Temporary inactivation of follicular dendritic cells delays neuroinvasion of scrapie

Mabbott, Neil A.; Mackay, Fabienne; Minns, Fiona; Bruce, Moira E.

doi:10.1038/77401

Cited by 221 publications

(159 citation statements)

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“…Several lines of evidence show that follicular dendritic cells are the principal sites for synthesis and accumulation of scrapiespecific PrP (PrP Sc ) and infectivity in the spleen, and that they contribute, directly or indirectly, to neuroinvasion (9,10,(20)(21)(22)(23). Formation and maintenance of mature FDCs require the presence of B cells expressing membrane-bound lymphotoxin-␣͞␤ (24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

“…infection, showing that in wild-type mice they must be acquiring prions from other cells. Because follicular dendritic cells (FDCs) are essential for the propagation of prions in the spleen (9,10), we propose that splenic B cells acquire prions from FDCs, with which they are closely associated. Thus, at least in the mouse, B cells are not instrumental in carrying infectivity to the CNS.…”

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confidence: 99%

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B lymphocyte-restricted expression of prion protein does not enable prion replication in prion protein knockout mice

Montrasio

Cozzio

Flechsig

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Prion replication in spleen and neuroinvasion after i.p. inoculation of mice is impaired in forms of immunodeficiency where mature B lymphocytes are lacking. In spleens of wild-type mice, infectivity is associated with B and T lymphocytes and stroma but not with circulating lymphocytes. We generated transgenic prion protein knockout mice overexpressing prion protein in B lymphocytes and found that they failed to accumulate prions in spleen after i.p. inoculation. We conclude that splenic B lymphocytes are not prion-replication competent and that they acquire prions from other cells, most likely follicular dendritic cells with which they closely associate and whose maturation depends on them.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

B lymphocyte-restricted expression of prion protein does not enable prion replication in prion protein knockout mice

Montrasio

Cozzio

Flechsig

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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“…Studies with mouse-passaged prions show that, following peripheral exposure, early prion accumulation and replication occur upon follicular dendritic cells (FDCs) within the secondary lymphoid tissues prior to the spread of infection to the CNS (termed 'neuroinvasion') (Brown et al, 1999;McCulloch et al, 2011). Prion replication upon FDCs is a critical stage in the neuroinvasion process, as disease susceptibility is impaired in their absence (Mabbott et al, 2000(Mabbott et al, , 2003Montrasio et al, 2000). While prion replication in Peyer's patches of the intestine and spleen appears to be dependent upon PrP C -expressing FDCs, data from an elegant study have revealed that some prion strains can also accumulate in association with high endothelial venules in lymph nodes (O'Connor et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Evidence of subclinical prion disease in aged mice following exposure to bovine spongiform encephalopathy

Brown

Mabbott

2014

Journal of General Virology

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The occurrence of variant Creutzfeldt–Jakob (vCJD) disease in humans was almost certainly the result of consumption of food contaminated with bovine spongiform encephalopathy (BSE) prions. Despite probable widespread exposure of the UK population to BSE-contaminated food in the 1980s, vCJD has been identified predominantly in young individuals, and there have been fewer cases of clinical disease than anticipated. The reasons for this are uncertain. Following peripheral exposure, many prions replicate within the lymphoid tissues before infecting the central nervous system. We have shown that the effects of host age on the microarchitecture of the spleen significantly impair susceptibility to mouse-adapted prions after peripheral exposure. The transmission of prions between different mammalian species is considered to be limited by the ‘species barrier’, which is dependent on several factors, including an intact immune system. Thus, cross-species prion transmission may be much less efficient in aged individuals. To test this hypothesis, we compared prion pathogenesis in groups of young (6–8 weeks old) and aged (600 days old) mice injected with primary BSE brain homogenate. We showed that prion pathogenesis was impaired dramatically in aged mice when compared with young animals. Whereas most young mice succumbed to clinical prion disease, all aged mice failed to develop clinical disease during their lifespans. However, the demonstration that prion accumulation was detected in the lymphoid tissues of some aged mice after injection with primary BSE brain homogenate, in the absence of clinical signs of prion disease, has important implications for human health.

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“…We could exclude the possibility that scrapie retardation in vaccinated mice resulted from a GC architecture made chaotic by multiple injections of loaded DCs (Brown et al, 1999;Heikenwalder et al, 2004;Mabbott et al, 2000;Montrasio et al, 2000). LN sections performed after mice had received five DC administrations show a normal GC architecture with abundant PrPSc deposits, a typical presence of tingible body macrophages, cells in mitosis and FDCs.…”

Section: Discussionmentioning

confidence: 99%

Mouse vaccination with dendritic cells loaded with prion protein peptides overcomes tolerance and delays scrapie

Bachy

Ballerini

Gourdain

et al. 2009

Journal of General Virology

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Prion diseases are presumed to be caused by the accumulation in the brain of a pathological protein called prion protein (PrP) scrapie which results from the transconformation of cellular PrP, a ubiquitous glycoprotein expressed in all mammals. Since all isoforms of PrP are perceived as self by the host immune system, a major problem in designing efficient immunoprophylaxis or immunotherapy is to overcome tolerance. The present study was aimed at investigating whether bone-marrow-derived dendritic cells (DCs) loaded with peptides previously shown to be immunogenic in PrP-deficient mice, can overcome tolerance in PrP-proficient wild-type mice and protect them against scrapie. Results show that, in such mice, peptide-loaded DCs elicit both lymphokine release by T cells and antibody secretion against native cellular PrP. Repeated recalls with peptide-loaded DCs reduces the attack rate of 139A scrapie inoculated intraperitoneally and retards disease duration by 40 days. Most interestingly, survival time in individual mice appears to be correlated with the level of circulating antibody against native cellular PrP. INTRODUCTIONPrion diseases, also called transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative disorders which progress slowly, induce severe neurological loss and are transmissible. The agent is most presumably the scrapie prion protein (PrP) or PrPSc, a misfolded protein, rich in beta-sheets, resulting from the transconformation of cellular PrP (PrPc). PrPc is a ubiquitous, membrane-anchored protein, which has been remarkably conserved through evolution, but whose function in health is still enigmatic. The presence of PrPSc in tissues of diseased individuals confirms the diagnosis TSE (Prusiner et al., 1998;Wisniewski et al., 1998).Prions do not spontaneously evoke antibody (Ab) or T-cell responses in diseased subjects, most likely because PrPSc, like PrPc, is not perceived as foreign or 'dangerous' (Matzinger, 1998) by the host immune system. In recent years, however, following encouraging immunotherapy results in Alzheimer's disease patients (Schenk et al., 1999), several teams have attempted to passively or actively generate adaptive immune responses against prions in wild-type (wt) mice and have shown that passive Ab treatment (Sigurdsson et al., 2003;White et al., 2003), constitutive transgenic secretion of anti-PrP IgM (Heppner et al., 2001) or active immunization using whole PrP (Sigurdsson et al., 2002), PrP peptides (Schwarz et al., 2003), PrP fragments (Bade et al., 2006) or DNA constructs encoding Prnp gene sequences (Fernandez-Borges et al., 2006) had beneficial effects on disease evolution.In order to identify major histocompatibility (MHC) class II-restricted T-cell epitopes in C57BL6 (B6)-H-2 b mice, we previously screened a bank of overlapping peptides of mouse PrP and identified two main epitopes. One is contained in peptide PrP , the other is shared by peptides PrP 143-172 and PrP . Immunization of mice made genetically deficient for PrP (Prnp 2/2 ) with PrP 97-1...

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Temporary inactivation of follicular dendritic cells delays neuroinvasion of scrapie

Cited by 221 publications

References 10 publications

B lymphocyte-restricted expression of prion protein does not enable prion replication in prion protein knockout mice

B lymphocyte-restricted expression of prion protein does not enable prion replication in prion protein knockout mice

Evidence of subclinical prion disease in aged mice following exposure to bovine spongiform encephalopathy

Mouse vaccination with dendritic cells loaded with prion protein peptides overcomes tolerance and delays scrapie

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