The Yin and Yang of Inflammation in Multiple Sclerosis

  • G. Giovannoni
Part of the Topics in Neuroscience book series (TOPNEURO)


Multiple sclerosis (MS) is a clinically heterogeneous disease [1]. On the one side of the spectrum is relapsing-remitting (RR) disease, characterized by attacks of neurological dysfunction due to focal central nervous system (CNS) inflammation, followed by recovery and a period of remission, and on the other side is primary progressive (PP) disease, which is progressive from the outset with no clinical relapses. Between these two extremes are patients who, after presenting with RR disease, subsequently go onto develop a secondary progressive (SP) course. SP disease can be further subdivided into relapsing and non-relapsing disease, depending on whether or not patients continue to have clinical relapses. Approximately 15%-30% of patients with RR disease do not enter the progressive phase of the disease and are classified retrospectively as having benign disease. Why such clinical heterogeneity occurs is currently unknown. Are RR and PPMS different diseases or are they part of the same clinical spectrum? Why do some patients develop progressive disease whilst others do not? Answers to these questions will not only improve our understanding of MS, but will also have major implications for the treatment of MS. Recent data support a complex role for inflammation in disease pathogenesis, with good and bad effects. This article will review the supporting data and propose a hypothesis to explain this paradox or yin and yang of inflammation.


Nitric Oxide Multiple Sclerosis Experimental Autoimmune Encephalomyelitis Experimental Allergic Encephalomyelitis Clinical Relapse 


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  1. 1.
    Lublin FD et al (1996) Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 46:907–911PubMedCrossRefGoogle Scholar
  2. 2.
    Cserr HF et al (1992) Cervical lymphatics, the blood-brain barrier and the immunoreactivity of the brain: a new view. Immunol Today 13:507–512PubMedCrossRefGoogle Scholar
  3. 3.
    Raine CS (1995) Multiple sclerosis: TNF revisited, with promise. Nat Med 1:211–214PubMedCrossRefGoogle Scholar
  4. 4.
    Maini R et al (1999) Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 354:1932–1939PubMedCrossRefGoogle Scholar
  5. 5.
    Moreland LW et al (1997) Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 337:141–147PubMedCrossRefGoogle Scholar
  6. 6.
    Hodgson H (1999) Prospects of new therapeutic approaches for Crohn’s disease. Lancet 353:425–426PubMedCrossRefGoogle Scholar
  7. 7.
    Rutgeerts et al (1999) Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn’s disease. Gastroenterology 117:761–769PubMedCrossRefGoogle Scholar
  8. 8.
    van Oosten BW (1996) Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology 47:1531–1534PubMedCrossRefGoogle Scholar
  9. 9.
    The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group (1999) TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology 53:457–465CrossRefGoogle Scholar
  10. 10.
    Liu J et al (1998) TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination. Nat Med 4:78–83PubMedCrossRefGoogle Scholar
  11. 11.
    Dal Canto RA et al (1999) Local delivery of TNF by retrovirus-transduced T lymphocytes exacerbates experimental autoimmune encephalomyelitis. Clin Immunol 90:10–14CrossRefGoogle Scholar
  12. 12.
    Giovannoni G et al (1998) The potential role of nitric oxide in multiple sclerosis. Mult Scler 4:212–216PubMedGoogle Scholar
  13. 13.
    Bagasara O et al (1995) Activation of the inducible form of nitric oxide synthase in the brains of patients with multiple sclerosis. Proc Natl Acad Sci U S A 92:12041–12045CrossRefGoogle Scholar
  14. 14.
    Bö L et al (1994) Induction of nitric oxide synthase in demyelinating regions of multiple sclerosis brains. Ann Neurol 36:778–786PubMedCrossRefGoogle Scholar
  15. 15.
    Cross AH et al (1998) Peroxynitrite formation within the central nervous system in active multiple sclerosis. J Neuroimmunol 88:45–56PubMedCrossRefGoogle Scholar
  16. 16.
    Vladimirova O et al (1998) Oxidative damage to DNA in plaques of MS brains. Mult Scler 4:413–418PubMedGoogle Scholar
  17. 17.
    Johnson AW et al (1995) Evidence for increased nitric oxide production in multiple sclerosis. J Neurol Neurosurg Psychiatry 58:107PubMedCrossRefGoogle Scholar
  18. 18.
    Giovannoni G et al (1997) Raised serum nitrate and nitrite levels in patients with multiple sclerosis. J Neurol Sci 145:77–81PubMedCrossRefGoogle Scholar
  19. 19.
    Giovannoni G et al (1997) Raised serum nitrate and nitrite concentrations in patients with multiple sclerosis correlate with lower clinical and MRI levels of disease activity. J Neuroimmunol 80:182Google Scholar
  20. 20.
    Giovannoni G et al (1999) Increased urinary nitric oxide metabolites in patients with multiple sclerosis correlates with early and relapsing disease. Mult Scler 5:335–341PubMedGoogle Scholar
  21. 21.
    Cross AH et al (1994) Aminoguanidine, an inhibitor of inducible nitric oxide synthase, ameliorates experimental autoimmune encephalomyelitis in SJL mice. J Clin Invest 93:2684–2690PubMedCrossRefGoogle Scholar
  22. 22.
    Zielasek J et al (1995) Administration of nitric oxide synthase inhibitors in experimental autoimmune neuritis and experimental autoimmune encephalomyelitis. J Neuroimmunol 58:81–88PubMedCrossRefGoogle Scholar
  23. 23.
    Ruuls SR et al (1996) Aggravation of experimental allergic encephalomyelitis (EAE) by administration of nitric oxide (NO) synthase inhibitors. Clin Exp Immunol 103:467–474PubMedCrossRefGoogle Scholar
  24. 24.
    Fenyk-Melody JE et al (1998) Experimental autoimmune encephalomyelitis is exacerbated in mice lacking the NOS2 gene. J Immunol 160:2940–2946PubMedGoogle Scholar
  25. 25.
    Sahrbacher UC et al (1998) Mice with an inactivation of the inducible nitric oxide synthase gene are susceptible to experimental autoimmune encephalomyelitis. Eur J Immunol 28:1332–1338PubMedCrossRefGoogle Scholar
  26. 26.
    Ding M et al (1998) Antisense knockdown of inducible nitric oxide synthase inhibits induction of experimental autoimmune encephalomyelitis in SJL/J mice. J Immunol 160:2560–2564PubMedGoogle Scholar
  27. 27.
    Kolb H et al (1998) Nitric oxide in autoimmune disease: cytotoxic or regulatory mediator? Immunol Today 19:556–561PubMedCrossRefGoogle Scholar
  28. 28.
    Chang RH et al (1997) Nitric oxide increased interleukin-4 expression in T lymphocytes. Immunology 90:364–369PubMedCrossRefGoogle Scholar
  29. 29.
    Mattner F et al (1993) The interleukin-12 subunit P40 specifically inhibits effects of the interleukin-12 heterodimer. Eur J Immunol 23:2203–2208CrossRefGoogle Scholar
  30. 30.
    Sicher SC et al (1994) Inhibition of macrophage Ia expression by nitric oxide. J Immunol 153:1293–1300PubMedGoogle Scholar
  31. 31.
    Habib A et al (1997) Regulation of the expression of cyclooxygenase-2 by nitric oxide in rat peritoneal macrophages. J Immunol 158:3845–3851PubMedGoogle Scholar
  32. 32.
    Kubes P et al (1991) Nitric oxide — an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A 88:4651–4655PubMedCrossRefGoogle Scholar
  33. 33.
    Adams MR et al (1997) L-arginine reduces human monocyte adhesion to vascular endothelium and endothelial expression of cell adhesion molecules. Circulation 95:662–668PubMedCrossRefGoogle Scholar
  34. 34.
    Okuda Y et al (1997) Nitric oxide via an inducible isoform of nitric oxide synthase is a possible factor to eliminate inflammatory cells from the central nervous system of mice with experimental allergic encephalomyelitis. J Neuroimunol 73:107–116CrossRefGoogle Scholar
  35. 35.
    Nathan C (1995) Inducible nitric oxide synthase: regulation subserves function. Curr Top Microbiol Immunol 196:1–4PubMedCrossRefGoogle Scholar
  36. 36.
    Wajant H et al (1999) TNF receptor associated factors in cytokine signaling. Cytokine Growth Factor Rev 10:15–26PubMedCrossRefGoogle Scholar
  37. 37.
    Stefanelli C et al (1999) Nitric oxide can function as either a killer molecule or an antiapoptotic effector in cardiomyocytes. Biochim Biophys Acta 1450:406–413PubMedCrossRefGoogle Scholar
  38. 38.
    Kerschensteiner M et al (1999) Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation? J Exp Med 189:865–870PubMedCrossRefGoogle Scholar
  39. 39.
    Ye P et al (1999) Insulin-like growth factor I protects oligodendrocytes from tumor necrosis factor-alpha-induced injury. Endocrinology 140:3063–3072PubMedCrossRefGoogle Scholar
  40. 40.
    Wilczak N et al (1997) Insulin-like growth factor-I receptors in normal appearing white matter and chronic plaques in multiple sclerosis. Brain Res 772:243–246PubMedCrossRefGoogle Scholar
  41. 41.
    Gveric D et al (1999) Insulin-like growth factors and binding proteins in multiple sclerosis plaques. Neuropathol Appl Neurobiol 25:215–225PubMedCrossRefGoogle Scholar
  42. 42.
    Cannella B (1999) Neuregulin and erbB receptor expression in normal and diseased human white matter. J Neuroimmunol 100:233–242PubMedCrossRefGoogle Scholar
  43. 43.
    Cohen IR et al (1999) Autoimmune maintenance and neuroprotection of the central nervous system. J Neuroimmunol 100:111–114PubMedCrossRefGoogle Scholar
  44. 44.
    Lucchinetti CF et al (1996) Distinct patterns of multiple sclerosis pathology indicates heterogeneity on pathogenesis. Brain Pathol 6:259–274PubMedCrossRefGoogle Scholar
  45. 45.
    Mann CL et al (2000) Glutathione S-transferase polymorphisms in MS: their relationship to disability. Neurology 54:552–557PubMedCrossRefGoogle Scholar
  46. 46.
    Losseff NA et al (1996) Progressive cerebral atrophy in multiple sclerosis. A serial MRI study. Brain 119:2009–2019PubMedCrossRefGoogle Scholar
  47. 47.
    Coles AJ et al (1999) Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol 46:296–304PubMedCrossRefGoogle Scholar
  48. 48.
    Eberhardt K et al (1998) Clinical course and remission rate in patients with early rheumatoid arthritis: relationship to outcome after 5 years. Br J Rheumatol 37:1324–1329PubMedCrossRefGoogle Scholar
  49. 49.
    Levin M et al (1999) Understanding the genetic basis of susceptibility to mycobacterial infection. Proc Assoc Am Physicians 111:308–312PubMedCrossRefGoogle Scholar

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© Springer-Verlag Italia 2004

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  • G. Giovannoni

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