Archives of Physical Medicine and Rehabilitation
Volume 88, Issue 11 , Pages 1384-1393 , November 2007

Clinical Correlates of Elevated Serum Concentrations of Cytokines and Autoantibodies in Patients With Spinal Cord Injury

  • Andrew L. Davies, MSc

      Affiliations

    • Graduate Program in Neuroscience, London, ON, Canada
    • University of Western Ontario, London, ON, Canada.
    • ,
  • Keith C. Hayes, PhD

      Affiliations

    • Department of Physical Medicine & Rehabilitation, London, ON, Canada
    • Lawson Health Research Institute, London, ON, Canada
    • University of Western Ontario, London, ON, Canada.
    • Corresponding Author InformationReprint requests to Keith C. Hayes, PhD, Parkwood Hospital/SJHC, 801 Commissioners Rd E, London, ON N6C 5J1, Canada
    • ,
  • Gregory A. Dekaban, PhD

      Affiliations

    • Department of Microbiology and Immunology, London, ON, Canada
    • Biotherapeutics Research Group, Robarts Research Institute, London, ON, Canada
    • University of Western Ontario, London, ON, Canada.

References 

  1. Yang L, Blumbergs PC, Jones NR, Manavis J, Sarvestani GT, Ghabriel MN. Early expression and cellular localization of proinflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in human traumatic spinal cord injury. Spine. 2004;29:966–971
  2. Kliesch WF, Cruse JM, Lewis RE, Bishop GR, Brackin B, Lampton JA. Restoration of depressed immune function in spinal cord injury patients receiving rehabilitation therapy. Paraplegia. 1996;34:82–90
  3. Cruse JM, Lewis RE, Roe DL, et al. Facilitation of immune function, healing of pressure ulcers, and nutritional status in spinal cord injury patients. Exp Mol Pathol. 2000;68:38–54
  4. Cruse JM, Keith JC, Bryant ML, Lewis RE. Immune system-neuroendocrine dysregulation in spinal cord injury. Immunol Res. 1996;15:306–314
  5. Cruse JM, Lewis RE, Bishop GR, et al. Adhesion molecules and wound healing in spinal cord injury. Pathobiology. 1996;64:193–197
  6. Cruse JM, Wang H, Lewis RE, et al. Cellular and molecular alterations in spinal cord injury patients with pressure ulcers: a preliminary report. Exp Mol Pathol. 2002;72:124–131
  7. Scivoletto G, Fuoco U, Morganti B, Cosentino E, Molinari M. Pressure sores and blood and serum dysmetabolism in spinal cord injury patients. Spinal Cord. 2004;42:473–476
  8. Norenberg MD, Smith J, Marcillo A. The pathology of human spinal cord injury: defining the problems. J Neurotrauma. 2004;21:429–440
  9. Hausmann ON. Post-traumatic inflammation following spinal cord injury. Spinal Cord. 2003;41:369–378
  10. Cruse JM, Lewis RE, Bishop GR, Kliesch WF, Gaitan E. Neuroendocrine-immune interactions associated with loss and restoration of immune system function in spinal cord injury and stroke patients. Immunol Res. 1992;11:104–116
  11. Cruse JM, Lewis RE, Bishop GR, Kliesch WF, Gaitan E, Britt R. Decreased immune reactivity and neuroendocrine alterations related to chronic stress in spinal cord injury and stroke patients. Pathobiology. 1993;61:183–192
  12. Iversen PO, Hjeltnes N, Holm B, et al. Depressed immunity and impaired proliferation of hematopoietic progenitor cells in patients with complete spinal cord injury. Blood. 2000;96:2081–2083
  13. Aziz N, Nishanian P, Fahey JL. Levels of cytokines and immune activation markers in plasma in human immunodeficiency virus infection: quality control procedures. Clin Diagn Lab Immunol. 1998;5:755–761
  14. Kowalczyk D. [Cytokines in children with immunodeficiencies] [Polish]. Folia Med Cracov. 1999;40:5–97
  15. Gurram M, Chirmule N, Wang XP, Ponugoti N, Pahwa S. Increased spontaneous secretion of interleukin 6 and tumor necrosis factor alpha by peripheral blood lymphocytes of human immunodeficiency virus-infected children. Pediatr Infect Dis J. 1994;13:496–501
  16. Maury CP, Lahdevirta J. Correlation of serum cytokine levels with haematological abnormalities in human immunodeficiency virus infection. J Intern Med. 1990;227:253–257
  17. Hayes KC, Hull TC, Delaney GA, et al. Elevated serum titers of proinflammatory cytokines and CNS autoantibodies in patients with chronic spinal cord injury. J Neurotrauma. 2002;19:753–761
  18. Manns PJ, McCubbin JA, Williams DP. Fitness, inflammation, and the metabolic syndrome in men with paraplegia. Arch Phys Med Rehabil. 2005;86:1176–1181
  19. Segal JL. Are cytokines pathogenic factors in the physiologic and metabolic sequelae of spinal cord injury?. [editorial] J Am Paraplegia Soc. 1992;15:209–210
  20. Segal JL, Gonzales E, Yousefi S, Jamshidipour L, Brunnemann SR. Circulating levels of IL-2R, ICAM-1, and IL-6 in spinal cord injuries. Arch Phys Med Rehabil. 1997;78:44–47
  21. Rebhun J, Botvin J. Complement elevation in spinal cord injury. Ann Allergy. 1980;44:287–288
  22. Rebhun J, Madorsky JG, Glovsky MM. Proteins of the complement system and acute phase reactants in sera of patients with spinal cord injury. Ann Allergy. 1991;66:335–338
  23. Frost F, Roach MJ, Kushner I, Schreiber P. Inflammatory C-reactive protein and cytokine levels in asymptomatic people with chronic spinal cord injury. Arch Phys Med Rehabil. 2005;86:312–317
  24. Dripps DJ, Brandhuber BJ, Thompson RC, Eisenberg SP. Interleukin-1 (IL-1) receptor antagonist binds to the 80-kDa IL-1 receptor but does not initiate IL-1 signal transduction. J Biol Chem. 1991;266:10331–10336
  25. Loscher CE, Mills KH, Lynch MA. Interleukin-1 receptor antagonist exerts agonist activity in the hippocampus independent of the interleukin-1 type I receptor. J Neuroimmunol. 2003;137:117–124
  26. Kuziel WA, Greene WC. Interleukin-2 and the IL-2 receptor: new insights into structure and function. J Invest Dermatol. 1990;94:27S–32S
  27. Malek TR. The main function of IL-2 is to promote the development of T regulatory cells. J Leukoc Biol. 2003;74:961–965
  28. Aggarwal BB. Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol. 2003;3:745–756
  29. Davies AL, Hayes KC, Shi R. Recombinant human TNFalpha induces concentration-dependent and reversible alterations in the electrophysiological properties of axons in mammalian spinal cord. J Neurotrauma. 2006;23:1261–1273
  30. Koller H, Siebler M, Hartung HP. Immunologically induced electrophysiological dysfunction: implications for inflammatory diseases of the CNS and PNS. Prog Neurobiol. 1997;52:1–26
  31. Koller H. TNF alpha in cerebrospinal fluid of meningitis patients reduces astrocytes membrane potential. J Neuroimmunol. 1997;76:185–188
  32. Naka T, Nishimoto N, Kishimoto T. The paradigm of IL-6: from basic science to medicine. Arthritis Res. 2002;4(Suppl 3):S233–S242
  33. De Jongh RF, Vissers KC, Meert TF, Booij LH, De Deyne CS, Heylen RJ. The role of interleukin-6 in nociception and pain. Anesth Analg. 2003;96:1096–1103
  34. Sommer C, Kress M. Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci Lett. 2004;361:184–187
  35. Lacroix S, Chang L, Rose-John S, Tuszynski MH. Delivery of hyper-interleukin-6 to the injured spinal cord increases neutrophil and macrophage infiltration and inhibits axonal growth. J Comp Neurol. 2002;454:213–228
  36. Sredni-Kenigsbuch D. TH1/TH2 cytokines in the central nervous system. Int J Neurosci. 2002;112:665–703
  37. Banks WA, Kastin AJ, Broadwell RD. Passage of cytokines across the blood-brain barrier. Neuroimmunomodulation. 1995;2:241–248
  38. Pan W, Zhang L, Liao J, Csernus B, Kastin AJ. Selective increase in TNF alpha permeation across the blood-spinal cord barrier after SCI. J Neuroimmunol. 2003;134:111–117
  39. Hayes KC, Davies AL, Ashki N, Kramer JK, Close TE. Re (Ditunno JF, Little JW, Tessler A, Burns AS: Spinal shock revisited: a four-phase model). Spinal Cord. 2004;42:383–395Spinal Cord 2007;45:395-6
  40. Weber F, Rudel R, Aulkemeyer P, Brinkmeier H. Anti-GM1 antibodies can block neuronal voltage-gated sodium channels. Muscle Nerve. 2000;23:1414–1420
  41. Siddall PJ, Taylor DA, Cousins MJ. Classification of pain following spinal cord injury. Spinal Cord. 1997;35:69–75
  42. McCaffery M, Pasero C. Pain clinic manual. 2nd ed.. St. Louis: Mosby; 1999;
  43. Lin VW, Cardenas DD. Spinal cord medicine principles and practice. New York: Demos; 2003;
  44. Steensberg A, Fischer CP, Keller C, Møller K, Pedersen BK. IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. Am J Physiol Endocrinol Metab. 2003;285:E433–E437
  45. Romagnani S. The Th1/Th2 paradigm. Immunol Today. 1997;18:263–266
  46. Skowera A, Hotopf M, Sawicka E, et al. Cellular immune activation in Gulf War veterans. J Clin Immunol. 2004;24:66–73
  47. Segal JL, Brunnemann SR. Circulating levels of soluble interleukin 2 receptors are elevated in the sera of humans with spinal cord injury. J Am Paraplegia Soc. 1992;16:30–33
  48. Segal JL. Spinal cord injury: are interleukins a molecular link between neuronal damage and ensuing pathobiology?. Perspect Biol Med. 1993;36:222–240
  49. Wang R, Rogers AM, Rush BJ, Russell JH. Induction of sensitivity to activation-induced death in primary CD4+ cells: a role for interleukin-2 in the negative regulation of responses by mature CD4+ T cells. Eur J Immunol. 1996;26:2263–2270
  50. Furtado GC, Curotto de Lafaille MA, Kutchukhidze N, Lafaille JJ. Interleukin 2 signaling is required for CD4(+) regulatory T cell function. J Exp Med. 2002;196:851–857
  51. Kedzierska K, Crowe SM. Cytokines and HIV-1: interactions and clinical implications. Antivir Chem Chemother. 2001;12:133–150
  52. Clerici M. New research hypotheses in the immunopathogenesis of human immunodeficiency virus infection. Q J Nucl Med. 1995;39:163–168
  53. Popovich PG, Whitacre CC, Stokes BT. Is spinal cord injury an autoimmune disorder?. Neuroscientist. 1998;4:71–76
  54. Popovich PG, Stokes BT, Whitacre CC. Concept of autoimmunity following spinal cord injury: possible roles for T lymphocytes in the traumatized central nervous system. J Neurosci Res. 1996;45:349–363
  55. Schwartz M, Cohen I, Lazarov-Spiegler O, Moalem G, Yoles E. The remedy may lie in ourselves: prospects for immune cell therapy in central nervous system protection and repair. J Mol Med. 1999;77:713–717
  56. Schwartz M. Protective autoimmunity as a T-cell response to central nervous system trauma: prospects for therapeutic vaccines. Prog Neurobiol. 2001;65:489–496
  57. Schwartz M, Kipnis J. Protective autoimmunity: regulation and prospects for vaccination after brain and spinal cord injuries. Trends Mol Med. 2001;7:252–258
  58. Yoles E, Hauben E, Palgi O, et al. Protective autoimmunity is a physiological response to CNS trauma. [published erratum in: J Neurosci 2001;21:1a] J Neurosci. 2001;21:3740–3748
  59. Kipnis J, Mizrahi T, Hauben E, Shaked I, Shevach E, Schwartz M. Neuroprotective autoimmunity: naturally occurring CD4+CD25+ regulatory T cells suppress the ability to withstand injury to the central nervous system. Proc Natl Acad Sci U S A. 2002;99:15620–15625
  60. Kil K, Zang YC, Yang D, et al. T cell responses to myelin basic protein in patients with spinal cord injury and multiple sclerosis. J Neuroimmunol. 1999;98:201–207
  61. Kipnis J, Yoles E, Schori H, Hauben E, Shaked I, Schwartz M. Neuronal survival after CNS insult is determined by a genetically encoded autoimmune response. J Neurosci. 2001;21:4564–4571
  62. Shamash S, Reichert F, Rotshenker S. The cytokine network of Wallerian degeneration: tumor necrosis factor-alpha, interleukin-1alpha, and interleukin-1beta. J Neurosci. 2002;22:3052–3060
  63. Drojdahl N, Fenger C, Nielsen HH, Owens T, Finsen B. Dynamics of oligodendrocyte responses to anterograde axonal (Wallerian) and terminal degeneration in normal and TNF-transgenic mice. J Neurosci Res. 2004;75:203–217
  64. Otto G, Braconier J, Andreasson A, Svanborg C. Interleukin-6 and disease severity in patients with bacteremic and nonbacteremic febrile urinary tract infection. J Infect Dis. 1999;179:172–179
  65. Flatters SJ, Fox AJ, Dickenson AH. Spinal interleukin-6 (IL-6) inhibits nociceptive transmission following neuropathy. Brain Res. 2003;984:54–62
  66. Geiss A, Varadi E, Steinbach K, Bauer HW, Anton F. Psychoneuroimmunological correlates of persisting sciatic pain in patients who underwent discectomy. Neurosci Lett. 1997;237:65–68
  67. Wells MR, Racis SP, Vaidya U. Changes in plasma cytokines associated with peripheral nerve injury. J Neuroimmunol. 1992;39:261–268
  68. DeLeo JA, Colburn RW, Nichols M, Malhotra A. Interleukin-6-mediated hyperalgesia/allodynia and increased spinal IL-6 expression in a rat mononeuropathy model. J Interferon Cytokine Res. 1996;16:695–700
  69. Bonnefoy M, Coulon L, Bienvenu J, Boisson RC, Rys L. Implication of cytokines in the aggravation of malnutrition and hypercatabolism in elderly patients with severe pressure sores. Age Ageing. 1995;24:37–42
  70. Harris IR, Yee KC, Walters CE, et al. Cytokine and protease levels in healing and non-healing chronic venous leg ulcers. Exp Dermatol. 1995;4:342–349
  71. Cooper DM, Yu EZ, Hennessey P, Ko F, Robson MC. Determination of endogenous cytokines in chronic wounds. Ann Surg. 1994;219:688–691discussion 691-2
  72. Pan W, Kastin AJ. Increase in TNFalpha transport after SCI is specific for time, region, and type of lesion. Exp Neurol. 2001;170:357–363
  73. Dantzer R, Konsman JP, Bluthe RM, Kelley KW. Neural and humoral pathways of communication from the immune system to the brain: parallel or convergent?. Auton Neurosci. 2000;85:60–65
  74. Vitkovic L, Bockaert J, Jacque C. ”Inflammatory” cytokines: neuromodulators in normal brain?. J Neurochem. 2000;74:457–471
  75. Rose M, Griggs RC. Channelopathies of the nervous system. Oxford: Butterworth Heinemann; 2001;
  76. Köller H, Siebler M, Hartung HP. Immunologically induced electrophysiological dysfunction: implications for inflammatory diseases of the CNS and PNS. Prog Neurobiol. 1997;52:1–26
  77. Tonelli LH, Postolache TT. Tumor necrosis factor alpha, interleukin-1 beta, interleukin-6 and major histocompatibility complex molecules in the normal brain and after peripheral immune challenge. Neurol Res. 2005;27:679–684
  78. Davies AL, Hayes KC, Trombly R, Kramer JK, Close TE, Guest JD. Cytokine concentrations in the cerebrospinal fluid of individuals with chronic spinal cord injury undergoing surgery for syringomyelia or detethering [abstract]. Soc Neurosci Abstracts. 2006;86:15
  79. Heney D, Whicher JT. Factors affecting the measurement of cytokines in biological fluids: implications for their clinical measurement. Ann Clin Biochem. 1995;32(Pt 4):358–368

 Supported by the Parkwood Hospital Foundation and the Ontario Neurotrauma Foundation.

 No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated.

PII: S0003-9993(07)01342-1

doi: 10.1016/j.apmr.2007.08.004

Archives of Physical Medicine and Rehabilitation
Volume 88, Issue 11 , Pages 1384-1393 , November 2007

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