Lymphotoxin-alpha- and lymphotoxin-beta-deficient mice differ in susceptibility to scrapie: evidence against dendritic cell involvement in neuroinvasion - PubMed (original) (raw)

Lymphotoxin-alpha- and lymphotoxin-beta-deficient mice differ in susceptibility to scrapie: evidence against dendritic cell involvement in neuroinvasion

Michael B A Oldstone et al. J Virol. 2002 May.

Abstract

Transmissible spongiform encephalopathy or prion diseases are fatal neurodegenerative disorders of humans and animals often initiated by oral intake of an infectious agent. Current evidence suggests that infection occurs initially in the lymphoid tissues and subsequently in the central nervous system (CNS). The identity of infected lymphoid cells remains controversial, but recent studies point to the involvement of both follicular dendritic cells (FDC) and CD11c(+) lymphoid dendritic cells. FDC generation and maintenance in germinal centers is dependent on lymphotoxin alpha (LT-alpha) and LT-beta signaling components. We report here that by the oral route, LT-alpha -/- mice developed scrapie while LT-beta -/- mice did not. Furthermore, LT-alpha -/- mice had a higher incidence and shorter incubation period for developing disease following inoculation than did LT-beta -/- mice. Transplantation of lymphoid tissues from LT-beta -/- mice, which have cervical and mesenteric lymph nodes, into LT-alpha -/- mice, which do not, did not alter the incidence of CNS scrapie. In other studies, a virus that is tropic for and alters functions of CD11c(+) cells did not alter the kinetics of neuroinvasion of scrapie. Our results suggest that neither FDC nor CD11c(+) cells are essential for neuroinvasion after high doses of RML scrapie. Further, it is possible that an as yet unidentified cell found more abundantly in LT-alpha -/- than in LT-beta -/- mice may assist in the amplification of scrapie infection in the periphery and favor susceptibility to CNS disease following peripheral routes of infection.

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Figures

FIG. 1.

FIG. 1.

LT-α−/− mice and LT-β−/− mice differ in susceptibility to RML mouse scrapie administered orally or i.p. Control LT-α−/− mice and LT-β−/− mice were 8 weeks old when inoculated. For i.c. inoculation, four control mice, six LT-α−/− mice, and six LT-β−/− mice were used. For oral inoculation, 10 control mice, 10 LT-α−/− mice, and 10 LT-β−/− mice were injected. Similar results occurred after a repeat experiment with six LT-α−/− mice and six LT-β−/− mice. For i.p. inoculation, 10 control mice, 10 LT-α−/− mice, and 16 LT-β−/− mice were employed.

FIG. 2.

FIG. 2.

Lack of PrPsc expression in brains of LT-β−/− mice inoculated orally or i.p. with 107 LD50 of RML mouse scrapie (see Table 1). Lanes 2 and 3 represent two LT-α−/− mice inoculated orally, and lanes 7 and 8 show results for two other LT-α−/− mice inoculated i.p. All illustrate the expression of PrPsc. As displayed in lanes 4 and 5, no expression of PrPsc was evident in brains of LT-β−/− mice after oral inoculation or after i.p. inoculation, as in lanes 9 and 10. Similar results were found with additional samples from LT-α−/− and LT-β−/− mice as recorded in Table 1.

FIG. 3.

FIG. 3.

Transcripts of TNF-α or -β mRNA appear in brains of LT-α−/− mice receiving 107 LD50 of RML scrapie orally or i.p. These mice develop clinical disease, display histopathologic lesions, and express PrPsc associated with scrapie disease. In contrast, LT-β−/− mice after oral or i.p. inoculation, or RelB−/− mice after oral administration of scrapie, fail to develop scrapie disease or show transcripts of TNF-α or -β mRNA in their brains. Results were similar for three additional LT-β−/− mice and one RelB−/− mouse studied (data not shown). Each transcript level was normalized to the ubiquitous housekeeping L32 RNA.

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