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Elaborate interactions between the immune and nervous systems

Abstract

The immune system and the nervous system maintain extensive communication, including 'hardwiring' of sympathetic and parasympathetic nerves to lymphoid organs. Neurotransmitters such as acetylcholine, norepinephrine, vasoactive intestinal peptide, substance P and histamine modulate immune activity. Neuroendocrine hormones such as corticotropin-releasing factor, leptin and α-melanocyte stimulating hormone regulate cytokine balance. The immune system modulates brain activity, including body temperature, sleep and feeding behavior. Molecules such as the major histocompatibility complex not only direct T cells to immunogenic molecules held in its cleft but also modulate development of neuronal connections. Neurobiologists and immunologists are exploring common ideas like the synapse to understand properties such as memory that are shared in these two systems.

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Figure 1: Neural pathways involved in immune regulation.
Figure 2: The immune system targets various levels of the nervous system.

References

  1. 1

    Steinman, L. Connections between the immune system and the nervous system. Proc. Natl. Acad. Sci. USA 90, 7912–7914 (1993).

    CAS  PubMed  Article  Google Scholar 

  2. 2

    Felten, S.Y. et al. Noradrenergic sympathetic innervation of lymphoid organs. Prog. Allergy 43, 14–36 (1988).

    CAS  PubMed  Google Scholar 

  3. 3

    Livnat, S., Felten, S.Y., Carlson, S.L., Bellinger, D.L. & Felten, D.L. Involvement of peripheral and central catecholamine systems in neuroimmune interactions. J. Neuroimmunol. 10, 5–30 (1985).

    CAS  PubMed  Article  Google Scholar 

  4. 4

    Steinman, L., Conlon, P., Maki, R. & Foster, A. The intricate interplay among body weight, stress and the immune response to friend or foe. J. Clin. Invest. 111, 183–185 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5

    Blatteis, C.M. The afferent signaling of fever. J. Physiol. 526, 470 (2000).

    CAS  PubMed  Google Scholar 

  6. 6

    Li, S., Goorha, S., Ballou, L.R. & Blatteis, C.M. Intracerebroventricular interleukin 6, macrophage inflammatory protein 1β and IL-18: pyrogenic and PGE(2)-mediated? Brain Res. 992, 76–84 (2003).

    CAS  PubMed  Article  Google Scholar 

  7. 7

    Engblom, D. et al. Prostaglandins as inflammatory messengers across the blood brain barrier. J. Mol. Med. 80, 5–15 (2002).

    CAS  PubMed  Article  Google Scholar 

  8. 8

    Goehler, L.E. et al. Interleukin-1β in immune cells of the abdominal vagus nerve: a link between the immune and nervous systems? J. Neurosci. 19, 2799–2806 (1999).

    CAS  PubMed  Article  Google Scholar 

  9. 9

    Mosmann, T.R. & Coffman, R.L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145–73 (1989).

    CAS  PubMed  Article  Google Scholar 

  10. 10

    Wekerle, H. Tackling multiple sclerosis. Nature 420, 39–40 (2002).

    CAS  PubMed  Article  Google Scholar 

  11. 11

    Steinman, L., Martin, R., Bernard, C.C.A., Conlon, P. & Oksenberg, J.R. Multiple sclerosis: deeper understanding of its pathogenesis reveals new targets for therapy. Annu. Rev. Neurosci. 25, 491–505 (2002).

    CAS  PubMed  Article  Google Scholar 

  12. 12

    Zamvil, S. & Steinman, L. Diverse targets for intervention during inflammatory and neurodegenerative phases of multiple sclerosis. Neuron 38, 685–688 (2003).

    CAS  PubMed  Article  Google Scholar 

  13. 13

    Youssef, S. et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a TH2 bias and reverses paralysis in CNS autoimmune disease. Nature 420, 78–84 (2002).

    CAS  PubMed  Article  Google Scholar 

  14. 14

    Frankel, J. et al. Lack of isoprenoid products raises ex vivo interleukin 1β secretion in hyperimmunoglobulinemia D and periodic fever syndrome. Arthritis Rheum. 46, 2794–2803 (2002).

    Article  CAS  Google Scholar 

  15. 15

    Cartmell, T., Ball, C., Bristow, A.F., Mitchell, D. & Poole, S. Endogenous interleukin-10 is required for the defervescence of fever evoked by local lipopolysaccharide-induced and Staphylococcus aureus-induced inflammation in rats. J. Physiol. 549, 653–664 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16

    Boneberg, E.M. & Hartun, T. Febrile temperatures attenuate IL-1β release by inhibiting proteolytic processing of the proform and influence TH1/TH2 balance by favoring TH2 cytokines. J. Immunol. 171, 664–668 (2003).

    CAS  PubMed  Article  Google Scholar 

  17. 17

    Tracey, K.J. The inflammatory reflex. Nature 420, 853–859 (2002).

    CAS  PubMed  Article  Google Scholar 

  18. 18

    Borovikova, L.V. et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405, 458–462 (2000).

    CAS  PubMed  Article  Google Scholar 

  19. 19

    Woiciechowsky, C. et al. Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury. Nat. Med. 4, 808–813 (1998).

    CAS  PubMed  Article  Google Scholar 

  20. 20

    Sanders, V.M. et al. Differential expression of the β2-adrenergic receptor by Th1 and Th2 clones: Implications for cytokine production and B cell help. J. Immunol. 158, 4200–4210 (1997).

    CAS  PubMed  Google Scholar 

  21. 21

    Miller, L.E., Grifka, J., Scholmerich, J. & Straub, R.H. Norepinephrine from synovial tyrosine hydroxylase positive cells is a strong indicator of synovial inflammation in rheumatoid arthritis. J. Rheumatol. 29, 427–435 (2002).

    CAS  PubMed  Google Scholar 

  22. 22

    Voice, J.K. et al. Roles of vasoactive intestinal peptide (VIP) in the expression of different immune phenotypes by wild-type mice and T cell-targeted type II VIP receptor transgenic mice. J. Immunol. 170, 308–314 (2003).

    CAS  PubMed  Article  Google Scholar 

  23. 23

    Grimm, M.C. et al. Vasoactive intestinal peptide acts as a potent suppressor of inflammation in vivo by trans-deactivating chemokine receptors. J. Immunol. 171, 4990–4994 (2003).

    CAS  PubMed  Article  Google Scholar 

  24. 24

    Martinez, C. et al. Anti-inflammatory role in septic shock of pituitary adenylate cyclase-activating polypeptide receptor. Proc. Natl. Acad. Sci. USA 99, 1053–1058 (2002).

    CAS  PubMed  Article  Google Scholar 

  25. 25

    Brain, S.D. & Williams, T.J. Substance P regulates the vasoldilator activity of calcitonin gene-related peptide. Nature 335, 73–75 (1988).

    CAS  PubMed  Article  Google Scholar 

  26. 26

    Steinhoff, M. et al. Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat. Med. 6, 151–158 (2000).

    CAS  PubMed  Article  Google Scholar 

  27. 27

    Pedotti, R. et al. An unexpected version of horror autotoxicus: anaphylactic shock to a self-peptide. Nat. Immunol. 2, 216–222 (2001).

    CAS  PubMed  Article  Google Scholar 

  28. 28

    Jutel, M. et al. Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors. Nature 413, 420–425 (2001).

    CAS  PubMed  Article  Google Scholar 

  29. 29

    Poliak, S. et al. Stress and autoimmunity: The neuropeptides corticotropin releasing factor and urocortin suppress encephalomyelitis via effects on both the hypothalamic-pituitary-adrenal axis and the immune system. J. Immunol. 158, 5751–5756 (1997).

    CAS  PubMed  Google Scholar 

  30. 30

    Grabbe, S. et al. α-Melanocyte-stimulating hormone induces hapten-specific tolerance in mice. J. Immunol. 156, 473–478 (1996).

    CAS  PubMed  Google Scholar 

  31. 31

    Streilein, J.W., Okamoto, S., Sano, Y. & Taylor, A.W. Neural control of ocular immune privilege. Ann. NY Acad. Sci. 917, 297–306 (2000).

    CAS  PubMed  Article  Google Scholar 

  32. 32

    Fekete, C. & Liposits, Z. Histamine-immunoreactive neurons of the tuberomammillary nucleus are innervated by α-melanocyte stimulating hormone-containing axons. Brain Res. 969, 70–77 (2003).

    CAS  PubMed  Article  Google Scholar 

  33. 33

    Matarese, G. et al. Requirement for leptin in induction and progression of experimental autoimmune encephalomyelitis. J. Immunol. 166, 5909–5916 (2001).

    CAS  PubMed  Article  Google Scholar 

  34. 34

    Sanna, V. et al. Leptin surge precedes autoimmune encephalomyelitis and correlates with disease susceptibility, inflammatory anorexia and the development of pathogenic T cell responses. J. Clin. Invest. 111, 241–250 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35

    Baumann, H. et al. The full-length leptin receptor has signaling capabilities of interleukin 6-type cytokine receptors. Proc. Natl. Acad. Sci. USA 93, 8374–8378 (1996).

    CAS  PubMed  Article  Google Scholar 

  36. 36

    Demas, G.E. Splenic denervation blocks leptin-induced enhancement of humoral immunity in Siberian hamsters (Phodopus sungorus). Neuroendocrinology 76, 178–84 (2002).

    CAS  PubMed  Article  Google Scholar 

  37. 37

    Rayner, D.V. & Trayhurn, P. Regulation of leptin production: sympathetic nervous system interactions. J. Mol. Med. 79, 8–20 (2001).

    CAS  PubMed  Article  Google Scholar 

  38. 38

    Prinz, M. et al. Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion. Nature 425, 957–62 (2003).

    CAS  PubMed  Article  Google Scholar 

  39. 39

    Prinz, M. et al. Lymph nodal prion replication and neuroinvasion in mice devoid of follicular dendritic cells. Proc. Natl. Acad. Sci. USA 99, 919–924 (2002).

    CAS  PubMed  Article  Google Scholar 

  40. 40

    Malamud, V. et al. Tryptase activates peripheral blood mononuclear cells causing the synthesis and release of TNF, IL-6 and IL-1: possible relevance to multiple sclerosis. J. Neuroimmunol. 138, 115–122 (2003).

    CAS  PubMed  Article  Google Scholar 

  41. 41

    Lock, C. et al. Gene microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med. 8, 500–508 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42

    Pedotti, R. et al. Multiple elements of the allergic arm of the immune response modulate autoimmune demyelination. Proc. Natl. Acad. Sci. USA 100, 1867–1872 (2003).

    CAS  PubMed  Article  Google Scholar 

  43. 43

    Pedotti, R., DeVoss, J., Steinman, L. & Galli, S. Involvement of both 'allergic' and 'autoimmune' mechanisms in EAE, MS and other autoimmune diseases. Trends Immunol. 24, 479–484 (2003).

    CAS  PubMed  Article  Google Scholar 

  44. 44

    Woolley, D.E. & Tetlow, L.C. Mast cell activation and its relation to proinflammatory cytokine production in the rheumatoid lesion. Arthr. Res. 2, 65–74 (2000).

    CAS  Article  Google Scholar 

  45. 45

    Tanzola, M.B., Robbie-Ryan, M., Gutekunst, C.A. & Brown, M.A. Mast cells exert effects outside the central nervous system to influence experimental allergic encephalomyelitis disease course. J. Immunol. 171, 4385–4391 (2003).

    CAS  PubMed  Article  Google Scholar 

  46. 46

    Benoist, C. & Mathis, D. Mast cells in autoimmune disease. Nature 420, 875–878 (2002).

    CAS  PubMed  Article  Google Scholar 

  47. 47

    Lee, D.M. et al. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science 297, 1689–1692 (2002).

    CAS  PubMed  Article  Google Scholar 

  48. 48

    Tracey, K.J. et al. Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation. J. Exp. Med. 167, 1211–1227 (1988).

    CAS  PubMed  Article  Google Scholar 

  49. 49

    Webster, E.L. et al. Corticotropin releasing hormone (CRH) antagonist attenuates adjuvant induced arthritis: role of CRH in peripheral inflammation. J. Rheumatol. 29, 1252–1261 (2002).

    CAS  PubMed  Google Scholar 

  50. 50

    Dhabhar, F.S., Satoskar, A.R., Bluethmann, H., David, J.R. & McEwen, B.S. Stress-induced enhancement of skin immune function: a role for γ interferon. Proc. Natl. Acad. Sci. USA 97, 2846–2851 (2000).

    CAS  PubMed  Article  Google Scholar 

  51. 51

    Ader, R. & Cohen, N. Behaviorally conditioned immunosuppression. Psychosomatic Med. 37, 333–340 (1975).

    CAS  Article  Google Scholar 

  52. 52

    Ader, R. & Cohen, N. Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus. Science 215, 1534–1536 (1982).

    CAS  PubMed  Article  Google Scholar 

  53. 53

    Rogers, S.W. et al. Autoantibodies to glutamate receptor GluR3 in Rasmussen's encephalitis. Science 265, 648–651 (1994).

    CAS  PubMed  Article  Google Scholar 

  54. 54

    Counce, D., Limdi, N. & Kuzniecky, R. Rasmussen's encephalitis. Curr. Treat. Options Neurol. 3, 555–563 (2001).

    PubMed  Article  Google Scholar 

  55. 55

    Darnell, R.B. & Posner, J.B. Paraneoplastic syndromes involving the nervous system. N. Engl. J. Med. 349, 1543–1554 (2003).

    CAS  PubMed  Article  Google Scholar 

  56. 56

    Solimena, M., Folli, F., Aparisi, R., Pozza, G. & De Camilli, P. Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N. Engl. J. Med. 322, 1555–1560 (1990).

    CAS  PubMed  Article  Google Scholar 

  57. 57

    Baekkeskov, S. et al. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 347, 151–156 (1990).

    CAS  PubMed  Article  Google Scholar 

  58. 58

    Rosin, L. et al. Stiff-man syndrome in a woman with breast cancer: an uncommon central nervous system paraneoplastic syndrome. Neurology 50, 94–98 (1998).

    CAS  PubMed  Article  Google Scholar 

  59. 59

    Sakai, K., Mitchell, D., Tsukamoto, T. & Steinman, L. Isolation of a complementary cDNA clone encoding an autoantigen recognized by an anti-neuronal antibody from a patient with paraneoplastic cerebellar degeneration. Ann. Neurol. 28, 692–698 (1990).

    CAS  PubMed  Article  Google Scholar 

  60. 60

    Lennon, V.A. & Carnegie, P.R. Immunopharmacological disease: a break in tolerance to receptor sites. Lancet 1, 630–633 (1971).

    CAS  PubMed  Article  Google Scholar 

  61. 61

    Patrick, J. & Lindstrom, J. Autoimmune response to acetylcholine receptor. Science 180, 871–872 (1973).

    CAS  PubMed  Article  Google Scholar 

  62. 62

    Engel, A.G., Tsujihata, M., Lambert, E.H., Lindstrom, J.M. & Lennon, V.A. Experimental autoimmune myasthenia gravis: a sequential and quantitative study of the neuromuscular junction ultrastructure and electrophysiologic correlations. J. Neuropathol. Exp. Neurol. 35, 569–587 (1976).

    CAS  PubMed  Article  Google Scholar 

  63. 63

    Drachman, D.B., Angus, C.W., Adams, R.N., Michelson, J.D. & Hoffman, G.J. Myasthenic antibodies cross-link acetylcholine receptors to accelerate degradation. N. Engl. J. Med. 298, 1116–1122 (1978).

    CAS  PubMed  Article  Google Scholar 

  64. 64

    Steinman, L. & Mantegazza, R. The prospects for specific immunotherapy in myasthenia gravis. FASEB J. 4, 2726–2731 (1990).

    CAS  PubMed  Article  Google Scholar 

  65. 65

    Fetissov, S.O. et al. Autoantibodies against α-MSH, ACTH, and LHRH in anorexia and bulimia nervosa patients. Proc. Natl. Acad. Sci. USA 99, 17155–17160 (2002).

    CAS  PubMed  Article  Google Scholar 

  66. 66

    Steinman, L. Multiple sclerosis: A two stage disease. Nat. Immunol. 2, 762–765 (2001).

    CAS  PubMed  Article  Google Scholar 

  67. 67

    McGeer, E.G. & McGeer, P.L. Inflammatory processes in Alzheimer's disease. Prog. Neuropsychopharmacol. Biol. Psychiatry 27, 741–749 (2003).

    CAS  PubMed  Article  Google Scholar 

  68. 68

    Imamura, K. et al. Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson's disease brains. Acta Neuropathol (Berl) 106, 518–526 (2003).

    CAS  Article  Google Scholar 

  69. 69

    Moalem, G. et al. Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nat. Med. 5, 49–55 (1999).

    CAS  PubMed  Article  Google Scholar 

  70. 70

    Chabas, D. et al. The influence of the pro-inflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 294, 1731–1735 (2001).

    CAS  PubMed  Article  Google Scholar 

  71. 71

    Karpuj, M.V. et al. Prolonged survival and decreased abnormal movements in transgenic model of Huntington's disease, with administration of cystamine, a transglutaminase Inhibitor. Nat. Med. 8, 143–149 (2002).

    CAS  PubMed  Article  Google Scholar 

  72. 72

    Kerschensteiner, M., Stadelmann, C., Dechant, G., Wekerle, H. & Hohlfeld, R. Neurotrophic cross-talk between the nervous and immune systems: implications for neurological diseases. Ann. Neurol. 53, 292–304 (2003).

    CAS  PubMed  Article  Google Scholar 

  73. 73

    Villoslada, P. et al. Human nerve growth factor protects common marmosets against autoimmune encephalomyelitis by switching the balance of T helper cell type 1 and 2 cytokines within the central nervous system. J. Exp. Med. 191, 1799–1806 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74

    Feldmann, M. & Maini, R.N. Lasker Clinical Medical Research Award. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nat. Med. 9, 1245–1250 (2003).

    CAS  PubMed  Article  Google Scholar 

  75. 75

    Arnett, H.A. et al. TNF-α promotes proliferation of oligodendrocyte progenitors and remyelination. Nat. Neurosci. 4, 1116–1122 (2001).

    CAS  PubMed  Article  Google Scholar 

  76. 76

    Pluchino, S. et al. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 422, 688–694 (2003).

    CAS  PubMed  Article  Google Scholar 

  77. 77

    Steinman, L. Collateral damage repaired. Nature 422, 671–672 (2003).

    CAS  PubMed  Article  Google Scholar 

  78. 78

    Yednock, T. et al. Prevention of experimental autoimmune encephalomyelitis by antibodies against α4β1 integrin. Nature 356, 63–66 (1992).

    CAS  PubMed  Article  Google Scholar 

  79. 79

    Hood, L., Kronenberg, M. & Hunkapiller, T. T cell antigen receptors and the immunoglobulin supergene family. Cell 40, 225–229 (1985).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  80. 80

    Huh, G.S. et al. Functional requirement for class I MHC in CNS development and plasticity. Science 290, 2155–2159 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81

    Joly, E., Mucke, L. & Oldstone, M.B. Viral persistence in neurons explained by lack of major histocompatibility I expression. Science 253, 11283–11285 (1991).

    Article  Google Scholar 

  82. 82

    Neumann, H., Cavalie, A., Jenne, D.E. & Wekerle, H. Induction of MHC class I genes in neurons. Science 269, 549–552 (1995).

    CAS  PubMed  Article  Google Scholar 

  83. 83

    Steinman, L. The unexpected benefits of stealth. Neurology 42, 276–277 (1992).

    CAS  PubMed  Article  Google Scholar 

  84. 84

    Syken, J. & Schatz, C. Expression of T cell receptor β locus in central nervous system neurons. Proc. Natl. Acad. Sci. USA 100, 13048–13053 (2003).

    CAS  PubMed  Article  Google Scholar 

  85. 85

    Loconto, J. et al. Functional expression of murine V2R pheromone receptors involves selective association with the M10 and M1 families of MHC class Ib molecules. Cell 112, 607–618 (2003).

    CAS  PubMed  Article  Google Scholar 

  86. 86

    Ishii, T., Hirota, J. & Mombaerts, P. Combinatorial coexpression of neural and immune multigene families in mouse vomeronasal sensory neurons. Curr. Biol. 13, 394–400 (2003).

    CAS  PubMed  Article  Google Scholar 

  87. 87

    Kumanogoh, A. et al. Class IV semaphorin Sema4A enhances T cell activation and interacts with Tim-2. Nature 419, 629–633 (2002).

    CAS  Article  PubMed  Google Scholar 

  88. 88

    Kuchroo, V.K., Umetsu, D.T., DeKruyff, R.H. & Freeman, G.J. The TIM gene family: emerging roles in immunity and disease. Nat. Rev. Immunol. 3, 454–462 (2003).

    CAS  PubMed  Article  Google Scholar 

  89. 89

    Ueda, R & Sugiyama, S. Nerve impulse in the 19th century: it's nature and the method of research. Kgakushi Kenkyhu 42, 76–87 (2003).

    Google Scholar 

  90. 90

    Norcross, M.A. A synaptic basis for T-lymphocyte activation. Ann. Immunol. (Paris) 135, 113–134 (1984).

    Google Scholar 

  91. 91

    Huppa, J.B. & Davis, M.M. T-cell-antigen recognition and the immunological synapse. Nat. Rev. Immunol. 3, 973–83 (2003).

    CAS  PubMed  Article  Google Scholar 

  92. 92

    Dustin, M.L. & Colman, D.R. Neural and immunological synaptic relations. Science 298, 785–789 (2002).

    CAS  PubMed  Article  Google Scholar 

  93. 93

    Irvine, D., Purbhoo, M., Krogsgaard, M. & Davis, M.M. Direct observation of ligand recognition by T cells. Nature 419, 845–849 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94

    Baylor, D.A., Lamb, T.D. & Yau, K.W. Responses of retinal rods to single photons. J. Physiol. (Lond.) 288, 613–634 (1979).

    CAS  Google Scholar 

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Supported by the National Institutes of Health and the Phil N. Allen Trust.

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Steinman, L. Elaborate interactions between the immune and nervous systems. Nat Immunol 5, 575–581 (2004). https://doi.org/10.1038/ni1078

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