Social Stress Alters the Severity of an Animal Model of Multiple Sclerosis

  • Mary W. Meagher
  • Robin R. Johnson
  • Elisabeth Good
  • C. Jane Welsh


Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) and a leading cause of disability among young adults (Anderson et al., 1992; Jacobson et al., 1997; Noonan et al., 2002; Sorpedra and Martin, 2005). Common symptoms include loss of motor control or sensation in the limbs, loss of bowel or bladder control, neuropathic pain, optic neuritis, sexual dysfunction, and cognitive dysfunction. The etiology of MS remains uncertain; however, considerable evidence suggests that environmental factors interact with genetic factors to cause disease (Kurtzke and Hyllested, 1987; Noseworthy et al., 2000; Sospedra and Martin, 2005). Suspected environmental factors include viral infection and stress.


Multiple Sclerosis Stressful Life Event Social Stress Restraint Stress Demyelinating Disease 
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.


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  1. Acheson, E.D. (1977). Epidemiology of multiple sclerosis. Br. Med. Bull. 33:9–14PubMedGoogle Scholar
  2. Ackerman, K.D., Rabin, B.S., Heyman, R., and Baum, A. (2000). Stressful life events and disease activity in multiple sclerosis. Brain Behav. Immun. 14:77Google Scholar
  3. Akira, S., Hirano, T. Taga, T., and Kishimoto, T. (1990). Biology of multifunctional cytokines: IL-6 and related molecules (IL1 and TNF). FASEB J. 4:2860–2867.PubMedGoogle Scholar
  4. Allen, I., and Brankin, B.J. (1993). Pathogenesis of multiple sclerosis — the immune diathesis and the role of viruses. Neuropathol. Exp. Neurol. 52:95.Google Scholar
  5. Anderson, D.W., Ellenberg., J.H., Leventhal, C.M., Reingold, S.C., Rodriguez, M., and Silberberg, D.H. (1992). Revised estimate of the prevalence of multiple sclerosis in the United States. Ann. Neurol. 31:333–336.PubMedGoogle Scholar
  6. Aubert, C., Chamorro, M., and Brahic, M. (1987). Identification of Theiler’s infected cells in the central nervous system of the mouse during demyelinating disease. Microb. Pathogen. 3:319–326.Google Scholar
  7. Avitsur, R., Stark, J.L., and Sheridan, J.F. (2001). Social stress induces glucocorticoid resistance in subordinate animals. Hormones Behav. 39:247–257.Google Scholar
  8. Avitsur, R., Stark, J.L., Dhabhar, F.S., Padgett, D.A., and Sheridan, J.F. (2002). Social disruption-induced glucocorticoid resistance: Kinetics and site specificity. J. Neuroimmunol. 124(1–2):54–61.PubMedGoogle Scholar
  9. Avitsur, R., Padgett, D.A., Dhabhar, F.S., Stark, J.L., Kramer, K.A., Engler, H., and Sheridan, J.F. (2003a). Expression of glucocorticoid resistance following social stress requires a second signal. J. Leukoc. Biol. 74:507–513.PubMedGoogle Scholar
  10. Avitsur, R., Stark, J.L., Dhabhar, F.S., Kramer, K.A., and Sheridan, J.F. (2003b). Social experience alters the response to social stress in mice. Brain Behav. Immun. 17:426–437.PubMedGoogle Scholar
  11. Barak, O., Goshen, I., Ben-Hur, T., Weidenfeld, J., Taylor, A.N., and Yirmiya, R. (2002a). Involvement of brain cytokines in the neurobehavioral disturbances induced by HIV-1 glycoprotein 120. Brain Res. 933:98–108.PubMedGoogle Scholar
  12. Barak, O., Weidenfeld, J., Goshen, I., Ben-Hur, T., Taylor, A.N., and Yirmiya, R. (2002b). Intracerebral HIV-1 glycoprotein 120 produces sickness behavior and pituitary-adrenal activation in rats: role of prostaglandins. Brain Behav. Immun. 16:720–735.PubMedGoogle Scholar
  13. Biron, C.A. (1998). Role of early cytokines, including alpha and beta interferons ((IFN-a/b), in innate and adaptive immune responses to viral infections. Semin. Immunol. 10:383–390.PubMedGoogle Scholar
  14. Blanchard, R.J., McKittrick, C.R., and Blanchard, D.C. (2001). Animal models of social stress: Effects on behavior and brain neurochemical systems. Neurosci. Biobehav. Rev. 73:261–271.Google Scholar
  15. Borrow, P., Tonks, P., Welsh, C.J.R., and Nash, A.A. (1992). The role of CD8+ T cells in the acute and chronic phases of Theiler’s virus-induced disease in mice. J. Gen. Virol. 73:1861–1865.PubMedGoogle Scholar
  16. Borrow, P., Welsh, C.J.R., and Nash A.A. (1993). Study of the mechanisms by which CD4+ T cells contribute to protection in Theiler’s murine encephalomyelitis. Immunology 80:502–506.PubMedGoogle Scholar
  17. Borrow, P., Welsh, C.J.R., Dean, D., Tonks, P., Blakemore, W.F., and Nash, A.A. (1998). Investigation of the role of autoimmune responses to myelin in the pathogenesis of TMEV-induced demyelinating disease. Immunology 93:478–484.PubMedGoogle Scholar
  18. Brahic, M., Stroop, W.G., and Baringer, J.R. (1981). Theiler’s virus persists in glial cells during demyelinating disease. Cell 26:123–128.PubMedGoogle Scholar
  19. Campbell, T., Meagher, M.W., Sieve, A., Scott, B., Storts, R., Welsh, T.H., and Welsh, C.J. (2001). The effects of restraint stress on the neuropathogenesis of Theiler’s virus infection: I. Acute disease. Brain Behav. Immun. 15:235–254.PubMedGoogle Scholar
  20. Challoner, P.B., Smith, K.T., Parker, J.D., MacLeod, D.L., Coulter, S.N., Rose, T.M., Schultz, E.R., Bennett, J.L., Garber, R.L., Chang, M., Schad, P.A., Stewart, P.M., Nowinski, R.C., Brown, J.P., and Burmer, G.C. (1995). Plaque-associated expression of human herpesvirus 6 in multiple sclerosis. Proc. Natl. Acad. Sci. U.S.A. 92:7440–7444.PubMedGoogle Scholar
  21. Chancellor-Freeland, C., Zhu, G., Kage, R., Beller, D., Leeman, S., and Black, P. (1995). Substance P and stress-induced changes in macrophages. Ann. N.Y. Acad. Sci. 771:472–484.PubMedGoogle Scholar
  22. Chrousos, G.P. (1995). The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N. Engl. J. Med. 332(20):1351–1362.PubMedGoogle Scholar
  23. Clatch, R.J., Lipton, H.L., and Miller, S.D. (1987). Class II-restricted T cell responses in Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating disease. II. Survey of host immune responses and central nervous system virus titers in inbred mouse strains. Microb. Pathogen. 3:327–337.Google Scholar
  24. Clatch, R.J., Miller, S.D., Metzner, R., Dal Canto, M.C., and Lipton, H.L. (1990). Monocytes/macrophages isolated from the mouse central nervous system contain infectious Theiler’s murine encephalomyelitis virus (TMEV). Virolosy. 176:244–254.Google Scholar
  25. Cohen, S., Tyrrell, D.A.J., and Smith, A.P. (1991). Psychological stress in humans and susceptibility to the common cold. N. Engl. J. Med. 325:606–612.PubMedGoogle Scholar
  26. Cohen, S., Kaplan, J.R., Cunnick, J.E., Manuck, S.B., and Rabin, B.S. (1992). Chronic social stress, affiliation and cellular immune response in nonhuman primates. Psychol. Sci. 3:301–304.Google Scholar
  27. Cohen, S., Tyrrell, D.A.J., and Smith, A.P. (1993). Life events, perceived stress, negative affect and susceptibility to the common cold. J. Pers. Social Psychol. 64:131–140.Google Scholar
  28. Cohen, S., Line, S., Manuck, S.B., Rabin, B.S., Heise, E., and Kaplan, J.R. (1997). Chronic social stress, social status and susceptibility to upper respiratory infections in nonhuman primates. Psychosom. Med. 59:213–221.PubMedGoogle Scholar
  29. Croxford, J.L., Olson, J.K., and Miller, S.D. (2002). Epitope spreading and molecular mimicry as triggers of autoimmunity in the Theiler’s virus-induced demyelinating disease model of multiple sclerosis. Autoimmun. Rev. 1:251–260.PubMedGoogle Scholar
  30. Dal Canto, M.C., and Rabinowitz, S.G. (1982). Experimental models of virus-induced demyelination of the central nervous system. Ann. Neurol. 11:109–127.Google Scholar
  31. Dal Canto, M.C., Calenoff, M.A., Miller, S.D., and Vanderlugt, C.L. (2000). Lymphocytes from mice chronically infected with Theiler’s murine encephalomyelitis virus produce demyelination of organotypic cultures after stimulation with the major encephalitic epitope of myelin proteolipid protein. Epitope spreading in TMEV infection has functional activity. J. Neuroimmunol. 104:79–84.Google Scholar
  32. DeRijk, R.H., Eskandari, F., and Sternberg, E.M. (2004). Corticosteroid resistance in a subpopulation of multiple sclerosis patients as measured by ex vivo dexamethasone inhibition of LPS induced IL-6 production. J. Neuroimmunol. 151(1–2):180–188.PubMedGoogle Scholar
  33. Dethlefs, S., Brahic, M., and Larsson-Sciard, E.L. (1997). An early abundant cytotoxic T-lymphocyte response against Theiler’s virus is critical for preventing for viral persistence. J. Virol. 71:8875–8878.PubMedGoogle Scholar
  34. Dyment, D.A., Ebers, G.C., and Sadovnick, A.D. (2004). Genetics of multiple sclerosis. Lancet Neurol. 3:104–110.PubMedGoogle Scholar
  35. Elenkov, I.J., and Chrousos, G.P. (2002). Stress hormones, proinflammatory and antiinflammatory cytokines, and autoimmunity. Ann. N.Y. Acad. Sci. 966:290–303.PubMedGoogle Scholar
  36. Eugster, H.P., Frei, K., Kopf, M., Lassmann, H., and Fontana, A. (1998). IL-6-deficient mice resist myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. Eur. J. Immunol. 28:2178–2187.PubMedGoogle Scholar
  37. Fiette, L., Aubert, C., Brahic, M., and Ross, C.P. (1993). Theiler’s virus infection of b2-microglobulin deficient mice. J. Virol. 67:589–592.PubMedGoogle Scholar
  38. Fiette, L., Aubert, C., Ulrike, M., Huang, S., Aguet, M., Brahic, M., and Bureau, J.F. (1995). Theiler’s virus infection of 129Sv mice that lack the interferon a/b or IFN-g receptors. J. Exp. Med. 181:2069–2076.PubMedGoogle Scholar
  39. Filippini, G., Munari, L., Incorvaia, B., Ebers, G.C., Polman, C., D’Amico, R., and Rice, G.P. (2003). Interferons in relapsing remitting multiple sclerosis: a systematic review. Lancet 361(9357):545–552.PubMedGoogle Scholar
  40. Gerety, S.J., Clatch, R.J., Lipton, H.L., Goswami, R.G., Rundell, M.K., and Miller, S.D. (1991). Class II-restricted T cell responses in Theiler’s murine encephalomyelitis virus-induced demyelinating disease. IV Identification of an immunodominant T cell determinant, on the N-terminal end of the VP-2 capsid protein in susceptible SJL/J mice. J. Immunol. 146:4322–4326.Google Scholar
  41. Gilden, D.H. (2005). Infectious causes of multiple sclerosis. Lancet Neurol. 4: 195–202.PubMedGoogle Scholar
  42. Glaser, R., Kiecolt-Glaser, J.K., Bonneau, R., Malarkey, W., and Hughes, J. (1992). Stress-induced modulation of the immune response to recombinant hepatitis B vaccine. Psychosom. Med. 54:22–29.PubMedGoogle Scholar
  43. Glaser, R., Sheridan, J.F., Malarkey, W.B., MacCallum, R.C., and Kiecolt-Glaser, J.K. (2000). Chronic stress modulates the immune response to a pneumococcal pneumonia vaccine. Psychosom. Med. 62:804–807.PubMedGoogle Scholar
  44. Grant, I., Brown, G.W., Harris, T., McDonald, W.I., Patterson, T., and Trimble, M.R. (1989). Severely threatening events and marked life difficulties preceding onset or exacerbation of multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 52:8–13.PubMedGoogle Scholar
  45. Gutierrez, J., Vergara, M.J., Guerrero, M., Fernandez, O., Piedrola, G., Morales, P., and Maroto, M.C. (2002). Multiple sclerosis and human herpesvirus 6. Infection 30:145–149.PubMedGoogle Scholar
  46. Hernan, M.A., Zhang, S.M., Lipworth, L., Olek, M.J., and Ascherio, A. (2001). Multiple sclerosis and age at infection with common viruses. Epidemiology 12: 301–306.PubMedGoogle Scholar
  47. Jacobson, D.L., Gange, S.J., Rose, N.R., and Graham, N.M. (1997). Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin. Immunol. Immunopathol. 84(3):223–243.PubMedGoogle Scholar
  48. Johnson, R.T. (1994). The virology of demyelinating diseases. Ann. Neurol. 36(Suppl.):S54–60.PubMedGoogle Scholar
  49. Johnson, J.D., O’Connor, K.A., Deak, T., Stark, M., Watkins, L.R., and Maier, S.F. (2002). Prior stressor exposure sensitizes LPS-induced cytokine production. Brain Behav. Immunol. 16:461–476.Google Scholar
  50. Johnson, R.R., Storts, R., Welsh, T.H., Jr., Welsh, C.J., and Meagher, M.W. (2004a). Social stress alters the severity of acute Theiler’s virus infection. J. Neuroimmunol. 148:74–85.PubMedGoogle Scholar
  51. Johnson, R.R., Bridegam, P., Prentice, T.W., Welsh, T.H., Welsh, C.J.R., and Meagher, M.W. (2004b). Early life experience interacts with later social stress in the development of Theiler’s virus infection. Society for Neuroscience Abstracts. 30, 728.5.Google Scholar
  52. Johnson, R.R., Good, E.A., Hardin, E.A., Connoer, M.A., Prentice, T.W., Welsh, C.J.R., and Meagher, M.W. (2005a). Necessity of IL-6 in effects of social stress in acute Theiler’s virus infection. Soc. Neurosci. Abstr. 31:1012–1020.Google Scholar
  53. Johnson, R.R., Prentice, T.W., Bridegam, P., Young, C.R., Steelman, A.J., Welsh, T.H., Welsh, C.J.R., and Meagher, M.W. (2006a). Social stress alters the severity and onset of the chronic phase of Theiler’s virus infection (in press Journal of Neuroimmunol).Google Scholar
  54. Johnson, R.R., Bridegam, P., Prentice, T.W., Welsh, T.H., Welsh, C.J.R., and Meagher, M.W. (2006b). Early life experience interacts with later social stress in the development of acute and chronic Theiler’s virus infection (in preparation).Google Scholar
  55. Kaminsky, S.G., Nakamura, I., and Cudkowicz, G. (1987). Defective differentiation of natural killer cells in SJL mice. Role of the thymus. J. Immunol. 138:1020–1025.PubMedGoogle Scholar
  56. Kiecolt-Glaser, J., Glaser, R., Gravenstein, S., Malarkey, W.B., and Sheridan, J.F. (1996). Chronic stress alters the immune response to influenza virus vaccine in older adults. Proc. Natl. Acad. Sci. U.S.A. 93:3043–3047.PubMedGoogle Scholar
  57. Kohanawa, M., Nakane, A., and Minagawa, T. (1993). Endogenous gamma interferon produced in central nervous system by systemic infection with Theiler’s virus in mice. J. Neuroimmunol. 48:205–211.PubMedGoogle Scholar
  58. Kurtzke, J.F. (1993). Epidemiologic evidence for multiple sclerosis as an infection. Clin. Microbiol. Rev. 6:382–427.PubMedGoogle Scholar
  59. Kurtzke, J.F., and Hyllested, K. (1987). MS epidemiology in Faroe Islands. Rev. Neurol. 57:77–87.Google Scholar
  60. Laban, O., Dimitrijevic, M., von Hoersten, S., Markovic, B.M., and Jankovic, B.D. (1995). Experimental allergic encephalomyelitis in adult DA rats subjected to neonatal handling or gentling. Brain Res. 676:133–140.PubMedGoogle Scholar
  61. Levin, L.I., Munger, K.L., Rubertone, M.V., Peck, C.A., Lennette, E.T., Spiegelman, D., and Ascherio, A. (2003). Multiple sclerosis and Epstein-Barr virus. JAMA 289:1533–1536.PubMedGoogle Scholar
  62. Lipton, H.L. (1975). Theiler’s virus infection in mice: An unusual biphasic disease process leading to demyelination. Infect. Immun. 11:1147–1155.PubMedGoogle Scholar
  63. Lipton, H.L., Twaddle, G., and Jelachich, M.L. (1995). The predominant virus antigen burden is present in macrophages in Theiler’s murine encephalomyelitis virus-induced demyelinating disease. J. Virol. 69:2525–2533.PubMedGoogle Scholar
  64. Lindsley, M.D., Thiemann R., and Rodriguez, M. (1991). Cytotoxic T cells isolated from the central nervous system of mice infected with Theiler’s virus. J.Virol. 65: 6612–6620.PubMedGoogle Scholar
  65. Lowy M.T., Reder A.T., Antel J.P., and Meltzer, H.Y. (1984). Glucocorticoid resistance in depression: the dexamethasone suppression test and lymphocyte sensitivity to dexamethasone. Am. J. Psychiatry 141:1365–1370.PubMedGoogle Scholar
  66. Mack, C.L., Vanderlugt-Castaneda, C.L., Neville, K.L., and Miller, S.D. (2003). Microglia are activated to become competent antigen presenting and effector cells in the inflammatory environment of the Theiler’s virus model of multiple sclerosis. J. Neuroimmunol. 144:68–79.PubMedGoogle Scholar
  67. Maes, M., Bosmans, E., De Jongh, R., Kenis, G., Vandoolaeghe, E., and Neels, H. (1997). Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine 9:853–858.PubMedGoogle Scholar
  68. Majid A., Galetta S.L., Sweeney C.J., Robinson, C., Mahalingam, R., Smith, J., Forghani, B., and Gilden D.H. (2002). Epstein-Barr virus myeloradiculitis and encephalomyeloradiculitis. Brain 125:1–7.Google Scholar
  69. Martyn, C.N., Cruddas, M., and Compston, D.A. (1993). Symptomatic Epstein-Barr virus infection and multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 56:167–68.PubMedGoogle Scholar
  70. McEwen, B.S. (1998). Protective and damaging effects of stress mediators. N. Engl. J. Med. 338:171–179.PubMedGoogle Scholar
  71. McGavern, D.B., Zoecklein, L., Drescher, K.M., and Rodriguez, M. (1999). Quantitative assessment of neurologic deficits in a chronic progressive murine model of CNS demyelination. Exp. Neurol. 158:171–181.PubMedGoogle Scholar
  72. McGavern, D.B., Zoecklein, L., Sathornsumetee, S., and Rodriguez, M. (2000). Assessment of hindlimb gait as a powerful indicator of axonal loss in a murine model of progressive CNS demyelination. Brain Res. 877:396–400.PubMedGoogle Scholar
  73. Meaney, M.J. (2001). Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annu. Rev. Neurosci. 24: 1161–1192.PubMedGoogle Scholar
  74. Mendel, I., Katz, A., Kozak, N., Ben-Nun, A., and Revel, M. (1998). Interleukin-6 functions in autoimmune encephalomyelitis: a study in gene-targeted mice. Eur. J. Immunol. 28:1727–1737.PubMedGoogle Scholar
  75. Mi, W., Prentice, T.W., Young, C.R., Johnson, R.R., Sieve, A.N., Meagher, M.W., Welsh, C.J.R. (2006). Restraint Stress Decreases Virus-induced Pro-inflammatory Cytokine Expression during Acute Theiler’s Virus Infection. (in press J. Neuroimmunol.)Google Scholar
  76. Miller, S.D., VanDerlugt, C.L., Begolka, W.S., Pao, W., Yauch, R.L., Neville, K.L., Katz-Levy, Y., Carrizosa, A., and Kim, B.S. (1997). Persistent infection with Theiler’s virus leads to CNS autoimmunity via epitope spreading. Nat. Med. 3: 1133–1136.PubMedGoogle Scholar
  77. Miller, S.D., Olson, J.K., and Croxford J.L. (2001). Multiple pathways to induction of virus-induced autoimmune demyelination: Lessons from Theiler’s virus infection. J.Autoimmunol. 16:219–227.Google Scholar
  78. Miller, G.E., Cohen, S., and Ritchey, A.K. (2002). Chronic psychological stress and the regulation of pro-inflammatory cytokines: A glucocorticoid-resistance model. Health Psychol. 21(6):531–541.PubMedGoogle Scholar
  79. Mohr, D.C., Goodkin, D.E., Bacchetti, P., Boudewyn, A.C., Huang, L., Marrietta, P., Cheuk, W., and Dee, B. (2000). Psychological stress and the subsequent appearance of new brain MRI lesions in MS. Neurology 55:55–61.PubMedGoogle Scholar
  80. Mohr, D.C., Goodkin, D.E., Nelson, S., Cox, D., and Weiner, M. (2002). Moderating effects of coping on the relationship between stress and the development of new brain lesions in multiple sclerosis. Psychosom. Med. 64(5):803–809.PubMedGoogle Scholar
  81. Mohr, D.C., Hart, S.L., Julian, L., Cox, D., and Pelletier, D. (2004). Association between stressful life events and exacerbation in multiple sclerosis: a meta-analysis. Br. Med. J. 328(7442):731–735.Google Scholar
  82. Mohr, D.C. (2006). The relationship between stressful life events and inflammation among patients with multiple sclerosis. In C. Jane Welsh, Mary W. Meagher and Esther Sternberg (eds.), Neural and neuroendocrine mechanisms in host defense and autoimmunity. New York: Springer, pp. 225–273.Google Scholar
  83. Mohr, D.C., and Pelletier, D. (2006). A temporal framework for understanding the effects of stressful life events on inflammation in patients with multiple sclerosis. Brain Behav. Immun. 20:27–36.PubMedGoogle Scholar
  84. Moore, F.G., and Wolfson, C. (2002). Human herpes virus 6 and multiple sclerosis. Acta Neurol. Scand. 106:63–83.PubMedGoogle Scholar
  85. Murray, P.D., Pavelko, K.D., Leibowitz, J., Lin, X., and Rodriguez, M. (1998). CD4 (+) and CD8 (+) T cells make discrete contributions to demyelination and neurologic disease in a viral model of multiple sclerosis. J. Virol. 72:7320–7329.PubMedGoogle Scholar
  86. Nicholson, S.M., Peterson, J.D., Miller, S.D., Wang, K., Dal Canto, M.C., and Melvold, R.W. (1994). BALB/c substrain differences in susceptibility to Theiler’s murine encephalomyelitis virus-induced demyelinating disease. J. Neuroimmunol. 52: 19–24.PubMedGoogle Scholar
  87. Nisipeanu, P., and Korczyn, A.D. (1993). Psychological stress as risk factor for exacerbations in multiple sclerosis. Neurology 43:1311–1312.PubMedGoogle Scholar
  88. Noonan, C.W., Kathman, S.J., and White, M.C. (2002). Prevalence estimates for MS in the United States and evidence of an increasing trend for women. Neurology 58(1):136–138.PubMedGoogle Scholar
  89. Noseworthy, J.H., Lucchinetti, C., Rodriguez, M., and Weinshenker, B.G. (2000). Multiple sclerosis. N. Engl. J. Med. 343:938–952.PubMedGoogle Scholar
  90. Oleszak, E.L., Chang, J.R., Friedman, H., Katsetos, C.D., and Platsoucas, C.D. (2004). Theiler’s virus infection: a model for multiple sclerosis. Clin. Microbiol. Rev. 17: 174–207.PubMedGoogle Scholar
  91. Olson, J.K., Girvin, A.M., and Miller, S.D. (2001). Direct activation of innate and antigen-presenting functions of microglia following infection with Theiler’s virus. J. Virol. 75:9780–9789.PubMedGoogle Scholar
  92. Olson, J.K., Eagar, T.N., and Miller, S.D. (2002). Functional activation of myelin specific T cells by virus-induced molecular mimicry. J. Immunol. 169:2719–2726.PubMedGoogle Scholar
  93. Olson, J.K., Ludovic Croxford, J., and Miller, S.D. (2004). Innate and adaptive immune requirements for induction of autoimmune demyelinating disease by molecular mimicry. Mol. Immunol. 40:1103–1108.PubMedGoogle Scholar
  94. Padberg, F., Feneberg, W., Schmidt, S., Schwarz, M.J., Korschenhausen, D., Greenberg, B.D., Nolde, T., Muller, N., Trapmann, H., Konig, N., Moller, H.J., and Hampel, H. (1999). CSF and serum levels of soluble interleukin-6 receptors (sIL-6R and sgp130), but not of interleukin-6 are altered in multiple sclerosis. J. Neuroimmunol. 99:218–223.PubMedGoogle Scholar
  95. Padgett, D.A., Sheridan, J.F., Dorne, J., Berntson, G.G., Candelora, J., and Glaser, R. (1998). Social stress and the reactivation of latent herpes simplex virus type 1. Proc. Natl. Acad. Sci. U.S.A. 95:7231–7235.PubMedGoogle Scholar
  96. Palma, J.P., Kwon, D., Clipstone, N.A., and Kim, B.S. (2003). Infection with Theiler’s murine encephalomyelitis virus directly induces proinflammatory cytokines in primary astrocytes via NF-kappaB activation: Potential role for the initiation of demyelinating disease. J. Virol. 77:6322–6331.PubMedGoogle Scholar
  97. Persoons, J.H., Schornagel, K., Breve, J., Berkenbosch, F., and Kaal, G. (1995). Acute stress affects cytokines and nitric oxide production by alveolar macrophages differently. Am. J. Respir. Crit. Care Med. 152:619–624.PubMedGoogle Scholar
  98. Pollak, Y., Ovadia, H., Goshen, I., Gurevich, R., Monsa, K., Avitsur, R., and Yirmiya, R. (2000). Behavioral aspects of experimental autoimmune encephalomyelitis. J. Neuroimmunol. 104:31–36.PubMedGoogle Scholar
  99. Pullen, L.C., Miller, S.D., Dal Canto, M.C., and Kim, B.S. (1993). Class I-deficient resistant mice intracerebrally inoculated with Theiler’s virus show an increased T cell response to viral antigens and susceptibility to demyelination. Eur. J. Immunol. 23:2287–2293.PubMedGoogle Scholar
  100. Quan, N., Avitsur, R., Stark, J.L., He, L., Shah, M., Caliguiri, M., Padgett, D.A., Marucha, P.T., and Sheridan, J.F. (2001). Social stress increases the susceptibility to endotoxic shock. J. Neuroimmunol. 115:36–45.PubMedGoogle Scholar
  101. Quan, N., Avitsur, R., Stark, J.L., He, L., Lai, W., Dhabhar, F.S., and Sheridan, J.F. (2003). Molecular mechanisms of glucocorticoid resistance in splenocytes of socially stressed male mice. J. Neuroimmunol. 137:51–58.PubMedGoogle Scholar
  102. Rodriguez, M., Pavelko, K., and Coffman, R.L. (1995). Gamma interferon is critical for resistance to Theiler’s virus-induced demyelination. J. Virol. 69:7286–7290.PubMedGoogle Scholar
  103. Rodriguez, M., Pavelko, K.D., Njenga, M.K., Logan., W.C., and Wettstein, P.J. (1996). The balance between persistent virus infection and immune cells determines demyelination. J. Immunol. 157:5699–5709.PubMedGoogle Scholar
  104. Rodriguez, M., and Sriram, S. (1988). Successful therapy of Theiler’s virus-induced demyelination (DA strain) with monoclonal anti-Lyt2 antibody. J. Immunol. 140: 2950–2955.PubMedGoogle Scholar
  105. Roos, R.P., and Wollmann, R. (1984). DA strain of Theiler’s murine encephalomyelitis virus induces demyelination in nude mice. Ann. Neurol. 15:494–499.PubMedGoogle Scholar
  106. Rossi, P.C., McAllister, A., Fiette, L., and Brahic, M. (1991). Theiler’s virus infection induces a specific cytotoxic T lymphocyte response. Cell. Immunol. 138:341–348.Google Scholar
  107. Samoilova, E.B., Horton, J.L., Hilliard, B., Liu, T.S., and Chen, Y. (1998). IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis: Roles of IL-6 in the activation and differentiation of autoreactive T cells. J. Immunol. 161:6480–6486.PubMedGoogle Scholar
  108. Schonrock, L.M., Gawlowski, G., and Bruck, W. (2000). Interleukin-6 expression in human multiple sclerosis lesions. Neurosci. Lett. 294:45–48.PubMedGoogle Scholar
  109. Shanks, N., and Lightman, S.L. (2001). The maternal-neonatal neuro-immune interface: Are there long-term implications for inflammatory or stress-related disease? J. Clin. Invest. 108:1567–1573.PubMedGoogle Scholar
  110. Sibley, W.A., Bamford, C.R., and Clark, K. (1985). Clinical viral infections and multiple sclerosis. Lancet 1:1313–1315.PubMedGoogle Scholar
  111. Sieve, A.N., Steelman, A.J., Young, C.R., Storts, R., Welsh, T.H., Welsh, C.J., and Meagher, M.W. (2004). Chronic restraint stress during early Theiler’s virus infection exacerbates the subsequent demyelinating disease in SJL mice. J. Neuroimmunol. 155:103–118.PubMedGoogle Scholar
  112. Soldan, S.S., Leist, T.P., Juhng, K.N., McFarland, H.F., and Jacobson, S. (2000). Increased lymphoproliferative response to human herpesvirus type 6A variant in multiple sclerosis patients. Ann. Neurol. 47:306–313.PubMedGoogle Scholar
  113. Soldan, S.S., and Jacobson S. (2001). Role of viruses in etiology and pathogenesis of multiple sclerosis. Adv. Virus Res. 56:517–555.PubMedGoogle Scholar
  114. Sospedra, M., and Martin, R. (2005). Immunology of multiple sclerosis. Annu. Rev. Immunol. 23:683–747.PubMedGoogle Scholar
  115. Stark, J.L., Avitsur, R., Padgett, D.A., Campbell, K.A., Beck, F.M., and Sheridan, J.F. (2001). Social stress induces glucocorticoid resistance in macrophages. Am. J. Physiol. Regul. Integr. Comp. Physiol. 280(6):R1799–1805.PubMedGoogle Scholar
  116. Stark, J.L., Avitsur, R., Hunzeker, J., Padgett, D.A., and Sheridan, J.F. (2002). Interleukin-6 and the development of social disruption-induced glucocorticoid resistance. J. Neuroimmunol. 124(1–2):9–15.PubMedGoogle Scholar
  117. Stefferl, A., Storch, M.K., Linington, C., Stadelmann, C., Lassmann, H., Pohl, T., Holsboer, F., Tilders, F.J., and Reul, J.M. (2001). Disease progression in chronic relapsing experimental allergic encephalomyelitis is associated with reduced inflammation-driven production of corticosterone. Endocrinology 142(8):3616–3624.Google Scholar
  118. Stininssen, P., Raus, J., and Zhang, J. (1997). Autoimmune pathogenesis of multiple sclerosis: Role of autoreactive T lymphocytes and new immunotherapeutic strategies. Crit. Rev. Immunol. 17:33–75.Google Scholar
  119. Stratakis, C.A., Karl, M., Schulte, H.M., and Chrousos, G.P. (1994). Glucocorticosteroid resistance in humans. Elucidation of the molecular mechanisms and implications for pathophysiology. Ann. N.Y. Acad. Sci. 746:362–374.PubMedGoogle Scholar
  120. Tanaka, H., Akama, H., Ichikawa, Y., Makino, I., and Homma, M. (1992). Glucocorticoid receptor in patients with lupus nephritis: relationship between receptor levels in mononuclear leukocytes and effect of glucocorticoid therapy. J. Rheumatol. 19:878–883.PubMedGoogle Scholar
  121. Theil, D.J., Tsunoda, I., Libbey, J.E., Derfuss, T.J., and Fujinami, R.S. (2000). Alterations in cytokine but not chemokine mRNA expression during three distinct Theiler’s virus infections. J. Neuroimmunol. 104:22–30.PubMedGoogle Scholar
  122. Theiler, M. (1934). Spontaneous encephalomyelitis of mice—a new virus. Science 80:122.Google Scholar
  123. Tilder, F.J., and Schmidt, E.D. (1999). Cross-sensitization between immune and non-immune stressors. A role in depression? Adv. Exp. Med. Biol. 461:179–197.Google Scholar
  124. van Winsen, L.M., Muris, D.F., Polman, C.H., Dijkstra, C.D., van den Berg, T.K., and Uitdehaag, B.M. (2005). Sensitivity to glucocorticoids is decreased in relapsing remitting multiple sclerosis. J. Clin. Endocrinol. Metab. 90(2):734–740.PubMedGoogle Scholar
  125. Wandinger, K.P., Jabs, W., Siekhaus, A., Bubel, S., Trillenberg, P., Wagner, H., Wessel, K., Kirchner, H., and Hennig, H. (2000). Association between clinical disease activity and Epstein-Barr virus reactivation in MS. Neurology 55:178–184.PubMedGoogle Scholar
  126. Warren, S., Greenhill, S., and Warren, K.G. (1982). Emotional stress and the development of multiple sclerosis: case-control evidence of a relationship. J. Chronic Dis. 35:821–831.PubMedGoogle Scholar
  127. Welsh, C.J.R., Tonks, P., Nash, A.A., and Blakemore, W.F. (1987). The effect of L3T4 T cell depletion on the pathogenesis of Theiler’s murine encephalomyelitis virus infection in CBA mice. J. Gen. Virol. 68:1659–1667.PubMedGoogle Scholar
  128. Welsh, C.J.R., Blakemore, W.F., Tonks, P., Borrow, P., and Nash, A.A. (1989). Theiler’s murine encephalomyelitis virus infection in mice: A persistent viral infection of the central nervous system which induces demyelination. In N. Dimmock (ed.), Immune Responses,Virus Infection and Disease. Oxford: Oxford University Press, pp. 125–147.Google Scholar
  129. Welsh, C.J.R., Tonks, P., Borrow, P., and Nash, A.A. (1990). Theiler’s virus: An experimental model of virus-induced demyelination. Autoimmunity 6:105–112.PubMedGoogle Scholar
  130. Welsh, C.J.R., Sapatino, B.V., Rosenbaum, B., and Smith, R. (1995). Characteristics of cloned cerebrovascular endothelial cells following infection with Theiler’s virus. I. Acute Infection. J. Neuroimmunol. 62:119–125.PubMedGoogle Scholar
  131. Welsh, C.J., Mi, W., Sieve, A., Steelman, A.J., Johnson, R.R., Young, C.R., Prentice, T., Hammons, A., Storts, R., Welsh T., and Meagher, M.M. (2006). The effect of restraint stress on the neuropathogenesis of Theiler’s virus-induced demyelination, a murine model for multiple sclerosis. In C. Jane Welsh, Mary, W. Meagher and Esther Sternberg (eds.), Neural and neuroendocrine mechanisms in host defense and autoimmunity. New York: Springer, pp. 190–225.Google Scholar
  132. Zhou, D., Kusnecov, A.W., Shurin, M.R., DePaoli, M., and Rabin, B.S. (1993). Exposure to physical and psychological stressors elevates plasma interleukin 6: relationship to the activation of hypothalamic-pituitary-adrenal axis. Endocrinology 133:2523–2530.PubMedGoogle Scholar
  133. Zhu, G., Chancellor-Freeland, C., Berman, A., Kage, R., Leeman, S., Beller, D., and Black, P. (1995). Endogenous substance P mediates cold-water-stress induced increase in interleukin-6 section from peritoneal macrophages. J. Neurosci. 16: 3745–3752.Google Scholar

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© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Mary W. Meagher
  • Robin R. Johnson
  • Elisabeth Good
  • C. Jane Welsh

There are no affiliations available

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