Prions: Protein Aggregation and Infectious Diseases - Physiological ...
Prions: Protein Aggregation and Infectious Diseases - Physiological ...
Prions: Protein Aggregation and Infectious Diseases - Physiological ...
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1130 ADRIANO AGUZZI AND ANNA MARIA CALELLA<br />
but far less than FDC expression of CD21/35. Therefore,<br />
complement-mediated antigen trapping on FDCs is an<br />
important mechanism for lymphoid prion accumulation<br />
(530). The role of the classical complement cascade during<br />
peripheral prion infection certainly warrants further<br />
investigations, since complement is clearly an important<br />
determinant of pathogenesis yet its mechanics are not yet<br />
fully understood (14).<br />
B. Tropism of <strong>Prions</strong> for Inflammatory Foci<br />
Since proinflammatory cytokines <strong>and</strong> immune cells<br />
are involved in lymphoid prion replication, it is likely that<br />
chronic inflammatory conditions in nonlymphoid organs<br />
could affect the dynamics of prion distribution. Indeed,<br />
inclusion body myositis, an inflammatory disease of muscle,<br />
was reported to lead to the presence of large PrP Sc<br />
deposits in muscle (281). Many chronic inflammatory conditions,<br />
some of which are very common <strong>and</strong> include<br />
rheumatoid arthritis, type 1 diabetes, Crohn’s disease,<br />
Hashimoto’s disease <strong>and</strong> chronic obstructive pulmonary<br />
disease, result in organized inflammatory foci of B lymphocytes,<br />
FDCs, DCs, macrophages, <strong>and</strong> other immune<br />
cells associated with germinal centers (141, 224, 244, 489).<br />
In addition, tertiary follicles can be induced, <strong>and</strong> are<br />
surprisingly prevalent, in nonlymphoid organs by naturally<br />
occurring infections in ruminants (141, 502).<br />
Lymphoid follicles with prominent FDC networks<br />
can replicate prions in mice (210, 448), sheep (300), <strong>and</strong><br />
deer (200) (Fig. 8). In fact, in mice suffering from nephritis,<br />
hepatitis, or pancreatitis, prion accumulation occurs<br />
in otherwise prion-free organs (210). The presence of<br />
inflammatory foci consistently correlated with an upregulation<br />
of LTs <strong>and</strong> the ectopic induction of PrP C -expressing<br />
FDCs. Inflamed organs of mice lacking LT or LTR did<br />
not accumulate either PrP Sc or infectivity following prion<br />
inoculation. These data have raised concerns that analo-<br />
FIG. 8. Lymphoid follicles with prominent follicular dendritic cell<br />
(FDC) networks can replicate prions in mice, sheep, <strong>and</strong> deer. A: in<br />
prion-infected RIPLT-mouse, inflammatory foci in renal tissue overlap<br />
with PrP Sc deposition as shown by histoblot analysis of a renal cryosection<br />
blotted on a nitrocellulose membrane followed by proteinase K<br />
(PK) treatment <strong>and</strong> HE staininig. (Figure kindly provided by M. Heikenwalder.)<br />
B: in sheep infected with scrapie <strong>and</strong> presenting with mastitis,<br />
PrP Sc deposition in a mammary gl<strong>and</strong> coincides with tertiary follicles, as<br />
confirmed by petblot analysis of a paraffin section blotted on a nitrocellulose<br />
membrane, followed by PK treatment <strong>and</strong> HE staining. [Adapted<br />
from Ligios et al. (300).] C: in white-tailed deer experimentally inoculated<br />
with the agent of chronic wasting disease (CWD), PrP Sc is present<br />
in ectopic lymphoid tissue in the kidney. Note the presence of two<br />
lymphoid follicles subjacent to the uroepithelial layer <strong>and</strong> PrP Sc immunolabeling<br />
within the lymphoid follicles. (Figure kindly provided by<br />
A. N. Hamir.) HE, hematoxylin <strong>and</strong> eosin; IHC, immunohistochemistry;<br />
KM, medulla; RIPLT, transgenic mice expressing LT (lymphotoxin)<br />
under the control of the rat insulin promoter (RIP) in pancreatic -islet<br />
cells <strong>and</strong> renal proximal convoluted tubules.<br />
Physiol Rev VOL 89 OCTOBER 2009 www.prv.org<br />
gous phenomena might occur in farm animals, since these<br />
are commonly in contact with inflammogenic pathogens.<br />
Indeed, PrP Sc has been observed in the inflamed mammary<br />
gl<strong>and</strong>s of sheep with mastitis <strong>and</strong> which are also<br />
infected with scrapie (300). These observations indicate<br />
that inflammatory conditions induce accumulation <strong>and</strong><br />
replication of prions in organs previously considered to<br />
be free from prion infection.<br />
In addition, inflammatory conditions could result in<br />
the shedding of the prion agent by excretory organs,