PrP Expression, PrPSc Accumulation and Innervation of Splenic Compartments in Sheep Experimentally Infected with Scrapie

BACKGROUND: In prion disease, the peripheral expression of PrP(C) is necessary for the transfer of infectivity to the central nervous system. The spleen is involved in neuroinvasion and neural dissemination in prion diseases but the nature of this involvement is not known. The present study undertook the investigation of the spatial relationship between sites of PrP(Sc) accumulation, localisation of nerve fibres and PrP(C) expression in the tissue compartments of the spleen of scrapie-inoculated and control sheep. METHODOLOGY/PRINCIPAL FINDINGS: Laser microdissection and quantitative PCR were used to determine PrP mRNA levels and results were compared with immunohistochemical protocols to distinguish PrP(C) and PrP(Sc) in tissue compartments of the spleen. In sheep experimentally infected with scrapie, the major sites of accumulation of PrP(Sc) in the spleen, namely the lymphoid nodules and the marginal zone, expressed low levels of PrP mRNA. Double immunohistochemical labelling for PrP(Sc) and the pan-nerve fibre marker, PGP, was used to evaluate the density of innervation of splenic tissue compartments and the intimacy of association between PrP(Sc) and nerves. Some nerve fibres were observed to accompany blood vessels into the PrP(Sc)-laden germinal centres. However, the close association between nerves and PrP(Sc) was most apparent in the marginal zone. Other sites of close association were adjacent to the wall of the central artery of PALS and the outer rim of germinal centres. CONCLUSIONS/SIGNIFICANCE: The findings suggest that the degree of PrP(Sc) accumulation does not depend on the expression level of PrP(C). Though several splenic compartments may contribute to neuroinvasion, the marginal zone may play a central role in being the compartment with most apparent association between nerves and PrP(Sc)

Adrenergic β2 receptor activation stimulates anti-inflammatory properties of dendritic cells in vitro

Vagal nerve efferent activation has been shown to ameliorate the course of many inflammatory disease states. This neuromodulatory effect has been suggested to rest on acetylcholine receptor (AChR) activation on tissue macrophages or dendritic cells (DCs). In more recent studies, vagal anti-inflammatory activity was shown involve adrenergic, splenic, pathways. Here we provide evidence that the adrenergic, rather than cholinergic, receptor activation on bone marrow derived DCs results in enhanced endocytosis uptake, enhanced IL-10 production but a decreased IL-6, IL-12p70 and IL-23 production. In antigen specific T cell stimulation assays, adrenergic β2 receptor activation on bone marrow DCs led to an enhanced potential to induce Foxp3 positive suppressive Treg cells. These effects were independent of IL10-R activation, TGFβ release, or retinoic acid (RA) secretion. Hence, adrenergic receptor β2 activation modulates DC function resulting in skewing towards anti-inflammatory T cell phenotypes

Clinical performance and radiation dosimetry of no-carrier-added vs carrier-added 123I-metaiodobenzylguanidine (MIBG) for the assessment of cardiac sympathetic nerve activity

Purpose We hypothesized that assessment of myocardial sympathetic activity with no-carrier-added (nca) I-123-metaiodobenzylguanidine (MIBG) compared to carrier-added (ca) I-123-MIBG would lead to an improvement of clinical performance without major differences in radiation dosimetry. Methods In nine healthy volunteers, 15 min and 4 h planar thoracic scintigrams and conjugate whole-body scans were performed up to 48 h following intravenous injection of 185 MBq I-123-MIBG. The subjects were given both nca and ca I-123-MIBG. Early heart/mediastinal ratios (H/M), late H/M ratios and myocardial washout were calculated. The fraction of administered activity in ten source organs was quantified from the attenuation-corrected geometric mean counts in conjugate views. Radiation-absorbed doses were estimated with OLINDA/EXM software. Results Both early and late H/M were higher for nca I-123-MIBG (ca I-123-MIBG early H/M 2.46 +/- 0.15 vs nca I-123-MIBG 2.84 +/- 0.15, p = 0.001 and ca I-123-MIBG late H/M 2.69 +/- 0.14 vs nca I-123-MIBG 3.34 +/- 0.18, p = 0.002). Myocardial washout showed a longer retention time for nca I-123-MIBG (p <0.001). The effective dose equivalent (adult male model) for nca I-123-MIBG was similar to that for ca I-123-MIBG (0.025 +/- 0.002 mSv/MBq vs 0.026 +/- 0.002 mSv/MBq, p = 0.055, respectively). Conclusion No-carrier-added I-123-MIBG yields a higher relative myocardial uptake and is associated with a higher myocardial retention. This difference between nca I-123-MIBG and ca I-123-MIBG in myocardial uptake did not result in major differences in estimated absorbed doses. Therefore, nca I-123-MIBG is to be preferred over ca I-123-MIBG for the assessment of cardiac sympathetic activit