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Neuroaxonal dystrophy in HTLV-1-associated myelopathy/tropical spastic paraparesis: neuropathologic and neuroimmunologic correlations

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Summary

Detailed neuropathologic and immunohistologic analysis of a case of serologically and polymerase chain reaction-confirmed human immunodeficiency virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is reported in a 73-year-old North American black woman. In addition to the usual neuropathologic features of HAM/TSP, including tractal degeneration of the spinal cord, leptomeningeal and perivascular fibrosis, perivascular demyelination and chronic inflammation, neuroaxonal spheroids were prominent in the spinal cord. Neuroaxonal dystrophy was characterized by neurofilamentous masses that were immunoreactive for phosphorylated neurofilament epitopes, but not ubiquitin. Neuroimmunologic analysis of the inflammatory reaction revealed a prevalence of CD8+ T cells and class I major histocompatibility molecules (MHC) (HLA-ABC and β2-microglobulin), but very few CD4+ T cells. Microglia were highly reactive for class II MHC (HLA-DRα) and this was attributed to activation, rather than CD4 interaction, since CD4 presence was minimal. Inflammatory cytokine immunoreactivity was also detected in glia. It is concluded that the cumulative effects of cytotoxic T cell (CD8) infiltration and the possible involvement of cytokines were responsible for the unusual degree of neuroaxonal dystrophy and vascular fibrosis, as well as the observed demyelination in this case.

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References

  1. Bhagavati S, Ehrlich G, Kula RW, Kwok S, Sninsky J, Udani V, Poiesz BJ (1988) Detection of human T-cell lymphoma/leukemia virus type I DNA and antigen in spinal fluid and blood of patients with chronic progressive myelopathy. N Engl J Med 318:1141–1147

    Google Scholar 

  2. Bhigjee AI, Wiley CA, Wachsman W, Anenomori T, Pirie D, Bill PLA, Windsor I (1991) HTLV-I-associated myelopathy: clinicopathologic correlation with localization of provirus to spinal cord. Neurology 41:1990–1992

    Google Scholar 

  3. Dalakas MC, Stoner G, Elder G, Geroni M, Madden D, Roman G, Sever JL (1988) Tropical spastic paraparesis: clinical, immunological, and virological studies in two patients from Martinique. Ann Neurol 23 [Suppl]:S136–142

    Google Scholar 

  4. Denel TF (1987) Polypeptide growth factors: roles in normal and abnormal cell growth. Annu Rev Cell Biol 3:443

    Google Scholar 

  5. Fujihara K, Itoyama Y, Yu F, Kubo C, Goto I (1991) Cellular immune surveillance against HTLV-I infected T lymphocytes in HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). J Neurol Sci 105:99–107

    Google Scholar 

  6. Garth DE, Greenberg S, Abbott MA (1990) Detection of human T cell lymphoma/leukemia viruses. In: Iniss MA, Gelfand DH, Sninsky JJ, White TJ (eds) PCR protocols. Academic Press, New York, pp 325–336

    Google Scholar 

  7. Gassain A, Barin F, Vernant JC, Gout O, Maurs L, Calender A, De-Thé G (1985) antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet II:407–410

    Google Scholar 

  8. Gessain A, Saal F, Giron ML, Lasneret J, Lagaye S, Gout O, De-Thé G, Sigaux F, Peries J (1990) Cell surface phenotype and human T lymphotropic virus type I antigen expression in 12 T cell lines derived from peripheral blood and cerebrospinal fluid of West Indian, Guyanese and African patients with tropical spastic paraparesis. J Gen Virol 71:333–341

    Google Scholar 

  9. Griffin JW, Cork LC, Hoffman PN, Price DL (1984) Experimental models of motor neuron degeneration. In: Dyck PJ, Thomas PK, Lambert EH, Bunge R (eds) Peripheral Neuropathy, 2nd edn. Saunders, Philadelphia, pp 621–635

    Google Scholar 

  10. Hirayama M, Miyadai T, Yokochi T, Sato K, Kubota T, Jida M, Fujiki N (1988) Infection of human T-lymphotropic virus type I to astrocytes in vitro with induction of the class II major histocompatibility complex. Neurosci Lett 92:34–39

    Google Scholar 

  11. Hsu SM, Raine L, Fanger H (1981) A comparative study of the peroxidase-antiperoxidase method and an avidin-biotin complex method for studying polypeptide hormones with radioimmunoassay antibodies. Am J Clin Pathol 75:734–738

    Google Scholar 

  12. Ijichi S, Eiraku N, Osame M, Izumo S, Kubota R, Maruyama I, Matsumoto M, Niimura T, Sonoda S (1989) Activated T lymphocytes in cerebrospinal fluid of patients with HTLV-I-associated myelopathy (HAM/TSP). J Neuroimmunol 25:251–254

    Google Scholar 

  13. Itoyama Y, Kira J, Fujii N, Goto I, Yamamoto N (1989) Increases in helper inducer T cells and activated T cells in HTLV-I-associated myelopathy. Ann Neurol 26:257–262

    Google Scholar 

  14. Iwasaki Y (1990) Pathology of chronic myelopathy associated with HTLV-I infection (HAM/TSP). J Neurol Sci 96:103–123

    Google Scholar 

  15. Iwasaki Y, Ohara Y, Kobayashi I, Akizuki S (1992) Infiltration of helper/inducer T lymphocytes heralds central nervous system damage in human T-cell leukemia virus infection. Am J Pathol 140:1003–1008

    Google Scholar 

  16. Izumo S, Higuchi I, Ijichi T, Tashiro A, Osame M, Yoshimi K, Motokura F, Okumuma A (1989) Neuropathological study in two autopsy cases of HTLV-I associated myelopathy (HAM). In: Iwasaki Y (ed) Neuropathology of HAM/TSP in Japan. Proceedings of the First Workshop on Neuropathology of Retrovirus Infections, Tohoku University Medical Journal (Suppl), Sendai, pp 7–17

  17. Jacobson S (1992) Immune response to retroviruses in the central nervous system. Semin Neurosci 4:285–290

    Google Scholar 

  18. Jacobson S, Zaninovic V, Mora C, Rodgers-Johnson P, Sheremata WA, Gibbs CJ Jr., Gajdusek DC, McFarlin DE (1988) Immunological findings in neurological diseases associated with antibodies to HTLV-I: activated lymphocytes in tropical spastic paraparesis. Ann Neurol 23 [Suppl]:S196–200

    Google Scholar 

  19. Jacobson S, Raine CS, Mingioli ES, McFarlin DE (1988) Isolation of an HTLV-I-like retrovirus from patients with tropical spastic paraparesis. Nature 331:540–543

    Google Scholar 

  20. Jacobson S, Shida H, McFarlin DE, Fauci AS, Koenig S (1990) Circulating CD8+ cytotoxic T lymphocytes specific for HTLV-I pX in patients with HTLV-I-associated neurological disease. Nature 348:245–248

    Google Scholar 

  21. Jacobson S, Gupta A, Mattson D, Mingioli E, McFarlin DE (1990) Immunological studies in tropical spastic paraparesis. Ann Neurol 27:149–156

    Google Scholar 

  22. Kira J, Itoyama Y, Koyanagi Y, Tateishi J, Kishikawa M, Akizuki S, Kobayashi I, Toki N, Sueishi K, Sato H, Sakaki Y, Yamamoto N, Goto I (1992) Presence of HTLV-I proviral DNA in central nervous system of patients with HTLV-I-associated myelopathy. Ann Neurol 31:39–45

    Google Scholar 

  23. Kobayashi I, Ota K, Yamamoto K, Murakami H, Maruyama S, Kasazima T, Masuda A (1989) Clinical and pathological observations in HTLV-I associated myelopathy. In: Iwasaki Y (ed) Neuropathology of HAM/TSP in Japan. Proceedings of the First Workshop on Neuropathology of Retrovirus Infections, Tohoku University Medical Journal (Suppl), Sendai, pp 33–46

  24. Ksiezak-Reding H, Dickson DW, Davies P, Yen SH (1987) Recognition of tau epitopes by anti-neurofilament antibodies that stain Alzheimer neurofibrillary tangles. Proc Natl Acad Sci USA 84:3410–3414

    Google Scholar 

  25. Le J, Vilcek J (1987) Tumor necrosis factor and interleukin 1: cytokines with multiple overlapping biological activities. Lab Invest 56:234–248

    Google Scholar 

  26. Macchi B, Caronti B, Pezzella M, Bonmassar E, Lauro G (1991) Effect of human T lymphotropic retrovirus-I exposure on cultured human glioma cell lines. Acta Neuropathol 81:670–674

    Google Scholar 

  27. Matsumoto M, Sugimoto M, Nakashima H, Imamura F, Kawano O, Uyama E, Takatsu K, Araki S (1990) Spontaneous T cell proliferation and release of soluble interleukin-2 receptors in patients with HTLV-I-associated myelopathy. Am J Trop Med Hyg 42:365–373

    Google Scholar 

  28. Mattiace LA, Davies P, Dickson DW (1990) Detection of HLA-DR on microglia in the human brain is a function of both clinical and technical factors. Am J Pathol 136:1101–1114

    Google Scholar 

  29. Moore GRW, Traugott U, Scheinberg LC, Raine CS (1989) Tropical spastic paraparesis: a model of virus-induced, cytotoxic T-cell-mediated demyelination? Ann Neurol 26:523–530

    Google Scholar 

  30. 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

    Google Scholar 

  31. Parhad IM, Griffin JW, Price DL, Clark AW, Cork LC, Miller NR, Hoffman PN (1982) Intoxication with β, β'-iminodipropionitrile. A model of optic disc swelling. Lab Invest 46:186–195

    Google Scholar 

  32. Robert AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta LA, Falanga V, Kehrl JH, Fauci AS (1986) Transforming growth factor type β: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation formation in vitro. Proc Natl Acad Sci USA 83:4167–4171

    Google Scholar 

  33. Robertson WB, Cruickshank EK (1972) Jamaican (tropical) myeloneuropathy. In: Minckler J (ed) Pathology of the nervous system, vol 3. McGraw-Hill, New York, pp 2466–2476

    Google Scholar 

  34. Sawada M, Suzumura A, Yoshida M, Marunouchi T (1990) Human T-cell leukemia virus type I trans activator induces class I major histocompatibility complex antigen expression in glial cells. J Virol 64:4002–4006

    Google Scholar 

  35. Selmaj KW, Farooq M, Norton WT, Raine CS, Brosnan CF (1990) Proliferation of astrocytes in vitro in response to cytokines: a primary role for tumor necrosis factor. J Immunol 144:129–135

    Google Scholar 

  36. Smith CR, Dickson D, Samkoff L (1992) Recurrent encephalopathy and seizures in a US native with HTLV-1 associated myelopathy/tropical spastic paraparesis: a clinicopathologic study. Neurology 42:658–661

    Google Scholar 

  37. Varga J, Jimenez SA (1986) Stimulation of normal human fibroblast collagen production and processing by transforming growth factor-β. Biochem Biophys Res Commun 138:974–980

    Google Scholar 

  38. Vernant JC, Maurs L, Gessain A, Barin F, Gout O, Delaporte JM, Sanhadji K, Buisson G, De-Thé G (1987) Endemic tropical spastic parapapresis associated with human T-lymphotropic virus type I: a clinical and seroepidemiological study of 25 cases. Ann Neurol 21:123–130

    Google Scholar 

  39. Watabe K, Saida T, Kim SU (1989) Human and simian glial cells infected by human T-lymphotropic virus type I in culture. J Neuropathol Exp Neurol 48:610–619

    Google Scholar 

  40. Yoshida M, Osame M, Kawai H, Toita M, Kuwasaki N, Nishida Y, Hiraki Y, Takahashi K, Nomura K, Sonoda S, Eiraku N, Ijichi S, Usuku K (1989) Increased replication of HTLV-I in HTLV-I-associated myelopathy. Ann Neurol 26:331–335

    Google Scholar 

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Authors and Affiliations

  1. Department of Pathology (Neuropathology), Albert Einstein College of Medicine, 1300 Morris Park Avenue, 10461, Bronx, NY, USA

    Elizabeth Wu, Dennis W. Dickson & Cedric S. Raine

  2. Department of Neurology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, 10461, Bronx, NY, USA

    Dennis W. Dickson & Cedric S. Raine

  3. Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Avenue, 10461, Bronx, NY, USA

    Cedric S. Raine

  4. the Rose F. Kennedy Center of Research in Mental Retardation and Human Development, Albert Einstein College of Medicine, 1300 Morris Park Avenue, 10461, Bronx, NY, USA

    Elizabeth Wu, Dennis W. Dickson & Cedric S. Raine

  5. Neuroimmunology Branch, NINDS, National Institutes of Health, Bethesda, Maryland, USA

    Steven Jacobson

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  1. Elizabeth Wu
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  2. Dennis W. Dickson
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  4. Cedric S. Raine
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Supported in part by grants NS 07098, NS 08952, NS 11920 and MH 47667 from the NIH; and RG 1001-G-7 from the National Multiple Sclerosis Society.

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Wu, E., Dickson, D.W., Jacobson, S. et al. Neuroaxonal dystrophy in HTLV-1-associated myelopathy/tropical spastic paraparesis: neuropathologic and neuroimmunologic correlations. Acta Neuropathol 86, 224–235 (1993). https://doi.org/10.1007/BF00304136

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  • DOI: https://doi.org/10.1007/BF00304136

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