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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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Related in: MedlinePlus

Western Blotting (WB) analysis for PrPSc in ovine mammary glands with chronic mastitis.Lines: 1–2 =  brain from a naturally scrapie-affected (Scr+) or scrapie-free (Scr-) sheep. Lines: 3–4–8 =  mammary glands from scrapie-affected sheep displaying lymphofollicular mastitis. Lines: 5–6–7 =  mammary glands from scrapie-affected sheep displaying granulomatous mastitis. Line 9 =  mammary gland from a scrapie-affected sheep displaying lymphoproliferative/non-lymphofollicular mastitis. Line 10 =  palatine tonsil from a naturally scrapie-affected sheep showing PrPSc in mammary gland with lymphofollicular mastitis. Among the mammary glands, positive WB signals were observed only in the case of lymphofollicular mastitis.
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pone-0062830-g005: Western Blotting (WB) analysis for PrPSc in ovine mammary glands with chronic mastitis.Lines: 1–2 =  brain from a naturally scrapie-affected (Scr+) or scrapie-free (Scr-) sheep. Lines: 3–4–8 =  mammary glands from scrapie-affected sheep displaying lymphofollicular mastitis. Lines: 5–6–7 =  mammary glands from scrapie-affected sheep displaying granulomatous mastitis. Line 9 =  mammary gland from a scrapie-affected sheep displaying lymphoproliferative/non-lymphofollicular mastitis. Line 10 =  palatine tonsil from a naturally scrapie-affected sheep showing PrPSc in mammary gland with lymphofollicular mastitis. Among the mammary glands, positive WB signals were observed only in the case of lymphofollicular mastitis.

Mentions: In this respect, considering that both the lung and the ileum have a constitutive “associated lymphoid tissue” which is not physiologically present within the mammary gland parenchyma, WB analysis at the mammary gland level was considered adequate for establishing an exclusive PrPSc deposition inside newly formed lymphoid follicles. Clear-cut evidence of PrPSc deposition was found in 5 out of 7 mammary glands affected by lymphofollicular mastitis, as also demonstrated by IHC. Furthermore, WB analysis did not detect any evidence of PrPSc deposition in the 3 sheep affected by granulomatous mastitis, still in agreement with IHC results (Table 1; Figure 5).


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)

Western Blotting (WB) analysis for PrPSc in ovine mammary glands with chronic mastitis.Lines: 1–2 =  brain from a naturally scrapie-affected (Scr+) or scrapie-free (Scr-) sheep. Lines: 3–4–8 =  mammary glands from scrapie-affected sheep displaying lymphofollicular mastitis. Lines: 5–6–7 =  mammary glands from scrapie-affected sheep displaying granulomatous mastitis. Line 9 =  mammary gland from a scrapie-affected sheep displaying lymphoproliferative/non-lymphofollicular mastitis. Line 10 =  palatine tonsil from a naturally scrapie-affected sheep showing PrPSc in mammary gland with lymphofollicular mastitis. Among the mammary glands, positive WB signals were observed only in the case of lymphofollicular mastitis.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3643908&req=5

pone-0062830-g005: Western Blotting (WB) analysis for PrPSc in ovine mammary glands with chronic mastitis.Lines: 1–2 =  brain from a naturally scrapie-affected (Scr+) or scrapie-free (Scr-) sheep. Lines: 3–4–8 =  mammary glands from scrapie-affected sheep displaying lymphofollicular mastitis. Lines: 5–6–7 =  mammary glands from scrapie-affected sheep displaying granulomatous mastitis. Line 9 =  mammary gland from a scrapie-affected sheep displaying lymphoproliferative/non-lymphofollicular mastitis. Line 10 =  palatine tonsil from a naturally scrapie-affected sheep showing PrPSc in mammary gland with lymphofollicular mastitis. Among the mammary glands, positive WB signals were observed only in the case of lymphofollicular mastitis.
Mentions: In this respect, considering that both the lung and the ileum have a constitutive “associated lymphoid tissue” which is not physiologically present within the mammary gland parenchyma, WB analysis at the mammary gland level was considered adequate for establishing an exclusive PrPSc deposition inside newly formed lymphoid follicles. Clear-cut evidence of PrPSc deposition was found in 5 out of 7 mammary glands affected by lymphofollicular mastitis, as also demonstrated by IHC. Furthermore, WB analysis did not detect any evidence of PrPSc deposition in the 3 sheep affected by granulomatous mastitis, still in agreement with IHC results (Table 1; Figure 5).

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