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A lympho-follicular microenvironment is required for pathological prion protein deposition in chronically inflamed tissues from scrapie-affected sheep.

Maestrale C, Di Guardo G, Cancedda MG, Marruchella G, Masia M, Sechi S, Macciocu S, Santucciu C, Petruzzi M, Ligios C - PLoS ONE (2013)

Bottom Line: We demonstrated that ectopic PrP(Sc) deposition occurs exclusively in the context of lymphofollicular inflammatory sites, inside newly formed and well-organized lymphoid follicles harboring follicular dendritic cells.A significantly more consistent expression of lymphotoxin α and β mRNA was detected in lymphofollicular inflammation compared to the other two types, with lymphotoxin α and β signaling new lymphoid follicles' formation and, likely, the occurrence of ectopic PrP(Sc) deposition inside them.Our findings suggest that, in sheep co-affected by scrapie and chronic inflammatory conditions, only newly formed lymphoid follicles provide a suitable micro-environment that supports the scrapie agent's replication in inflammatory sites, with an increased risk of prion shedding through body secretions/excretions.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Sanità Animale, Istituto Zooprofilattico Sperimentale della Sardegna, Sassari, Italy.

ABSTRACT
In sheep scrapie, pathological prion protein (PrP(Sc)) deposition occurs in the lymphoreticular and central nervous systems. We investigated PrP(Sc) distribution in scrapie-affected sheep showing simultaneous evidence of chronic lymphofollicular, lymphoproliferative/non-lymphofollicular, and/or granulomatous inflammations in their mammary gland, lung, and ileum. To do this, PrP(Sc) detection was carried out via immunohistochemistry and Western Blotting techniques, as well as through inflammatory cell immunophenotyping. Expression studies of gene coding for biological factors modulating the host's inflammatory response were also carried out. We demonstrated that ectopic PrP(Sc) deposition occurs exclusively in the context of lymphofollicular inflammatory sites, inside newly formed and well-organized lymphoid follicles harboring follicular dendritic cells. On the contrary, no PrP(Sc) deposition was detected in granulomas, even when they were closely located to newly formed lymphoid follicles. A significantly more consistent expression of lymphotoxin α and β mRNA was detected in lymphofollicular inflammation compared to the other two types, with lymphotoxin α and β signaling new lymphoid follicles' formation and, likely, the occurrence of ectopic PrP(Sc) deposition inside them. Our findings suggest that, in sheep co-affected by scrapie and chronic inflammatory conditions, only newly formed lymphoid follicles provide a suitable micro-environment that supports the scrapie agent's replication in inflammatory sites, with an increased risk of prion shedding through body secretions/excretions.

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Inflammatory lesion patterns and PrPSc deposition in ovine lungs.Micrographs show the inflammatory lesions’ morphology and PrPSc deposition in lungs from sheep simultaneously affected by scrapie and parasitic bronchopneumonia caused by nematodes. Representative patterns of lymphofollicular (A) and lymphofollicular (arrows) associated with granulomatous (arrowheads) inflammation (B and D). A histologically normal ovine lung is also shown (C). PrPSc deposits (arrows) are visible within newly formed lymphoid follicles adjacent to granulomatous lesions (E and F). Micrograph F is a higher magnification of the red line-enclosed area shown in micrograph E. Hematoxylin-eosin (H&E) stain (A, B, C, and D); PrPSc immunohistochemistry (IHC) with F99 as primary antibody and Mayer’s hematoxylin counterstain (E and F). Scale bar = 100 µm.
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pone-0062830-g002: Inflammatory lesion patterns and PrPSc deposition in ovine lungs.Micrographs show the inflammatory lesions’ morphology and PrPSc deposition in lungs from sheep simultaneously affected by scrapie and parasitic bronchopneumonia caused by nematodes. Representative patterns of lymphofollicular (A) and lymphofollicular (arrows) associated with granulomatous (arrowheads) inflammation (B and D). A histologically normal ovine lung is also shown (C). PrPSc deposits (arrows) are visible within newly formed lymphoid follicles adjacent to granulomatous lesions (E and F). Micrograph F is a higher magnification of the red line-enclosed area shown in micrograph E. Hematoxylin-eosin (H&E) stain (A, B, C, and D); PrPSc immunohistochemistry (IHC) with F99 as primary antibody and Mayer’s hematoxylin counterstain (E and F). Scale bar = 100 µm.

Mentions: In the lung tissue from 8 out of the 27 sheep included in this study (Table 1), we detected pale or dark subpleural nodules 2–15 mm in diameter, which were mainly seen affecting the caudal lobes. These areas were consistent with inflammatory foci caused by different species of nematode parasites, such as Muellerius spp. and Cystocaulus spp., two lungworms of sheep which are commonly found in both larval and adult forms within bronchiolar and alveolar lumina. Histologically, we observed focal or multifocal interstitial pneumonia characterized by lymphoid cell infiltrates, along with a variable number of newly formed lymphoid follicles. Additionally, in 3 out of the 8 sheep with pneumonic lesions, well-organized fibro-cellular granulomas containing multinucleate giant cells, epithelioid cells, macrophages, and lymphocytes were seen in close association with newly formed lymphoid follicles (Figure 2).


A lympho-follicular microenvironment is required for pathological prion protein deposition in chronically inflamed tissues from scrapie-affected sheep.

Maestrale C, Di Guardo G, Cancedda MG, Marruchella G, Masia M, Sechi S, Macciocu S, Santucciu C, Petruzzi M, Ligios C - PLoS ONE (2013)

Inflammatory lesion patterns and PrPSc deposition in ovine lungs.Micrographs show the inflammatory lesions’ morphology and PrPSc deposition in lungs from sheep simultaneously affected by scrapie and parasitic bronchopneumonia caused by nematodes. Representative patterns of lymphofollicular (A) and lymphofollicular (arrows) associated with granulomatous (arrowheads) inflammation (B and D). A histologically normal ovine lung is also shown (C). PrPSc deposits (arrows) are visible within newly formed lymphoid follicles adjacent to granulomatous lesions (E and F). Micrograph F is a higher magnification of the red line-enclosed area shown in micrograph E. Hematoxylin-eosin (H&E) stain (A, B, C, and D); PrPSc immunohistochemistry (IHC) with F99 as primary antibody and Mayer’s hematoxylin counterstain (E and F). Scale bar = 100 µm.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3643908&req=5

pone-0062830-g002: Inflammatory lesion patterns and PrPSc deposition in ovine lungs.Micrographs show the inflammatory lesions’ morphology and PrPSc deposition in lungs from sheep simultaneously affected by scrapie and parasitic bronchopneumonia caused by nematodes. Representative patterns of lymphofollicular (A) and lymphofollicular (arrows) associated with granulomatous (arrowheads) inflammation (B and D). A histologically normal ovine lung is also shown (C). PrPSc deposits (arrows) are visible within newly formed lymphoid follicles adjacent to granulomatous lesions (E and F). Micrograph F is a higher magnification of the red line-enclosed area shown in micrograph E. Hematoxylin-eosin (H&E) stain (A, B, C, and D); PrPSc immunohistochemistry (IHC) with F99 as primary antibody and Mayer’s hematoxylin counterstain (E and F). Scale bar = 100 µm.
Mentions: In the lung tissue from 8 out of the 27 sheep included in this study (Table 1), we detected pale or dark subpleural nodules 2–15 mm in diameter, which were mainly seen affecting the caudal lobes. These areas were consistent with inflammatory foci caused by different species of nematode parasites, such as Muellerius spp. and Cystocaulus spp., two lungworms of sheep which are commonly found in both larval and adult forms within bronchiolar and alveolar lumina. Histologically, we observed focal or multifocal interstitial pneumonia characterized by lymphoid cell infiltrates, along with a variable number of newly formed lymphoid follicles. Additionally, in 3 out of the 8 sheep with pneumonic lesions, well-organized fibro-cellular granulomas containing multinucleate giant cells, epithelioid cells, macrophages, and lymphocytes were seen in close association with newly formed lymphoid follicles (Figure 2).

Bottom Line: We demonstrated that ectopic PrP(Sc) deposition occurs exclusively in the context of lymphofollicular inflammatory sites, inside newly formed and well-organized lymphoid follicles harboring follicular dendritic cells.A significantly more consistent expression of lymphotoxin α and β mRNA was detected in lymphofollicular inflammation compared to the other two types, with lymphotoxin α and β signaling new lymphoid follicles' formation and, likely, the occurrence of ectopic PrP(Sc) deposition inside them.Our findings suggest that, in sheep co-affected by scrapie and chronic inflammatory conditions, only newly formed lymphoid follicles provide a suitable micro-environment that supports the scrapie agent's replication in inflammatory sites, with an increased risk of prion shedding through body secretions/excretions.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Sanità Animale, Istituto Zooprofilattico Sperimentale della Sardegna, Sassari, Italy.

ABSTRACT
In sheep scrapie, pathological prion protein (PrP(Sc)) deposition occurs in the lymphoreticular and central nervous systems. We investigated PrP(Sc) distribution in scrapie-affected sheep showing simultaneous evidence of chronic lymphofollicular, lymphoproliferative/non-lymphofollicular, and/or granulomatous inflammations in their mammary gland, lung, and ileum. To do this, PrP(Sc) detection was carried out via immunohistochemistry and Western Blotting techniques, as well as through inflammatory cell immunophenotyping. Expression studies of gene coding for biological factors modulating the host's inflammatory response were also carried out. We demonstrated that ectopic PrP(Sc) deposition occurs exclusively in the context of lymphofollicular inflammatory sites, inside newly formed and well-organized lymphoid follicles harboring follicular dendritic cells. On the contrary, no PrP(Sc) deposition was detected in granulomas, even when they were closely located to newly formed lymphoid follicles. A significantly more consistent expression of lymphotoxin α and β mRNA was detected in lymphofollicular inflammation compared to the other two types, with lymphotoxin α and β signaling new lymphoid follicles' formation and, likely, the occurrence of ectopic PrP(Sc) deposition inside them. Our findings suggest that, in sheep co-affected by scrapie and chronic inflammatory conditions, only newly formed lymphoid follicles provide a suitable micro-environment that supports the scrapie agent's replication in inflammatory sites, with an increased risk of prion shedding through body secretions/excretions.

Show MeSH
Related in: MedlinePlus