Abstract
Transmissible spongiform encephalopathies (TSEs) or prion diseases are infectious neurological disorders of man and animals, characterised by abnormal disease-associated prion protein (PrPd) accumulations in the brain and lymphoreticular system (LRS). Prior to neuroinvasion, TSE agents often accumulate to high levels within the LRS, apparently without affecting immune function. However, our analysis of scrapie-affected sheep shows that PrPd accumulations within the LRS are associated with morphological changes to follicular dendritic cells (FDCs) and tingible body macrophages (TBMs). Here we examined FDCs and TBMs in the mesenteric lymph nodes (MLNs) of scrapie-affected mice by light and electron microscopy. In MLNs from uninfected mice, FDCs could be morphologically categorised into immature, mature and regressing forms. However, in scrapie-affected MLNs this maturation cycle was adversely affected. FDCs characteristically trap and retain immune complexes on their surfaces, which they display to B-lymphocytes. In scrapie-affected MLNs, some FDCs were found where areas of normal and abnormal immune complex retention occurred side by side. The latter co-localised with PrPd plasmalemmal accumulations. Our data suggest this previously unrecognised morphology represents the initial stage of an abnormal FDC maturation cycle. Alterations to the FDCs included PrPd accumulation, abnormal cell membrane ubiquitin and excess immunoglobulin accumulation. Regressing FDCs, in contrast, appeared to lose their membrane-attached PrPd. Together, these data suggest that TSE infection adversely affects the maturation and regression cycle of FDCs, and that PrPd accumulation is causally linked to the abnormal pathology observed. We therefore support the hypothesis that TSEs cause an abnormality in immune function.
Highlights
Transmissible spongiform encephalopathies (TSEs) or prion diseases are a family of slowly progressive neurodegenerative disorders, consisting of infectious, familial and sporadic forms of disease in both animals and man
Before processing for electron microscopical analysis, mesenteric lymph nodes (MLNs) sections from control and terminally-scrapie-affected mice were first prepared from a selection of tissue blocks for light microscopy and immunolabelled to detect PrPd, IgG, IgM and ubiquitin
Titres of TSE agent infectivity accumulate to high levels with the lymphoreticular system (LRS) before neuroinvasion, current dogma suggests that pathology in TSE-affected hosts is restricted to the CNS
Summary
Transmissible spongiform encephalopathies (TSEs) or prion diseases are a family of slowly progressive neurodegenerative disorders, consisting of infectious, familial and sporadic forms of disease in both animals and man. They are characterised by the accumulation of an abnormal post-translationally modified form of the host encoded cell surface glycoprotein - prion protein (PrP), which has been shown to associate with infectivity [1]. The role of the LRS in the pathogenesis of TSEs has been extensively studied [5,6], with follicular dendritic cells (FDCs) being shown to accumulate PrPd at the cell surface following scrapie infection in mice [7] and in sheep [8]. In contrast to established dogma, morphological evidence supported by immunological studies is beginning to show that the adverse effects of TSE infection may not be confined to the CNS
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