Skip to main content

Neuroimmune Mechanisms of Cerebellar Development and Its Developmental Disorders: Bidirectional Link Between the Immune System and Nervous System

Part of the Contemporary Clinical Neuroscience book series (CCNE)

Abstract

Understanding the cross talk between the immune system and cerebellum development has noticeable implications for understanding and management of neurodevelopmental disorders. Our knowledge about cerebellar developmental maturation and remodeling is improving. Immune cells have different functions in a healthy state, but those functions are compromised during developmental stages in mammals. In this chapter, we highlight the evidence that indicates an important role of the immune system within the cerebellum and brain. We discuss the contribution of different immune responses in the development of the cerebellum and its associated disorders and highlight current understanding of the mechanisms and insights involved in these processes. Immune pathways that have a crucial role in cerebellar development are likely to become therapeutic targets for several neurodevelopmental disorders. Therefore, this information may suggest new therapeutic approaches to developmental disorders of the cerebellum through suppression or activation of selected immune pathways.

Keywords

This is a preview of subscription content, log in via an institution.

Abbreviations

AICA:

Anterior inferior cerebellar artery

ALRs:

AIM2-like receptors

ALS:

Amyotrophic lateral sclerosis

ANS:

Autonomic nervous system

APCs:

Antigen-presenting cells

BBB:

Blood–brain barrier

CCL:

C-C motif chemokine ligand

CNS:

Central nervous system

Cop-1:

Copolymer 1

CSF:

Cerebrospinal fluid

DAMPs:

Damage-associated molecular patterns

DC:

Dendritic cells

EAE:

Experimental autoimmune encephalomyelitis

EGL:

External granule cell layer

FOXP3:

Forkhead box P3

GAD:

Glutamic acid decarboxylase antibodies

GIT:

Gastrointestinal tract

HE:

Hashimoto’s encephalopathy

HSP:

Heat shock proteins

IBS:

Irritable bowel syndrome

IFN:

Interferon

Ig:

Immunoglobulin

IGL:

Internal granule cell layer

IL:

Interleukin

LGP2:

Laboratory of genetics and physiology 2

MDA5:

Melanoma differentiation-associated gene 5

MHC:

Major histocompatibility

MIP:

Macrophage inflammatory protein

MSA:

Multiple system atrophy

NLRs:

Nod-like receptors

OPCA:

Olivopontocerebellar

P2X7R:

Purinergic receptor P2X7

PACA:

Primary autoimmune cerebellar ataxia

PAMPs:

Pathogen-associated molecular patterns

PICA:

Posterior inferior cerebellar artery

PRRs:

Pattern recognition receptors

(RAG)-1:

Recombination activating gene

Rig1:

Retinoic acid-inducible gene-1

RLRs:

RIG-like receptors

Rora:

Retinoic acid-related orphan receptor alpha

ROS:

Reactive oxygen species

SCA:

Superior cerebellar artery

SCID:

Severe combined immunodeficiency

SND:

Striatonigral

SOCS3:

Suppressor of cytokine signaling 3

TGF:

Tumor growth factor

Th:

T helper

TLRs:

Toll-like receptors

TNF:

Tumor necrosis factor

Treg:

Regulatory T cells

URL:

Upper rhombic lip

References

  1. Glickstein M, Strata P, Voogd J. Cerebellum: history. Neuroscience. 2009;162(3):549–59.

    CAS  PubMed  Google Scholar 

  2. Dantzer R. Innate immunity at the forefront of psychoneuroimmunology. Brain Behav Immun. 2004;18(1):1–6.

    Article  CAS  PubMed  Google Scholar 

  3. Jiang C-L, Lu C-L, Liu X-Y. The molecular basis for bidirectional communication between the immune and neuroendocrine systems. Domest Anim Endocrinol. 1998;15(5):363–9.

    Article  CAS  PubMed  Google Scholar 

  4. Manto MU, Jissendi P. Cerebellum: links between development, developmental disorders and motor learning. The cerebellum: from development to learning. Front Neuroanat. 2007:6;1. doi:10.3389/fnana.2012.00001.

  5. Deverman BE, Patterson PH. Cytokines and CNS development. Neuron. 2009;64(1):61–78.

    Article  CAS  PubMed  Google Scholar 

  6. Zhu J-N, Zhang Y-P, Song Y-N, Wang J-J. Cerebellar interpositus nuclear and gastric vagal afferent inputs reach and converge onto glycemia-sensitive neurons of the ventromedial hypothalamic nucleus in rats. Neurosci Res. 2004;48(4):405–17.

    Article  PubMed  Google Scholar 

  7. Cavdar S, ŞAN T, Aker R, ŞEHİRLİ Ü, Onat F. Cerebellar connections to the dorsomedial and posterior nuclei of the hypothalamus in the rat. J Anat. 2001;198(1):37–45.

    Google Scholar 

  8. Cavdar S, Onat F, Aker R, ŞEHİRLİ Ü, ŞAN T, Raci YH. The afferent connections of the posterior hypothalamic nucleus in the rat using horseradish peroxidase. J Anat. 2001;198(4):463–72.

    Google Scholar 

  9. Wang J, Pu Y, Wang T. Influences of cerebellar interpositus nucleus and fastigial nucleus on neuronal activity of lateral hypothalamic area. Sci China Ser C Life Sci. 1997;40(2):176–83.

    Article  CAS  Google Scholar 

  10. Haines D, Dietrichs E. An HRP study of hypothalamo-cerebellar and cerebello-hypothalamic connections in squirrel monkey (saimiri sciureus). J Comp Neurol. 1984;229(4):559–75.

    Google Scholar 

  11. King JS, Cummings SL, Bishop GA. Peptides in cerebellar circuits. Prog Neurobiol. 1992;39(4):423–42.

    Article  CAS  PubMed  Google Scholar 

  12. Lind R, Swanson L, Ganten D. Organization of angiotensin II immunoreactive cells and fibers in the rat central nervous system. Neuroendocrinology. 1985;40(1):2–24.

    Article  CAS  PubMed  Google Scholar 

  13. Koibuchi N. The role of thyroid hormone on cerebellar development. Cerebellum. 2008;7(4):530–3.

    Article  CAS  PubMed  Google Scholar 

  14. Koibuchi N, Jingu H, Iwasaki T, Chin WW. Current perspectives on the role of thyroid hormone in growth and development of cerebellum. Cerebellum. 2003;2(4):279.

    Article  CAS  PubMed  Google Scholar 

  15. Hajo F, Patel A, Bala R. Effect of thyroid deficiency on the synaptic organization of the rat cerebellar cortex. Brain Res. 1973;50(2):387–401.

    Article  Google Scholar 

  16. De Vito P, Incerpi S, Pedersen JZ, Luly P, Davis FB, Davis PJ. Thyroid hormones as modulators of immune activities at the cellular level. Thyroid. 2011;21(8):879–90.

    Article  PubMed  CAS  Google Scholar 

  17. Janeway CA. The immune system evolved to discriminate infectious nonself from noninfectious self. Immunol Today. 1992;13(1):11–6.

    Article  CAS  PubMed  Google Scholar 

  18. Kigerl KA, Lai W, Rivest S, Hart RP, Satoskar AR, Popovich PG. Toll-like receptor (TLR)-2 and TLR-4 regulate inflammation, gliosis, and myelin sparing after spinal cord injury. J Neurochem. 2007;102(1):37–50.

    Google Scholar 

  19. Ransohoff RM, Brown MA. Innate immunity in the central nervous system. J Clin Invest. 2012;122(4):1164–71.

    Google Scholar 

  20. Colton CA, Wilcock DM. Assessing activation states in microglia. CNS Neurol Disord-Drug Targets (Formerly Curr Drug Targets-CNS Neurol Disord). 2010;9(2):174–91.

    CAS  Google Scholar 

  21. Rock FL, Hardiman G, Timans JC, Kastelein RA, Bazan JF. A family of human receptors structurally related to Drosophila Toll. Proc Natl Acad Sci. 1998;95(2):588–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yao L, Kan EM, Lu J, Hao A, Dheen ST, Kaur C, et al. Toll-like receptor 4 mediates microglial activation and production of inflammatory mediators in neonatal rat brain following hypoxia: role of TLR4 in hypoxic microglia. J Neuroinflammation. 2013;10(1):23.

    Google Scholar 

  23. Basu A, Krady JK, Levison SW. Interleukin-1: a master regulator of neuroinflammation. J Neurosci Res. 2004;78(2):151–6.

    Google Scholar 

  24. Dinarello CA, Simon A, Van Der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. 2012;11(8):633–52.

    Google Scholar 

  25. Karikó K, Ni H, Capodici J, Lamphier M, Weissman D. mRNA is an endogenous ligand for Toll-like receptor 3. J Biol Chem. 2004;279(13):12542–50.

    Article  PubMed  CAS  Google Scholar 

  26. DeMarco RA, Fink MP, Lotze MT. Monocytes promote natural killer cell interferon gamma production in response to the endogenous danger signal HMGB1. Mol Immunol. 2005;42(4):433–44.

    Article  CAS  PubMed  Google Scholar 

  27. Yu M, Wang H, Ding A, Golenbock DT, Latz E, Czura CJ, et al. HMGB1 signals through toll-like receptor (TLR) 4 and TLR2. Shock. 2006;26(2):174–9.

    Article  CAS  PubMed  Google Scholar 

  28. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464(7285):104–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci. 2005;8(6):752–8.

    Google Scholar 

  30. Brudek T, Winge K, Agander TK, Pakkenberg B. Screening of Toll-like receptors expression in multiple system atrophy brains. Neurochem Res. 2013;38(6):1252–9.

    Article  CAS  PubMed  Google Scholar 

  31. Kigerl KA, de Rivero Vaccari JP, Dietrich WD, Popovich PG, Keane RW. Pattern recognition receptors and central nervous system repair. Exp Neurol. 2014;258:5–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bsibsi M, Ravid R, Gveric D, van Noort JM. Broad expression of Toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol. 2002;61(11):1013–21.

    Article  CAS  PubMed  Google Scholar 

  33. Okun E, Griffioen KJ, Lathia JD, Tang S-C, Mattson MP, Arumugam TV. Toll-like receptors in neurodegeneration. Brain Res Rev. 2009;59(2):278–92.

    Article  CAS  PubMed  Google Scholar 

  34. Di Virgilio F. The therapeutic potential of modifying inflammasomes and NOD-like receptors. Pharmacol Rev. 2013;65(3):872–905.

    Article  PubMed  CAS  Google Scholar 

  35. Martinon F, Burns K, Tschopp J. The Inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol Cell. 2002;10(2):417–26.

    Article  CAS  PubMed  Google Scholar 

  36. Fernandes-Alnemri T, Wu J, Yu J, Datta P, Miller B, Jankowski W, et al. The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation. Cell Death Differ. 2007;14(9):1590–604.

    Article  CAS  PubMed  Google Scholar 

  37. Abulafia DP, de Rivero Vaccari JP, Lozano JD, Lotocki G, Keane RW, Dietrich WD. Inhibition of the inflammasome complex reduces the inflammatory response after thromboembolic stroke in mice. J Cereb Blood Flow Metab. 2009;29(3):534–44.

    Article  CAS  PubMed  Google Scholar 

  38. Minkiewicz J, Rivero Vaccari JP, Keane RW. Human astrocytes express a novel NLRP2 inflammasome. Glia. 2013;61(7):1113–21.

    Article  PubMed  Google Scholar 

  39. Shi F, Yang Y, Kouadir M, Fu Y, Yang L, Zhou X, et al. Inhibition of phagocytosis and lysosomal acidification suppresses neurotoxic prion peptide-induced NALP3 inflammasome activation in BV2 microglia. J Neuroimmunol. 2013;260(1):121–5.

    Article  CAS  PubMed  Google Scholar 

  40. de Rivero Vaccari JP, Lotocki G, Marcillo AE, Dietrich WD, Keane RW. A molecular platform in neurons regulates inflammation after spinal cord injury. J Neurosci. 2008;28(13):3404–14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Couturier J, Stancu I-C, Schakman O, Pierrot N, Huaux F, Kienlen-Campard P, et al. Activation of phagocytic activity in astrocytes by reduced expression of the inflammasome component ASC and its implication in a mouse model of Alzheimer disease. J Neuroinflammation. 2016;13(1):1–13.

    Article  CAS  Google Scholar 

  42. Gustin A, Kirchmeyer M, Koncina E, Felten P, Losciuto S, Heurtaux T, et al. NLRP3 inflammasome is expressed and functional in mouse brain microglia but not in astrocytes. PLoS One. 2015;10(6):e0130624.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Walsh JG, Muruve DA, Power C. Inflammasomes in the CNS. Nat Rev Neurosci. 2014;15(2):84–97.

    Article  CAS  PubMed  Google Scholar 

  44. Andoh T, Kishi H, Motoki K, Nakanishi K, Kuraishi Y, Muraguchi A. Protective effect of IL-18 on kainate- and IL-1β-induced cerebellar ataxia in mice. J Immunol. 2008;180(4):2322–8.

    Article  CAS  PubMed  Google Scholar 

  45. Goines PE, Ashwood P. Cytokine dysregulation in autism spectrum disorders (ASD): possible role of the environment. Neurotoxicol Teratol. 2013;36:67–81.

    Article  CAS  PubMed  Google Scholar 

  46. Savarin C, Bergmann CC. Neuroimmunology of central nervous system viral infections: the cells, molecules and mechanisms involved. Curr Opin Pharmacol. 2008;8(4):472–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Szabo A, Bene K, Gogolák P, Réthi B, Lányi Á, Jankovich I, et al. RLR-mediated production of interferon-β by a human dendritic cell subset and its role in virus-specific immunity. J Leukoc Biol. 2012;92(1):159–69.

    Article  CAS  PubMed  Google Scholar 

  48. Duan X, Ponomareva L, Veeranki S, Panchanathan R, Dickerson E, Choubey D. Differential roles for the interferon-inducible IFI16 and AIM2 innate immune sensors for cytosolic DNA in cellular senescence of human fibroblasts. Mol Cancer Res. 2011;9(5):589–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Adamczak SE. Molecular recognition of DNA by the AIM2 inflammasome induces neuronal pyroptosis: implications in infection and host tissue damage. Open Access Dissertations. 2012; 854.

    Google Scholar 

  50. Husemann J, Loike JD, Anankov R, Febbraio M, Silverstein SC. Scavenger receptors in neurobiology and neuropathology: their role on microglia and other cells of the nervous system. Glia. 2002;40(2):195–205.

    Article  PubMed  Google Scholar 

  51. Edele F, Molenaar R, Gütle D, Dudda JC, Jakob T, Homey B, et al. Cutting edge: instructive role of peripheral tissue cells in the imprinting of T cell homing receptor patterns. J Immunol. 2008;181(6):3745–9.

    Article  CAS  PubMed  Google Scholar 

  52. Desalvo MK, Mayer N, Mayer F, Bainton RJ. Physiologic and anatomic characterization of the brain surface glia barrier of Drosophila. Glia. 2011;59(9):1322–40.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Banerjee S, Bhat MA. Neuron-glial interactions in blood-brain barrier formation. Annu Rev Neurosci. 2007;30:235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kwidzinski E, Mutlu L, Kovac A, Bunse J, Goldmann J, Mahlo J, et al. Self-tolerance in the immune privileged CNS: lessons from the entorhinal cortex lesion model. Advances in research on neurodegeneration: Austria, Springer; 2003. p. 29–49.

    Google Scholar 

  55. Malipiero U, Koedel U, Pfister H-W, Levéen P, Bürki K, Reith W, et al. TGFβ receptor II gene deletion in leucocytes prevents cerebral vasculitis in bacterial meningitis. Brain. 2006;129(9):2404–15.

    Article  PubMed  Google Scholar 

  56. Tremblay M-È, Stevens B, Sierra A, Wake H, Bessis A, Nimmerjahn A. The role of microglia in the healthy brain. J Neurosci. 2011;31(45):16064–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kaur C, Sivakumar V, Zou Z, Ling E-A. Microglia-derived proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1beta induce Purkinje neuronal apoptosis via their receptors in hypoxic neonatal rat brain. Brain Struct Funct. 2014;219(1):151–70.

    Article  CAS  PubMed  Google Scholar 

  58. Lenz KM, Nugent BM, Haliyur R, McCarthy MM. Microglia are essential to masculinization of brain and behavior. J Neurosci. 2013;33(7):2761–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012;74(4):691–705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cuadros MA, Rodriguez-Ruiz J, Calvente R, Almendros A, Marin-Teva JL, Navascues J. Microglia development in the quail cerebellum. J Comp Neurol. 1997;389(3):390–401.

    Article  CAS  PubMed  Google Scholar 

  61. Perez-Pouchoulen M, VanRyzin JW, McCarthy MM. Morphological and phagocytic profile of microglia in the developing rat cerebellum. ENEURO. 2015;2(4):0036–15. 2015

    Article  Google Scholar 

  62. Marin-Teva JL, Dusart I, Colin C, Gervais A, Van Rooijen N, Mallat M. Microglia promote the death of developing Purkinje cells. Neuron. 2004;41(4):535–47.

    Article  CAS  PubMed  Google Scholar 

  63. Streit WJ. Microglia and macrophages in the developing CNS. Neurotoxicology. 2001;22(5):619–24.

    Article  CAS  PubMed  Google Scholar 

  64. Schwartz M, Kipnis J, Rivest S, Prat A. How do immune cells support and shape the brain in health, disease, and aging? J Neurosci. 2013;33(45):17587–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Nathan C. Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol. 2006;6(3):173–82.

    Article  CAS  PubMed  Google Scholar 

  66. Mantovani A, Cassatella MA, Costantini C, Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol. 2011;11(8):519–31.

    Article  CAS  PubMed  Google Scholar 

  67. Morita K, Miura M, Paolone DR, Engeman TM, Kapoor A, Remick DG, et al. Early chemokine cascades in murine cardiac grafts regulate T cell recruitment and progression of acute allograft rejection. J Immunol. 2001;167(5):2979–84.

    Article  CAS  PubMed  Google Scholar 

  68. Halloran P, Fairchild R. The puzzling role of CXCR3 and its ligands in organ allograft rejection. Am J Transplant. 2008;8(8):1578–9.

    Article  CAS  PubMed  Google Scholar 

  69. Klein RS, Rubin JB, Gibson HD, DeHaan EN, Alvarez-Hernandez X, Segal RA, et al. SDF-1α induces chemotaxis and enhances Sonic hedgehog-induced proliferation of cerebellar granule cells. Development. 2001;128(11):1971–81.

    Article  CAS  PubMed  Google Scholar 

  70. Stumm RK, Rummel J, Junker V, Culmsee C, Pfeiffer M, Krieglstein J, et al. A dual role for the SDF-1/CXCR4 chemokine receptor system in adult brain: isoform-selective regulation of SDF-1 expression modulates CXCR4-dependent neuronal plasticity and cerebral leukocyte recruitment after focal ischemia. J Neurosci. 2002;22(14):5865–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Rostène W, Dansereau MA, Godefroy D, Van Steenwinckel J, Goazigo ARL, Mélik-Parsadaniantz S, et al. Neurochemokines: a menage a trois providing new insights on the functions of chemokines in the central nervous system. J Neurochem. 2011;118(5):680–94.

    Article  PubMed  CAS  Google Scholar 

  72. Wingate RJ. The rhombic lip and early cerebellar development. Curr Opin Neurobiol. 2001;11(1):82–8.

    Article  CAS  PubMed  Google Scholar 

  73. Zhu Y, Yu T, Zhang X-C, Nagasawa T, Wu JY, Rao Y. Role of the chemokine SDF-1 as the meningeal attractant for embryonic cerebellar neurons. Nat Neurosci. 2002;5(8):719–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ozawa PMM, Ariza CB, Ishibashi CM, Fujita TC, Banin-Hirata BK, Oda JMM, et al. Role of CXCL12 and CXCR4 in normal cerebellar development and medulloblastoma. Int J Cancer. 2016;138(1):10–3.

    Google Scholar 

  75. Daré E, Schulte G, Karovic O, Hammarberg C, Fredholm BB. Modulation of glial cell functions by adenosine receptors. Physiol Behav. 2007;92(1):15–20.

    Article  PubMed  CAS  Google Scholar 

  76. Lécuyer M-A, Kebir H, Prat A. Glial influences on BBB functions and molecular players in immune cell trafficking. Biochimica et Biophysica Acta (BBA)-Mol Basis Dis. 2016;1862(3):472–82.

    Article  CAS  Google Scholar 

  77. Abbott NJ. Astrocyte–endothelial interactions and blood–brain barrier permeability. J Anat. 2002;200(5):523–34.

    Article  Google Scholar 

  78. Wu F, Zou Q, Ding X, Shi D, Zhu X, Hu W, et al. Complement component C3a plays a critical role in endothelial activation and leukocyte recruitment into the brain. J Neuroinflammation. 2016;13(1):1–14.

    Article  CAS  Google Scholar 

  79. Hindinger C, Bergmann CC, Hinton DR, Phares TW, Parra GI, Hussain S, et al. IFN-γ signaling to astrocytes protects from autoimmune mediated neurological disability. PLoS One. 2012;7(7):e42088.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Jehs T, Faber C, Juel HB, Nissen MH. Astrocytoma cells upregulate expression of pro-inflammatory cytokines after co-culture with activated peripheral blood mononuclear cells. APMIS. 2011;119(8):551–61.

    Article  CAS  PubMed  Google Scholar 

  81. Yang J, Tao H, Liu Y, Zhan X, Liu Y, Wang X, et al. Characterization of the interaction between astrocytes and encephalitogenic lymphocytes during the development of experimental autoimmune encephalitomyelitis (EAE) in mice. Clin Exp Immunol. 2012;170(3):254–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Markiewski MM, Lambris JD. The role of complement in inflammatory diseases from behind the scenes into the spotlight. Am J Pathol. 2007;171(3):715–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Brennan FH, Anderson AJ, Taylor SM, Woodruff TM, Ruitenberg MJ. Complement activation in the injured central nervous system: another dual-edged sword? J Neuroinflammation. 2012;9(1):1.

    Article  Google Scholar 

  84. Veerhuis R, Nielsen HM, Tenner AJ. Complement in the brain. Mol Immunol. 2011;48(14):1592–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Davoust N, Jones J, Stahel PF, Ames RS, Barnum SR. Receptor for the C3a anaphylatoxin is expressed by neurons and glial cells. Glia. 1999;26(3):201–11.

    Article  CAS  PubMed  Google Scholar 

  86. Arumugam TV, Woodruff TM, Lathia JD, Selvaraj PK, Mattson MP, Taylor SM. Neuroprotection in stroke by complement inhibition and immunoglobulin therapy. Neuroscience. 2009;158(3):1074–89.

    Article  CAS  PubMed  Google Scholar 

  87. Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, et al. The classical complement cascade mediates CNS synapse elimination. Cell. 2007;131(6):1164–78.

    Article  CAS  PubMed  Google Scholar 

  88. Perry VH, O’connor V. C1q: the perfect complement for a synaptic feast? Nat Rev Neurosci. 2008;9(11):807–11.

    Article  CAS  PubMed  Google Scholar 

  89. Shatz CJ. MHC class I: an unexpected role in neuronal plasticity. Neuron. 2009;64(1):40–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Hua Y, Xi G, Keep RF, Hoff JT. Complement activation in the brain after experimental intracerebral hemorrhage. J Neurosurg. 2000;92(6):1016–22.

    Article  CAS  PubMed  Google Scholar 

  91. Ghoshal D, Sinha S, Sinha A, Bhattacharyya P. Immunosuppressive effect of vestibulo-cerebellar lesion in rats. Neurosci Lett. 1998;257(2):89–92.

    Article  CAS  PubMed  Google Scholar 

  92. Peng Y-P, Qiu Y-H, Chao B-B, Wang J-J. Effect of lesions of cerebellar fastigial nuclei on lymphocyte functions of rats. Neurosci Res. 2005;51(3):275–84.

    Article  CAS  PubMed  Google Scholar 

  93. Ellwardt E, Walsh JT, Kipnis J, Zipp F. Understanding the role of T cells in CNS homeostasis. Trends Immunol. 2016;37(2):154–65.

    Article  CAS  PubMed  Google Scholar 

  94. Kipnis J, Yoles E, Porat Z, Cohen A, Mor F, Sela M, et al. T cell immunity to copolymer 1 confers neuroprotection on the damaged optic nerve: possible therapy for optic neuropathies. Proc Natl Acad Sci. 2000;97(13):7446–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Xie L, Choudhury GR, Winters A, Yang SH, Jin K. Cerebral regulatory T cells restrain microglia/macrophage-mediated inflammatory responses via IL-10. Eur J Immunol. 2015;45(1):180–91.

    Article  CAS  PubMed  Google Scholar 

  96. Luchtman DW, Ellwardt E, Larochelle C, Zipp F. IL-17 and related cytokines involved in the pathology and immunotherapy of multiple sclerosis: current and future developments. Cytokine Growth Factor Rev. 2014;25(4):403–13.

    Article  CAS  PubMed  Google Scholar 

  97. Liblau RS, Gonzalez-Dunia D, Wiendl H, Zipp F. Neurons as targets for T cells in the nervous system. Trends Neurosci. 2013;36(6):315–24.

    Article  CAS  PubMed  Google Scholar 

  98. Ahmad SF, Zoheir KM, Ansari MA, Nadeem A, Bakheet SA, AL-Ayadhi LY, et al. Dysregulation of Th1, Th2, Th17, and T regulatory cell-related transcription factor signaling in children with autism. doi:10.1007/s12035-016-9977-0. Mol Neurobiol. 2016:1–11.

  99. Campbell SJ, Wilcockson DC, Butchart AG, Perry VH, Anthony DC. Altered chemokine expression in the spinal cord and brain contributes to differential interleukin-1beta-induced neutrophil recruitment. J Neurochem. 2002;83:432–41.

    Article  CAS  PubMed  Google Scholar 

  100. Estes ML, McAllister AK. Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Nat Rev Neurosci. 2015;16(8):469–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Hill KE, Clawson SA, Rose JW, Carlson NG, Greenlee JE. Cerebellar Purkinje cells incorporate immunoglobulins and immunotoxins in vitro: implications for human neurological disease and immunotherapeutics. J Neuroinflammation. 2009;6(1):1–12.

    Google Scholar 

  102. Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol. 2008;7(4):327–40.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Chen S, Su H-S. Selective labeling by propidium iodide injected into the lateral cerebral ventricle of the rat. Brain Res. 1989;483(2):379–83.

    Article  CAS  PubMed  Google Scholar 

  104. Saini V, Weisz A, Hoffman J. Paraneoplastic Cerebellar Degeneration (PCD) Syndrome in Diffuse Large B-cell Lymphoma (DLBCL): expanding the spectrum of malignancies associated with cerebellar degeneration (P5. 260). Neurology. 2016;86(16 Supplement):P5–260.

    Google Scholar 

  105. Mitoma H, Hadjivassiliou M, Honnorat J. Guidelines for treatment of immune-mediated cerebellar ataxias. Cerebellum Ataxias. 2015;2:14.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Jarius S, Wildemann B. ‘Medusa head ataxia’: the expanding spectrum of Purkinje cell antibodies in autoimmune cerebellar ataxia. Part 1: anti-mGluR1, anti-Homer-3, anti-Sj/ITPR1 and anti-CARP VIII. J Neuroinflammation. 2015;12(1):1.

    Google Scholar 

  107. Hadjivassiliou M. Chapter 11 – immune-mediated acquired ataxias. In: Sankara HS, Alexandra D, editors. Handbook of clinical neurology. Vol. 103. Elsevier; 2012. p. 189–99.

    Google Scholar 

  108. Cooke W, Smith WT. Neurological disorders associated with adult celiac disease. United States. Brain. 1966;89(4):683–722.

    Google Scholar 

  109. Wiendl H, Mehling M, Dichgans J, Melms A, Bürk K. The humoral response in the pathogenesis of gluten ataxia. Neurology. 2003;60(8):1397–9.

    Article  CAS  PubMed  Google Scholar 

  110. Vojdani A, O’Bryan T, Green J, McCandless J, Woeller K, Vojdani E, et al. Immune response to dietary proteins, gliadin and cerebellar peptides in children with autism. Nutr Neurosci. 2004;7(3):151–61.

    Article  CAS  PubMed  Google Scholar 

  111. Boscolo S, Sarich A, Lorenzon A, Passoni M, Rui V, Stebel M, et al. Gluten ataxia. Ann N Y Acad Sci. 2007;1107(1):319–28.

    Article  CAS  PubMed  Google Scholar 

  112. Sanger GJ, Lee K. Hormones of the gut–brain axis as targets for the treatment of upper gastrointestinal disorders. Nat Rev Drug Discov. 2008;7(3):241–54.

    Article  CAS  PubMed  Google Scholar 

  113. Heijtz RD, Wang S, Anuar F, Qian Y, Björkholm B, Samuelsson A, et al. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci. 2011;108(7):3047–52.

    Article  CAS  PubMed Central  Google Scholar 

  114. Maynard CL, Elson CO, Hatton RD, Weaver CT. Reciprocal interactions of the intestinal microbiota and immune system. Nature. 2012;489(7415):231–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Li Q, Zhou J-M. The microbiota–gut–brain axis and its potential therapeutic role in autism spectrum disorder. Neuroscience. 2016;324:131–9.

    Article  CAS  PubMed  Google Scholar 

  116. Korponay-Szabó IR, Halttunen T, Szalai Z, Laurila K, Kiraly R, Kovacs J, et al. In vivo targeting of intestinal and extraintestinal transglutaminase 2 by coeliac autoantibodies. Gut. 2004;53(5):641–8.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Hadjivassiliou M, Mäki M, Sanders D, Williamson C, Grünewald R, Woodroofe N, et al. Autoantibody targeting of brain and intestinal transglutaminase in gluten ataxia. Neurology. 2006;66(3):373–7.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This was supported by grants from the Canadian Foundation for Innovation, Crohn’s and Colitis Canada, Research Manitoba, Children’s Hospital Research Institute of Manitoba, Canadian Institutes of Health Research to JEG, and University of Manitoba, Research Manitoba and Health Sciences Foundation – Mindel and Tom Olenick Research Award in Immunology to NE.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jean-Eric Ghia .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Eissa, N., Kermarrec, L., Ghia, JE. (2017). Neuroimmune Mechanisms of Cerebellar Development and Its Developmental Disorders: Bidirectional Link Between the Immune System and Nervous System. In: Marzban, H. (eds) Development of the Cerebellum from Molecular Aspects to Diseases. Contemporary Clinical Neuroscience. Springer, Cham. https://doi.org/10.1007/978-3-319-59749-2_13

Download citation

Publish with us

Policies and ethics