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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 the ileum of sheep with scrapie and paratuberculosis.Sheep #1: Granulomatous enteritis is shown, with inflammatory gut lesions exhibiting a “lepromatous” morphology (A); by means of IHC, PrPSc deposition is apparent inside a constitutive lymphoid follicle of ileal Peyer’s patches (arrowhead), while no PrPSc-positive immunostaining is detectable within the surrounding granulomatous inflammatory foci, in which consistent numbers of acid-fast bacilli (M. avium subsp. paratuberculosis, MAP) are present inside epithelioid macrophages (arrows); a higher magnification of the above lymphoid follicle, harboring PrPSc aggregates, is shown in the inset (C). Sheep # 2: Granulomatous enteritis is shown, with inflammatory gut lesions exhibiting a “tuberculoid” morphology (B); no IHC evidence of PrPSc deposition is observed inside a microgranuloma (D, arrow). H&E stain (A-B); Ziehl-Neelsen stain and PrPSc IHC with F99 as primary antibody (C, see also “Materials and Methods”); PrPSc IHC with F99 as primary antibody and Mayer’s hematoxylin counterstain (D). Scale bars = 100 µm and 50 µm (inset of C).
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pone-0062830-g003: Inflammatory lesion patterns and PrPSc deposition in the ileum of sheep with scrapie and paratuberculosis.Sheep #1: Granulomatous enteritis is shown, with inflammatory gut lesions exhibiting a “lepromatous” morphology (A); by means of IHC, PrPSc deposition is apparent inside a constitutive lymphoid follicle of ileal Peyer’s patches (arrowhead), while no PrPSc-positive immunostaining is detectable within the surrounding granulomatous inflammatory foci, in which consistent numbers of acid-fast bacilli (M. avium subsp. paratuberculosis, MAP) are present inside epithelioid macrophages (arrows); a higher magnification of the above lymphoid follicle, harboring PrPSc aggregates, is shown in the inset (C). Sheep # 2: Granulomatous enteritis is shown, with inflammatory gut lesions exhibiting a “tuberculoid” morphology (B); no IHC evidence of PrPSc deposition is observed inside a microgranuloma (D, arrow). H&E stain (A-B); Ziehl-Neelsen stain and PrPSc IHC with F99 as primary antibody (C, see also “Materials and Methods”); PrPSc IHC with F99 as primary antibody and Mayer’s hematoxylin counterstain (D). Scale bars = 100 µm and 50 µm (inset of C).

Mentions: Two out of the 27 sheep under investigation were affected by a severe transmural granulomatous ileitis suggestive of paratuberculosis, which was subsequently confirmed histochemically (ZN), biomolecularly (RT-PCR), and by means of serology against MAP. In the first of these two cases, lesions were characterized by a “lepromatous-type” morphology, with epithelioid cells containing numerous MAP organisms (multibacillary form), lymphocytes, and plasma cells infiltrating the lamina propria. In the second case, we observed numerous intramural “tuberculoid-like” granulomas with macrophages, multinucleate giant cells, and rare lymphocytes surrounded by an outer fibroblastic reactive wall (Figure 3). In this latter case, no MAP organisms were observed (paucibacillary form).


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 the ileum of sheep with scrapie and paratuberculosis.Sheep #1: Granulomatous enteritis is shown, with inflammatory gut lesions exhibiting a “lepromatous” morphology (A); by means of IHC, PrPSc deposition is apparent inside a constitutive lymphoid follicle of ileal Peyer’s patches (arrowhead), while no PrPSc-positive immunostaining is detectable within the surrounding granulomatous inflammatory foci, in which consistent numbers of acid-fast bacilli (M. avium subsp. paratuberculosis, MAP) are present inside epithelioid macrophages (arrows); a higher magnification of the above lymphoid follicle, harboring PrPSc aggregates, is shown in the inset (C). Sheep # 2: Granulomatous enteritis is shown, with inflammatory gut lesions exhibiting a “tuberculoid” morphology (B); no IHC evidence of PrPSc deposition is observed inside a microgranuloma (D, arrow). H&E stain (A-B); Ziehl-Neelsen stain and PrPSc IHC with F99 as primary antibody (C, see also “Materials and Methods”); PrPSc IHC with F99 as primary antibody and Mayer’s hematoxylin counterstain (D). Scale bars = 100 µm and 50 µm (inset of C).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3643908&req=5

pone-0062830-g003: Inflammatory lesion patterns and PrPSc deposition in the ileum of sheep with scrapie and paratuberculosis.Sheep #1: Granulomatous enteritis is shown, with inflammatory gut lesions exhibiting a “lepromatous” morphology (A); by means of IHC, PrPSc deposition is apparent inside a constitutive lymphoid follicle of ileal Peyer’s patches (arrowhead), while no PrPSc-positive immunostaining is detectable within the surrounding granulomatous inflammatory foci, in which consistent numbers of acid-fast bacilli (M. avium subsp. paratuberculosis, MAP) are present inside epithelioid macrophages (arrows); a higher magnification of the above lymphoid follicle, harboring PrPSc aggregates, is shown in the inset (C). Sheep # 2: Granulomatous enteritis is shown, with inflammatory gut lesions exhibiting a “tuberculoid” morphology (B); no IHC evidence of PrPSc deposition is observed inside a microgranuloma (D, arrow). H&E stain (A-B); Ziehl-Neelsen stain and PrPSc IHC with F99 as primary antibody (C, see also “Materials and Methods”); PrPSc IHC with F99 as primary antibody and Mayer’s hematoxylin counterstain (D). Scale bars = 100 µm and 50 µm (inset of C).
Mentions: Two out of the 27 sheep under investigation were affected by a severe transmural granulomatous ileitis suggestive of paratuberculosis, which was subsequently confirmed histochemically (ZN), biomolecularly (RT-PCR), and by means of serology against MAP. In the first of these two cases, lesions were characterized by a “lepromatous-type” morphology, with epithelioid cells containing numerous MAP organisms (multibacillary form), lymphocytes, and plasma cells infiltrating the lamina propria. In the second case, we observed numerous intramural “tuberculoid-like” granulomas with macrophages, multinucleate giant cells, and rare lymphocytes surrounded by an outer fibroblastic reactive wall (Figure 3). In this latter case, no MAP organisms were observed (paucibacillary form).

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