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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0802695v1 183/8/5199    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Brown, K. L. Articles by Mabbott, N. A. PubMed PubMed Citation Articles by Brown, K. L. Articles by Mabbott, N. A.

The Effects of Host Age on Follicular Dendritic Cell Status Dramatically Impair Scrapie Agent Neuroinvasion in Aged Mice¹

Karen L. Brown,^2* Gwennaelle J. Wathne,^* Jill Sales, Moira E. Bruce,^* and Neil A. Mabbott^2*

^*The Roslin Institute and Royal (Dick) School of Veterinary Sciences, University of Edinburgh, Roslin, United Kingdom; and Biomathematics & Statistics Scotland, Edinburgh, United Kingdom

Following peripheral exposure, many transmissible spongiform encephalopathy (TSE) agents accumulate first in lymphoid tissues before spreading to the CNS (termed neuroinvasion) where they cause neurodegeneration. Early TSE agent accumulation upon follicular dendritic cells (FDCs) in lymphoid follicles appears critical for efficient neuroinvasion. Most clinical cases of variant Creutzfeldt-Jakob disease have occurred in young adults, although the reasons behind this apparent age-related susceptibility are uncertain. Host age has a significant influence on immune function. As FDC status and immune complex trapping is reduced in aged mice (600 days old), we hypothesized that this aging-related decline in FDC function might impair TSE pathogenesis. We show that coincident with the effects of host age on FDC status, the early TSE agent accumulation in the spleens of aged mice was significantly impaired. Furthermore, following peripheral exposure, none of the aged mice developed clinical TSE disease during their lifespans, although most mice displayed histopathological signs of TSE disease in their brains. Our data imply that the reduced status of FDCs in aged mice significantly impairs the early TSE agent accumulation in lymphoid tissues and subsequent neuroinvasion. Furthermore, the inefficient neuroinvasion in aged individuals may lead to significant levels of subclinical TSE disease in the population.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by funding from the European Commission, UK Biotechnology and Biological Sciences Research Council, and the Medical Research Council.

² Address correspondence and reprint requests to Dr. Karen L. Brown and Dr. Neil A. Mabbott, The Roslin Institute and Royal (Dick) School of Veterinary Sciences, University of Edinburgh, Roslin, Midlothian EH25 9PS, U.K. E-mail: karen.brown{at}roslin.ed.ac.uk and neil.mabbott{at}roslin.ed.ac.uk

³ Abbreviations used in this paper: TSE, transmissible spongiform encephalopathy; FDC, follicular dendritic cell; PrP, prion protein; vCJD, variant Creutzfeldt-Jakob disease; BSE, bovine spongiform encephalopathy; CR, complement receptor; i.c., intracerebral; TH, tyrosine hydroxylase; PK, proteinase K.

⁴ The online version of this article contains supplemental material.