1887

Abstract

Up to 15% of free-ranging mule deer in northeastern Colorado and southeastern Wyoming, USA, are afflicted with a prion disease, or transmissible spongiform encephalopathy (TSE), known as chronic wasting disease (CWD). CWD is similar to a subset of TSEs including scrapie and variant Creutzfeldt–Jakob disease in which the abnormal prion protein isoform, PrP, accumulates in lymphoid tissue. Experimental scrapie studies have indicated that this early lymphoid phase is an important constituent of prion replication interposed between mucosal entry and central nervous system accumulation. To identify the lymphoid target cells associated with PrP, we used triple-label immunofluorescence and high-resolution confocal microscopy on tonsils from naturally infected deer in advanced disease. We detected PrP primarily extracellularly in association with follicular dendritic and B cell membranes as determined by frequent co-localization with antibodies against membrane bound immunoglobulin and CD21. There was minimal co-localization with cytoplasmic labels for follicular dendritic cells (FDC). This finding could indicate FDC capture of PrP, potentially in association with immunoglobulin or complement, or PrP conversion on FDC. In addition, scattered tingible body macrophages in the germinal centre contained coarse intracytoplasmic aggregates of PrP, reflecting either phagocytosis of PrP on FDC processes, apoptotic FDC or B cells, or actual PrP replication within tingible body macrophages. To compare lymphoid cell targets in early and advanced disease, we also examined: (i) PrP distribution in lymphoid cells of fawns within 3 months of oral CWD exposure and (ii) tonsil biopsies from preclinical deer with naturally acquired CWD. These studies revealed that the early lymphoid cellular distribution of PrP was similar to that in advanced disease, i.e. in a pattern suggesting FDC association. We conclude that in deer, PrP accumulates primarily extracellularly and associated with FDCs and possibly B cells – a finding which raises questions as to the cells responsible for pathological prion production.

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2002-10-01
2019-10-22
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References

  1. Andreoletti, O., Berthon, P., Marc, D., Sarradin, P., Grosclaude, J., van Keulen, L., Schelcher, F., Elsen, J. M. & Lantier, F. ( 2000; ). Early accumulation of PrPSc in gut-associated lymphoid and nervous tissues of susceptible sheep from a Romanov flock with natural scrapie. Journal of General Virology 81, 3115-3126.
    [Google Scholar]
  2. Bachelet, M., Adrie, C. & Polla, B. S. ( 1998; ). Macrophages and heat shock proteins. Research in Immunology 149, 727-732.[CrossRef]
    [Google Scholar]
  3. Betjes, M. G., Haks, M. C., Tuk, C. W. & Beelen, R. H. ( 1991; ). Monoclonal antibody EBM11 (anti-CD68) discriminates between dendritic cells and macrophages after short-term culture. Immunobiology 183, 79-87.[CrossRef]
    [Google Scholar]
  4. Bolton, D. C., Rudelli, R. D., Currie, J. R. & Bendheim, P. E. ( 1991; ). Copurification of Sp33–37 and scrapie agent from hamster brain prior to detectable histopathology and clinical disease. Journal of General Virology 72, 2905-2913.[CrossRef]
    [Google Scholar]
  5. Brown, K. L., Stewart, K., Ritchie, D. L., Mabbott, N. A., Williams, A., Fraser, H., Morrison, W. I. & Bruce, M. E. ( 1999; ). Scrapie replication in lymphoid tissues depends on prion protein-expressing follicular dendritic cells. Nature Medicine 5, 1308-1312.[CrossRef]
    [Google Scholar]
  6. Brown, K. L., Stewart, K., Ritchie, D., Fraser, H., Morrison, W. I. & Bruce, M. E. ( 2000; ). Follicular dendritic cells in scrapie pathogenesis. Archives of Virology Supplementum 16, 13-21.
    [Google Scholar]
  7. Bruce, M. E., McConnell, I., Will, R. G. & Ironside, J. W. ( 2001; ). Detection of variant Creutzfeldt–Jakob disease infectivity in extraneural tissues. Lancet 358, 208-209.[CrossRef]
    [Google Scholar]
  8. Carbone, A., Poletti, A., Volpe, R. & Manconi, R. ( 1988; ). S-100 protein detection in ‘follicular macrophages’ of mouse lymphoid organs by ABC immunoperoxidase method. International Journal of Biological Markers 3, 36-40.
    [Google Scholar]
  9. Foster, J., Goldmann, W., Parnham, D., Chong, A. & Hunter, N. ( 2001; ). Partial dissociation of PrPSc deposition and vacuolation in the brains of scrapie and BSE experimentally affected goats. Journal of General Virology 82, 267-273.
    [Google Scholar]
  10. Fray, M. D., Supple, E. A., Morrison, W. I. & Charleston, B. ( 2000; ). Germinal centre localization of bovine viral diarrhoea virus in persistently infected animals. Journal of General Virology 81, 1669-1673.
    [Google Scholar]
  11. Fujiwara, M., Tsunoda, R., Shigeta, S., Yokota, T. & Baba, M. ( 1999; ). Human follicular dendritic cells remain uninfected and capture human immunodeficiency virus type 1 through CD54–CD11a interaction. Journal of Virology 73, 3603-3607.
    [Google Scholar]
  12. Garssen, G. J., Van Keulen, L. J., Farquhar, C. F., Smits, M. A., Jacobs, J. G., Bossers, A., Meloen, R. H. & Langeveld, J. P. ( 2000; ). Applicability of three anti-PrP peptide sera including staining of tonsils and brainstem of sheep with scrapie. Microscopy Research and Technique 50, 32-39.[CrossRef]
    [Google Scholar]
  13. Giorno, R. ( 1985; ). Immunohistochemical analysis of the distribution of vimentin in human peripheral lymphoid tissues. Anatomical Record 211, 43-47.[CrossRef]
    [Google Scholar]
  14. Grouard, G., Durand, I., Filgueira, L., Banchereau, J. & Liu, Y. J. ( 1996; ). Dendritic cells capable of stimulating T cells in germinal centres. Nature 384, 364-367.[CrossRef]
    [Google Scholar]
  15. Hadlow, W. J., Kennedy, R. C. & Race, R. E. ( 1982; ). Natural infection of Suffolk sheep with scrapie virus. Journal of Infectious Diseases 146, 657-664.[CrossRef]
    [Google Scholar]
  16. Heggebø, R., Press, C. M., Gunnes, G., Lie, K. I., Tranulis, M. A., Ulvund, M., Groschup, M. H. & Landsverk, T. ( 2000; ). Distribution of prion protein in the ileal Peyer’s patch of scrapie-free lambs and lambs naturally and experimentally exposed to the scrapie agent. Journal of General Virology 81, 2327-2337.
    [Google Scholar]
  17. Heinen, E., Tsunoda, R., Marcoty, C., Antoine, N., Bosseloir, A., Cormann, N. & Simar, L. ( 1993; ). Follicular dendritic cells: isolation procedures, short and long term cultures. Advances in Experimental Medicine and Biology 329, 333-338.
    [Google Scholar]
  18. Hill, A. F., Butterworth, R. J., Joiner, S., Jackson, G., Rossor, M. N., Thomas, D. J., Frosh, A., Tolley, N., Bell, J. E., Spencer, M., King, A., Al-Sarraj, S., Ironside, J. W., Lantos, P. L. & Collinge, J. ( 1999; ). Investigation of variant Creutzfeldt–Jakob disease and other human prion diseases with tonsil biopsy samples. Lancet 353, 183-189.[CrossRef]
    [Google Scholar]
  19. Hilton, D. A., Fathers, E., Edwards, P., Ironside, J. W. & Zajicek, J. ( 1998; ). Prion immunoreactivity in appendix before clinical onset of variant Creutzfeldt–Jakob disease [letter]. Lancet 352, 703-704.[CrossRef]
    [Google Scholar]
  20. Jeffrey, M., McGovern, G., Martin, S., Goodsir, C. M. & Brown, K. L. ( 2000; ). Cellular and subcellular localization of PrP in the lymphoreticular system of mice and sheep. Archives of Virology Supplementum 16, 23-38.
    [Google Scholar]
  21. Jeffrey, M., Ryder, S., Martin, S., Hawkins, S. A., Terry, L., Berthelin-Baker, C. & Bellworthy, S. J. ( 2001; ). Oral inoculation of sheep with the agent of bovine spongiform encephalopathy (BSE). 1. Onset and distribution of disease-specific PrP accumulation in brain and viscera. Journal of Comparative Pathology 124, 280-289.[CrossRef]
    [Google Scholar]
  22. Joling, P., Bakker, L. J., Van Strijp, J. A., Meerloo, T., de Graaf, L., Dekker, M. E., Goudsmit, J., Verhoef, J. & Schuurman, H. J. ( 1993; ). Binding of human immunodeficiency virus type-1 to follicular dendritic cells in vitro is complement dependent. Journal of Immunology 150, 1065-1073.
    [Google Scholar]
  23. Kimberlin, R. H. & Walker, C. A. ( 1989; ). Pathogenesis of scrapie in mice after intragastric infection. Virus Research 12, 213-220.[CrossRef]
    [Google Scholar]
  24. Kindblom, L. G., Jacobsen, G. K. & Jacobsen, M. ( 1982; ). Immunohistochemical investigations of tumors of supposed fibroblastic–histiocytic origin. Human Pathology 13, 834-840.[CrossRef]
    [Google Scholar]
  25. Kitamoto, T., Muramoto, T., Mohri, S., Doh-Ura, K. & Tateishi, J. ( 1991; ). Abnormal isoform of prion protein accumulates in follicular dendritic cells in mice with Creutzfeldt–Jakob disease. Journal of Virology 65, 6292-6295.
    [Google Scholar]
  26. Klein, M. A., Frigg, R., Flechsig, E., Raeber, A. J., Kalinke, U., Bluethmann, H., Bootz, F., Suter, M., Zinkernagel, R. M. & Aguzzi, A. ( 1997; ). A crucial role for B cells in neuroinvasive scrapie [see comments]. Nature 390, 687-690.
    [Google Scholar]
  27. Klein, M. A., Frigg, R., Raeber, A. J., Flechsig, E., Hegyi, I., Zinkernagel, R. M., Weissmann, C. & Aguzzi, A. ( 1998; ). PrP expression in B lymphocytes is not required for prion neuroinvasion. Nature Medicine 4, 1429-1433.[CrossRef]
    [Google Scholar]
  28. Klein, M. A., Kaeser, P. S., Schwarz, P., Weyd, H., Xenarios, I., Zinkernagel, R. M., Carroll, M. C., Verbeek, J. S., Botto, M., Walport, M. J., Molina, H., Kalinke, U., Acha-Orbea, H. & Aguzzi, A. ( 2001; ). Complement facilitates early prion pathogenesis. Nature Medicine 7, 488-492.[CrossRef]
    [Google Scholar]
  29. Korth, C., Stierli, B., Streit, P., Moser, M., Schaller, O., Fischer, R., Schulz-Schaeffer, W., Kretzschmar, H., Raeber, A., Braun, U., Ehrensperger, F., Hornemann, S., Glockshuber, R., Riek, R., Billeter, M., Wuthrich, K. & Oesch, B. ( 1997; ). Prion (PrPSc)-specific epitope defined by a monoclonal antibody. Nature 390, 74-77.[CrossRef]
    [Google Scholar]
  30. Laszlo, L., Lowe, J., Self, T., Kenward, N., Landon, M., McBride, T., Farquhar, C., McConnell, I., Brown, J., Hope, J. and others ( 1992; ). Lysosomes as key organelles in the pathogenesis of prion encephalopathies. Journal of Pathology 166, 333–341.[CrossRef]
    [Google Scholar]
  31. Lezmi, S., Bencsik, A. & Baron, T. ( 2001; ). CNA42 monoclonal antibody identifies FDC as PrPsc accumulating cells in the spleen of scrapie affected sheep. Veterinary Immunology and Immunopathology 82, 1-8.[CrossRef]
    [Google Scholar]
  32. Mabbott, N. A., Mackay, F., Minns, F. & Bruce, M. E. ( 2000; ). Temporary inactivation of follicular dendritic cells delays neuroinvasion of scrapie. Nature Medicine 6, 719-720.[CrossRef]
    [Google Scholar]
  33. Mabbott, N. A., Bruce, M. E., Botto, M., Walport, M. J. & Pepys, M. B. ( 2001; ). Temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays onset of scrapie. Nature Medicine 7, 485-487.[CrossRef]
    [Google Scholar]
  34. McBride, P. A., Eikelenboom, P., Kraal, G., Fraser, H. & Bruce, M. E. ( 1992; ). PrP protein is associated with follicular dendritic cells of spleens and lymph nodes in uninfected and scrapie-infected mice. Journal of Pathology 168, 413-418.[CrossRef]
    [Google Scholar]
  35. McKinley, M. P., Bolton, D. C. & Prusiner, S. B. ( 1983; ). A protease-resistant protein is a structural component of the scrapie prion. Cell 35, 57-62.[CrossRef]
    [Google Scholar]
  36. Manuelidis, L., Zaitsev, I., Koni, P., Lu, Z. Y., Flavell, R. A. & Fritch, W. ( 2000; ). Follicular dendritic cells and dissemination of Creutzfeldt–Jakob disease. Journal of Virology 74, 8614-8622.[CrossRef]
    [Google Scholar]
  37. Miller, M. W., Williams, E. S., McCarty, C. W., Spraker, T. R., Kreeger, T. J., Larsen, C. T. & Thorne, E. T. ( 2000; ). Epidemiology of chronic wasting disease in free-ranging cervids. Journal of Wildlife Diseases 36, 676-690.[CrossRef]
    [Google Scholar]
  38. Montrasio, F., Frigg, R., Glatzel, M., Klein, M. A., Mackay, F., Aguzzi, A. & Weissmann, C. ( 2000; ). Impaired prion replication in spleens of mice lacking functional follicular dendritic cells. Science 288, 1257-1259.[CrossRef]
    [Google Scholar]
  39. Morikawa, K., Oseko, F. & Morikawa, S. ( 1995; ). A role for ferritin in hematopoiesis and the immune system. Leukaemia & Lymphoma 18, 429-433.[CrossRef]
    [Google Scholar]
  40. O’Rourke, K. I., Baszler, T. V., Miller, J. M., Spraker, T. R., Sadler-Riggleman, I. & Knowles, D. P. ( 1998; ). Monoclonal antibody F89/160.1.5 defines a conserved epitope on the ruminant prion protein. Journal of Clinical Microbiology 36, 1750-1755.
    [Google Scholar]
  41. Race, R., Jenny, A. & Sutton, D. ( 1998; ). Scrapie infectivity and proteinase K-resistant prion protein in sheep placenta, brain, spleen, and lymph node: implications for transmission and antemortem diagnosis. Journal of Infectious Diseases 178, 949-953.[CrossRef]
    [Google Scholar]
  42. Raymond, I., Al Saati, T., Tkaczuk, J., Chittal, S. & Delsol, G. ( 1997; ). CNA.42, a new monoclonal antibody directed against a fixative-resistant antigen of follicular dendritic reticulum cells. American Journal of Pathology 151, 1577-1585.
    [Google Scholar]
  43. Ritchie, D. L., Brown, K. L. & Bruce, M. E. ( 1999; ). Visualization of PrP protein and follicular dendritic cells in uninfected and scrapie infected spleen. Journal of Cellular Pathology 1, 3-10.
    [Google Scholar]
  44. Schmitz, J., van Lunzen, J., Tenner-Racz, K., Grossschupff, G., Racz, P., Schmitz, H., Dietrich, M. & Hufert, F. T. ( 1994; ). Follicular dendritic cells retain HIV-1 particles on their plasma membrane, but are not productively infected in asymptomatic patients with follicular hyperplasia. Journal of Immunology 153, 1352-1359.
    [Google Scholar]
  45. Sigurdson, C. J., Williams, E. S., Miller, M. W., Spraker, T. R., O’Rourke, K. I. & Hoover, E. A. ( 1999; ). Oral transmission and early lymphoid tropism of chronic wasting disease PrPres in mule deer fawns (Odocoileus hemionus). Journal of General Virology 80, 2757-2764.
    [Google Scholar]
  46. Sigurdson, C. J., Spraker, T. R., Miller, M. W., Oesch, B. & Hoover, E. A. ( 2001; ). PrPCWD in the myenteric plexus, vagosympathetic trunk and endocrine glands of deer with chronic wasting disease. Journal of General Virology 82, 2327-2334.
    [Google Scholar]
  47. Somerville, R. A., Birkett, C. R., Farquhar, C. F., Hunter, N., Goldmann, W., Dornan, J., Grover, D., Hennion, R. M., Percy, C., Foster, J. & Jeffrey, M. ( 1997; ). Immunodetection of PrPSc in spleens of some scrapie-infected sheep but not BSE-infected cows. Journal of General Virology 78, 2389-2396.
    [Google Scholar]
  48. Spraker, T. R., Miller, M. W., Williams, E. S., Getzy, D. M., Adrian, W. J., Schoonveld, G. G., Spowart, R. A., O’Rourke, K. I., Miller, J. M. & Merz, P. A. ( 1997; ). Spongiform encephalopathy in free-ranging mule deer (Odocoileus hemionus), white-tailed deer (Odocoileus virginianus) and Rocky Mountain elk (Cervus elaphus nelsoni) in northcentral Colorado. Journal of Wildlife Diseases 33, 1-6.[CrossRef]
    [Google Scholar]
  49. Spraker, T. R., O’Rourke, K. I., Balachandran, A., Zink, R. R., Cummings, B. A., Miller, M. W. & Powers, B. E. ( 2002a; ). Validation of monoclonal antibody F99/97.6.1 for immunohistochemical staining of brain and tonsil in mule deer (Odocoileus hemionus) with chronic wasting disease. Journal of Veterinary Diagnostic Investigation 14, 3-7.[CrossRef]
    [Google Scholar]
  50. Spraker, T. R., Zink, R. R., Cummings, B. A., Wild, M. A., Miller, M. W. & O’Rourke, K. I. ( 2002b; ). Comparison of histological lesions and immunohistochemical staining of protease-resistant prion protein in a naturally-occurring spongiform encephalopathy of free-ranging mule deer (Odocoileus hemionus) with those of chronic wasting disease of captive mule deer. Veterinary Pathology 39, 110-119.[CrossRef]
    [Google Scholar]
  51. Summers, K. L., Hock, B. D., McKenzie, J. L. & Hart, D. N. ( 2001; ). Phenotypic characterization of five dendritic cell subsets in human tonsils. American Journal of Pathology 159, 285-295.[CrossRef]
    [Google Scholar]
  52. Szakal, A. K., Kosco, M. H. & Tew, J. G. ( 1988; ). A novel in vivo follicular dendritic cell-dependent iccosome-mediated mechanism for delivery of antigen to antigen-processing cells. Journal of Immunology 140, 341-353.
    [Google Scholar]
  53. Tsunoda, R., Nakayama, M., Onozaki, K., Heinen, E., Cormann, N., Kinet-Denoel, C. & Kojima, M. ( 1990; ). Isolation and long-term cultivation of human tonsil follicular dendritic cells. Virchows Archiv B Cell Pathology Including Molecular Pathology 59, 95-105.[CrossRef]
    [Google Scholar]
  54. van Keulen, L. J., Schreuder, B. E., Meloen, R. H., Poelen-van den Berg, M., Mooij-Harkes, G., Vromans, M. E. & Langeveld, J. P. ( 1995; ). Immunohistochemical detection and localization of prion protein in brain tissue of sheep with natural scrapie. Veterinary Pathology 32, 299-308.[CrossRef]
    [Google Scholar]
  55. van Keulen, L. J., Schreuder, B. E., Meloen, R. H., Mooij-Harkes, G., Vromans, M. E. & Langeveld, J. P. ( 1996; ). Immunohistochemical detection of prion protein in lymphoid tissues of sheep with natural scrapie. Journal of Clinical Microbiology 34, 1228-1231.
    [Google Scholar]
  56. van Keulen, L. J., Schreuder, B. E., Vromans, M. E., Langeveld, J. P. & Smits, M. A. ( 2000; ). Pathogenesis of natural scrapie in sheep. Archives of Virology Supplementum 16, 57-71.
    [Google Scholar]
  57. Wells, G. A., Hawkins, S. A., Green, R. B., Austin, A. R., Dexter, I., Spencer, Y. I., Chaplin, M. J., Stack, M. J. & Dawson, M. ( 1998; ). Preliminary observations on the pathogenesis of experimental bovine spongiform encephalopathy (BSE): an update. Veterinary Record 142, 103-106.[CrossRef]
    [Google Scholar]
  58. Williams, E. S. & Young, S. ( 1992; ). Spongiform encephalopathies in Cervidae. Revue Scientifique et Technique Office International des Epizooties 11, 551-567.
    [Google Scholar]
  59. Williams, E. S. & Young, S. ( 1993; ). Neuropathology of chronic wasting disease of mule deer (Odocoileus hemionus) and elk (Cervus elaphus nelsoni). Veterinary Pathology 30, 36-45.[CrossRef]
    [Google Scholar]
  60. Williams, E. S. & Miller, M. W. (2000). Pathogenesis of chronic wasting disease in orally exposed mule deer (Odocoileus hemionus): preliminary results. In Wildlife Disease Association Conference, pp. 29. Jackson, WY.
  61. Zabel, M. D. & Weis, J. H. ( 2001; ). Cell-specific regulation of the CD21 gene. International Immunopharmacology 1, 483-493.[CrossRef]
    [Google Scholar]
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