Institute for Animal Health, Neuropathogenesis Unit, Ogston Building, West Mains Road, Edinburgh EH9 3JF, UK1
Author for correspondence: Neil Mabbott. Fax +44 131 668 3872. e-mail neil.mabbott{at}bbsrc.ac.uk
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Introduction |
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Natural TSE infections are most often acquired by peripheral exposure. For example, the consumption of contaminated feed was most likely involved in the spread of BSE amongst cattle (Wilesmith et al., 1991 ). Furthermore, consumption of BSE-infected meat is thought to be responsible for the emergence of variant (v) CJD in humans (Bruce et al., 1997
; Hill et al., 1997a
). Sporadic CJD in humans can be transmitted iatrogenically through transplantation of CJD-contaminated tissues or pituitary-derived hormones, but so far there is no indication that vCJD has been transmitted in this manner. Most of our understanding of the pathogenesis of TSEs has come from the study of experimental sheep or rodent scrapie models. Following experimental peripheral infection with scrapie, infectivity and PrPSc rapidly accumulate in lymphoid tissues (Kimberlin & Walker, 1979
; Farquhar et al., 1994
; Brown et al., 1999b
; Beekes & McBride, 2000
; Heggebø et al., 2000
; Mabbott et al., 2000
b), long before either is detectable in the central nervous system (CNS). Likewise, PrPSc is first detected in lymphoid tissues draining the gastro-intestinal tract following experimental oral inoculation of mule deer fawns (Odocoileus hemionus) with CWD (Sigurdson et al., 1999
). Although the infection route of natural sheep scrapie is not known, PrPSc is first detected in Peyers patches and gut-associated lymphoid tissues (Andréoletti et al., 2000
; Heggebø et al., 2000
) prior to detection within other lymphoid tissues and the CNS (van Keulen et al., 1999
), implying that this disease is also acquired orally.
Lymphoid tissues play an important role in transmission in some TSE models, as genetic asplenia or splenectomy of mice, shortly before or after a peripheral scrapie challenge, significantly extends the incubation period (Fraser & Dickinson, 1978 ). The involvement of lymphoid tissues in TSE pathogenesis may be TSE strain-dependent, as BSE in cattle (Somerville et al., 1997
) and sporadic CJD in humans (Hill et al., 1999
) appear to be confined to nervous tissues. However, in patients with vCJD (Hilton et al., 1998
; Hill et al., 1999
; Bruce et al., 2001
), most sheep with natural scrapie (van Keulen et al., 1996
) or rodents experimentally infected with scrapie (McBride et al., 1992
; Brown et al., 1999b
; Beekes & McBride, 2000
; Jeffrey et al., 2000
; Mabbott et al., 2000b
), infectivity accumulates in lymphoid tissues and abnormal forms of PrP are readily detected on follicular dendritic cells (FDCs) and tingible body macrophages within germinal centres (GCs). For many years FDCs have been considered likely targets for TSE replication in lymphoid tissues as they appear to express high levels of PrP even in uninfected mice (McBride et al., 1992
). But as FDCs are intimately associated with lymphocytes, which also express PrPc (Cashman et al., 1990
; Mabbott et al., 1997
), further research was necessary to differentiate the roles of FDCs, macrophages and lymphocytes in scrapie pathogenesis.
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The role of T lymphocytes in TSE pathogenesis |
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The role of B lymphocytes in TSE pathogenesis |
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Role of FDCs in TSE pathogenesis |
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Studies using chimeric mice with a mismatch in PrP status between FDCs and other cells of the immune system
An alternative approach used in the study of the pathogenesis of both ME7 and RML scrapie strains has been to use mice in which PrPc, the host prion protein, is expressed on FDCs but not lymphocytes and vice versa. The ontogeny of FDCs is still uncertain (Kapasi et al., 1998 ; Tkachuk et al., 1998
; Endres et al., 1999
), but in adult mice, they are not considered to be haemopoietic in origin but to derive from stromal precursor cells in the spleen and lymph nodes. FDC maturation in mice deficient in or depleted of lymphocytes can be induced by grafting with lymphocytes or haemopoietic cells (bone marrow or foetal liver cells) as a source of lymphocytes (Fig. 2
; Kapasi et al., 1993
). As a consequence, the lymphocytes of graft origin induce the maturation of FDC precursor cells of recipient origin. By grafting bone marrow from PrP-deficient (Prnp-/-) mice into PrP-expressing (Prnp+/+) mice, and vice versa, we and others have created chimeric mice with a mis-match in PrP expression between FDCs and surrounding lymphocytes (Blättler et al., 1997
; Klein et al., 1998
; Brown et al., 1999b
). Using these models, immunolabelling for PrP on FDCs was only seen when the recipient expressed a functional PrP gene, and was independent of the PrP status of the lymphocytes (Brown et al., 1999b
; Table 1
). This provides strong evidence that FDCs themselves produce PrPc rather than acquiring it from other PrP-expressing cells. Following peripheral challenge of these mice with the ME7 scrapie strain, high levels of infectivity accumulate in the spleen only in the presence of PrP-expressing FDCs (Brown et al., 1999b
; Table 1
). This accumulation is independent of PrP expression by the donor bone marrow or lymphocytes, and provides further evidence that FDCs are critical for the pathogenesis of the ME7 scrapie strain.
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The role of macrophages in TSE pathogenesis |
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Molecular interactions between TSEs and FDCs |
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The evidence to date would suggest that FDCs are ideal sites for scrapie replication in lymphoid tissues because they are long-lived cells that express high levels of PrPc and are specialized to trap and retain unprocessed antigens (Fig. 3). Conventional viruses including human immunodeficiency virus type 1 (Racz & Tenner-Racz, 1995
), porcine circovirus (Rosell et al., 2000
) and bovine viral diarrhoea virus (Collins et al., 1999
) have also been detected in association with FDCs, suggesting TSEs may not be the only infectious agents to exploit the unique characteristics of these cells.
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Are FDCs potential targets for therapeutic intervention in TSE disease? |
---|
Another cytokine produced by B lymphocytes which is critical for the development of mature FDCs is membrane LT1
2 (Matsumoto et al., 1996a
; Koni et al., 1997
; Chaplin & Fu, 1998
; Fig. 1
). Signals are mediated through the LT
receptor (LT
R; Endres et al., 1999
) expressed on the FDC or its precursor (Fig. 1
). Specific neutralization of the LT
R signalling pathway through treatment with a fusion protein consisting of LT
R and human immunoglobulin (LT
R-Ig; Force et al., 1995
) leads to the temporary disappearance of mature FDCs within 72 h for approximately 28 days (Mackay & Browning, 1998
; Fig. 5
). Experiments have shown that a single treatment with LT
R-Ig before or shortly after peripheral scrapie challenge blocks the accumulation of PrPSc and infectivity in the spleen and significantly impairs neuroinvasion (Mabbott et al., 2000a
; Montrasio et al., 2000
). These effects are most likely due to a loss of mature PrPc-expressing FDCs, although effects on other cell types in lymphoid tissues cannot be excluded. Therefore, as predicted, strategies that temporarily inactivate FDCs, such as blockade of the LT
R signalling pathway, may present an opportunity for early intervention in peripherally transmitted TSE diseases.
|
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How do TSEs reach the CNS from the lymphoid tissues? |
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|
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Why is PrPc expressed within lymphoid tissues? |
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In the lymphoid tissues, FDCs express high levels of PrPc (McBride et al., 1992 ; Brown et al., 1999b
; Mabbott et al., 2000a
), whereas expression on lymphocytes is low or undetectable (Cashman et al., 1990
; Mabbott et al., 1997
; Kubosaki et al., 2001
; Liu et al., 2001
). The function of PrPc in the normal cellular physiology of lymphoid tissues is also unknown. Both neurones and FDCs are long-lived, mitotically inactive cells and the expression of high levels of PrPc on both of these cell types suggests it may share a common function. Accumulating evidence suggests PrPc binds copper (Brown et al., 1997
; Stockel et al., 1998
) and may act as an antioxidant with superoxide dismutase activity (Brown et al., 1999a
). It is possible that PrPc may play a role in the long-term survival of FDCs within lymphoid tissues through protection from oxidative stress. Another study suggests that cell surface expression of PrPc by FDCs could play a role in the non-specific binding of immune complexes by these cells (Jeffrey et al., 2000
). Ultrastructural analysis of spleens from scrapie-infected mice shows abnormal PrP accumulation occurs upon the highly convoluted FDC processes in regions associated with immune complex trapping. Furthermore, the hyperplastic appearance of the FDCs and complexity of their dendritic processes would suggest these cells are highly stimulated in TSE-infected lymphoid tissues (Jeffrey et al., 2000
).
Likewise, little is known about the role PrPc plays in lymphocyte function (Mabbott et al., 1997 ; Liu et al., 2001
), although studies have shown expression is regulated during lymphocyte development in the bone marrow and thymus (Kubosaki et al., 2001
; Liu et al., 2001
), and following mitogen activation (Cashman et al., 1990
; Mabbott et al., 1997
). Whatever the function of PrPc in the host immune system is, the lymphoid tissues of PrP-deficient mice appear to develop normally (Bueler et al., 1992
; Manson et al., 1994
). Therefore, it is possible that PrPc may only play a subtle role in the development or function of the immune system, or that the effects of PrPc are compensated by another gene in PrP-deficient mice.
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Conclusions |
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