The role of draining lymphoid tissues in TSE agent neuroinvasion
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αß⁻/⁻
Transmissible spongiform encephalopathies (TSEs) are a group of fatal neurodegenerative diseases. The causative agent for these diseases is unknown. After peripheral inoculation, accumulation and replication of the agent has been found to occur in lymphoid tissues prior to spreading to the CNS and brain where pathology is caused. Within lymphoid tissues, follicular dendritic cells (FDCs) are critical for the accumulation of the TSE agent. Elowever, specifically which lymphoid tissues neuroinvasion occurs from is unclear. The aims of this thesis were to determine the importance of draining lymphoid tissue in pathogenesis of the ME7 strain of scrapie agent after inoculation via the oral, scarification or intra-peritoneal (i.p.) routes. The formation of most lymphoid tissue is critically dependent on lymphotoxin (LT) a|3 signalling through LTßR during gestation. Mice in which this signalling has been interrupted, either through in ntero treatment with LTßR-Ig or by genetic deficiency of LTα or LTß, lack various lymphoid tissues. LTα⁻/⁻ mice and LTß⁻/⁻ mice also lack FDCs so these were reconstituted with wild-type (WT) bone marrow, thus restoring FDCs without inducing the formation of missing lymphoid tissues. After oral inoculation Peyer's patches (PPs) within the intestine were found to be crucial for pathogenesis as mice lacking PPs did not develop disease. Isolated lymphoid follicles (ILFs) which resemble PPs have recently been described in the murine small intestine and are thought to compensate for PP-deficiency. ILFs were investigated here and found to contain FDCs and, as a result support neuroinvasion of the scrapie agent in the absence of PPs. Mice lacking inguinal lymph nodes (ILNs) displayed decreased susceptibility to scrapie disease after inoculation via scarification of the skin of the thigh. This demonstrated that the ILNs are important, but neuroinvasion could occur from other tissues in some cases. The cranial mediastinal lymph nodes (CMLNs) drain the peritoneal cavity. Investigations in this thesis revealed both LTα⁻/⁻ mice and LTß⁻/⁻ mice lack these nodes. LTα⁻/⁻ mice were less susceptible and had delayed onset of disease compared to WT mice whereas LTß⁻/⁻ mice were as susceptible and developed disease in the same timeframe as WT mice after i.p. inoculation. This demonstrated that the CMLN is dispensable for neuroinvasion via the i.p. route, but raised the possibility that lymphoid tissue present in LTß⁻/⁻ mice and absent from LTα⁻/⁻ mice was important in supporting neuroinvasion. In all three routes the lack of draining lymphoid tissue had an effect on the pathogenesis of disease demonstrating the importance of these tissues in the peripheral pathogenesis of TSEs.
Transmissible spongiform encephalopathies (TSEs) are a group of fatal neurodegenerative diseases. The causative agent for these diseases is unknown. After peripheral inoculation, accumulation and replication of the agent has been found to occur in lymphoid tissues prior to spreading to the CNS and brain where pathology is caused. Within lymphoid tissues, follicular dendritic cells (FDCs) are critical for the accumulation of the TSE agent. Elowever, specifically which lymphoid tissues neuroinvasion occurs from is unclear. The aims of this thesis were to determine the importance of draining lymphoid tissue in pathogenesis of the ME7 strain of scrapie agent after inoculation via the oral, scarification or intra-peritoneal (i.p.) routes. The formation of most lymphoid tissue is critically dependent on lymphotoxin (LT) a|3 signalling through LTßR during gestation. Mice in which this signalling has been interrupted, either through in ntero treatment with LTßR-Ig or by genetic deficiency of LTα or LTß, lack various lymphoid tissues. LTα⁻/⁻ mice and LTß⁻/⁻ mice also lack FDCs so these were reconstituted with wild-type (WT) bone marrow, thus restoring FDCs without inducing the formation of missing lymphoid tissues. After oral inoculation Peyer's patches (PPs) within the intestine were found to be crucial for pathogenesis as mice lacking PPs did not develop disease. Isolated lymphoid follicles (ILFs) which resemble PPs have recently been described in the murine small intestine and are thought to compensate for PP-deficiency. ILFs were investigated here and found to contain FDCs and, as a result support neuroinvasion of the scrapie agent in the absence of PPs. Mice lacking inguinal lymph nodes (ILNs) displayed decreased susceptibility to scrapie disease after inoculation via scarification of the skin of the thigh. This demonstrated that the ILNs are important, but neuroinvasion could occur from other tissues in some cases. The cranial mediastinal lymph nodes (CMLNs) drain the peritoneal cavity. Investigations in this thesis revealed both LTα⁻/⁻ mice and LTß⁻/⁻ mice lack these nodes. LTα⁻/⁻ mice were less susceptible and had delayed onset of disease compared to WT mice whereas LTß⁻/⁻ mice were as susceptible and developed disease in the same timeframe as WT mice after i.p. inoculation. This demonstrated that the CMLN is dispensable for neuroinvasion via the i.p. route, but raised the possibility that lymphoid tissue present in LTß⁻/⁻ mice and absent from LTα⁻/⁻ mice was important in supporting neuroinvasion. In all three routes the lack of draining lymphoid tissue had an effect on the pathogenesis of disease demonstrating the importance of these tissues in the peripheral pathogenesis of TSEs.
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