FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2110554208> ?p ?o ?g. }

• W2110554208 endingPage "1309" @default.
• W2110554208 startingPage "1301" @default.
• W2110554208 abstract "Transmissible spongiform encephalopathies are fatal neurodegenerative diseases. Infection by the oral route is assumed to be important, although its pathogenesis is not understood. Using prion protein (PrP) knockout mice, we investigated the sequence of events during the invasion of orally administered PrPs through the intestinal mucosa and the spread into lymphoid tissues and the peripheral nervous system. Orally administered PrPs were incorporated by intestinal epitheliocytes in the follicle-associated epithelium and villi within 1 hour. PrP-positive cells accumulated in the subfollicle region of Peyer's patches a few hours thereafter. PrP-positive cells spread toward the mesenteric lymph nodes and spleen after the accumulation of PrPs in the Peyer's patches. The number of PrP molecules in the mesenteric lymph nodes and spleen peaked at 2 days and 6 days after inoculation, respectively. The epitheliocytes in the follicle-associated epithelium incorporating PrPs were annexin V-positive microfold cells and PrP-positive cells in Peyer's patches and spleen were CD11b-positive and CD14-positive macrophages. Additionally, PrP-positive cells in Peyer's patches and spleen were detected in the vicinity of peripheral nerve fibers in the early stages of infection. These results indicate that orally delivered PrPs were incorporated by microfold cells promptly after challenge and that macrophages might act as a transporter of incorporated PrPs from the Peyer's patches to other lymphoid tissues and the peripheral nervous system. Transmissible spongiform encephalopathies are fatal neurodegenerative diseases. Infection by the oral route is assumed to be important, although its pathogenesis is not understood. Using prion protein (PrP) knockout mice, we investigated the sequence of events during the invasion of orally administered PrPs through the intestinal mucosa and the spread into lymphoid tissues and the peripheral nervous system. Orally administered PrPs were incorporated by intestinal epitheliocytes in the follicle-associated epithelium and villi within 1 hour. PrP-positive cells accumulated in the subfollicle region of Peyer's patches a few hours thereafter. PrP-positive cells spread toward the mesenteric lymph nodes and spleen after the accumulation of PrPs in the Peyer's patches. The number of PrP molecules in the mesenteric lymph nodes and spleen peaked at 2 days and 6 days after inoculation, respectively. The epitheliocytes in the follicle-associated epithelium incorporating PrPs were annexin V-positive microfold cells and PrP-positive cells in Peyer's patches and spleen were CD11b-positive and CD14-positive macrophages. Additionally, PrP-positive cells in Peyer's patches and spleen were detected in the vicinity of peripheral nerve fibers in the early stages of infection. These results indicate that orally delivered PrPs were incorporated by microfold cells promptly after challenge and that macrophages might act as a transporter of incorporated PrPs from the Peyer's patches to other lymphoid tissues and the peripheral nervous system. Transmissible spongiform encephalopathies (TSEs), or prion diseases, are fatal neurodegenerative diseases that infect humans and both wild and domestic animals. They include Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep, and bovine spongiform encephalopathy (BSE) in cattle.1Aguzzi A. Prion diseases of humans and farm animals: epidemiology, genetics and pathogenesis.J Neurochem. 2006; 97: 1726-1739Crossref PubMed Scopus (89) Google Scholar The common neuropathological features within the central nervous system (CNS) of TSEs are seen as a spongiform pathology, neuronal loss,2Masters C.L. Richardson Jr, E.P. Subacute spongiform encephalopathy (Creutzfeldt-Jakob Disease) The nature and progression of spongiform change.Brain. 1978; 101: 333-344Crossref PubMed Scopus (307) Google Scholar glial activation,3van Everbroeck B. Dobbeleir I. De Waele M. De Leenheir E. Lubke U. Martin J.J. Cras P. Extracellular protein deposition correlates with glial activation and oxidative stress in Creutzfeldt-Jakob and Alzheimer's disease.Acta Neuropathol. 2004; 108: 194-200PubMed Google Scholar and the accumulation of an abnormal and protease-resistant conformer of the scrapie-associated prion proteins (PrP-res or PrPSc),4van Keulen L.J. Vromans M.E. Dolstra C.H. Bossers A. van Zijderveld F.G. Pathogenesis of bovine spongiform encephalopathy in sheep.Arch Virol. 2008; 153: 445-453Crossref PubMed Scopus (58) Google Scholar which are closely associated with the infection.5Bolton D.C. McKinley M.P. Prusiner S.B. Identification of a protein that purifies with the scrapie prion.Science. 1982; 218: 1309-1311Crossref PubMed Scopus (1013) Google Scholar It has been reported that variant CJD in humans is most likely to have occurred because of the transmission of BSE after the consumption of beef contaminated with the BSE agent.6Hill A.F. Desbruslais M. Joiner S. Sidle K.C. Gowland I. Collinge J. Doey L.J. Lantos P. The same prion strain causes vCJD and BSE.Nature. 1997; 389: 448-450Crossref PubMed Scopus (1206) Google Scholar Therefore, the oral route of TSE infection is widely assumed to be important under natural conditions. Many of the infectious agents accumulate in the gut-associated lymphoid tissues (GALT) after oral infection, such as the Peyer's patches and mesenteric lymph nodes (MLN) before spreading to the CNS.7Mabbott N. Turner M. Prions and the blood and immune systems.Haematologica. 2005; 90: 542-548PubMed Google Scholar It is necessary for the infectious agents to cross the intestinal epithelium before they can accumulate in the GALT. In addition, there are microfold cells (M cells) within the follicle-associated epithelium (FAE) that are specialized for the transepithelial transport of macromolecules and particles.8Neutra M.R. Frey A. Kraehenbuhl J.P. Epithelial M cells: gateways for mucosal infection and immunization.Cell. 1996; 86: 345-348Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar One in vitro study has demonstrated that M cells actively transcytose the scrapie agents into the basolateral side of the epithelium.9Heppner F.L. Christ A.D. Klein M.A. Prinz M. Fried M. Kraehenbuhl J.P. Aguzzi A. Transepithelial prion transport by M cells.Nat Med. 2001; 7: 976-977Crossref PubMed Scopus (188) Google Scholar However, it is still a matter of controversy as to whether M cells may be involved in the in vivo transport of the infectious agents across the intestinal epithelium. After alimentary uptake of the infectious agents, they accumulate in the GALT and the lymphoreticular systems (eg, the spleen and other peripheral lymph nodes) long before they are detected in the CNS.10Maignien T. Lasmézas C.I. Beringue V. Dormont D. Deslys J.P. Pathogenesis of the oral route of infection of mice with scrapie and bovine spongiform encephalopathy agents.J Gen Virol. 1999; 80: 3035-3042Crossref PubMed Scopus (148) Google Scholar As the GALT and the lymphoreticular systems are highly innervated, they are believed to be important sites for the infectious agents to gain contact with the nervous system (ie, neuroinvasion).11Vulchanova L. Casey M.A. Crabb G.W. Kennedy W.R. Brown D.R. Anatomical evidence for enteric neuroimmune interactions in Peyer's patches.J Neuroimmunol. 2007; 185: 64-74Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar Once neuroinvasion occurs, the infectious agents reach their initial CNS target sites by spreading in a retrograde direction along efferent nerve fibers.12McBride P.A. Schulz-Schaeffer W.J. Donaldson M. Bruce M. Diringer H. Kretzschmar H.A. Beekes M. Early spread of scrapie from the gastrointestinal tract to the central nervous system involves autonomic fibers of the splanchnic and vagus nerves.J Virol. 2001; 75: 9320-9327Crossref PubMed Scopus (210) Google Scholar In the lymphoid tissues, it is believed that the macrophages, dendritic cells (DCs), and follicular dendritic cells (FDCs) are involved in the transportation and replication of the infectious agents. Macrophages are prevalent candidates for both spread13Andréoletti O. Berthon P. Marc D. Sarradin P. Grosclaude J. van Keulen L. Schelcher F. Elsen J.M. Lantier F. Early accumulation of PrPSc in gut-associated lymphoid and nervous tissues of susceptible sheep from a Romanov flock with natural scrapie.J Gen Virol. 2000; 81: 3115-3126Crossref PubMed Scopus (380) Google Scholar and clearance14Carp R.I. Callahan S.M. In vitro interaction of scrapie agent and mouse peritoneal macrophages.Intervirology. 1981; 16: 8-13Crossref PubMed Scopus (45) Google Scholar of the infectious agents. DCs can capture and retain protein antigens in a nondegraded state.15Huang F.P. Platt N. Wykes M. Major J.R. Powell T.J. Jenkins C.D. MacPherson G.G. A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes.J Exp Med. 2000; 191: 435-444Crossref PubMed Scopus (780) Google Scholar, 16Huang F.P. Farquhar C.F. Mabbott N.A. Bruce M.E. MacPherson G.G. Migrating intestinal dendritic cells transport PrPSc from the gut.J Gen Virol. 2002; 83: 267-271Crossref PubMed Scopus (171) Google Scholar These characteristics suggest that the macrophages and DCs may act as a transporter of the infectious agents from the gut to lymphoid tissues. FDCs express high levels of cellular PrPs (PrPc), and therefore an early accumulation of PrPSc is seen in them.17Kitamoto T. Muramoto T. Mohri S. Doh-Ura K. Tateishi J. Abnormal isoform of prion protein accumulates in follicular dendritic cells in mice with Creutzfeldt-Jakob disease.J Virol. 1991; 65: 6292-6295Crossref PubMed Google Scholar, 18Miyazawa K. Kanaya T. Tanaka S. Takakura I. Watanabe K. Ohwada S. Kitazawa H. Rose M.T. Sakaguchi S. Katamine S. Yamaguchi T. Aso H. Immunohistochemical characterization of cell types expressing the cellular prion protein in the small intestine of cattle and mice.Histochem Cell Biol. 2007; 127: 291-301Crossref PubMed Scopus (16) Google Scholar Many studies of the alimentary pathogenesis of TSEs have been conducted to elucidate how infectious agents spread from the GALT to the CNS, although this has not been clearly determined yet. Therefore, the aim of the present study was to reveal the cells involved in the early stages of the pathogenesis of oral TSE infection, such as the sites of entry, spread, and neuroinvasion. All procedures involving animals were conducted in accordance with the Guidelines for Animals Experimentation of Tohoku University, Nagasaki University, and the University of Tokushima. PrPc knockout mice (Ngsk Prnp0/0 mice, male, 3 weeks old)19Sakaguchi S. Katamine S. Shigematsu K. Nakatani A. Moriuchi R. Nishida N. Kurokawa K. Nakaoke R. Sato H. Jishage K. Kuno J. Noda T. Miyamoto T. Accumulation of proteinase K-resistant prion protein (PrP) is restricted by the expression level of normal PrP in mice inoculated with a mouse-adapted strain of the Creutzfeldt-Jakob disease agent.J Virol. 1995; 69: 7586-7592Crossref PubMed Google Scholar were used in this study and supplied by BioResource Bank, the Institute for Enzyme Research, the University of Tokushima (Tokushima, Japan). Ngsk Prnp0/0 mice ectopically express doppel in the tissues where PrPc is expressed.20Li A. Sakaguchi S. Shigematsu K. Atarashi R. Roy B.C. Nakaoke R. Arima K. Okimura N. Kopacek J. Katamine S. Physiological expression of the gene for PrP-like protein.PrPLP/Dpl, by brain endothelial cells and its ectopic expression in neurons of PrP-deficient mice ataxic due to purkinje cell degeneration Am J Pathol. 2000; 157: 1447-1452Google Scholar However, it has been observed that the ectopic expression of doppel does not modulate prion accumulation in the brain of the mice.21Moore C.R. Mastrangelo P. Bouzamondo E. Heinrich C. Legname G. Prusiner S.B. Hood L. Westaway D. DeArmond J.S. Tremblay P. Doppel-induced cerebellar degeneration in transgenic mice.Proc Natl Acad Sci USA. 2001; 98: 15288-15293Crossref PubMed Scopus (132) Google Scholar, 22Tuzi N.L. Gall E. Melton D. Manson J.C. Expression of doppel in the CNS of mice does not modulate transmissible spongiform encephalopathy disease.J Gen Virol. 2002; 83: 705-711Crossref PubMed Scopus (52) Google Scholar Therefore, Ngsk Prnp0/0 mice can be used to monitor the fate of orally administered PrPs incorparated from the gut lumen. All mice were clinically healthy and free of infectious disease. In this study, we used a rabbit antibody against the sequence of amino acids between 1 and 50 at the N-terminus of human PrPc (diluted 1:300; IBL, Gunma, Japan)18Miyazawa K. Kanaya T. Tanaka S. Takakura I. Watanabe K. Ohwada S. Kitazawa H. Rose M.T. Sakaguchi S. Katamine S. Yamaguchi T. Aso H. Immunohistochemical characterization of cell types expressing the cellular prion protein in the small intestine of cattle and mice.Histochem Cell Biol. 2007; 127: 291-301Crossref PubMed Scopus (16) Google Scholar to detect PrP-positive cells in Peyer's patches, MLN, and spleen. To identify the cell types of PrP-positive cells, we stained the Peyer's patches and spleen with various antibodies against specific cell phenotypes. These were CD45R/B220 for B cells,23Coffman R.L. Surface antigen expression and immunoglobulin gene rearrangement during mouse pre-B cell development.Immunol Rev. 1982; 69: 5-23Crossref PubMed Scopus (443) Google Scholar CD14 and CD11b for macrophages,24Matsuura K. Ishida T. Setoguchi M. Higuchi Y. Akizuki S. Yamamoto S. Upregulation of mouse CD14 expression in Kupffer cells by lipopolysaccharide.J Exp Med. 1994; 179: 1671-1676Crossref PubMed Scopus (117) Google Scholar, 25Whiteland J.L. Nicholls S.M. Shimeld C. Easty D.L. Williams N.A. Hill T.J. Immunohistochemical detection of T-cell subsets and other leukocytes in paraffin-embedded rat and mouse tissues with monoclonal antibodies.J Histochem Cytochem. 1995; 43: 313-320Crossref PubMed Scopus (100) Google Scholar, 9Heppner F.L. Christ A.D. Klein M.A. Prinz M. Fried M. Kraehenbuhl J.P. Aguzzi A. Transepithelial prion transport by M cells.Nat Med. 2001; 7: 976-977Crossref PubMed Scopus (188) Google Scholar CD3 for T cells,26Owen J.L. Iragavarapu-Charyulu V. Gunja-Smith Z. Herbert L.M. Grosso J.F. Lopez D.M. Up-regulation of matrix metalloproteinase-9 in T lymphocytes of mammary tumor bearers: role of vascular endothelial growth factor.J Immunol. 2003; 171: 4340-4351PubMed Google Scholar Annexin V for M cells and DCs,27Verbrugghe P. Waelput W. Dieriks B. Waeytens A. Vandesompele J. Cuvelier C.A. Murine M cells express annexin V specifically.J Pathol. 2006; 209: 240-249Crossref PubMed Scopus (49) Google Scholar and clusterin for FDCs28Huber C. Thielen C. Seeger H. Schwarz P. Montrasio F. Wilson M.R. Heinen E. Fu Y.X. Miele G. Aguzzi A. Lymphotoxin-beta receptor-dependent genes in lymph node and follicular dendritic cell transcriptomes.J Immunol. 2005; 174: 5526-5536PubMed Google Scholar (Table 1).Table 1Primary Antibodies Used in this StudyAntibodiesSpecificitySpeciesDeveloped inClone nameDilutionProducts⁎Products from IBL (Gunma, Japan), BD Pharmingen (San Diego, CA), AbD Serotec (Oxford, UK), Santa Cruz Biotechnology (Santa Cruz, CA).PrPPrion protein18HumanRabbit1:300IBLCD45R/B220B cells23MouseRatRA3-6B21:1000BD PharmingenCD14Macrophages24MouseRatrmC5-31:50BD PharmingenDCDendritic cells31Breel M. Mebius R.E. Kraal G. Dendritic cells of the mouse recognized by two monoclonal antibodies.Eur J Immunol. 1987; 17: 1555-1559Crossref PubMed Scopus (90) Google ScholarMouseRatMIDC-81:50AbD SerotecFDCFollicular dendritic cells30Balogh P. Aydar Y. Tew J.G. Szakal A.K. Appearance and phenotype of murine follicular dendritic cells expressing VCAM-1.Anat Rec. 2002; 268: 160-168Crossref PubMed Scopus (37) Google ScholarMouseRatFDC-M11:50BD PharmingenCD3T cells26Owen J.L. Iragavarapu-Charyulu V. Gunja-Smith Z. Herbert L.M. Grosso J.F. Lopez D.M. Up-regulation of matrix metalloproteinase-9 in T lymphocytes of mammary tumor bearers: role of vascular endothelial growth factor.J Immunol. 2003; 171: 4340-4351PubMed Google ScholarMouseGoat1:50Santa Cruz BiotechnologyCD11bMacrophages25Whiteland J.L. Nicholls S.M. Shimeld C. Easty D.L. Williams N.A. Hill T.J. Immunohistochemical detection of T-cell subsets and other leukocytes in paraffin-embedded rat and mouse tissues with monoclonal antibodies.J Histochem Cytochem. 1995; 43: 313-320Crossref PubMed Scopus (100) Google ScholarMouseRatM1/701:300AbD SerotecAnnexin VM cells and dendritic cells27Verbrugghe P. Waelput W. Dieriks B. Waeytens A. Vandesompele J. Cuvelier C.A. Murine M cells express annexin V specifically.J Pathol. 2006; 209: 240-249Crossref PubMed Scopus (49) Google ScholarHumanGoat1:50Santa Cruz BiotechnologyClusterinFollicular dendritic cells28Huber C. Thielen C. Seeger H. Schwarz P. Montrasio F. Wilson M.R. Heinen E. Fu Y.X. Miele G. Aguzzi A. Lymphotoxin-beta receptor-dependent genes in lymph node and follicular dendritic cell transcriptomes.J Immunol. 2005; 174: 5526-5536PubMed Google ScholarMouseGoat1:300Santa Cruz BiotechnologyPGP 9.5Protein gene product 9.532Thompson R.J. Doran J.F. Jackson P. Dhillon A.P. Rode J. PGP 9.5 — a new marker for vertebrate neurons and neuroendocrine cells.Brain Res. 1983; 278: 224-228Crossref PubMed Scopus (661) Google ScholarHumanRabbitAbD SerotecDC, dendritic cells; FDC, follicular dendritic cell; PGP, protein gene product; PrP, prion protein. Products from IBL (Gunma, Japan), BD Pharmingen (San Diego, CA), AbD Serotec (Oxford, UK), Santa Cruz Biotechnology (Santa Cruz, CA). Open table in a new tab DC, dendritic cells; FDC, follicular dendritic cell; PGP, protein gene product; PrP, prion protein. As a source of infection, we used Fukuoka-1 strain CJD derived from human Gerstmann-Sträussler-Scheinker disease.29Tateishi J. Ohta M. Koga M. Sato Y. Kuroiwa Y. Transmission of chronic spongiform encephalopathy with kuru plaques from humans to small rodents.Ann Neurol. 1979; 5: 581-584Crossref PubMed Scopus (159) Google Scholar Brains were obtained from healthy ddY mice which were normal or at the terminal stage of disease or infected-ddY mice and then kept at −80°C. Brains were homogenized to 10% (w/v) in cold PBS. PrPc knockout mice were orally challenged with 200 μL of brain homogenate using a sterile disposable oral gastric tube (Fuchigami-Kikai, Kyoto, Japan) and sacrificed at 15 and 30 minutes, 1, 2, 4, 6, 8, and 10 hours, 2 and 6 days, and 4 and 10 weeks after the challenge. At each time point, Peyer's patches from the duodenum, jejunum, ileum, MLN, and spleen were obtained from three mice. All tissues were fixed in periodate lysine paraformaldehyde (PLP) overnight at 4°C. The fixed samples were paraffin-embedded or snap-frozen in OCT compound (Sakura Finetechnical, Tokyo, Japan). Sections (3-μm thick) from paraffin-embedded tissues were mounted on silane-coated slides, de-paraffinized in xylene and rehydrated in a series of graded ethanol solutions and transferred to PBS. The slides were placed in Target Retrieval Solution (Dako, Carpinteria, CA) and heated in an autoclave at 121°C for 5 minutes as the antigen retrieval technique.18Miyazawa K. Kanaya T. Tanaka S. Takakura I. Watanabe K. Ohwada S. Kitazawa H. Rose M.T. Sakaguchi S. Katamine S. Yamaguchi T. Aso H. Immunohistochemical characterization of cell types expressing the cellular prion protein in the small intestine of cattle and mice.Histochem Cell Biol. 2007; 127: 291-301Crossref PubMed Scopus (16) Google Scholar After cooling, the slides were rinsed three times in PBS and the background blocking was performed with normal goat serum (Vector Laboratories, Burlingame, CA) for 20 minutes before incubation with a specific primary antibody. The sections were incubated with polyclonal anti-PrPc antibody at 4°C overnight, rinsed five times in PBS, and incubated with biotinylated goat anti-rabbit IgG (diluted 1:200; Vector Laboratories) for 40 minutes. The sections were treated with an ABC-PO kit (Vector Laboratories) for 1 hour, visualized by 3, 3′-diaminobenzidine tetrahydrochloride (DAB) and then counterstained with Mayer's hematoxylin. Finally, the sections were observed for PrP-staining using light microscopy. To test the specificity of the immunostaining for murine tissue, negative controls were run in which the primary antibody was omitted or replaced with an irrelevant rabbit IgG purified with a protein A column (diluted 1:300, code #17312, IBL)18Miyazawa K. Kanaya T. Tanaka S. Takakura I. Watanabe K. Ohwada S. Kitazawa H. Rose M.T. Sakaguchi S. Katamine S. Yamaguchi T. Aso H. Immunohistochemical characterization of cell types expressing the cellular prion protein in the small intestine of cattle and mice.Histochem Cell Biol. 2007; 127: 291-301Crossref PubMed Scopus (16) Google Scholar (see Supplemental Figure S1 at http://ajp.amjpathol.org). First, we dual-stained with polyclonal anti-PrPc antibody and several anti-cell marker antibodies. Heating in an autoclave was used as the method of antigen retrieval, and then the slides could be stained with polyclonal anti-PrPc antibody, but not with several of the anti-cell marker antibodies. In contrast, after each treatment for the detection of several of the anti-cell markers, the slides nonspecifically stained with polyclonal anti-PrPc antibody; therefore, we immunohistochemically re-stained the sections using the same slides.18Miyazawa K. Kanaya T. Tanaka S. Takakura I. Watanabe K. Ohwada S. Kitazawa H. Rose M.T. Sakaguchi S. Katamine S. Yamaguchi T. Aso H. Immunohistochemical characterization of cell types expressing the cellular prion protein in the small intestine of cattle and mice.Histochem Cell Biol. 2007; 127: 291-301Crossref PubMed Scopus (16) Google Scholar Each re-stained section was re-stained once with an anti-cell marker antibody after the PrP staining. Briefly, to identify the cell types staining positive for PrPs, 3-μm-thick sections of Peyer's patches and 5-μm-thick sections of spleen were used for immunohistochemical re-staining. After immunohistochemical detection of challenged PrPs, the sections were observed by light microscope, and thereafter were stained for several cell marker antibodies. Pretreatment was needed to stain with anti-CD11b antibody and anti-annexin V antibody. To stain with anti-CD11b antibody, the sections were predigested with 0.0025% trypsin in 0.1% calcium chloride (pH 7.5) at 37°C for 5 minutes. For staining with anti-annexin V antibody, the sections were placed in Target Retrieval Solution (Dako) and heated in an autoclave at 121°C for 5 minutes. This pretreatment was not needed for staining with the anti-CD45R/B220, anti-CD14, anti-DC, anti-FDC, anti-CD3, anti-clusterin, and anti-protein gene product 9.5 antibodies. After these treatments, the sections were rinsed three times in PBS, blocked again with normal goat serum or normal chicken serum, and then incubated with various antisera against cell surface markers at 4°C overnight. The sections were rinsed with PBS, incubated with Alexa Fluor 488-labeled goat anti-rat IgG or chicken anti-goat IgG (diluted 1:400; Invitrogen, Eugene, OR) for 1 hour and counterstained with propidium iodide (PI; Sigma, Saint Louis, MO). The sections were observed by confocal laser microscopy (MRC-1024; BioRad, Hercules, CA), and after microscopic observation, the coverslips were removed from the slides and counterstained with Mayer's hematoxylin. To analyze the PrPs distribution of the same position on the section, we reobserved the same section using light microscopy. We investigated sequentially how PrPs administered by the oral route invaded the intestine and then spread. However, PrPc are commonly expressed in several lymphoid tissues and organs besides the brain. Whereas it would be very difficult to detect and trace relatively small amounts of PrPs delivered by the oral route, we used PrPc knockout mice in these experiments to remove the noise of normal PrPc. Figure 1 shows the distribution of PrP-positive cells in the Peyer's patches of the duodenum. After the oral challenge of 10% Fukuoka-1 strain CJD-infected brain homogenate to PrPc knockout mice, PrP-positive cells were not detected in any of the samples at 15 or 30 minutes. At 1 hour after the oral challenge, we were able to detect PrP-positive particles in the cytoplasm of villus epitheliocytes and some cells of the FAE (Figure 1, A–C). In the subepithelial dome (SED) of Peyer's patches, PrP-positive cells were also detected (Figure 1, B and C). Surprisingly, numerous PrP-positive cells had already accumulated at the subfollicle region of Peyer's patches (Figure 1, B and D). By 4 hours after the challenge, PrP-positive cells were observed in the SED and the subfollicle region of the Peyer's patch, as it was at 1 hour (Figure 1, E and F). However, we could not detect PrP-positive cells in duodenal Peyer's patches later than 8 hours after the challenge (Figure 1, G and H). These results and Supplemental Figure S1 (available at http://ajp.amjpathol.org) additionally indicate that the positive reactions are a specific reaction against orally challenged PrPs with our immunohistochemical method. Table 2 summarizes the pattern of distribution of PrP-positive cells in the Peyer's patches of the duodenum, jejunum, and ileum after the oral challenge. In the Peyer's patches of the jejunum and ileum, PrP-positive cells were detected 2 hours after the challenge. The number of PrP-positive cells reached a peak in the Peyer's patches of the jejunum and ileum at 4 to 8 hours and at 6 hours after the inoculation, respectively. The pattern of distribution of the PrP-positive cells in the jejunum and ileum was the same as for the Peyer's patches of the duodenum. PrP-positive cells had disappeared from the jejunal and ileal Peyer's patches after 10 hours of the challenge.Table 2Summary of Distribution of PrP-Positive Cells in Small Intestine Peyer's Patches of PrPc Knockout Mice at Various Times after an Oral ChallengeTime after oral challengeDuodenum PPJejunum PPIleum PP1 hourVE, FAE, SED, SFNDND2 hours—SED, FSED, F4 hoursSED, SFSED, F, IFR, SFIFR6 hoursNDSED, F, IFR, SFF, IFR, SF8 hoursNDSED, F, IFR, SFND10 hoursNDF⁎Only 1 or 2 prion protein (PrP)-positive cells were detected in a photograph., IFR⁎Only 1 or 2 prion protein (PrP)-positive cells were detected in a photograph., SF⁎Only 1 or 2 prion protein (PrP)-positive cells were detected in a photograph.—2 daysSED⁎Only 1 or 2 prion protein (PrP)-positive cells were detected in a photograph.SED⁎Only 1 or 2 prion protein (PrP)-positive cells were detected in a photograph., F⁎Only 1 or 2 prion protein (PrP)-positive cells were detected in a photograph., SF⁎Only 1 or 2 prion protein (PrP)-positive cells were detected in a photograph.—6 daysSED⁎Only 1 or 2 prion protein (PrP)-positive cells were detected in a photograph.SED⁎Only 1 or 2 prion protein (PrP)-positive cells were detected in a photograph., F⁎Only 1 or 2 prion protein (PrP)-positive cells were detected in a photograph., IFR⁎Only 1 or 2 prion protein (PrP)-positive cells were detected in a photograph.ND—, not determined.ND, PrP-positive cells are not detected; F, follicle; FAE, follicle-associated epithelium; IFR, interfollicular region; PP, Peyer's patches; SED, subepithelial dome; SF, subfollicle; VE, villus epithelium. Only 1 or 2 prion protein (PrP)-positive cells were detected in a photograph. Open table in a new tab —, not determined. ND, PrP-positive cells are not detected; F, follicle; FAE, follicle-associated epithelium; IFR, interfollicular region; PP, Peyer's patches; SED, subepithelial dome; SF, subfollicle; VE, villus epithelium. Next, we investigated the distribution of PrP-positive cells in the MLN, which was the draining lymph nodes of the Peyer's patches. PrP-positive cells in the MLN were observed mainly around vessels in the follicles and in the interfollicular region (Figure 2, A and B). The number of PrP-positive cells clearly declined between 2 and 6 days after the challenge and then disappeared by 4 weeks after the challenge (Figure 2, A–D). In the spleen, PrP-positive cells were well detected around vessels until 4 weeks after the challenge and were mainly observed in the red pulp, except for the samples taken on day 6, when the PrP-positive cells were mainly found in the white pulp (Figure 3, A–F). However, PrP-positive cells disappeared from the spleen by 10 weeks after the challenge (Figure 3, G and H). Table 3 summarizes the transition of a number of PrP-positive cells detected in the MLN and spleen. PrP-positive cells were detected in the MLN earlier than in the spleen. The number in the MLN and spleen reached a peak at 2 days and at 6 days after the challenge, respectively. These data imply that there is quite a difference in the period during which PrP-positive cells can be detected between the MLN and the spleen, and that they disappear in the MLN earlier than in the spleen.Table 3Transition of Number of PrP-Positive Cells Detected in the MLN and Spleen of PrPc Knockout Mice at Various Times after an Oral ChallengeTime after oral challengeMLNSpleen2 days++++6 days++++4 weeksND++10 weeksNDND+, several PrP-positive cells detected; ++, PrP-positive cells detected at an intermediate level; +++, numerous PrP-positive cells detected.MLN, mesenteric lymph nodes; ND, PrP-positive cells not detected; PrP, prion protein; PrPc, cellular prion protein. Open table in a new tab +, several PrP-positive cells detected; ++, PrP-positive cells detected at an intermediate level; +++, numerous PrP-positive cells detected. MLN, mesenteric lymph nodes; ND, PrP-positive cells not detected; PrP, prion protein; PrPc, cellular prion protein. We performed an oral inoculation of normal brain homogenate to PrPc knockout mice (Ngsk Prnp0/0). Mic" @default.
• W2110554208 created "2016-06-24" @default.
• W2110554208 creator A5007363105 @default.
• W2110554208 creator A5009909384 @default.
• W2110554208 creator A5020639857 @default.
• W2110554208 creator A5022691582 @default.
• W2110554208 creator A5031516587 @default.
• W2110554208 creator A5049822961 @default.
• W2110554208 creator A5056112100 @default.
• W2110554208 creator A5057544670 @default.
• W2110554208 creator A5058147147 @default.
• W2110554208 creator A5063971627 @default.
• W2110554208 creator A5072570533 @default.
• W2110554208 creator A5079685940 @default.
• W2110554208 creator A5084201443 @default.
• W2110554208 creator A5085135960 @default.
• W2110554208 creator A5086786743 @default.
• W2110554208 date "2011-09-01" @default.
• W2110554208 modified "2023-09-30" @default.
• W2110554208 title "Orally Administered Prion Protein Is Incorporated by M Cells and Spreads into Lymphoid Tissues with Macrophages in Prion Protein Knockout Mice" @default.
• W2110554208 cites W1481471471 @default.
• W2110554208 cites W1502117212 @default.
• W2110554208 cites W1505037806 @default.
• W2110554208 cites W1549404680 @default.
• W2110554208 cites W1578176285 @default.
• W2110554208 cites W1777433224 @default.
• W2110554208 cites W1829344915 @default.
• W2110554208 cites W1974764248 @default.
• W2110554208 cites W1985273834 @default.
• W2110554208 cites W2001279129 @default.
• W2110554208 cites W2003111539 @default.
• W2110554208 cites W2003558173 @default.
• W2110554208 cites W2017565148 @default.
• W2110554208 cites W2018290520 @default.
• W2110554208 cites W2020830047 @default.
• W2110554208 cites W2027255721 @default.
• W2110554208 cites W2028877565 @default.
• W2110554208 cites W2031990959 @default.
• W2110554208 cites W2036645353 @default.
• W2110554208 cites W2045159090 @default.
• W2110554208 cites W2045452322 @default.
• W2110554208 cites W2045562971 @default.
• W2110554208 cites W2046031736 @default.
• W2110554208 cites W2049028981 @default.
• W2110554208 cites W2051391548 @default.
• W2110554208 cites W2056343156 @default.
• W2110554208 cites W2056914045 @default.
• W2110554208 cites W2059510153 @default.
• W2110554208 cites W2079453971 @default.
• W2110554208 cites W2080403454 @default.
• W2110554208 cites W2080811931 @default.
• W2110554208 cites W2087869665 @default.
• W2110554208 cites W2088386171 @default.
• W2110554208 cites W2090214365 @default.
• W2110554208 cites W2106922949 @default.
• W2110554208 cites W2111896347 @default.
• W2110554208 cites W2119749560 @default.
• W2110554208 cites W2120130639 @default.
• W2110554208 cites W2140027784 @default.
• W2110554208 cites W2148222156 @default.
• W2110554208 cites W2150030958 @default.
• W2110554208 cites W2150497169 @default.
• W2110554208 cites W2152074543 @default.
• W2110554208 cites W2155463696 @default.
• W2110554208 cites W2156023394 @default.
• W2110554208 cites W2157233598 @default.
• W2110554208 cites W2157364728 @default.
• W2110554208 cites W2165684825 @default.
• W2110554208 cites W2167842421 @default.
• W2110554208 cites W2185932558 @default.
• W2110554208 doi "https://doi.org/10.1016/j.ajpath.2011.05.058" @default.
• W2110554208 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3157171" @default.
• W2110554208 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/21763679" @default.
• W2110554208 hasPublicationYear "2011" @default.
• W2110554208 type Work @default.
• W2110554208 sameAs 2110554208 @default.
• W2110554208 citedByCount "40" @default.
• W2110554208 countsByYear W21105542082012 @default.
• W2110554208 countsByYear W21105542082013 @default.
• W2110554208 countsByYear W21105542082014 @default.
• W2110554208 countsByYear W21105542082015 @default.
• W2110554208 countsByYear W21105542082016 @default.
• W2110554208 countsByYear W21105542082017 @default.
• W2110554208 countsByYear W21105542082018 @default.
• W2110554208 countsByYear W21105542082019 @default.
• W2110554208 countsByYear W21105542082020 @default.
• W2110554208 countsByYear W21105542082021 @default.
• W2110554208 countsByYear W21105542082022 @default.
• W2110554208 countsByYear W21105542082023 @default.
• W2110554208 crossrefType "journal-article" @default.
• W2110554208 hasAuthorship W2110554208A5007363105 @default.
• W2110554208 hasAuthorship W2110554208A5009909384 @default.
• W2110554208 hasAuthorship W2110554208A5020639857 @default.
• W2110554208 hasAuthorship W2110554208A5022691582 @default.
• W2110554208 hasAuthorship W2110554208A5031516587 @default.
• W2110554208 hasAuthorship W2110554208A5049822961 @default.
• W2110554208 hasAuthorship W2110554208A5056112100 @default.
• W2110554208 hasAuthorship W2110554208A5057544670 @default.

• next