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Scrapie replication in lymphoid tissues depends on prion protein-expressing follicular dendritic cells

Nature Medicine volume 5, pages 1308–1312 (1999)Cite this article

Abstract

The immune system is central in the pathogenesis of scrapie and other transmissible spongiform encephalopathies (TSEs) or 'prion' diseases1. After infecting by peripheral (intraperitoneal or oral) routes, most TSE agents replicate in spleen and lymph nodes before neuroinvasion2. Characterization of the cells supporting replication in these tissues is essential to understanding early pathogenesis and may indicate potential targets for therapy, for example, in 'new variant' Creutzfeldt-Jakob disease. The host 'prion' protein (PrP) is required for TSE agent replication3,4 and accumulates in modified forms in infected tissues. Abnormal PrP is detected readily on follicular dendritic cells (FDCs) in lymphoid tissues of patients with 'new variant' Creutzfeldt-Jakob disease5, sheep with natural scrapie6 and mice experimentally infected with scrapie7. The normal protein is present on FDCs in uninfected mice7 and, at lower levels, on lymphocytes8. Studies using severe combined immunodeficiency (SCID) mice, with and without bone marrow (BM) grafts, have indicated involvement of FDCs and/or lymphocytes in scrapie pathogenesis9. To clarify the separate roles of FDCs and lymphocytes, we produced chimeric mice with a mismatch in PrP status between FDCs and other cells of the immune system, by grafting bone marrow from PrP-deficient knockout mice4 into PrP-expressing mice and vice versa. Using these chimeric models, we obtained strong evidence that FDCs themselves produce PrP and that replication of a mouse-passaged scrapie strain in spleen depends on PrP-expressing FDCs rather than on lymphocytes or other bone marrow-derived cells.

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Figure 1: FACS analysis of spleen cells from BM-grafted uninfected mice, stained with PrP-specific antibody (open histograms) or unstained (shaded histograms).
Figure 2: Confocal analysis of double immunofluorescent labeling of FDC networks (red) or PrP (green) in spleen sections from uninfected PrP chimeric mice.
Figure 3: Immunolabeling for PrP or FDC networks (red) in spleens from uninfected mice 28 d after BM reconstitution.
Figure 4: Immunolabeling for PrP or FDC networks in spleens from BM-reconstituted mice, 10 weeks after challenge with scrapie.

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Acknowledgements

The authors thank I. McConnell, M. Brady and L. Gray for their excellent technical support. This work was supported by the BBSRC and MRC.

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Authors and Affiliations

  1. Institute for Animal Health, Neuropathogenesis Unit, Ogston Building, West Mains Road, Edinburgh, EH9 3JF, UK

    K.L. Brown, K. Stewart, D.L. Ritchie, N.A. Mabbott, H. Fraser & M.E. Bruce

  2. Department of Veterinary Pathology, Glasgow University Veterinary School, Bearsden Road, Glasgow, G61 1QH, UK

    A. Williams

  3. Institute for Animal Health, Compton, Newbury , RG20 7NN, Berkshire, UK

    W.I. Morrison

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  1. K.L. Brown
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Correspondence to M.E. Bruce.

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Brown, K., Stewart, K., Ritchie, D. et al. Scrapie replication in lymphoid tissues depends on prion protein-expressing follicular dendritic cells. Nat Med 5, 1308–1312 (1999). https://doi.org/10.1038/15264

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