Neural Regulation of the Immune Response

  • Paul Forsythe
  • John Bienenstock
Part of the Allergy Frontiers book series (ALLERGY, volume 2)


Increased knowledge of the interactions between the brain and the immune system holds considerable promise for expanding our understanding of the mechanisms underlying health and disease. All divisions of the nervous system (sympathetic, parasympathetic, and sensory) utilize intimate associations with inflammatory cells to regulate immune responses. Such interactions are essential for survival during stress or infection and to modulate immune responses in inflammatory disease. This chapter describes the major routes by which the immune system and the nervous system communicate, how such communication impacts adaptive and innate immune responses and discusses the implications for these interactions in relation classical immune conditioning and the influence of psychological stress on the exacerbation and severity of allergic disorders.


Respiratory Syncytial Virus Sympathetic Nervous System Airway Inflammation Vagus Nerve Vasoactive Intestinal Peptide 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Sternberg EM (2006) Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol 6: 318–328PubMedCrossRefGoogle Scholar
  2. 2.
    Tracey KJ (2002) The inflammatory reflex. Nature 420: 853–859PubMedCrossRefGoogle Scholar
  3. 3.
    Tracey KJ, Czura CJ, Ivanova S (2001) Mind over immunity. FASEB J 15: 1575–1576PubMedCrossRefGoogle Scholar
  4. 4.
    Glaser R, Kiecolt-Glaser JK (2005) Stress-induced immune dysfunction: implications for health. Nat Rev Immunol 5: 243–251PubMedCrossRefGoogle Scholar
  5. 5.
    Lamberts SW, Verleun T, Oosterom R, de Jong F, Hackeng WH (1984) Corticotropin-releasing factor (ovine) and vasopressin exert a synergistic effect on adrenocorticotropin release in man. J Clin Endocrinol Metab 58: 298–303PubMedCrossRefGoogle Scholar
  6. 6.
    Antoni FA (1993) Vasopressinergic control of pituitary adrenocorticotropin secretion comes of age. Front Neuroendocrinol 14: 76–122PubMedCrossRefGoogle Scholar
  7. 7.
    Olsen NJ, Kovacs WJ (2002) Hormones, pregnancy, and rheumatoid arthritis. J Gend Specif Med 5: 28–37PubMedGoogle Scholar
  8. 8.
    Johnson RW, Arkins S, Dantzer R, Kelley KW (1997) Hormones, lymphohemopoietic cytokines and the neuroimmune axis. Comp Biochem Physiol A-Physiol 116: 183–201PubMedCrossRefGoogle Scholar
  9. 9.
    Barnes PJ (1998) Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clin Sci (Lond) 94: 557–572Google Scholar
  10. 10.
    Adcock IM, Ito K (2000) Molecular mechanisms of corticosteroid actions. Monaldi Arch Chest Dis 55: 256–266PubMedGoogle Scholar
  11. 11.
    DeRijk R, Michelson D, Karp B, et al. (1997) Exercise and circadian rhythm-induced variations in plasma cortisol differentially regulate interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF alpha) production in humans: high sensitivity of TNF alpha and resistance of IL-6. J Clin Endocrinol Metab 82: 2182–2191PubMedCrossRefGoogle Scholar
  12. 12.
    Elenkov IJ, Chrousos GP (1999) Stress hormones, Th1/Th2 patterns, pro/anti-inflammatory cytokines and susceptibility to disease. Trends Endocrinol Metab 10: 359–368PubMedCrossRefGoogle Scholar
  13. 13.
    Black PH (1994) Central nervous system-immune system interactions: psychoneuroendo-crinology of stress and its immune consequences. Antimicrob Agents Chemother 38: 1–6PubMedGoogle Scholar
  14. 14.
    Kin NW, Sanders VM (2006) It takes nerve to tell T and B cells what to do. J Leukocyte Biol 79: 1093–1104PubMedCrossRefGoogle Scholar
  15. 15.
    Wrona D (2006) Neural-immune interactions: an integrative view of the bidirectional relationship between the brain and immune systems. J Neuroimmunol 172: 38–58PubMedCrossRefGoogle Scholar
  16. 16.
    Romano TA, Felten SY, Olschowka JA, Felten DL (1994) Noradrenergic and peptidergic innervation of lymphoid organs in the beluga, Delphinapterus leucas: an anatomical link between the nervous and immune systems. J Morphol 221: 243–259PubMedCrossRefGoogle Scholar
  17. 17.
    Felten DL, Felten S Y, Bellinger DL, Lorton D (1992) Noradrenergic and peptidergic innervation of secondary lymphoid organs: role in experimental rheumatoid arthritis. Eur J Clin Invest 22 Suppl 1: 37–41PubMedGoogle Scholar
  18. 18.
    Bienenstock J, Croitoru K, Ernst PB, Stanisz AM (1989) Nerves and neuropeptides in the regulation of mucosal immunity. Adv Exp Med Biol 257: 19–26PubMedGoogle Scholar
  19. 19.
    Bienenstock J, Denburg J, Scicchitano R, Stead R, Perdue M, Stanisz A (1988) Role of neuropeptides, nerves and mast cells in intestinal immunity and physiology. Monogr Allergy 24: 134–143PubMedGoogle Scholar
  20. 20.
    Tracey KJ (2007) Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest 117: 289–296PubMedCrossRefGoogle Scholar
  21. 21.
    Pavlov VA, Tracey KJ (2006) Controlling inflammation: the cholinergic anti-inflammatory pathway. Biochem Soc Trans 34: 1037–1040PubMedCrossRefGoogle Scholar
  22. 22.
    Shepherd AJ, Downing JE, Miyan JA (2005) Without nerves, immunology remains incomplete in vivo veritas. Immunology 116: 145–163PubMedCrossRefGoogle Scholar
  23. 23.
    Berczi I, Chalmers IM, Nagy E, Warrington RJ (1996) The immune effects of neuropeptides. Bailliere Clin Rheumatol 10: 227–257Google Scholar
  24. 24.
    Panuncio AL, De La Pena S, Gualco G, Reissenweber N (1999) Adrenergic innervation in reactive human lymph nodes. J Anat 194 (Pt 1): 143–146PubMedCrossRefGoogle Scholar
  25. 25.
    Civantos Calzada B, Aleixandre de Artinano A (2001) Alpha-adrenoceptor subtypes. Pharmacol Res 44: 195–208PubMedCrossRefGoogle Scholar
  26. 26.
    Molenaar P (2003) The ‘state’ of beta-adrenoceptors. Brit J Pharmacol 140: 1–2CrossRefGoogle Scholar
  27. 27.
    Kavelaars A (2002) Regulated expression of alpha-1 adrenergic receptors in the immune system. Brain Behav Immun 16: 799–807PubMedCrossRefGoogle Scholar
  28. 28.
    Kavelaars A, van Der Voort CR, Heijnen CJ (1999) Adrenergic receptor subtypes in human peripheral blood lymphocytes. Hypertension 34: e5PubMedGoogle Scholar
  29. 29.
    Heijnen CJ, Kavelaars A (1999) The importance of being receptive. J Neuroimmunol 100: 197–202PubMedCrossRefGoogle Scholar
  30. 30.
    Burnstock G (1987) Mechanisms of interaction of peptide and nonpeptide vascular neurotransmitter systems. J Cardiovasc Pharmacol 10 Suppl 12: S74–81PubMedCrossRefGoogle Scholar
  31. 31.
    MacNeil BJ, Jansen AH, Greenberg AH, Nance DM (1996) Activation and selectivity of splenic sympathetic nerve electrical activity response to bacterial endotoxin. Am J Physiol 270: R264–270PubMedGoogle Scholar
  32. 32.
    Pardini BJ, Jones SB, Filkins JP (1983) Cardiac and splenic norepinephrine turnovers in endotoxic rats. Am J Physiol 245: H276–283PubMedGoogle Scholar
  33. 33.
    Kohm AP, Tang Y, Sanders VM, Jones SB (2000) Activation of antigen-specific CD4+ Th2 cells and B cells in vivo increases norepinephrine release in the spleen and bone marrow. J Immunol 165: 725–733PubMedGoogle Scholar
  34. 34.
    Madden KS, Felten S Y, Felten DL, Sundaresan PR, Livnat S (1989) Sympathetic neural modulation of the immune system. I. Depression of T cell immunity in vivo and vitro following chemical sympathectomy. Brain Behav Immun 3: 72–89PubMedCrossRefGoogle Scholar
  35. 35.
    Callahan TA, Moynihan JA (2002) Contrasting pattern of cytokines in antigen- versus mitogen-stimulated splenocyte cultures from chemically denervated mice. Brain Behav Immun 16: 764–773PubMedCrossRefGoogle Scholar
  36. 36.
    Alaniz RC, Thomas SA, Perez-Melgosa M, et al. (1999) Dopamine beta-hydroxylase deficiency impairs cellular immunity. Proc Natl Acad Sci USA 96: 2274–2278PubMedCrossRefGoogle Scholar
  37. 37.
    Swanson MA, Lee WT, Sanders VM (2001) IFN-gamma production by Th1 cells generated from naive CD4+ T cells exposed to norepinephrine. J Immunol 166: 232–240PubMedGoogle Scholar
  38. 38.
    Ramer-Quinn DS, Swanson MA, Lee WT, Sanders VM (2000) Cytokine production by naive and primary effector CD4+ T cells exposed to norepinephrine. Brain Behav Immun 14: 239–255PubMedCrossRefGoogle Scholar
  39. 39.
    Hassani H, Lucas G, Rozell B, Ernfors P (2005) Attenuation of acute experimental colitis by preventing NPY Y1 receptor signaling. Am J Physiol Gastrointest Liver Physiol 288: G550–556PubMedCrossRefGoogle Scholar
  40. 40.
    Wheway J, Mackay CR, Newton RA, et al. (2005) A fundamental bimodal role for neuropeptide Y1 receptor in the immune system. J Exp Med 202: 1527–1538PubMedCrossRefGoogle Scholar
  41. 41.
    Sanders VM, Straub RH (2002) Norepinephrine, the beta-adrenergic receptor, and immunity. Brain Behav Immun 16: 290–332PubMedCrossRefGoogle Scholar
  42. 42.
    Takahashi H, Tsuda Y, Kobayashi M, Herndon DN, Suzuki F (2004) Increased norepinephrine production associated with burn injuries results in CCL2 production and type 2 T cell generation. Burns 30: 317–321PubMedCrossRefGoogle Scholar
  43. 43.
    Takahashi H, Kobayashi M, Tsuda Y, Herndon DN, Suzuki F (2005) Contribution of the sympathetic nervous system on the burn-associated impairment of CCL3 production. Cytokine 29: 208–214PubMedCrossRefGoogle Scholar
  44. 44.
    Levite M, Chowers Y (2001) Nerve-driven immunity: neuropeptides regulate cytokine secretion of T cells and intestinal epithelial cells in a direct, powerful and contextual manner. Ann Oncol 12 Suppl 2: S19–25PubMedCrossRefGoogle Scholar
  45. 45.
    Sanders VM (1995) The role of adrenoceptor-mediated signals in the modulation of lymphocyte function. Adv Neuroimmunol 5: 283–298PubMedCrossRefGoogle Scholar
  46. 46.
    Sanders VM, Baker RA, Ramer-Quinn DS, Kasprowicz DJ, Fuchs BA, Street NE (1997) Differential expression of the beta2-adrenergic receptor by Th1 and Th2 clones: implications for cytokine production and B cell help. J Immunol 158: 4200–4210PubMedGoogle Scholar
  47. 47.
    Fearon DT, Locksley RM (1996) The instructive role of innate immunity in the acquired immune response. Science 272: 50–53PubMedCrossRefGoogle Scholar
  48. 48.
    Coqueret O, Dugas B, Mencia-Huerta JM, Braquet P (1995) Regulation of IgE production from human mononuclear cells by beta 2-adrenoceptor agonists. Clin Exp Allergy 25: 304–311PubMedCrossRefGoogle Scholar
  49. 49.
    Irwin M (1994) Stress-induced immune suppression: role of brain corticotropin releasing hormone and autonomic nervous system mechanisms. Adv Neuroimmunol 4: 29–47PubMedCrossRefGoogle Scholar
  50. 50.
    Zurier RB, Weissmann G, Hoffstein S, Kammerman S, Tai HH (1974) Mechanisms of lysosomal enzyme release from human leukocytes. II. Effects of cAMP and cGMP, autonomic agonists, and agents which affect microtubule function. J Clin Invest 53: 297–309PubMedCrossRefGoogle Scholar
  51. 51.
    Weiss M, Schneider EM, Tarnow J, et al. (1996) Is inhibition of oxygen radical production of neutrophils by sympathomimetics mediated via beta-2 adrenoceptors? J Pharmacol Exp Ther 278: 1105–1113PubMedGoogle Scholar
  52. 52.
    Barnett CC, Jr., Moore EE, Partrick DA, Silliman CC (1997) Beta-adrenergic stimulation down-regulates neutrophil priming for superoxide generation, but not elastase release. J Surg Res 70: 166–170PubMedCrossRefGoogle Scholar
  53. 53.
    Maestroni GJ (2005) Adrenergic modulation of dendritic cells function: relevance for the immune homeostasis. Curr Neurovasc Res 2: 169–173PubMedCrossRefGoogle Scholar
  54. 54.
    Lubahn CL, Schaller JA, Bellinger DL, Sweeney S, Lorton D (2004) The importance of timing of adrenergic drug delivery in relation to the induction and onset of adjuvant-induced arthritis. Brain Behav Immun 18: 563–571PubMedCrossRefGoogle Scholar
  55. 55.
    Lorton D, Lubahn C, Klein N, Schaller J, Bellinger DL (1999) Dual role for noradrenergic innervation of lymphoid tissue and arthritic joints in adjuvant-induced arthritis. Brain Behav Immun 13: 315–334PubMedCrossRefGoogle Scholar
  56. 56.
    Belvisi MG (2003) Sensory nerves and airway inflammation: role of A delta and C-fibres. Pulm Pharmacol Ther 16: 1–7PubMedCrossRefGoogle Scholar
  57. 57.
    Darsow U, Ring J (2001) Neuroimmune interactions in the skin. Curr Opin Allergy Clin Immunol 1: 435–439PubMedGoogle Scholar
  58. 58.
    Felten DL, Felten S Y, Carlson SL, Olschowka JA, Livnat S (1985) Noradrenergic and peptidergic innervation of lymphoid tissue. J Immunol 135: 755s–765sPubMedGoogle Scholar
  59. 59.
    Levite M (1998) Neuropeptides, by direct interaction with T cells, induce cytokine secretion and break the commitment to a distinct T helper phenotype. Proc Natl Acad Sci USA 95: 12544–12549PubMedCrossRefGoogle Scholar
  60. 60.
    Gerard NP, Garraway LA, Eddy RL, Jr., et al. (1991) Human substance P receptor (NK-1): organization of the gene, chromosome localization, and functional expression of cDNA clones. Biochemistry 30: 10640–10646PubMedCrossRefGoogle Scholar
  61. 61.
    Mousli M, Bronner C, Landry Y, Bockaert J, Rouot B (1990) Direct activation of GTP-binding regulatory proteins (G-proteins) by substance P and compound 48/80. FEBS Lett 259: 260–262PubMedCrossRefGoogle Scholar
  62. 62.
    Lee HR, Ho WZ, Douglas SD (1994) Substance P augments tumor necrosis factor release in human monocyte-derived macrophages. Clin Diagn Lab Immunol 1: 419–423PubMedGoogle Scholar
  63. 63.
    Delgado AV, McManus AT, Chambers JP (2003) Production of tumor necrosis factor-alpha, interleukin 1-beta, interleukin 2, and interleukin 6 by rat leukocyte subpopulations after exposure to substance P. Neuropeptides 37: 355–361PubMedCrossRefGoogle Scholar
  64. 64.
    Tomioka M, Goto T, Lee TD, Bienenstock J, Befus AD (1989) Isolation and characterization of lung mast cells from rats with bleomycin-induced pulmonary fibrosis. Immunology 66: 439–444PubMedGoogle Scholar
  65. 65.
    van der Kleij HP, Ma D, Redegeld FA, Kraneveld AD, Nijkamp FP, Bienenstock J (2003) Functional expression of neurokinin 1 receptors on mast cells induced by IL-4 and stem cell factor. J Immunol 171: 2074–2079PubMedGoogle Scholar
  66. 66.
    Stucchi AF, Shofer S, Leeman S, et al. (2000) NK-1 antagonist reduces colonic inflammation and oxidative stress in dextran sulfate-induced colitis in rats. Am J Physiol Gastrointest Liver Physiol 279: G1298–1306PubMedGoogle Scholar
  67. 67.
    Nessler S, Stadelmann C, Bittner A, et al. (2006) Suppression of autoimmune encephalomyelitis by a neurokinin-1 receptor antagonist—a putative role for substance P in CNS inflammation. J Neuroimmunol 179: 1–8PubMedCrossRefGoogle Scholar
  68. 68.
    Stanisz AM, Befus D, Bienenstock J (1986) Differential effects of vasoactive intestinal peptide, substance P, and somatostatin on immunoglobulin synthesis and proliferations by lymphocytes from Peyer's patches, mesenteric lymph nodes, and spleen. J Immunol 136: 152–156PubMedGoogle Scholar
  69. 69.
    Hart R, Dancygier H, Wagner F, Lersch C, Classen M (1990) Effect of substance P on immunoglobulin and interferon-gamma secretion by cultured human duodenal mucosa. Immunol Lett 23: 199–204PubMedCrossRefGoogle Scholar
  70. 70.
    Pascual DW, McGhee JR, Kiyono H, Bost KL (1991) Neuroimmune modulation of lymphocyte function—I. Substance P enhances immunoglobulin synthesis in lipopolysaccharide activated murine splenic B cell cultures. Int Immunol 3: 1223–1229Google Scholar
  71. 71.
    Pascual DW, Beagley KW, Kiyono H, McGhee JR (1995) Substance P promotes Peyer's patch and splenic B cell differentiation. Adv Exp Med Biol 371A: 55–59PubMedGoogle Scholar
  72. 72.
    Delgado M (2003) VIP: a very important peptide in T helper differentiation. Trends Immunol 24: 221–224PubMedCrossRefGoogle Scholar
  73. 73.
    Foey AD, Field S, Ahmed S, et al. (2003) Impact of VIP and cAMP on the regulation of TNF-alpha and IL-10 production: implications for rheumatoid arthritis. Arthritis Res Ther 5: R317–328PubMedCrossRefGoogle Scholar
  74. 74.
    Gomariz R, Leceta J, Martinez C, Abad C, Ganea D, Delgado M (2000) Anti-inflammatory actions of VIP/PACAP. Role in endotoxemia. Ann N Y Acad Sci 921: 284–288PubMedCrossRefGoogle Scholar
  75. 75.
    Delgado M, Leceta J, Sun W, Gomariz RP, Ganea D (2000) VIP and PACAP induce shift to a Th2 response by upregulating B7.2 expression. Ann N Y Acad Sci 921: 68–78PubMedGoogle Scholar
  76. 76.
    Wang H Y, Jiang X, Gozes I, Fridkin M, Brenneman DE, Ganea D (1999) Vasoactive intestinal peptide inhibits cytokine production in T lymphocytes through cAMP-dependent and cAMP-independent mechanisms. Regul Peptides 84: 55–67CrossRefGoogle Scholar
  77. 77.
    Voice JK, Dorsam G, Chan RC, Grinninger C, Kong Y, Goetzl EJ (2002) Immunoeffector and immunoregulatory activities of vasoactive intestinal peptide. Regul Peptides 109: 199–208CrossRefGoogle Scholar
  78. 78.
    Delgado M, Reduta A, Sharma V, Ganea D (2004) VIP/PACAP oppositely affects immature and mature dendritic cell expression of CD80/CD86 and the stimulatory activity for CD4(+) T cells. J Leukocyte Biol 75: 1122–1130PubMedCrossRefGoogle Scholar
  79. 79.
    Ganea D, Delgado M (2001) Neuropeptides as modulators of macrophage functions. Regulation of cytokine production and antigen presentation by VIP and PACAP. Arch Immunol Ther Exp (Warsz) 49: 101–110Google Scholar
  80. 80.
    Delgado M, Gonzalez-Rey E, Ganea D (2006) Vasoactive intestinal peptide: the dendritic cell —> regulatory T cell axis. Ann N Y Acad Sci 1070: 233–238PubMedCrossRefGoogle Scholar
  81. 81.
    Delgado M, Chorny A, Gonzalez-Rey E, Ganea D (2005) Vasoactive intestinal peptide generates CD4+ CD25+ regulatory T cells in vivo. J Leukocyte Biol 78: 1327–1338PubMedCrossRefGoogle Scholar
  82. 82.
    Chorny A, Gonzalez-Rey E, Fernandez-Martin A, Ganea D, Delgado M (2006) Vasoactive intestinal peptide induces regulatory dendritic cells that prevent acute graft-versus-host disease while maintaining the graft-versus-tumor response. Blood 107: 3787–3794PubMedCrossRefGoogle Scholar
  83. 83.
    Boirivant M, Fais S, Annibale B, Agostini D, Delle Fave G, Pallone F (1994) Vasoactive intestinal polypeptide modulates the in vitro immunoglobulin A production by intestinal lamina propria lymphocytes. Gastroenterology 106: 576–582PubMedGoogle Scholar
  84. 84.
    Ohkubo N, Miura S, Serizawa H, et al. (1994) In vivo effect of chronic administration of vasoactive intestinal peptide on gut-associated lymphoid tissues in rats. Regul Peptides 50: 127–135CrossRefGoogle Scholar
  85. 85.
    Fujieda S, Waschek JA, Zhang K, Saxon A (1996) Vasoactive intestinal peptide induces S(alpha)/S(mu) switch circular DNA in human B cells. J Clin Invest 98: 1527–1532PubMedCrossRefGoogle Scholar
  86. 86.
    Kimata H, Fujimoto M (1995) Induction of IgA1 and IgA2 production in immature human fetal B cells and pre-B cells by vasoactive intestinal peptide. Blood 85: 2098–2104PubMedGoogle Scholar
  87. 87.
    Wang F, Millet I, Bottomly K, Vignery A (1992) Calcitonin gene-related peptide inhibits interleukin 2 production by murine T lymphocytes. J Biol Chem 267: 21052–21057PubMedGoogle Scholar
  88. 88.
    Fox FE, Kubin M, Cassin M, et al. (1997) Calcitonin gene-related peptide inhibits proliferation and antigen presentation by human peripheral blood mononuclear cells: effects on B7, interleukin 10, and interleukin 12. J Invest Dermatol 108: 43–48PubMedCrossRefGoogle Scholar
  89. 89.
    Umeda Y, Takamiya M, Yoshizaki H, Arisawa M (1988) Inhibition of mitogen-stimulated T lymphocyte proliferation by calcitonin gene-related peptide. Biochem Biophys Res Commun 154: 227–235PubMedCrossRefGoogle Scholar
  90. 90.
    Fernandez S, Knopf MA, McGillis JP (2000) Calcitonin-gene related peptide (CGRP) inhibits interleukin-7-induced pre-B cell colony formation. J Leukocyte Biol 67: 669–676PubMedGoogle Scholar
  91. 91.
    Hosoi J, Murphy GF, Egan CL, et al. (1993) Regulation of Langerhans cell function by nerves containing calcitonin gene-related peptide. Nature 363: 159–163PubMedCrossRefGoogle Scholar
  92. 92.
    Asahina A, Hosoi J, Beissert S, Stratigos A, Granstein RD (1995) Inhibition of the induction of delayed-type and contact hypersensitivity by calcitonin gene-related peptide. J Immunol 154: 3056–3061PubMedGoogle Scholar
  93. 93.
    Carucci JA, Ignatius R, Wei Y, et al. (2000) Calcitonin gene-related peptide decreases expression of HLA-DR and CD86 by human dendritic cells and dampens dendritic cell-driven T cell-proliferative responses via the type I calcitonin gene-related peptide receptor. J Immunol 164: 3494–3499PubMedGoogle Scholar
  94. 94.
    Bienenstock J, Befus D (1984) Gut- and bronchus-associated lymphoid tissue. Am J Anat 170: 437–445PubMedCrossRefGoogle Scholar
  95. 95.
    Nohr D, Weihe E (1991) The neuroimmune link in the bronchus-associated lymphoid tissue (BALT) of cat and rat: peptides and neural markers. Brain Behav Immun 5: 84–101PubMedCrossRefGoogle Scholar
  96. 96.
    Inoue N, Magari S, Sakanaka M (1990) Distribution of peptidergic nerve fibers in rat bronchus-associated lymphoid tissue: light microscopic observations. Lymphology 23: 155–160PubMedGoogle Scholar
  97. 97.
    O'Dorisio MS (1988) Neuropeptide modulation of the immune response in gut associated lymphoid tissue. Int J Neurosci 38: 189–198PubMedCrossRefGoogle Scholar
  98. 98.
    Veres TZ, Rochlitzer S, Shevchenko M, et al. (2007) Spatial interactions between dendritic cells and sensory nerves in allergic airway inflammation. Am J Respir Cell Mol Biol 37: 553–561PubMedCrossRefGoogle Scholar
  99. 99.
    Kowalski ML, Didier A, Lundgren JD, Igarashi Y, Kaliner MA (1997) Role of sensory innervation and mast cells in neurogenic plasma protein exudation into the airway lumen. Respirology 2: 267–274PubMedCrossRefGoogle Scholar
  100. 100.
    Baluk P (1997) Neurogenic inflammation in skin and airways. J Invest Dermatol Symp Proc 2: 76–81Google Scholar
  101. 101.
    Alving K (1991) Airways vasodilatation in the immediate allergic reaction. Involvement of inflammatory mediators and sensory nerves. Acta Physiol Scand Suppl 597: 1–64Google Scholar
  102. 102.
    Piedimonte G, Hegele RG, Auais A (2004) Persistent airway inflammation after resolution of respiratory syncytial virus infection in rats. Pediatr Res 55: 657–665PubMedCrossRefGoogle Scholar
  103. 103.
    Piedimonte G (2003) Contribution of neuroimmune mechanisms to airway inflammation and remodeling during and after respiratory syncytial virus infection. Pediatr Infect Dis J 22: S66–74; discussion S74–65PubMedCrossRefGoogle Scholar
  104. 104.
    Dakhama A, Park JW, Taube C, et al. (2005) Alteration of airway neuropeptide expression and development of airway hyperresponsiveness following respiratory syncytial virus infection. Am J Physiol Lung Cell Mol Physiol 288: L761–770PubMedCrossRefGoogle Scholar
  105. 105.
    Kay AB, Ali FR, Heaney LG, et al. (2007) Airway expression of calcitonin gene-related peptide in T-cell peptide-induced late asthmatic reactions in atopics. Allergy 62: 495–503PubMedCrossRefGoogle Scholar
  106. 106.
    Borovikova LV, Ivanova S, Zhang M, et al. (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405: 458–462PubMedCrossRefGoogle Scholar
  107. 107.
    Bernik TR, Friedman SG, Ochani M, et al. (2002) Pharmacological stimulation of the cholinergic antiinflammatory pathway. J Exp Med 195: 781–788PubMedCrossRefGoogle Scholar
  108. 108.
    Pavlov VA, Ochani M, Yang LH, et al. (2007) Selective alpha7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis. Crit Care Med 35: 1139–1144PubMedCrossRefGoogle Scholar
  109. 109.
    Pavlov VA, Tracey KJ (2005) The cholinergic anti-inflammatory pathway. Brain Behav Immun 19: 493–499PubMedCrossRefGoogle Scholar
  110. 110.
    Wang H, Yu M, Ochani M, et al. (2003) Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421: 384–388PubMedCrossRefGoogle Scholar
  111. 111.
    Borovikova LV, Ivanova S, Nardi D, et al. (2000) Role of vagus nerve signaling in CNI-1493-mediated suppression of acute inflammation. Auton Neurosci 85: 141–147PubMedCrossRefGoogle Scholar
  112. 112.
    Arredondo J, Nguyen VT, Chernyavsky AI, et al. (2003) Functional role of alpha7 nicotinic receptor in physiological control of cutaneous homeostasis. Life Sci 72: 2063–2067PubMedCrossRefGoogle Scholar
  113. 113.
    Saeed RW, Varma S, Peng-Nemeroff T, et al. (2005) Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation. J Exp Med 201: 1113–1123PubMedCrossRefGoogle Scholar
  114. 114.
    Kawashima K, Yoshikawa K, Fujii YX, Moriwaki Y, Misawa H (2007) Expression and function of genes encoding cholinergic components in murine immune cells. Life Sci 80: 2314–2319PubMedCrossRefGoogle Scholar
  115. 115.
    Ghia JE, Blennerhassett P, Kumar-Ondiveeran H, Verdu EF, Collins SM (2006) The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model. Gastroenterology 131: 1122–1130PubMedCrossRefGoogle Scholar
  116. 116.
    Huston JM, Ochani M, Rosas-Ballina M, et al. (2006) Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J Exp Med 203: 1623–1628PubMedCrossRefGoogle Scholar
  117. 117.
    Luyer MD, Greve JW, Hadfoune M, Jacobs JA, Dejong CH, Buurman WA (2005) Nutritional stimulation of cholecystokinin receptors inhibits inflammation via the vagus nerve. J Exp Med 202: 1023–1029PubMedCrossRefGoogle Scholar
  118. 118.
    van der Kleij HP, Forsythe P, Bienenstock J (2007) The vagus nerve is involved in constitutive downregulation of acute and chronic intestinal inflammation through the alpha7 nicotinic receptor pathway. Gastroenterology 132: A-51Google Scholar
  119. 119.
    George MS, Nahas Z, Borckardt JJ, et al. (2007) Vagus nerve stimulation for the treatment of depression and other neuropsychiatric disorders. Expert Rev Neurother 7: 63–74PubMedCrossRefGoogle Scholar
  120. 120.
    Ader R, Cohen N (1975) Behaviorally conditioned immunosuppression. Psychosom Med 37: 333–340PubMedGoogle Scholar
  121. 121.
    Goebel MU, Trebst AE, Steiner J, et al. (2002) Behavioral conditioning of immunosuppres-sion is possible in humans. FASEB J 16: 1869–1873PubMedCrossRefGoogle Scholar
  122. 122.
    Djuric VJ, Markovic BM, Lazarevic M, Jankovic BD (1988) Anaphylactic shock-induced conditioned taste aversion. II. Correlation between taste aversion and indicators of anaphy-lactic shock. Brain Behav Immun 2: 24–31PubMedCrossRefGoogle Scholar
  123. 123.
    Ader R (1987) Conditioned immune responses: adrenocortical influences. Prog Brain Res 72: 79–90PubMedCrossRefGoogle Scholar
  124. 124.
    Russell M, Dark KA, Cummins RW, Ellman G, Callaway E, Peeke HV (1984) Learned histamine release. Science 225: 733–734PubMedCrossRefGoogle Scholar
  125. 125.
    Gorczynski RM, Kennedy M (1984) Associative learning and regulation of immune responses. Prog Neuropsychopharmacol Biol Psychiatry 8: 593–600PubMedCrossRefGoogle Scholar
  126. 126.
    Ader R, Cohen N (1982) Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus. Science 215: 1534–1536PubMedCrossRefGoogle Scholar
  127. 127.
    Costa-Pinto FA, Basso AS, Britto LR, Malucelli BE, Russo M (2005) Avoidance behavior and neural correlates of allergen exposure in a murine model of asthma. Brain Behav Immun 19: 52–60PubMedCrossRefGoogle Scholar
  128. 128.
    Ader R, Kelly K, Moynihan JA, Grota LJ, Cohen N (1993) Conditioned enhancement of antibody production using antigen as the unconditioned stimulus. Brain Behav Immun 7: 334–343PubMedCrossRefGoogle Scholar
  129. 129.
    Exton MS, Herklotz J, Westermann J, Schedlowski M (2001) Conditioning in the rat: an in vivo model to investigate the molecular mechanisms and clinical implications of brainimmune communication. Immunol Rev 184: 226–235PubMedCrossRefGoogle Scholar
  130. 130.
    Hiramoto RN, Rogers CF, Demissie S, et al. (1997) Psychoneuroendocrine immunology: site of recognition, learning and memory in the immune system and the brain. Int J Neurosci 92: 259–285PubMedGoogle Scholar
  131. 131.
    Janz LJ, Green-Johnson J, Murray L, et al. (1996) Pavlovian conditioning of LPS-induced responses: effects on corticosterone, splenic NE, and IL-2 production. Physiol Behav 59: 1103–1109PubMedCrossRefGoogle Scholar
  132. 132.
    Irie M, Nagata S, Endo Y (2004) Diazepam attenuates conditioned histamine release in guinea pigs. Int J Psychophysiol 51: 231–238PubMedCrossRefGoogle Scholar
  133. 133.
    Irie M, Nagata S, Endo Y (2002) Fasting stress exacerbates classical conditioned histamine release in guinea pigs. Life Sci 72: 689–698PubMedCrossRefGoogle Scholar
  134. 134.
    MacQueen G, Marshall J, Perdue M, Siegel S, Bienenstock J (1989) Pavlovian conditioning of rat mucosal mast cells to secrete rat mast cell protease II. Science 243: 83–85PubMedCrossRefGoogle Scholar
  135. 135.
    Gauci M, Husband AJ, Saxarra H, King MG (1994) Pavlovian conditioning of nasal tryptase release in human subjects with allergic rhinitis. Physiol Behav 55: 823–825PubMedCrossRefGoogle Scholar
  136. 136.
    Castes M, Hagel I, Palenque M, Canelones P, Corao A, Lynch NR (1998) Classic conditioning and placebo effects in the bronchodilator response of asthmatic children. Neuroimmunomodulation 5: 70Google Scholar
  137. 137.
    Pacheco-Lopez G, Niemi MB, Kou W, Harting M, Fandrey J, Schedlowski M (2005) Neural substrates for behaviorally conditioned immunosuppression in the rat. J Neurosci 25: 2330–2337PubMedCrossRefGoogle Scholar
  138. 138.
    Goldstein DS, Kopin IJ (2007) Evolution of concepts of stress. Stress 10: 109–120PubMedCrossRefGoogle Scholar
  139. 139.
    Dhabhar FS, Satoskar AR, Bluethmann H, David JR, McEwen BS (2000) Stress-induced enhancement of skin immune function: A role for gamma interferon. Proc Natl Acad Sci USA 97: 2846–2851PubMedCrossRefGoogle Scholar
  140. 140.
    Dhabhar FS, McEwen BS (1999) Enhancing versus suppressive effects of stress hormones on skin immune function. Proc Natl Acad Sci USA 96: 1059–1064PubMedCrossRefGoogle Scholar
  141. 141.
    Dhabhar FS, McEwen BS (1996) Stress-induced enhancement of antigen-specific cell-mediated immunity. J Immunol 156: 2608–2615PubMedGoogle Scholar
  142. 142.
    Dhabhar FS, McEwen BS (1997) Acute stress enhances while chronic stress suppresses cell-mediated immunity in vivo: a potential role for leukocyte trafficking. Brain Behav Immun 11: 286–306PubMedCrossRefGoogle Scholar
  143. 143.
    Pavlov VA, Wang H, Czura CJ, Friedman SG, Tracey KJ (2003) The cholinergic antiinflammatory pathway: a missing link in neuroimmunomodulation. Mol Med 9: 125–134PubMedGoogle Scholar
  144. 144.
    Janszky I, Ericson M, Lekander M, et al. (2004) Inflammatory markers and heart rate variability in women with coronary heart disease. J Intern Med 256: 421–428PubMedCrossRefGoogle Scholar
  145. 145.
    Krantz DS, Sheps DS, Carney RM, Natelson BH (2000) Effects of mental stress in patients with coronary artery disease: evidence and clinical implications. JAMA 283: 1800–1802PubMedCrossRefGoogle Scholar
  146. 146.
    Vettore M V, Leao AT, Monteiro Da Silva AM, Quintanilha RS, Lamarca GA (2003) The relationship of stress and anxiety with chronic periodontitis. J Clin Periodontol 30: 394–402PubMedCrossRefGoogle Scholar
  147. 147.
    Mawdsley JE, Rampton DS (2005) Psychological stress in IBD: new insights into pathogenic and therapeutic implications. Gut 54: 1481–1491PubMedCrossRefGoogle Scholar
  148. 148.
    Levenstein S, Prantera C, Varvo V, et al. (2000) Stress and exacerbation in ulcerative colitis: a prospective study of patients enrolled in remission. Am J Gastroenterol 95: 1213–1220PubMedCrossRefGoogle Scholar
  149. 149.
    Martinelli V (2000) Trauma, stress and multiple sclerosis. Neurol Sci 21: S849–852PubMedCrossRefGoogle Scholar
  150. 150.
    Mizokami T, Wu Li A, El-Kaissi S, Wall JR (2004) Stress and thyroid autoimmunity. Thyroid 14: 1047–1055PubMedCrossRefGoogle Scholar
  151. 151.
    Potter PT, Zautra AJ (1997) Stressful life events' effects on rheumatoid arthritis disease activity. J Consult Clin Psychol 65: 319–323PubMedCrossRefGoogle Scholar
  152. 152.
    Liu LY, Coe CL, Swenson CA, Kelly EA, Kita H, Busse WW (2002) School examinations enhance airway inflammation to antigen challenge. Am J Respir Crit Care Med 165: 1062–1067PubMedGoogle Scholar
  153. 153.
    Rietveld S, van Beest I, Everaerd W (1999) Stress-induced breathlessness in asthma. Psychol Med 29: 1359–1366PubMedCrossRefGoogle Scholar
  154. 154.
    Koh KB, Hong CS (1993) The relationship of stress with serum IgE level in patients with bronchial asthma. Yonsei Med J 34: 166–174PubMedGoogle Scholar
  155. 155.
    McQuaid EL, Fritz GK, Nassau JH, Lilly MK, Mansell A, Klein RB (2000) Stress and airway resistance in children with asthma. J Psychosom Res 49: 239–245PubMedCrossRefGoogle Scholar
  156. 156.
    Joachim RA, Quarcoo D, Arck PC, Herz U, Renz H, Klapp BF (2003) Stress enhances airway reactivity and airway inflammation in an animal model of allergic bronchial asthma. Psychosom Med 65: 811–815PubMedCrossRefGoogle Scholar
  157. 157.
    Forsythe P, Ebeling C, Gordon JR, Befus AD, Vliagoftis H (2004) Opposing effects of short-and long-term stress on airway inflammation. Am J Respir Crit Care Med 169: 220–226PubMedCrossRefGoogle Scholar
  158. 158.
    Okuyama K, Ohwada K, Sakurada S, et al. (2007) The distinctive effects of acute and chronic psychological stress on airway inflammation in a murine model of allergic asthma. Allergol Int 56: 29–35PubMedCrossRefGoogle Scholar
  159. 159.
    Portela Cde P, Tiberio Ide F, Leick-Maldonado EA, Martins MA, Palermo-Neto J (2002) Effects of diazepam and stress on lung inflammatory response in OVA-sensitized rats. Am J Physiol Lung Cell Mol Physiol 282: L1289–1295PubMedGoogle Scholar
  160. 160.
    Tohda Y, Nanbu Y, Tanaka A, Kubo H, Fukuoka M, Nakajima S (1998) Role of substance P in increased airway hypersensitivity following induced stress in a guinea pig asthma model. J Investig Allergol Clin Immunol 8: 340–345PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Paul Forsythe
    • 1
  • John Bienenstock
    • 1
  1. 1.The Brain-Body Institute and Department of Pathology and Molecular MedicineMcMaster University, and St. Joseph's HealthcareHamiltonCanada

Personalised recommendations