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From the Institute of Neuropathology,* University Hospital of Zürich, Zürich, Switzerland; the Institute of Experimental Immunology, University Hospital of Zürich, Zürich, Switzerland; the Institute of Internal Medicine, University Hospital of Zürich, Section of Clinical Immunology, Zürich, Switzerland; and the Institute of Genetics, University of Cologne, Cologne, Germany
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Abstract |
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4ß7 integrin; PPs of ß7-/- mice are normal in number but are atrophic and almost entirely devoid of B cells. Here we report that minimal infectious dose and disease incubation after oral exposure to logarithmic dilutions of prion inoculum were similar in ß7-/- and wild-type mice, and PPs of both ß7-/- and wild-type mice contained 3–4 log LD50/g prion infectivity 
125 days after challenge. Despite marked reduction of B cells, M cells were present in ß7-/- mice. In contrast, mice deficient in both tumor necrosis factor and lymphotoxin- (TNF-/- x LT-/-) or in lymphocytes (RAG-1-/-, µMT), in which numbers of PPs are reduced in number, were highly resistant to oral challenge, and their intestines were virtually devoid of prion infectivity at all times after challenge. Therefore, lymphoreticular requirements for enteric and for intraperitoneal uptake of prions differ from each other. Although susceptibility to prion infection following oral challenge correlates with the number of PPs, it is remarkably independent of the number of PP-associated lymphocytes.
B lymphocytes play a crucial role in peripheral prion pathogenesis: mice devoid of B lymphocytes do not develop disease after intraperitoneal exposure.8
This is possibly because B lymphocytes induce maturation of follicular dendritic cells (FDCs) by providing tumor necrosis factor- (TNF-) and lymphotoxin /ß (LT/ß) trimers to lymphoid organs.9
Early PrPSc deposition can be detected in FDCs within B cell follicles in lymphoid tissues of patients with vCJD10
and in rodents inoculated with scrapie by peripheral routes.11
In mouse spleens, mature FDCs have been shown to be crucial for both prion replication and PrPSc accumulation,12,13
although prion replication in lymph nodes can occur in the absence of mature FDCs.14
In contrast, the role of intestinal B cells in prion pathogenesis following oral challenge is still unclear.
Intestinal mucosal immunity provides an important level of defense against foreign pathogens. The ability of B and T lymphocytes to be recruited to the site of infection is critical for an effective immune response. This process is mediated by homing receptors on effector cells with cognate ligands at peripheral or mucosal sites.15
Integrin 4ß7 plays an important role in the homing of activated lymphocytes to PPs and to the intestinal lamina propria.16
ß7 Integrin-deficient (ß7-/-) mice suffer from severely-reduced cellularity of PPs (>90% less B and T cells)17
and from impaired intestinal immunity in a variety of disease models.18-20
With the exception of the GALT, lymphoid organs of ß7-/- mice are otherwise normal. These mice are therefore well-suited to dissect the role of mucosa-associated immune tissue, including B cells, in the pathogenesis of enterically-initiated prion disease.
In addition, B lymphocytes exert an important organogenic role in the GALT21,22
and are likely to be involved in the B cell-dependent development of the follicle-associated epithelium (FAE).23
However, splenic lymphocytes can acquire prion infectivity,24
and it is unclear whether their role in prion pathogenesis is restricted to the generation and maintenance of FDCs13
or whether they may also be involved in prion trafficking.25
To dissect the organogenetic effects from trafficking components, we administered prions orally to TNF-/-/LT-/- mice, which have normal lymphocyte counts but lack the two cytokines TNF- and LT,26
to B cell-deficient µMT mice,27
and to RAG-1-/- mice28
which lack all T and B lymphocytes. While there were no recognizable PPs in TNF-/-/LT-/- mice, unexpectedly we found that µMT and RAG-1-/- mice had some FDC-M1-positive cells in their atrophic Peyer’s patches, but not in spleen nor in lymph nodes. However, these FDC-like structures were not sufficient for enteric prion replication.
Here we show that prion replication in the GALT and subsequent neuroinvasion was independent of B cells within the mucosa-associated lymphatic tissue and that the remaining M cells are most likely important for this process. TNF-/-/LT-/-, µMT, and RAG-1-/- mice were highly resistant to oral challenge, and their intestines were virtually devoid of prion infectivity at all times after challenge. Therefore, lymphoreticular requirements for enteric and intraperitoneal uptake of prions differ, and the presence of intramucosal B lymphocytes does not appear to be important for prion pathogenesis following oral challenge.
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Materials and Methods |
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C57BL/6, Sv129 x BL/6, µMT,27
RAG-1-/-,28
and TNF-/-/LT-/-26
mice were bred at the Institute of Laboratory Animal Science of the University of Zurich and maintained under specific pathogen-free conditions. Wild-type mice were obtained originally from the Jackson Laboratory, Bar Harbor, ME.
Alkaline Phosphatase Detection
For detection of alkaline phosphatase (AP) activity, fixed whole PPs were studied. Segments of the small intestine containing one PP were excised, opened, and pinned on dental wax. Tissues were fixed for 10 minutes in Baker formalin calcium medium (pH 6) on ice. At this stage, villi were removed using a binocular microscope, and incubated with 125 nmol/L Tris buffer (pH 9.2) at 37°C for 5 minutes and then incubated in Tris buffer containing naphthol AS-BI phosphate (Sigma, Deisenhofen, Germany) with constant shaking for 10 minutes. The reaction was stopped with ice-cold buffer. Goblet cells were detected by incubating tissue briefly in 1% Alcian blue dissolved in 3% acetic acid. Whole-mount FAEs were then used to enumerate AP-negative M cells as a percentage of the total cell population within the FAE. Statistical significance was determined using the unpaired Student’s t-test. Values of P < 0.05 were considered as significant.
Challenge with Scrapie Prions
Mice were fed with logarithmic dilutions of 10% heat- and sarcosyl-treated brain homogenate prepared from mice infected with the Rocky Mountain Laboratory (RML) scrapie strain (passage 4.1). 8 log LD50 of the prion homogenate RML were administered via gastrolavage directly into the stomach. Smaller amounts (see Table 1
) were administered by feeding a mixture of brain homogenate with food pellets. For intraperitoneal inoculations, 6 log LD50 of scrapie inoculum was administered. Mice were monitored on alternate days, and scrapie was diagnosed according to standard clinical criteria.
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Bioassays were performed on 1% homogenates of spleens or of PBS-perfused small intestines (containing Peyer’s patches). Tissues were homogenized in PBS/BSA with a microhomogenizer and passed several times through 18-gauge and 22-gauge needles. Following preparation of a homogeneous suspension, centrifugation was performed at 500 x g for 5 minutes. Supernatants (30 µl) were inoculated intracerebrally into groups of at least four tga20 mice.29 The titer of the standard inoculum (7.9 log 10 of 50% lethal dose (LD50)/ml, corresponding to 8.9 log LD50/g of brain tissue) was determined by the 50% endpoint calculation method.30 The relationship y = 11.45 - 0.088 (y, log LD50 x ml-1 of homogenate; x, incubation time in days to terminal disease) was calculated by linear regression.25,31 Indicator mice were sacrificed after development of terminal scrapie and infectivity titers were calculated.
Histology and Immunohistochemistry
Paraffin sections (2 µm) and cryostat sections (10 µm) from brain, spleen and PPs were stained with hematoxylin and eosin. Immunostaining for GFAP was performed using rabbit GFAP antisera (1:300 dilution; DAKO, Carpinteria, CA) and detected with biotinylated swine anti-rabbit serum (1:250 dilution; DAKO), avidin-peroxidase and diaminobenzidine (Sigma). Antibodies reactive against the follicular dendritic cell marker FDC-M1 (clone 4C11; 1:300 dilution) or the pan-B cell marker CD45R/B220 (BD Pharmingen, San Diego, CA) were used for immunohistochemistry of frozen sections as previously described.32
Western Blot Analysis
Tissue homogenates were adjusted to protein concentrations of 5 mg/ml (brain) or 8 mg/ml (spleen) and treated with proteinase K (20 µg/ml, 30 minutes, 37°C). 50 µg (brain) or 80 µg (spleen) of total protein of each sample were electrophoresed through a 12% SDS-PAGE gel. Proteins were transferred to nitrocellulose membranes by semi-dry blotting. Membranes were blocked with Tris-buffered saline containing 0.1% Tween 20, pH 8.0 (TBST)/5% nonfat milk, incubated with antibodies 6H4 (for brain protein) or 1B3 (for spleen protein), and detected using alkaline phosphatase-linked anti-mouse (6H4) or anti-rabbit (1B3) sera followed by development by enhanced chemiluminescence (ECL; Amersham, Uppsala, Sweden).
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Results |
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To evaluate the extent to which the absence of 4ß7 integrin, TNF/lymphotoxin, and B and T cells affects the presence of PPs, mice were examined anatomically. PPs of wild-type mice of the C57BL/6 and 129SvxBL6 genetic background were easily visible to the naked eye, whereas in ß7-/-, RAG-1-/-, and µMT mice PPs were undetectable by gross inspection. However, when small intestines were inflated with saline buffer (PBS) and transilluminated under a dissecting microscope (16x magnification), numerous small Peyer’s patches could be discerned (Figure 1)
. The number and location (data not shown) of Peyer’s patches in ß7-/- mice (n = 6–10, mean 8.0 ± 1.5) were similar to wild-type mice (n = 6–11, mean 7.3 ± 1.5). A comparison with Student’s t-test, however, yielded a P value of >0.05, indicating that the number of Peyer’s patches in the two groups was not significantly different. In contrast, the number of PPs in B cell-deficient µMT mice were significantly reduced (0–7, mean 2.5 ± 2.2; P < 0.01 if compared to the respective wild-type control). Combined B cell and T cell deficiency in RAG-1-/- mice further reduced the number of PPs (0–5, mean 2.0 ± 1.7; P < 0.01). The absence of TNF- and lymphotoxin- (LT) completely prevented the formation of visible Peyer’s patches (P < 0.01).
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Peyer’s Patches of ß7-/-, RAG-1-/-, and µMT Mice Are Atrophic but Contain FDCs
To determine whether the absence of 4ß7 integrin and lymphocytes alters the cellular composition of secondary lymphoid organs, we studied spleen and PPs by immunohistochemistry using antisera reactive against the B lymphocyte marker B220 and with the FDC marker M1 (Figure 2)
. The germinal center histology of spleens of ß7-/- mice was indistinguishable from wild-type spleens. B cell zones were distinct and contained FDC-M1-positive cells of normal shape and localization.
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/LT-deficient mice, although a small number of B cells were still present in the small intestine of these mice. Lymphoid organ structure of spleens of TNF-/LT-deficient mice was severely impaired, without any separation between T and B cell zones, and FDCs were undetectable. No FDC-M1 positive cells were detected in the spleens of RAG-1-/- and µMT mice, in agreement with earlier reports.22 Unexpectedly, clusters of cells reactive with FDC-M1 and CD35 (CR1, not shown) were consistently detected in the small atrophic Peyer’s patches of RAG-1-/- and µMT mice. Immunostaining also revealed a number of B220 positive cells in spleens and PPs. The majority of these B220-positive cells are most likely NK cells, because the antibody used (CD45R/B220) reacts with an epitope on the extracellular domain of the CD45 glycoprotein, which is expressed on lytically active subsets of lymphokine-activated killer cells such as NK cells and their progenitors in addition to B lymphocytes.33 The smaller B220+ cell population in the PPs of RAG-1-/- and µMT mice most likely consist of immature B cells which are still able to produce functional immunoglobulins of the A class even in the absence of surface, membrane-bound IgM or IgD, therefore representing a developmental pro-B cell block in these strains.34
ß7-/- Intestinal Epithelium Contains M Cells Despite Depleted Intraepithelial B Cells
M cells of the FAE are believed to be important antigen sampling sites, and can act as entry sites for pathogens. To determine whether the absence or reduction of lymphocytes alters the composition of the FAE, we performed immunostaining of PPs of wild-type, ß7-/-, RAG-1-/- and µMT with antibodies reactive against specific markers for M cells (Figure 3, A–D)
. M cells, visualized histochemically by their reduced AP activity,35
were readily detectable in the FAE of wild-type mice (Figure 3A)
. In ß7-/-, µMT, and RAG-1-/- (Figure 3, B, C, and D
, respectively), both PPs and AP-negative M cells were apparent. The presence of PPs and AP-negative M cells was further confirmed by scanning electron microscopy, which allowed visualization of the disorganized brush border of these cells (data not shown).
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We then estimated the relative number of intestinal M cells per total epithelial cells within the FAE by counting AP-negative M cells under 400x magnification by light microscopy (Figure 3E)
. The relative number of M cells was increased in the FAE of ß7-/- (mean: 15.4 ± 4.0 vs. 6.7 ± 1.8 for 129Sv x BL/6 mice, P < 0.01), RAG-1-/- (mean: 13.5 ± 2.3 vs. 7.2 ± 2.7 for BL/6, P < 0.05) and µMT (mean: 14.2 ± 2.8 compared to BL/6, P < 0.05) tissues. These data indicate that the differentiation program of the FAE, including M cells, is maintained even in the absence of proper B cell numbers.
Unimpaired Scrapie Pathogenesis in ß7-Deficient Mice
To determine the contribution of different components of the GALT to the intestinal uptake of orally-delivered prions, mice were challenged with logarithmic dilutions of scrapie inoculum. Attack rate and time to terminal disease were measured. Following high-dose oral infection (8 log LD50) all ß7-/- mice, Sv129 x C57BL/6 wild-type mice, and 9 of 10 C57BL/6 wild-type mice developed clinical signs of scrapie with similar incubation times of 213 to 230 days (Table 1)
. These results indicate that ß7-/- mice are highly susceptible to disease via oral administration of prions. Accordingly, accumulation of PK-resistant PrPSc was readily detectable in brains and spleens of clinically sick ß7-/- and wild-type mice (Figure 4)
. Moreover, topography and intensity of spongiosis and gliosis were similar in clinically sick ß7-/- mice compared to clinically sick wild-type mice (Figure 5)
. Importantly, the use of lower prion inocula via the oral route significantly decreased the susceptibility to disease in these mice compared to i.p. challenge. A 10-fold dilution of the scrapie inoculum reduced the scrapie attack rate to 50% in ß7-/- and to 50 to 25% in the different wild-type mice. Further dilution of the inoculum did not evoke scrapie in mice of any genotype.
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-/-/LT-/- mice partially resistant, to prions administered i.p. Wild-type mice can be experimentally infected via the i.p. route with prion inocula of less than 3 intracerebral log LD50, yet the minimal dose for oral infection is 7 intracerebral log LD50 of scrapie inoculum. Therefore, these results confirm previous observations that the oral route of prion infection is relatively inefficient in mice.
In contrast to wild-type or ß7-/- animals, mice deficient for LT and TNF- and mice lacking mature B cells were virtually resistant to orally-administered prions, even when extremely large inocula were used. This provides evidence that neither small intestines from TNF-/- x LT-/- mice nor atrophic PPs of RAG-1-/- and µMT mice are sufficient as entry sites of prions.
Although PPs of the small intestine are potential entry sites for pathogens, draining lymph nodes and the spleen provide lymphoid sites with a mechanism for pathogen clearance. However, RAG-1-/-, µMT, and TNF-/- x LT-/- mice were highly resistant to i.p. infection with prions (Table 1)
,8
and therefore the phase of peripheral prion replication is also impaired in these mice. Accordingly, PrPSc was undetectable in brains and spleens of clinically healthy RAG-1-/-, µMT, and TNF-/- x LT-/- mice at the indicated postinfection time points.
Peyer’s Patches of ß7-/- but Not RAG-1-/- and µMT Mice Are Sites of Peripheral Prion Replication
We then investigated peripheral prion replication in PPs and spleens of ß7-/-, RAG-1-/-, and µMT mice following oral challenge. PPs (Figure 6
, red symbols) and spleens (Figure 6
, blue symbols) were collected at various time points after oral (8 log LD50) or i.p. (6 log LD50) infection until terminal disease. Infectivity titers were determined by transmission of homogenized tissues to indicator mice. For those TNF-/- x LT-/- mice which lacked all PPs, selected portions of the small intestine were dissected and used for transmission studies.
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With the exception of trace levels of infectivity in spleens and PPs of RAG-1-/- and TNF-/- x LT-/- mice at latter time points, we found no evidence for infectivity in any spleen and PP of challenged RAG-1-/- (diamonds), µMT (squares), and TNF-/- x LT-/- (triangles) mice. Therefore, the absence of PPs in mice deficient in TNF- and LT prevents gastroenteric invasion of prions.
Even more surprisingly, PPs of RAG-1-/- and µMT mice were devoid of infectivity despite the presence of FDC-M1-positive cell cluster (Figure 2)
. As previously mentioned, it is probable that these cells are FDC-like since they are CD35-positive and have also been reported to be dependent on LTß signaling.21
However, it is not obvious whether these cells represent functionally inactive FDCs. The data presented here appear to suggest that ablation of mature B cells, which are the primary sources of LT and LTß, abolishes the induction of FDC-M1-positive cells in the spleen, but not in PPs.
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Discussion |
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4ß7-/- mice with prion inocula of less than 3 log LD50 via the i.p. route. In contrast, the minimal dose for infection via the oral route was 7 log LD50 of scrapie inoculum. This indicates that the intestinal mucosa constitutes an effective barrier for prions. This may be due to potential antiprion effects of mucosal immunity, or because transepithelial prion transport is rate-limiting.
Our data appear to indicate that proper homing of B lymphocytes to the enteric mucosa is not a compulsory prerequisite for enteric prion uptake. This finding is surprising, since B cells are crucially important for peritoneal prion pathogenesis,8
and 4ß7-/- mice with marked reduction of enteric lymphocytes display significant alterations in various models of intestinal inflammation and infection.18,19,20
The GALT consists of highly-organized PPs in the small intestine, and intraepithelial lymphocytes are present throughout the length of the gastrointestinal tract. The intestinal surfaces of PPs are characterized by the presence of "domes," which are regions free of intestinal villi.36 At these domes, M cells are able to tunnel pathogens through the cytoplasm to the basal surface, where deep invaginations of their membrane allow close contact with lymphocytes and macrophages.37
Surprisingly, we found no evidence of scrapie infectivity in the atrophic PPs of B cell-deficient µMT and RAG-1-/- mice orally challenged with prions, despite the presence of M cells in these mice.21,22 We estimated that the number of M cells in B cell deficient mice was approximately 150 to 840 times less than in wild-type mice.22 It is possible that this reduction in M cell numbers also leads to strong functional impairment, such that sufficient prion replication in B cell-deficient mice may no longer be possible. In view of the presence of FDC-M1-positive cells within PPs of µMT and RAG-1-/- mice, the absence of detectable prion infectivity in PPs of these mice is also surprising, since mature B cells are believed to be required to support FDC maturation in adult peripheral lymphoid tissues.38 Whether these FDC-M1-positive cells represent mature FDCs, precursors of FDCs, or an unrelated cell type remains to be established. However, it should be noted that we have been able to determine that these cells are also CD35 (CR1) positive (data not shown) and are highly sensitive to LTßR-Ig fusion protein treatment,21 indicating that they share several features in common with splenic FDCs. Importantly, we were unable to detect cells reactive for FDC markers in spleens or lymph nodes of µMT and RAG-1-/- mice (data not shown).
Three major cell types are known to express LTß for the induction of FDCs in adult mice: T, B, and NK cells. NK cells are the only LTß+ cells retained in µMT and RAG-1-/- mice. It is conceivable that these cells may supply the LTß signals and indeed, LTß+CD4+CD3- cell populations have been observed in developing Peyer’s patches.39
The relatively high resistance of B cell-deficient mice to oral prion challenge is in agreement with our earlier observations that following i.p. inoculation, RAG-1-/-, RAG-2-/-, and µMT mice failed to establish prion replication in the spleen and did not develop scrapie for >600 days.8 However although accumulation of PrPSc has been observed in the brains of some B cell-deficient mice,40 we found no cases of subclinical disease on oral administration of prions, as assessed by Western blot analysis of brain homogenates.
As described repeatedly,8,14,25 B cell-deficient mice were entirely resistant to i.p. administered prions, while TNF/LT deficient mice were partially resistant. These findings differ from those reported by Mabbott et al41 and suggest that the importance of B lymphocytes in prion pathogenesis might go beyond their role in FDC maintenance.
The data outlined here indicate that the requirements for oral and i.p. pathogenesis differ profoundly. The significant reduction of mucosal lymphocytes seen in ß7-/- mice is not limiting for oral prion uptake. FDCs are unlikely to be rate limiting, since there was a marked reduction in number of these cells in sensitive ß7-/- mice, and they were not completely abolished in fully protected RAG-1-/- and µMT mice. Instead, absolute resistance to oral prion infection was achieved here if Peyer’s patches or B cells were totally absent.
It is unclear which elements, lacking from RAG-1-/- and µMT mice, are necessary for pathogenesis following oral prion challenge in ß7-/- mice. Epithelial M cells are certainly plausible candidates, since they efficiently transcytose prion infectivity from the apical to the basolateral compartment in an in vitro co-culture system.42 M cells are still present in RAG-1-/- mice, but their functionality is dependent on the presence of mature B cells,22 which are still present in small numbers in ß7-/- mice. Since there is a lack of isolated M cell-specific genes, it is not yet possible to address this directly in vivo, for example, by using transgenesis and lineage ablation strategies.
The findings reported here indicate that the pathophysiology of prion infection after oral uptake relies on mechanisms and cellular components significantly different from the established requirements for the intraperitoneal route (lymphocytes, FDCs). Clearer understanding of the process involved in mucosal passage of prions will be crucial in dealing effectively with orally-transmitted prion diseases, such as bovine spongiform encephalopathy, vCJD, and chronic wasting disease.
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Acknowledgements |
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Footnotes |
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Supported by grants from the Bundesamt für Bildung und Wissenschaft, the Migros Foundation, the National Center for Competence in Research on Neural Plasticity and Repair, and the Swiss National Foundation (A.A.). M.P. was a postdoctoral fellow of the Deutsche Forschungsgemeinschaft (Pr 577/2–1), F.L.H. is supported by the Stammbach foundation, and M.G. is supported by the Forschungskredit der Universität Zürich.
Accepted for publication December 18, 2002.
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(4)ß(7) independent pathway for CD8(+) T cell-mediated intestinal immunity to rotavirus. J Clin Invest 2000, 106:1541-1552[Medline]
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+ CD3(-) cells in the embryonic intestine induces the organizing center of Peyer’s patches. Int Immunol 1999, 11:643-655-deficient, but not interleukin-6-deficient, mice resist peripheral infection with scrapie. J Virol 2000, 74:3338-3344This article has been cited by other articles:
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  S. Cordier-Dirikoc and J. Chabry Temporary Depletion of CD11c+ Dendritic Cells Delays Lymphoinvasion after Intraperitonal Scrapie Infection J. Virol., September 1, 2008; 82(17): 8933 - 8936. [Abstract] [Full Text] [PDF]
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 T. Kanaya, K. Miyazawa, I. Takakura, W. Itani, K. Watanabe, S. Ohwada, H. Kitazawa, M. T. Rose, H. R. McConochie, H. Okano, et al. Differentiation of a murine intestinal epithelial cell line (MIE) toward the M cell lineage Am J Physiol Gastrointest Liver Physiol, August 1, 2008; 295(2): G273 - G284. [Abstract] [Full Text] [PDF]
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 C. R. Raymond, P. Aucouturier, and N. A. Mabbott In Vivo Depletion of CD11c+ Cells Impairs Scrapie Agent Neuroinvasion from the Intestine J. Immunol., December 1, 2007; 179(11): 7758 - 7766. [Abstract] [Full Text] [PDF]
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Y. Friedman-Levi, H. Ovadia, R. Hoftberger, O. Einstein, O. Abramsky, H. Budka, and R. Gabizon Fatal Neurological Disease in Scrapie-Infected Mice Induced for Experimental Autoimmune Encephalomyelitis J. Virol., September 15, 2007; 81(18): 9942 - 9949. [Abstract] [Full Text] [PDF]
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S. Sethi, K. M. Kerksiek, T. Brocker, and H. Kretzschmar Role of the CD8+ Dendritic Cell Subset in Transmission of Prions J. Virol., May 1, 2007; 81(9): 4877 - 4880. [Abstract] [Full Text] [PDF]
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B. R. Glaysher and N. A. Mabbott Role of the GALT in Scrapie Agent Neuroinvasion from the Intestine J. Immunol., March 15, 2007; 178(6): 3757 - 3766. [Abstract] [Full Text] [PDF]
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 R. C. Angers, S. R. Browning, T. S. Seward, C. J. Sigurdson, M. W. Miller, E. A. Hoover, and G. C. Telling Prions in Skeletal Muscles of Deer with Chronic Wasting Disease Science, February 24, 2006; 311(5764): 1117 - 1117. [Abstract] [Full Text] [PDF]
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