective roles of adaptive immunity in neurodegenerative disorders. Transl Neurodegener 3:25PubMedCentralCrossRefPubMedGoogle Scholar
  3. Baruch K, Rosenzweig N, Kertser A, Deczkowska A, Sharif AM, Spinrad A, Tsitsou-Kampeli A, Sarel A, Cahalon L, Schwartz M (2015) Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer’s disease pathology. Nat Commun 6:7967PubMedCentralCrossRefPubMedGoogle Scholar
  4. Beers DR, Henkel JS, Zhao W, Wang J, Huang A, Wen S, Liao B, Appel SH (2011) Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. Brain 134:1293–1314PubMedCentralCrossRefPubMedGoogle Scholar
  5. Benner EJ, Mosley RL, Destache CJ, Lewis TB, Jackson-Lewis V, Gorantla S, Nemachek C, Green SR, Przedborski S, Gendelman HE (2004) Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson’s disease. Proc Natl Acad Sci U S A 101:9435–9440PubMedCentralCrossRefPubMedGoogle Scholar
  6. Benner EJ, Banerjee R, Reynolds AD, Sherman S, Pisarev VM, Tsiperson V, Nemachek C, Ciborowski P, Przedborski S, Mosley RL, Gendelman HE (2008) Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One 3:e1376PubMedCentralCrossRefPubMedGoogle Scholar
  7. Candore G, Caruso C, Jirillo E, Magrone T, Vasto S (2010) Low grade inflammation as a common pathogenetic denominator in age-related diseases: novel drug targets for anti-ageing strategies and successful ageing achievement. Curr Pharm Des 16:584–596CrossRefPubMedGoogle Scholar
  8. Castelo-Branco C, Soveral I (2014) The immune system and aging: a review. Gynecol Endocrinol 30:16–22CrossRefPubMedGoogle Scholar
  9. Chan A, Yan J, Csurhes P, Greer J, McCombe P (2015) Circulating brain derived neurotrophic factor (BDNF) and frequency of BDNF positive T cells in peripheral blood in human ischemic stroke: effect on outcome. J Neuroimmunol 286:42–47CrossRefPubMedGoogle Scholar
  10. Chao Y, Wong SC, Tan EK (2014) Evidence of inflammatory system involvement in Parkinson’s disease. Biomed Res Int 2014:308654PubMedCentralPubMedGoogle Scholar
  11. Chiu IM, Morimoto ET, Goodarzi H, Liao JT, O’Keeffe S, Phatnani HP, Muratet M, Carroll MC, Levy S, Tavazoie S, Myers RM, Maniatis T (2013) A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep 4:385–401PubMedCentralCrossRefPubMedGoogle Scholar
  12. Deleidi M, Gasser T (2013) The role of inflammation in sporadic and familial Parkinson’s disease. Cell Mol Life Sci 70:4259–4273CrossRefPubMedGoogle Scholar
  13. Dexter DT, Jenner P (2013) Parkinson disease: from pathology to molecular disease mechanisms. Free Radic Biol Med 62:132–144CrossRefPubMedGoogle Scholar
  14. Di Bona D, Scapagnini G, Candore G, Castiglia L, Colonna-Romano G, Duro G, Nuzzo D, Iemolo F, Lio D, Pellicano M, Scafidi V, Caruso C, Vasto S (2010) Immune-inflammatory responses and oxidative stress in Alzheimer’s disease: therapeutic implications. Curr Pharm Des 16:684–691CrossRefPubMedGoogle Scholar
  15. Evans MC, Couch Y, Sibson N, Turner MR (2013) Inflammation and neurovascular changes in amyotrophic lateral sclerosis. Mol Cell Neurosci 53:34–41CrossRefPubMedGoogle Scholar
  16. Fulop T, Dupuis G, Baehl S, Le Page A, Bourgade K, Frost E, Witkowski JM, Pawelec G, Larbi A, Cunnane S (2015) From inflamm-aging to immune-paralysis: a slippery slope during aging for immune-adaptation. Biogerontology. doi: 10.1007/s10522-015-9615-7 Google Scholar
  17. Gauberti M, Vivien D (2015) Letter by gauberti and vivien regarding article, “amplification of regulatory T cells using a CD28 superagonist reduces brain damage after ischemic stroke in mice”. Stroke 46:e50–e51CrossRefPubMedGoogle Scholar
  18. Gesuete R, Stevens SL, Stenzel-Poore MP (2016) Role of circulating immune cells in stroke and preconditioning-induced protection. Acta Neurochir Suppl 121:39–44PubMedGoogle Scholar
  19. Ghochikyan A, Mkrtichyan M, Petrushina I, Movsesyan N, Karapetyan A, Cribbs DH, Agadjanyan MG (2006) Prototype Alzheimer’s disease epitope vaccine induced strong Th2-type anti-abeta antibody response with alum to quil a adjuvant switch. Vaccine 24:2275–2282PubMedCentralCrossRefPubMedGoogle Scholar
  20. Graber JJ, Dhib-Jalbut S (2009) Protective autoimmunity in the nervous system. Pharmacol Ther 121:147–159Google Scholar
  21. Ha D, Stone DK, Mosley RL, Gendelman HE (2012) Immunization strategies for Parkinson’s disease. Parkinsonism Relat Disord 18(Suppl 1):S218–S221CrossRefPubMedGoogle Scholar
  22. Heneka MT, Golenbock DT, Latz E (2015) Innate immunity in Alzheimer’s disease. Nat Immunol 16:229–236CrossRefPubMedGoogle Scholar
  23. Henkel JS, Beers DR, Zhao W, Appel SH (2009) Microglia in ALS: the good, the bad, and the resting. J NeuroImmune Pharmacol 4:389–398CrossRefPubMedGoogle Scholar
  24. Hooten KG, Beers DR, Zhao W, Appel SH (2015) Protective and toxic neuroinflammation in amyotrophic lateral sclerosis. Neurotherapeutics 12:364–375CrossRefPubMedGoogle Scholar
  25. Hutter-Saunders JA, Mosley RL, Gendelman HE (2011) Pathways towards an effective immunotherapy for Parkinson’s disease. Expert Rev Neurother 11:1703–1715PubMedCentralCrossRefPubMedGoogle Scholar
  26. Ince PG, Highley JR, Kirby J, Wharton SB, Takahashi H, Strong MJ, Shaw PJ (2011) Molecular pathology and genetic advances in amyotrophic lateral sclerosis: an emerging molecular pathway and the significance of glial pathology. Acta Neuropathol 122:657–671CrossRefPubMedGoogle Scholar
  27. Koronyo Y, Salumbides BC, Sheyn J, Pelissier L, Li S, Ljubimov V, Moyseyev M, Daley D, Fuchs DT, Pham M, Black KL, Rentsendorj A, Koronyo-Hamaoui M (2015) Therapeutic effects of glatiramer acetate and grafted CD115(+) monocytes in a mouse model of Alzheimer’s disease. Brain 138:2399–2422CrossRefPubMedGoogle Scholar
  28. Kosloski LM, Kosmacek EA, Olson KE, Mosley RL, Gendelman HE (2013) GM-CSF induces neuroprotective and anti-inflammatory responses in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxicated mice. J Neuroimmunol 265:1–10CrossRefPubMedGoogle Scholar
  29. Lashley T, Rohrer JD, Mead S, Revesz T (2015) Review: an update on clinical, genetic and pathological aspects of frontotemporal lobar degenerations. Neuropathol Appl Neurobiol. doi: 10.1111/nan.12250 Google Scholar
  30. Latta CH, Brothers HM, Wilcock DM (2015) Neuroinflammation in Alzheimer’s disease; a source of heterogeneity and target for personalized therapy. Neuroscience 302:103–111CrossRefPubMedGoogle Scholar
  31. Liao B, Zhao W, Beers DR, Henkel JS, Appel SH (2012) Transformation from a neuroprotective to a neurotoxic microglial phenotype in a mouse model of ALS. Exp Neurol 237:147–152PubMedCentralCrossRefPubMedGoogle Scholar
  32. Lucke-Wold BP, Turner RC, Logsdon AF, Simpkins JW, Alkon DL, Smith KE, Chen YW, Tan Z, Huber JD, Rosen CL (2015) Common mechanisms of Alzheimer’s disease and ischemic stroke: the role of protein kinase C in the progression of age-related neurodegeneration. J Alzheimers Dis 43:711–724PubMedCentralPubMedGoogle Scholar
  33. Martorana A, Bulati M, Buffa S, Pellicano M, Caruso C, Candore G, Colonna-Romano G (2012) Immunosenescence, inflammation and Alzheimer’s disease. Longev Healthspan 1:8PubMedCentralCrossRefPubMedGoogle Scholar
  34. Mhatre SD, Tsai CA, Rubin AJ, James ML, Andreasson KI (2015) Microglial malfunction: the third rail in the development of Alzheimer’s disease. Trends Neurosci 38:621–636CrossRefPubMedGoogle Scholar
  35. Michaud M, Balardy L, Moulis G, Gaudin C, Peyrot C, Vellas B, Cesari M, Nourhashemi F (2013) Proinflammatory cytokines, aging, and age-related diseases. J Am Med Dir Assoc 14:877–882CrossRefPubMedGoogle Scholar
  36. Mosley RL, Gendelman HE (2010) Control of neuroinflammation as a therapeutic strategy for amyotrophic lateral sclerosis and other neurodegenerative disorders. Exp Neurol 222:1–5PubMedCentralCrossRefPubMedGoogle Scholar
  37. Mosley RL, Benner EJ, Kadiu I, Thomas M, Boska MD, Hasan K, Laurie C, Gendelman HE (2006) Neuroinflammation, oxidative stress and the pathogenesis of Parkinson’s disease. Clin Neurosci Res 6:261–281PubMedCentralCrossRefPubMedGoogle Scholar
  38. Mosley RL, Hutter-Saunders JA, Stone DK, Gendelman HE (2012) Inflammation and adaptive immunity in Parkinson’s disease. Cold Spring Harb Perspect Med 2:a009381PubMedCentralCrossRefPubMedGoogle Scholar
  39. Na SY, Mracsko E, Liesz A, Hunig T, Veltkamp R (2015) Amplification of regulatory T cells using a CD28 superagonist reduces brain damage after ischemic stroke in mice. Stroke 46:212–220CrossRefPubMedGoogle Scholar
  40. Nassif M, Matus S, Castillo K, Hetz C (2010) Amyotrophic lateral sclerosis pathogenesis: a journey through the secretory pathway. Antioxid Redox Signal 13:1955–1989CrossRefPubMedGoogle Scholar
  41. Nikodemova M, Small AL, Smith SM, Mitchell GS, Watters JJ (2014) Spinal but not cortical microglia acquire an atypical phenotype with high VEGF, galectin-3 and osteopontin, and blunted inflammatory responses in ALS rats. Neurobiol Dis 69:43–53PubMedCentralCrossRefPubMedGoogle Scholar
  42. Peters OM, Ghasemi M, Brown Jr RH (2015) Emerging mechanisms of molecular pathology in ALS. J Clin Invest 125:2548Google Scholar
  43. Pride M, Seubert P, Grundman M, Hagen M, Eldridge J, Black RS (2008) Progress in the active immunotherapeutic approach to Alzheimer’s disease: clinical investigations into AN1792-associated meningoencephalitis. Neurodegener Dis 5:194–196CrossRefPubMedGoogle Scholar
  44. Reynolds A, Laurie C, Mosley RL, Gendelman HE (2007a) Oxidative stress and the pathogenesis of neurodegenerative disorders. Int Rev Neurobiol 82:297–325CrossRefPubMedGoogle Scholar
  45. Reynolds AD, Banerjee R, Liu J, Gendelman HE, Mosley RL (2007b) Neuroprotective activities of CD4 + CD25+ regulatory T cells in an animal model of Parkinson’s disease. J Leukoc Biol 82:1083–1094CrossRefPubMedGoogle Scholar
  46. Reynolds AD, Glanzer JG, Kadiu I, Ricardo-Dukelow M, Chaudhuri A, Ciborowski P, Cerny R, Gelman B, Thomas MP, Mosley RL, Gendelman HE (2008) Nitrated alpha-synuclein-activated microglial profiling for Parkinson’s disease. J Neurochem 104:1504–1525CrossRefPubMedGoogle Scholar
  47. Reynolds AD, Stone DK, Mosley RL, Gendelman HE (2009a) Nitrated {alpha}-synuclein-induced alterations in microglial immunity are regulated by CD4+ T cell subsets. J Immunol 182:4137–4149PubMedCentralCrossRefPubMedGoogle Scholar
  48. Reynolds AD, Stone DK, Mosley RL, Gendelman HE (2009b) Proteomic studies of nitrated alpha-synuclein microglia regulation by CD4 + CD25+ T cells. J Proteome Res 8:3497–3511PubMedCentralCrossRefPubMedGoogle Scholar
  49. Reynolds AD, Stone DK, Hutter JA, Benner EJ, Mosley RL, Gendelman HE (2010) Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson’s disease. J Immunol 184:2261–2271PubMedCentralCrossRefPubMedGoogle Scholar
  50. Saresella M, Calabrese E, Marventano I, Piancone F, Gatti A, Calvo MG, Nemni R, Clerici M (2010) PD1 negative and PD1 positive CD4+ T regulatory cells in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis 21:927–938Google Scholar
  51. Saunders JA, Estes KA, Kosloski LM, Allen HE, Dempsey KM, Torres-Russotto DR, Meza JL, Santamaria PM, Bertoni JM, Murman DL, Ali HH, Standaert DG, Mosley RL, Gendelman HE (2012) CD4+ regulatory and effector/memory T cell subsets profile motor dysfunction in Parkinson’s disease. J NeuroImmune Pharmacol 7:927–938Google Scholar
  52. Schuhmann MK, Kraft P, Stoll G, Lorenz K, Meuth SG, Wiendl H, Nieswandt B, Sparwasser T, Beyersdorf N, Kerkau T, Kleinschnitz C (2015) CD28 superagonist-mediated boost of regulatory T cells increases thrombo-inflammation and ischemic neurodegeneration during the acute phase of experimental stroke. J Cereb Blood Flow Metab 35:6–10PubMedCentralCrossRefPubMedGoogle Scholar
  53. Schwartz M, Baruch K (2014) Breaking peripheral immune tolerance to CNS antigens in neurodegenerative diseases: boosting autoimmunity to fight-off chronic neuroinflammation. J Autoimmun 54:8–14CrossRefPubMedGoogle Scholar
  54. Sheean RK, Weston RH, Perera N, D'Amico A, Nutt SL, Turner BJ (2015) Effect of thymic stimulation of CD4+ T cell expansion on disease onset and progression in mutant SOD1 mice. J Neuroinflammation 12:40Google Scholar
  55. Sibon I, de Toffol B, Azulay JP, Sellal F, Thomas-Anterion C, Leger JM, Pierrot-Deseilligny C (2015) American Academy of Neurology, Washington, 18–25 April 2015. Rev Neurol (Paris) 171:581–601Google Scholar
  56. Su XW, Simmons Z, Mitchell RM, Kong L, Stephens HE, Connor JR (2013) Biomarker-based predictive models for prognosis in amyotrophic lateral sclerosis. JAMA Neurol 70:1505–1511PubMedGoogle Scholar
  57. Tada S, Okuno T, Hitoshi Y, Yasui T, Honorat JA, Takata K, Koda T, Shimagami H, Chi-Jing C, Namba A, Sugimoto T, Sakoda S, Mochizuki H, Kikutani H, Nakatsuji Y (2014) Partial suppression of M1 microglia by janus kinase 2 inhibitor does not protect against neurodegeneration in animal models of amyotrophic lateral sclerosis. J Neuroinflammation 11:179PubMedCentralCrossRefPubMedGoogle Scholar
  58. Thomas R, Sharifi N (2012) SOD mimetics: a novel class of androgen receptor inhibitors that suppresses castration-resistant growth of prostate cancer. Mol Cancer Ther 11:87–97PubMedCentralCrossRefPubMedGoogle Scholar
  59. Toly-Ndour C, Lui G, Nunes MM, Bruley-Rosset M, Aucouturier P, Dorothee G (2011) MHC-independent genetic factors control the magnitude of CD4+ T cell responses to amyloid-beta peptide in mice through regulatory T cell-mediated inhibition. J Immunol 187:4492–4500CrossRefPubMedGoogle Scholar
  60. Veltkamp R, Na SY, Liesz A (2015) Response to letter regarding article, “amplification of regulatory T cells using a CD28 superagonist reduces brain damage after ischemic stroke in mice”. Stroke 46:e52CrossRefPubMedGoogle Scholar
  61. Vucic S, Kiernan MC (2009) Pathophysiology of neurodegeneration in familial amyotrophic lateral sclerosis. Curr Mol Med 9:255–272CrossRefPubMedGoogle Scholar
  62. Wang F, Shen X, Li S, Chen L, Wang Y, Qin J, Zhou G, Peng Y, Feng X, Li R, Liang C (2015) Splenocytes derived from young WT mice prevent AD progression in APPswe/PSENldE9 transgenic mice. Oncotarget 6:20851–20862CrossRefPubMedGoogle Scholar
  63. Yamada M (2015) Cerebral amyloid angiopathy: emerging concepts. J Stroke 17:17–30PubMedCentralCrossRefPubMedGoogle Scholar
  64. Yang H, Yang H, Xie Z, Wei L, Bi J (2013) Systemic transplantation of human umbilical cord derived mesenchymal stem cells-educated T regulatory cells improved the impaired cognition in AbetaPPswe/PS1dE9 transgenic mice. PLoS One 8:e69129PubMedCentralCrossRefPubMedGoogle Scholar
  65. Zhang F, Jiang L (2015) Neuroinflammation in Alzheimer’s disease. Neuropsychiatr Dis Treat 11:243–256Google Scholar
  66. Zhao W, Beers DR, Appel SH (2013) Immune-mediated mechanisms in the pathoprogression of amyotrophic lateral sclerosis. J NeuroImmune Pharmacol 8:888–899PubMedCentralCrossRefPubMedGoogle Scholar
  67. Zhao Y, Bhattacharjee S, Jones BM, Hill J, Dua P, Lukiw WJ (2014) Regulation of neurotropic signaling by the inducible, NF-kB-sensitive miRNA-125b in Alzheimer’s disease (AD) and in primary human neuronal-glial (HNG) cells. Mol Neurobiol 50:97–106Google Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Center for Neurodegenerative Disorders, University of Nebraska Medical CenterDepartment of Pharmacology and Experimental NeuroscienceOmahaUSA

Personalised recommendations