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IMMUNOBIOLOGY
From the Nuffield Department of Biochemistry and
Cellular Science, University of Oxford, and National Blood Service,
John Radcliffe Hospital, Oxford, United Kingdom; and Department of
Biomedical Sciences, UMIST, Manchester, United Kingdom.
Abnormal isoforms of the prion protein (PrPSc) that
cause prion diseases are propagated and spread within the body by
"carrier" cell(s). Cells of the immune system have been strongly
implicated in this process. In particular, PrPSc is known
to accumulate on follicular dendritic cells (FDCs) in individuals
affected by variant Creutzfeld-Jakob disease. However, FDCs do not
migrate widely and the natural history of prion disorders suggests
other cells may be required for the transport of PrPSc from
the site of ingestion to lymphoid organs and the central nervous
system. Substantial evidence suggests that the spread of
PrPSc requires bone marrow-derived cells that express
normal cellular prion protein (PrPC). This study examined
the expression of PrPC on bone marrow-derived cells that
interact with lymphoid follicles. High levels of PrPC are
present on myeloid dendritic cells (DCs) that surround the splenic
white pulp. These myeloid DCs are ontologically and functionally distinct from the FDCs. Consistent with these observations, expression of PrPC was strongly induced during the generation of
mature myeloid DCs in vitro. In these cells PrPC
colocalized with major histocompatibility complex class II molecules at
the level of light microscopy. Furthermore, given the close anatomic
and functional connection of myeloid DCs with lymphoid follicles, these
results raise the possibility that myeloid DCs may play a role in the
propagation of PrPSc in humans.
(Blood. 2001;98:3733-3738) The recent emergence of variant Creutzfeld-Jakob
Disease (vCJD) in humans has raised the specter of large-scale primary
and secondary infections in human populations.1-4 In late
stages of vCJD infection, abnormal prion protein
(PrPSc) accumulates, particularly in brain, leading
to a distinctive clinical and pathologic disorder.5
However, preventive and therapeutic strategies will be most effective
if targeted at the initial pathways through which ingested
PrPSc is propagated within the body and transferred to
nerve tissue.
It is now widely accepted that follicular dendritic cells (FDCs) have
an important role in the pathogenesis of prion disease. Histopathologic
studies of mice and other species exposed to PrPSc have
highlighted the accumulation of PrPSc on the FDCs in
lymphoid follicles.6-8 Furthermore, in a mouse model, it
has now been shown that FDCs are required for the replication of
PrPSc that precedes neuroinvasion.9,10 In
support of this view, B-cell-deficient mice, which fail to form
functional lymphoid follicles,11,12 are resistant to
PrPSc infection. However, involvement of FDCs alone is not
sufficient to explain how infective forms of the prion protein are
transferred from the gastrointestinal tract to the lymphoid organs and
the central nervous system (CNS). FDCs reside within B-cell areas of
lymphoid organs where they bind and retain antigens on their cell
surface over months or even years.13 The cells have a slow turnover and are not believed to recirculate. Moreover, cellular (PrPC) has not been found to be associated with the FDCs of
enteric tissue.14
It is important therefore to understand how FDCs in central lymphoid
organs become exposed to PrPSc and how PrPSc
may be transferred from FDCs to other tissues. In this regard, evidence
suggests that circulating cells may have a role. Results from animal
models have emphasized that infective material can be isolated from the
cellular fraction of the spleen soon after the ingestion of
PrPSc,15 whereas in mice, marrow-derived cells
have been shown to be required for the propagation and spread of
PrPSc.16
Attention has therefore focused on the circulating cells that express
normal PrPC and that may therefore act as carrier cells for
the spread and circulation of its abnormal isoform.17,18
In humans, peripheral B and T lymphocytes express PrPC at
low levels, whereas higher levels of PrPC have been found
on subsets of natural killer (NK) cells, platelets, and
monocytes.19-21 However, the expression of
PrPC on blood cells in the peripheral circulation does not
provide a full description of the possible routes of propagation and
spread of PrPSc. Recent evidence suggests that the
expression of PrPC may vary with the developmental
stage of cells and with their activation state21,22; thus
the expression of PrPC on circulating cells will not
necessarily reflect the expression of the molecule on the derived,
differentiated, or activated cells within tissues.
Understanding the cellular expression of the normal form of the prion
protein (PrPC) within lymphoid tissues may provide
important clues to the pathogenesis of prion disorders. We have
therefore studied the expression of PrPC on cells within
human spleen, focusing particularly on those cells that interact
closely with lymphoid follicles and with FDCs. We describe a
distinctive cellular and intracellular distribution of PrPC
that may have important implications for its normal function and the
spread of its abnormal isoforms(s).
Immunohistochemistry and immunocytology
Cryostat tissue sections of spleen (8 µm) were fixed in acetone and
examined using dual-color immunofluorescence. Cell surface antigens
were detected with the antibodies shown in Table
1.
Antibody-labeled cells were then detected using class-specific goat antisera to either mouse or rabbit immunoglobulin (fluorescein isothiocyanate [FITC] or Texas red conjugated as indicated) (Cambridge Bioscience, Cambridge, United Kingdom). Fluorescence-labeled sections were viewed and images captured using standard immunofluorescence microscopy and video capture equipment. The immunocytology of monocyte-derived dendritic cells (DCs) was also studied. DCs were cultured (see below), washed 4 times with cold phosphate-buffered saline (PBS), and allowed to attach and spread on glass slides or coverslips for 60 minutes. Preparations were air dried and fixed in acetone/methanol. DCs were immunostained and visualized as described above for cryostat sections. Western blot analysis Tissue samples or centrifuged cell pellets were lysed directly in boiling sample buffer. Protein concentrations were compared using scanning densitometry of Coomassie-stained gels. Human serum was diluted 1:2 in PBS and mixed with double-strength sample buffer. Samples were run on 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to polyvinylidene difluoride (PVDF) membrane. PrPC was detected using Mab 6H4 and goat antimouse horseradish peroxidase (HRP) conjugate (Dako) and visualized using enhanced chemoluminescence (Amersham Life Sciences, Amersham, United Kingdom) according to the manufacturer's instructions.Generation and assessment of DCs Immature myeloid DCs were derived from peripheral blood cells using standard procedures.23,24 Briefly, monocytes were cultivated in RPMI 1640 supplemented with 2 mM glutamine, 50 µg/mL kanamycin, 1% nonessential amino acids (Gibco BRL, Glasgow, United Kingdom), 10% human AB serum, and 50 ng/mL each of interleukin 4 (IL-4; specific activity > 2 × 106 U/mg; Peprotech, London, United Kingdom) and granulocyte-macrophage colony-stimulating factor (GM-CSF; specific activity > 1 × 107 U/mg; Schering-Plough, Welwyn Garden City, United Kingdom). After 6 days, DCs were matured with 100 ng/mL lipopolysaccharide (LPS; Salmonella typhimurium) for 48 hours. PrPC present in culture medium was assessed using Western blotting and densitometry and was found to be less than 10% of that expressed by the harvested DCs. Immature DCs expressed the surface molecules CD54 (clone 6.5B5), CD40 (clone LOB7/6), CD86 (clone BU63), and HLA DR (clone BF-1) as confirmed by staining with the respective monoclonal antibodies and fluorescence-activated cell sorter (FACScan; Becton Dickinson, Oxford, United Kingdom) analysis. Expression of CD14 was low. On maturation with LPS, 98% of DCs expressed CD83 (clone HB15b) (Serotec, Oxford, United Kingdom) and the levels of expression of CD54, CD40, CD86, and HLA-DR were increased. Early endocytotic vesicles in immature DCs were labeled by exposure of cells to FITC-dextran (1mg/mL; Molecular Probes, Leiden, Netherlands) for 7 minutes and for 15 minutes at 4°C and 37°C.Amplification of the PrP gene Total RNA was prepared from immature myeloid DCs generated from monocytes (7 days after culture with IL-4 and GM-SCF as described above), mature LPS-stimulated myeloid DCs, and on 2 independent preparations of monocytes freshly isolated from peripheral blood. The gene encoding PrP was amplified by reverse transcription-polymerase chain reaction (RT-PCR) using the Titan One Tube RT-PCR Kit (Roche), used according to manufacturer's instructions or by PCR using Taq polymerase (Roche). RNA (200 pg) or genomic DNA (50 ng) was used in the respective reactions. The primers 5'-GGCAGTGACTATGAGGACCGTTAC-3' and 5'-GGCTTGACCAGCATCTCAGGTCTA-3' were used to amplify the PrP gene to generate a 528-bp product. The primers 5'-CCATGTTCGTCATGGGTGTGAACCA-3' and 5'-GCCAGTAGGCAGGGATGATGATGTT-3' were used to amplify a 251-bp product by RT-PCR from the glyceraldehyde-3-phosphate dehydrogenase (G3PDH) gene in RNA prepared from all cell types as a positive control (data not shown).
PrPC is strongly expressed by myeloid DCs in spleen The cellular expression of the normal form of prion protein PrPC was assessed in normal human spleen using immunohistochemistry. The expression of PrPC was weak or absent on most cell types and on stromal elements, and in contrast to the reported accumulation of PrPSc within lymphoid follicles in infected tissue, strong expression of PrP was not detected within lymphoid follicles in these normal spleen sections. However, cells that strongly expressed PrPC were scattered throughout the splenic red pulp and particularly concentrated adjacent to the marginal zone of the white pulp (Figure 1). To establish the identity of these cells we performed immunocytochemistry with lineage-specific antibodies. Double immunofluorescence staining revealed that these PrPC+ cells also expressed CD13, CD11c, and CD86, but did not express markers of FDCs (CR4/23), T cells (CD3), B cells (CD20 and CD79), or macrophages (CD68) (Figure 2 and data not shown). We concluded that the distribution of the PrPC-expressing cells and their expression of lineage-defining antigens was consistent with the distribution and phenotype of myeloid DCs.
Prion protein expression is specifically up-regulated during the generation of myeloid DCs in vitro To confirm our findings that myeloid DCs strongly express prion protein, we generated DCs from monocytes. Such cells are widely used as a model of myeloid DCs23,24; these DCs generated in vitro cannot fully model cells in tissues that receive different stimuli and may vary in phenotype. However, DCs of splenic red pulp and marginal zone share many features with cells of monocyte lineage,25 and thus monocyte-derived DCs were selected as a relevant system to confirm our in vivo findings. Freshly isolated peripheral blood monocytes express PrPC at low levels.20 We found that during the differentiation of monocytes to immature DCs in vitro the surface expression of PrPC increased 4-fold; this increased further when the DCs were matured with LPS to give an approximately 8-fold increase compared to monocytes (Figure 3A,B). When the total cellular expression of PrPC was determined by SDS-PAGE and Western blotting a similar trend of increased expression was observed; however, increases in total expression were much greater than for surface expression, suggesting a significant intracellular pool of PrPC in myeloid DCs (Figure 3C). By contrast, macrophages generated from monocytes in vitro and subsequently exposed to LPS showed only a 3-fold increase in the surface expression of PrPC (Figure 3B) and a small increase in the total level of expression of PrPC (Figure 3C).
We were also interested in whether the glycoforms of PrPC expressed by myeloid DCs derived in vitro resembled the in vivo glycoforms of PrPC found in spleen. PrPC is glycosylated in a tissue-specific manner, and these differences are reflected by corresponding changes in the apparent molecular weight of these species on SDS-PAGE.26 When molecular weights of forms of PrPC found in lysates from monocyte-derived DCss were compared with those from brain or spleen, the distributions of apparent molecular weights most closely resembled those of spleen (Figure 3D). Finally, nonquantitative RT-PCR of total RNA from myeloid DCs showed that the PrP gene was transcribed in these cells (Figure 3E). We concluded that the expression of PrPC was strongly up-regulated during the differentiation and maturation of myeloid DCs in vitro. The intracellular localization of prion protein In mice, previous studies have suggested a functional role for PrPC in T-cell activation. We were, therefore, interested in determining the intracellular localization of PrPC within different functional compartments of the myeloid DCs, in particular those associated with adhesion or antigen processing. We allowed cultured monocyte-derived DCs to adhere and spread on glass slides, and used dual-fluorescence immunostaining to determine the colocalization of PrPC with cytoskeleton, major histocompatibility complex (MHC) class II, or endosomes within those cells. These experiments showed that PrPC distribution was separate from that of adhesion plaque components mediating contact with the substratum or adjacent cells. PrPC was also absent from endocytotic vesicles visualized by the uptake of FITC-dextran (Figure 4A,B). In contrast, when the distribution of PrPC was compared with that of MHC class II molecules in immature and mature DCs, a striking colocalization was revealed at the level of light microscopy (Figure 4C).
In tissue from animals infected by transmissible spongiform encephalopathy, and in humans suffering vCJD, PrPSc is particularly concentrated on FDCs.6-8 In the present study we show that in the absence of prion disease, high levels of expression of the normal form of prion protein in human spleen occur principally on myeloid DCs immediately adjacent to the white pulp, whereas FDCs do not strongly express PrPC. In prion diseases FDCs heavily express PrPSc. PrPC is also found on FDCs in most, but not all, studies of mice.27,28 We are not aware of previous studies of myeloid DCs, but recent reports in sheep have identified PrPSc on myeloid cells with a "dendritic morphology"29; also PrPC expression has been identified on related microglial cells within the CNS.30 The distinction between FDCs and myeloid DCs is important because the 2 cell types are ontologically and functionally distinct.26 Myeloid DCs are derived from bone marrow precursor cells or from monocytes and their precursors and are readily identified within circulating cell populations. In spleen, myeloid DCs are found in the red pulp and immediately adjacent to the white pulp. The cells migrate into the lymphoid areas after receiving a maturation stimulus where they are powerful mediators of T-cell activation. The origin of FDCs remains controversial; although evidence is accumulating that they too may be derived from bone marrow cells,31 their turnover and repopulation is slow, and they are not believed to recirculate.32 In spleen, FDCs are confined to lymphoid follicles and present surface-bound antigen to maturing B cells. The high levels of expression of PrPC on myeloid DCs, but not on surrounding macrophage cells, suggests that PrPC is selectively up-regulated during the ontogeny of myeloid DCs in vivo. Our data showing a distinct cellular and subcellular expression of
PrPC in antigen- presenting cells may help shed light on
the, as yet, undefined functional role of PrPC.
PrPC is a glycosylphosphatidylinositol
(GPI)-linked molecule that may be expressed at the cell
surface or be associated with intracellular vesicles.33,34
It has recently been shown that GPI-linked molecules localize within
lipid rafts where they may play an important role in costimulatory
functions, including activation of T cells (reviewed by Ilangumaran and
coworkers35). The protein has a high-affinity copper-binding site and has structural homology with signal
peptidases,36 although no enzyme function has been
demonstrated for PrPC. The protein has a widespread tissue
distribution, but is particularly expressed in neurologic tissue and on
cells of the immune system. Recent reports have shown an increase in
PrPC expression in monocytes stimulated by
Consistent with such a role, we have shown that the prion protein was
colocalized with MHC class II molecules in immature and mature myeloid
DCs. The colocalization of PrPC with MHC class II molecules
reported in the present study does not define the function of
PrPC; indeed, the MHC class II compartment is large, and
our study does not precisely identify the role of PrPC
within that compartment. Nevertheless, the coexpression of
PrPC with MHC class II in monocyte-derived DCs is
consistent with a potential role for PrPC in the
stimulation of a variety of immunologic cells. Indeed, in mice,
PrPC has been indirectly linked to a role in T-cell
activation by observations that peptides from PrPC may
directly induce T-cell activation.37,38 Although there have been no detailed reports of immune function in
PrPC Our findings may be relevant to the spread of abnormal forms of prion protein. The spread of PrPSc in an infected host must require the conversion of PrPC to PrPSc. In mice high titers of infectivity occur in the spleen soon after intraperitoneal inoculation with PrPSc, and subsequent spread to the CNS can be retarded, though not prevented, by splenectomy.15 PrPSc has been detected on FDCs, B cells, and T cells in the lymphoid follicles of mice, and recently, FDCs have been shown to be required for transmission of PrPSc in mice.9 However, splenic infectivity can be restored in PrPC knockout mice using transplanted normal bone marrow, suggesting an importance for a rapidly repopulated bone marrow-derived cell population,16 and in some mouse models spread of PrPSc from peripheral tissues to the CNS occurs in the absence of functional FDCs or T lymphocytes.46 These findings strongly suggest that PrPSc transmission and propagation is a complex process requiring the interaction of several cell types. In the present study we have established that the PrPC expressed by myeloid DCs is the major reservoir of normal prion protein in human spleen. The relationship between levels of PrPC expression, and the susceptibility of a cell to PrPSc infection, is not simple; overexpression of PrPC within an organism confers an increased susceptibility to prion diseases,47,48 but this is not true for all tissues or cell types. This suggests the characteristics of the cell(s) expressing PrPC are also important. Dendritic cells are derived from precursors within the bone marrow and migrate widely.49-52 They make early contact with ingested or inoculated antigen and can transport it to secondary lymphoid organs, where there is extensive interaction with other immune cell types including B cells and other cells within the germinal centers.53 Given our novel findings we suggest these myeloid-derived DCs may be important in the spread of prion disease and that monocyte-derived DCs may provide a model for the study of PrPC function in human cells.
We would like to thank Professor K. Gatter for his help and encouragement in this work, Dr John Kurtz for helpful comments on the manuscript, Robin Roberts-Gant and Kingsley Micklem for their skilled and dedicated help in the preparation of the figures and other members of the Cellular Science Research Laboratory and Medical Informatics Unit at the John Radcliffe Hospital in Oxford for their help and advice.
Submitted August 23, 2000; accepted July 31, 2001.
Supported by the University of Oxford, the National Blood Service, and the Wellcome Trust. B.C.U. was supported by the Sir E. P. Abraham Trust (Oxford), and D.J.R. was a Wellcome Trust Senior Fellow in Clinical Science and a Howard Hughes International Research Scholar.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: David J. Roberts, National Blood Service, Oxford Centre, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom; e-mail: droberts{at}imm.ox.ac.uk.
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© 2001 by The American Society of Hematology.
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  A. Flores-Langarica, Y. Sebti, D. A. Mitchell, R. B. Sim, and G. G. MacPherson Scrapie Pathogenesis: The Role of Complement C1q in Scrapie Agent Uptake by Conventional Dendritic Cells J. Immunol., February 1, 2009; 182(3): 1305 - 1313. [Abstract] [Full Text] [PDF]
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 S. Tsutsui, J. N. Hahn, T. A. Johnson, Z. Ali, and F. R. Jirik Absence of the Cellular Prion Protein Exacerbates and Prolongs Neuroinflammation in Experimental Autoimmune Encephalomyelitis Am. J. Pathol., October 1, 2008; 173(4): 1029 - 1041. [Abstract] [Full Text] [PDF]
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 R. Linden, V. R. Martins, M. A. M. Prado, M. Cammarota, I. Izquierdo, and R. R. Brentani Physiology of the Prion Protein Physiol Rev, April 1, 2008; 88(2): 673 - 728. [Abstract] [Full Text] [PDF]
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 O. Andrievskaia, J. Algire, A. Balachandran, and K. Nielsen Prion protein in sheep urine J Vet Diagn Invest, March 1, 2008; 20(2): 141 - 146. [Abstract] [Full Text] [PDF]
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 L. Austbo, A. Espenes, I. Olsaker, C. McL. Press, and G. Skretting Lymphoid follicles of the ileal Peyer's patch of lambs express low levels of PrP, as demonstrated by quantitative real-time RT-PCR on microdissected tissue compartments, in situ hybridization and immunohistochemistry. J. Gen. Virol., November 1, 2006; 87(Pt 11): 3463 - 3471. [Abstract] [Full Text] [PDF]
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 A. Didier, R. Dietrich, M. Steffl, M. Gareis, M. H. Groschup, S. Muller-Hellwig, E. Martlbauer, and W. M. Amselgruber Cellular Prion Protein in the Bovine Mammary Gland Is Selectively Expressed in Active Lactocytes J. Histochem. Cytochem., November 1, 2006; 54(11): 1255 - 1261. [Abstract] [Full Text] [PDF]
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G. Martinez del Hoyo, M. Lopez-Bravo, P. Metharom, C. Ardavin, and P. Aucouturier Prion Protein Expression by Mouse Dendritic Cells Is Restricted to the Nonplasmacytoid Subsets and Correlates with the Maturation State J. Immunol., November 1, 2006; 177(9): 6137 - 6142. [Abstract] [Full Text] [PDF]
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C. Ballerini, P. Gourdain, V. Bachy, N. Blanchard, E. Levavasseur, S. Gregoire, P. Fontes, P. Aucouturier, C. Hivroz, and C. Carnaud Functional Implication of Cellular Prion Protein in Antigen-Driven Interactions between T Cells and Dendritic Cells. J. Immunol., June 15, 2006; 176(12): 7254 - 7262. [Abstract] [Full Text] [PDF]
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 C. Rybner-Barnier, C. Jacquemot, C. Cuche, G. Dore, L. Majlessi, M.-M. Gabellec, A. Moris, O. Schwartz, J. Di Santo, A. Cumano, et al. Processing of the bovine spongiform encephalopathy-specific prion protein by dendritic cells. J. Virol., May 1, 2006; 80(10): 4656 - 4663. [Abstract] [Full Text] [PDF]
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 B. C. Urban, T. T. Hien, N. P. Day, N. H. Phu, R. Roberts, E. Pongponratn, M. Jones, N. T. H. Mai, D. Bethell, G. D. H. Turner, et al. Fatal Plasmodium falciparum Malaria Causes Specific Patterns of Splenic Architectural Disorganization Infect. Immun., April 1, 2005; 73(4): 1986 - 1994. [Abstract] [Full Text] [PDF]
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A. Khalili-Shirazi, S. Quaratino, M. Londei, L. Summers, M. Tayebi, A. R. Clarke, S. H. Hawke, G. S. Jackson, and J. Collinge Protein Conformation Significantly Influences Immune Responses to Prion Protein J. Immunol., March 15, 2005; 174(6): 3256 - 3263. [Abstract] [Full Text] [PDF]
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K. M. Luhr, E. K. Nordstrom, P. Low, H.-G. Ljunggren, A. Taraboulos, and K. Kristensson Scrapie Protein Degradation by Cysteine Proteases in CD11c+ Dendritic Cells and GT1-1 Neuronal Cells J. Virol., May 1, 2004; 78(9): 4776 - 4782. [Abstract] [Full Text] [PDF]
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M. Lotscher, M. Recher, L. Hunziker, and M. A. Klein Immunologically Induced, Complement-Dependent Up-Regulation of the Prion Protein in the Mouse Spleen: Follicular Dendritic Cells Versus Capsule and Trabeculae J. Immunol., June 15, 2003; 170(12): 6040 - 6047. [Abstract] [Full Text] [PDF]
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N. C. Kaneider, A. Kaser, S. Dunzendorfer, H. Tilg, and C. J. Wiedermann Sphingosine Kinase-Dependent Migration of Immature Dendritic Cells in Response to Neurotoxic Prion Protein Fragment J. Virol., May 1, 2003; 77(9): 5535 - 5539. [Abstract] [Full Text] [PDF]
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 P. Aucouturier and C. Carnaud The immune system and prion diseases: a relationship of complicity and blindness J. Leukoc. Biol., December 1, 2002; 72(6): 1075 - 1083. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
-interferon.
/