Follicular Dendritic Cell Dedifferentiation by Treatment with an Inhibitor of the Lymphotoxin Pathway Dramatically Reduces Scrapie Susceptibility

Mabbott, Neil A.; Young, J.; McConnell, I.; Bruce, Moira E.

doi:10.1128/jvi.77.12.6845-6854.2003

Cited by 141 publications

(189 citation statements)

References 61 publications

(91 reference statements)

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“…Our observations support the role of FDC for scrapie pathogenesis 6 and are in line with experiments that report drastically reduced susceptibility of mice to scrapie on dedifferentiation of FDC. 20 Furthermore, the proximity of nerve endings and PrP sc in lymphoid follicles has been demonstrated. 14,31 Conversely, in this study the authors failed to observe a pattern of PrP sc accumulation in lymphoid tissues that would suggest travel of PrP sc through the lymphatic vessels or blood stream.…”

Section: Discussionmentioning

confidence: 98%

Biology of PrP^sc Accumulation in Two Natural Scrapie-Infected Sheep Flocks

Caplazi

O’Rourke²,

Wolf

et al. 2004

J VET Diagn Invest

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Abstract. Sheep scrapie is a prion disease that requires interaction of exogenous prions with host prion protein (PrP) supporting prion formation. Disease is associated with deposition of a host-generated conformational variant of PrP, PrP sc , in a variety of tissues, including brain, resulting in fatal spongiform encephalopathy. Efficiency of PrP sc formation is determined by polymorphisms in the PrP-coding sequence. This article adds to previous data of natural sheep scrapie, concentrating on the effect of host genotype and age on PrP sc accumulation patterns during preclinical and clinical disease. Two entire scrapie-infected, predominantly Suffolk-cross, sheep flocks euthanized for regulatory purposes were genotyped and analyzed for PrP sc deposition in various tissues using single-and dual-label immunohistochemistry. Scrapie, as defined by PrP sc deposition, occurred in 13/80 sheep. Preclinical disease was evident in nearly 70% of infected sheep, ranging in age from 14 months to 7 years. PrP sc accumulated systemically in the nervous tissue, various lymphoid tissues, both alimentary tract related and non-alimentary tract related, and the placenta. Clinical neurological illness was always associated with spongiform encephalopathy and PrP sc deposition in the brain. Only 6 of 9 sheep with preclinical scrapie had PrP sc deposition in the brain but widespread PrP sc deposition in peripheral lymphoid tissue, supporting previous data showing peripheral PrP sc accumulation preceding deposition in the brain. PrP sc colocalized with a marker for follicular dendritic cells throughout the lymphoid system. PrP sc also accumulated in the peripheral nervous system, particularly the nervous supply of the gastrointestinal tract. Abundant PrP sc was evident in trophoblast cells of placentomes but not in the endometrium, myometrium, or associated nervous plexus. PrP sc deposits were not observed in the mammary parenchyma or bone marrow. Scrapie susceptibility was defined genetically by PrP codon 171: PrP sc deposition was restricted to PrP genotype AA 136 RR 154 QQ 171 in 12/13 cases or AV 136 RR 154 QQ 171 in 1/13 cases. The earliest accumulation was observed in the single VRQ/ARQ heterozygous animal, consistent with the reported high scrapie susceptibility and brief incubation period observed in breeds with predominance of the V 136 R 154 Q 171 allele. Disease occurred within, as well as independent of, motherdaughter lines, suggesting both maternal and nonmaternal transmission in the flocks.

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Section: Discussionmentioning

confidence: 98%

Biology of PrP^sc Accumulation in Two Natural Scrapie-Infected Sheep Flocks

Caplazi

O’Rourke²,

Wolf

et al. 2004

J VET Diagn Invest

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“…In these tissues, PrP RES was observed within likely follicular dendritic cells, cells that have been shown to be important enablers of prion disease propagation and neuroinvasion. 21,[37][38][39][40][41][42][43] Detection of splenic PrP RES at a time point (60 dpi) preceding PrP RES detection in the brain (120 dpi) suggests that splenic-mediated neuroinvasion plays a role in Tg[CerPrP] mice, as has been theorized for scrapie prion transit via nerve fibers associated with follicular dendritic cell-rich splenic germinal centers as conduits to the thoracic spinal cord. 44,45 Although splenic-mediated neuroinvasion remains the most likely possibility, we cannot exclude the possibility of hematogenous neuroinvasion, a phenomenon that, although little investigated, finds support in the literature and in the detection of infectious prions in blood.…”

Section: Discussionmentioning

confidence: 99%

Pathogenesis of Chronic Wasting Disease in Cervidized Transgenic Mice

Seelig

Mason

Telling

et al. 2010

The American Journal of Pathology

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“…The infection initially targets follicular dendritic cells before spreading to the nearby nerves to reach the CNS (Mabbott et al 2003;Prinz et al 2003). In this respect, it is not clear how neuroinvasion takes place, although many data support ENS involvement.…”

mentioning

confidence: 99%

Nitric Oxide Synthase Immunoreactivity and NADPH-d Histochemistry in the Enteric Nervous System of Sarda Breed Sheep With Different PrP Genotypes in Whole-mount and Cryostat Preparations

Lalatta-Costerbosa

Mazzoni

Clavenzani

et al. 2006

J Histochem Cytochem.

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Until now, significant differences in the neurochemical pattern of enteric neurons have been demonstrated in all species studied; however, some strong similarities also occur across species, such as the occurrence of nitric oxide synthase immunoreactivity (NOS-IR) in inhibitory motor neurons to muscle. In consideration of the insufficient data regarding the enteric nervous system (ENS) of sheep, we investigated the myenteric plexus and submucosal plexus of the ovine ileum. Since the pivotal role of the ENS in the early pathogenesis of sheep scrapie, the “prototype” of prion diseases, has been suggested, we have focused our observations also on the host's PrP genotype. We have studied the morphology and distribution of NOS-IR neurons and their relationships with the enteric glia in whole-mount preparations and in cryostat sections. NOS-IR neurons, always encircled by glial processes, were located in both plexuses. Many NOS-IR fibers were seen in the circular muscle layer, in the submucosa, and in the mucosa. In the submucosa they were close to the lymphoid tissue. No differences in the distribution and percentage of NOS-IR fibers and neurons were observed among sheep carrying different PrP genotype, thus making unlikely their contribution in the determinism of susceptibility/resistance to scrapie infection.

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Follicular Dendritic Cell Dedifferentiation by Treatment with an Inhibitor of the Lymphotoxin Pathway Dramatically Reduces Scrapie Susceptibility

Cited by 141 publications

References 61 publications

Biology of PrP^sc Accumulation in Two Natural Scrapie-Infected Sheep Flocks

Biology of PrP^sc Accumulation in Two Natural Scrapie-Infected Sheep Flocks

Pathogenesis of Chronic Wasting Disease in Cervidized Transgenic Mice

Nitric Oxide Synthase Immunoreactivity and NADPH-d Histochemistry in the Enteric Nervous System of Sarda Breed Sheep With Different PrP Genotypes in Whole-mount and Cryostat Preparations

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Follicular Dendritic Cell Dedifferentiation by Treatment with an Inhibitor of the Lymphotoxin Pathway Dramatically Reduces Scrapie Susceptibility

Cited by 141 publications

References 61 publications

Biology of PrPsc Accumulation in Two Natural Scrapie-Infected Sheep Flocks

Biology of PrPsc Accumulation in Two Natural Scrapie-Infected Sheep Flocks

Pathogenesis of Chronic Wasting Disease in Cervidized Transgenic Mice

Nitric Oxide Synthase Immunoreactivity and NADPH-d Histochemistry in the Enteric Nervous System of Sarda Breed Sheep With Different PrP Genotypes in Whole-mount and Cryostat Preparations

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Biology of PrP^sc Accumulation in Two Natural Scrapie-Infected Sheep Flocks

Biology of PrP^sc Accumulation in Two Natural Scrapie-Infected Sheep Flocks