Journal of NeuroVirology

, Volume 8, Issue 5, pp 359–364

Pathological mechanisms of human T-cell lymphotropic virus type I-associated myelopathy (HAM/TSP)



The recent studies have greatly improved our understanding of the pathological mechanisms of human T cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The pathological mechanisms of HAM/TSP based on the histopathological, immunological, and molecular analysis with emphasis on the longitudinal alterations of the disease will be discussed. Immunohistological examination revealed the existence and the activation both of HTLV-I-infected CD4+ cells and HTLV-I-specific CD8+ cytotoxic T lymphocytes in the spinal cord lesions, which suggest that they play an important role in the pathogenesis. Increased expression of several cytokines, Fas/Fas ligand, adhesion molecules, and molecules influencing T cell migration in the lesions have been reported. These cell infiltrates and cytokines they secrete in the lesions may damage bystander neural tissue. Furthermore, longitudinal alterations in the affected spinal cords suggest that the inflammatory process is gradually decreased. Epidemiological studies show that less than 5% of infected individuals develop HAM/TSP and indicate that increased proviral load of HTLV-I is a strong predictor for the development of HAM/TSP. A recent study has shown that the autoantibody for the ribonuclear protein-A1 can cross-react with HTLV-I Tax protein and inhibit neuronal firing ex vivo, indicating that a molecular mimicry of the humoral immune response may be involved in the pathogenesis of HAM/TSP. Based on these studies, two hypotheses can be proposed for the pathogenesis of HAM/TSP, where cellular and humoral immune responses both play important roles.


human T cell lymphotropic virus type I (HTLV-I) HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) cytotoxic T lymphocytes autoantigen pathogenesis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abe M, Umehara F, Kubota R, Moritoyo T, Izumo S, Osame M (1999). Activation of macrophage/microglias with expression of MRP8 and MRP14 is associated with the lesional activities in the spinal cord lesions in HTLV-I associated myelopathy. J Neurol 246: 358–364.CrossRefPubMedGoogle Scholar
  2. Anderson P, Nagler-Anderson C, O’Brien C, Levine H, Watkins S, Slayter HS, Blue ML, Schlossman SF (1990). A monoclonal antibody reactive with a 15-kDa cytoplasmic granule-associated protein defines a subpopulation of CD8+ T lymphocytes. J Immunol 144: 574–582.PubMedGoogle Scholar
  3. Bangham C (2000). The immune response to HTLV-I. Curr Opin Immunol 12: 397–402.CrossRefPubMedGoogle Scholar
  4. Furukawa Y, Yamashita M, Usuku K, Izumo S, Nakagawa M, Osame M (2000). Phylogenetic subgroups of HTLV-I in tax gene and their association with different risk to HTLV-I-associated myelopathy/tropical spastic parapraresis. J Infect Dis 182: 1343–1349.CrossRefPubMedGoogle Scholar
  5. Gessain A, Barin F, Vernant JC, Gout O, Maurs L, Calender A, de The G (1985). Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet 2: 407–410.CrossRefPubMedGoogle Scholar
  6. Giraudon P, Burt S, Bernard A, Thomas N, Beeline MF (1996). Extracellular matrix-remodeling metalloproteinases and infection of the central nervous system with retrovirus human T-lymphotropic virus type I (HTLV-I). Prog Neurobiol 49: 169–184.CrossRefPubMedGoogle Scholar
  7. Hanon E, Stinchcombe JC, Saito M, Asquith BE, Taylor GP, Tanaka Y, Weber JN, Griffiths GM, Bangham CR (2000). Fratricide among CD8(+) T lymphocytes naturally infected with human T cell lymphotropic virus type I. Immunity 13: 657–664.CrossRefPubMedGoogle Scholar
  8. Inoue A, Koh CS, Sakai T, Yamazaki M, Yanagisawa N, Usuku K, Osame M (1997). Detection of the soluble form of the Fas molecule in patients with multiple sclerosis and human T-lymphotropic virus type I-associated myelopathy. J Neuroimmunol 75: 141–146.CrossRefPubMedGoogle Scholar
  9. Izumo S, Ijichi T, Higuchi I, Tashiro A, Takahashi K, Osame M (1992). Neuropathology of HTLV-I-associated myelopathy: A report of two autopsy cases. Acta Paediatr Jpn 34: 358–364.PubMedGoogle Scholar
  10. Jacobson S, Shida H, McFarlin DE, Fauci AS, Koenig S (1990). Circulating CD8+ cytotoxic lymphocytes specific for HTLV-I in patients with HTLV-I associated neurological disease. Nature 348: 245–248.CrossRefPubMedGoogle Scholar
  11. Jeffery KJM, Usuku K, Hall SE, Matsumoto W, Taylor GP, Procter J, Bunce M, Ogg GS, Welsh KI, Weber JN, Lloyd AL, Nowak MA, Nagai M, Kodama D, Izumo S, Osame M, Bangham CR (1999). HLA alleles determine human T-lymphotropic virus-I (HTLV-I) proviral load and the risk of HTLV-I-associated myelopathy. Proc Natl Acad Sci USA 96: 3848–3853.CrossRefPubMedGoogle Scholar
  12. Kaplan J, Osame M, Kubota H (1990). The risk of developing HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) among persons infected with HTLV-I. J AIDS 3: 1096–1101.Google Scholar
  13. Kawahigashi N, Furukawa Y, Saito M, Usuku K, Osame M (1998). Predominant expression of Fas ligand mRNA in CD8+ T lymphocytes in patients with HTLV-I-associated myelopathy. J Neuroimmunol 90: 199–206.CrossRefPubMedGoogle Scholar
  14. Kubota R, Osame M, Jacobson S (2000). Retrovirus: Human T-cell lymphotropic virus type I-associated diseases and immune dysfunction. In: Effects of Microbes on the Immune System. Cunningham MW, Fujinami RS (eds). Lippincott Williams & Wilkins: Philadelphia, pp 349–371.Google Scholar
  15. Kubota R, Umehara F, Izumo S, Ijichi S, Matsumuro K, Yashiki S, Fujiyoshi T, Sonoda S, Osame M (1994). HTLV-I proviral DNA amount correlates with infiltrating CD4+ lymphocytes in the spinal cord from patients with HTLV-I-associated myelopathy. J Neuroimmunol 53: 23–29.CrossRefPubMedGoogle Scholar
  16. Lehky TJ, Fox CH, Koenig S, Levin MC, Flerlage N, Izumo S, Sato E, Raine CS, Osame M, Jacobson S (1995). Detection of human T-lymphotropic virus type I (HTLV-I) tax mRNA in the central nervous system of HTLV-I-associated myelopathy/tropical spastic paraparesis patients by in situ hybridization. Ann Neurol 37: 167–175.CrossRefPubMedGoogle Scholar
  17. Levin MC, Lee SM, Kalume F, Morcos Y, Dohan FC, Jr, Hasty KA, Callaway JC, Zunt J, Desiderio DM, Stuart JM (2002). Autoimmunity due to molecular mimicry as a cause of neurological disease. Nat Med 8: 509–513.CrossRefPubMedGoogle Scholar
  18. Matsuoka E, Takenouchi H, Hashimoto K, Kashio N, Moritoyo T, Higuchi I, Isashiki Y, Sato E, Osame M, Izumo S (1998). Perivascular T-cells are infected with HTLV-I in the spinal cord lesions with HAM/TSP: Double staining of immunohistochemistry and PCR in situ hybridization. Acta Neuropathol 96: 340–346.CrossRefPubMedGoogle Scholar
  19. Moe Moe Aye, Matsuoka E, Moritoyo Umehara F, Suehara M, Hokezu Y, Yamanaka H, Isashiki Y, Osame M, Izumo S (2000). Histopathological analysis of four autopsy cases of HTLV-I-associated myelopathy/tropical spastic paraparesis: Inflammatory changes occur simultaneously in the entire central nervous system. Acta Neuropathol 100: 245–252.CrossRefGoogle Scholar
  20. Moritoyo T, Reinhart TA, Moritoyo H, Sato E, Izumo S, Osame M, Haase AT (1996). Human T-lymphotropic virus type I-associated myelopathy and tax gene expression in CD4+ T lymphocytes. Ann Neurol 40: 84–90.CrossRefPubMedGoogle Scholar
  21. Nagai M, Brennan MB, Sakai JA, Mora CA, Jacobson S (2001). CD8+ T cells are an in vivo reservoir for human T-cell lymphotropic virus type I. Blood 98: 1858–1861.CrossRefPubMedGoogle Scholar
  22. Nagai M, Jacobson S (2001). Immunopathogenesis of human T cell lymphotropic virus type I-associated myelopathy. Curr Opin Neurol 14: 381–386.CrossRefPubMedGoogle Scholar
  23. Nagai M, Usuku K, Matsumoto W, Kodama D, Takenouchi N, Moritoyo T, Hashiguchi S, Ichinose M, Bangham CR, Izumo S, Osame M (1998). Analysis of HTLV-I proviral load in 202 HAM/TSP patients and 243 asymptomatic HTLV-I carriers: High proviral load strongly predisposes to HAM/TSP. J Neuro Virol 4: 586–593.Google Scholar
  24. Nakagawa M, Izumo S, Ijichi S, Kubota H, Arimura K, Kawabata M, Osame M (1995). HTLV-I-associated myelopathy: Analysis of 213 patients based on clinical features and laboratory findings. J NeuroVirol 1: 50–61.CrossRefPubMedGoogle Scholar
  25. Osame M (1990). Review of WHO Kagoshima Meeting and Diagnostic Guidelines for HAM/TSP. In: Human Retrovirology: HTLV. Blattner WA (ed). Raven Press: New York, pp 191–197.Google Scholar
  26. Osame M, Arima H, Norimatsu K, Kawahira, Okatsu Y, Nagamatsu K, Igata A (1975). Epidemiostatistical studies of muscular atrophy in Southern Kyushu (Kagoshima and Okinawa prefectures). Jpn J Med 14: 230–231.Google Scholar
  27. Osame M, Igata A (1989). The history of discovery and clinico-epidemiology of HTLV-I-associated myelopathy (HAM). Jpn J Med 28: 412–414.PubMedGoogle Scholar
  28. Osame M, Matsumoto M, Usuku K, Izumo S, Ijichi N, Amitani H, Tara M, Igata A (1987). Chronic progressive myelopathy associated with elevated antibodies to human T-lymphotropic virus type I and adult T-cell leukemia like cells. Ann Neurol 21: 117–122.CrossRefPubMedGoogle Scholar
  29. Osame M, Usuku K, Izumo S, Ijichi N, Amitani H, Igata A, Matsumoto M, Tara M (1986). HTLV-I associated myelopathy, a new clinical entity. Lancet I: 1031–1032.CrossRefGoogle Scholar
  30. Saito M, Nakamura N, Nagai M, Shirakawa K, Sato H, Kawahigashi N, Furukawa Y, Usuku K, Nakagawa M, Izumo S, Osame M (1998). Increased levels of soluble Fas ligand in CSF of rapidly progressive HTLV-I-associated myelopathy/tropical spastic paraparesis. J Neuroimmunol 98: 221–226.CrossRefGoogle Scholar
  31. Tian Q, Streuli M, Saito H, Schlossman SF, Anderson P (1991). A polyadenylate binding protein localized to the granules of cytolytic lymphocytes induces DNA fragmentation in target cells. Cell 67: 629–639.CrossRefPubMedGoogle Scholar
  32. Umehara F, Abe M, Koeeda Y, Izumo S, Osame M (2000). Axonal damage revealed by accumulation of β-amyloid precursor protein in HTLV-I-associated myelopathy. J Neurol Sci 176: 95–101.CrossRefPubMedGoogle Scholar
  33. Umehara F, Itoh K, Michizono K, Abe M, Izumo S, Osame M (2002). Involvement of Fas/Fas ligand system in the spinal cords of HTLV-I-associated myelopathy. Acta Neuropathol 91: 343–350.CrossRefGoogle Scholar
  34. Umehara F, Izumo S, Nakagawa M, Ronquillo AT, Takahashi K, Sato E, Osame M (1993). Immunocytochemical analysis of the cellular infiltrate in the spinal cord lesions in HTLV-I-associated myelopathy. J Neuropathol Exp Neurol 52: 424–430.CrossRefPubMedGoogle Scholar
  35. Umehara F, Izumo S, Ronquillo AT, Matsumuro K, Osame M (1994a). Cytokine expression in the spinal cord lesions in HTLV-I-associated myelopathy. J Neuropathol Exp Neurol 53: 72–77.CrossRefPubMedGoogle Scholar
  36. Umehara F, Izumo S, Takeya M, Sato E, Osame M (1996). Expression of adhesion molecules and monocyte chemoattractant protein-1 (MCP-1) in the spinal cord lesions in HTLV-I-associated myelopathy. Acta Neuropathol 91: 343–350.CrossRefPubMedGoogle Scholar
  37. Umehara F, Nakamura A, Izumo S, Kubota R, Ijichi S, Kashio N, Hashimoto K, Usuku K, Sato E, Osame M (1994b). Apoptosis of T-lymphocytes in the spinal cord lesions in HTLV-I-associated myelopathy: A possible mechanism to control viral infection in the central nervous system. J Neuropathol Exp Neurol 53: 617–624.CrossRefPubMedGoogle Scholar
  38. Umehara F, Okada Y, Fujimoto N, Abe M, Izumo S, Osame M (1998). Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in HTLV-I-associated myelopathy. J Neuropathol Exp Neurol 57: 839–849.CrossRefPubMedGoogle Scholar
  39. World Health Organization (1989). Report of the scientific group on HTLV-I and associated diseases, Kagoshima, Japan, December 1988. Available from Manila, Philippines: World Health Organization, March 1989; Virus diseases. Human T-lymphotropic virus type I, HTLV-1. WHO Wkly Epidemiol Rec 49: 382–383. (Abstract.)Google Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2002

Authors and Affiliations

  1. 1.Third Department of Internal MedicineKagoshima University Faculty of MedicineKagoshimaJapan

Personalised recommendations