Heikenwaelder
Fakultäten » Medizinische Fakultät » Neuropathologie, Institut für » Prof. Dr. Adriano Aguzzi » Heikenwaelder
Completed research project
| Title / Titel | Ectopic generation of FDCs to elucidate the function of B-cells and FDCs in peripheral prion pathogenesis | ||||||||
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| Abstract (PDF, 14 KB) | |||||||||
| Summary / Zusammenfassung | In our laboratory we are working with mice as a disease model. Since it is known that after peripheral challenge with prions (RML) infectivity first arises in secondary lymphoid organs, such as spleen, mesenteric lymph node, and inguinal lymph node, we are interested to understand more about mechanisms and cells responsible for replication of prions in secondary lymphoid organs. Therefore this study focuses on a cell type identified in the last couple of years as the ¡§key player¡¨ responsible in peripheral replication and conversion of prions: The follicular dendritic cell (FDC). FDCs constitute a network within lymphoid organs, drive the organization of germinal centers and induce development of follicular and marginal B-lymphocytes. Maintenance of FDCs depends on signaling via the LTb receptor, mainly mediated by B-lymphocytes through membrane bound LTa/bƒnheterotrimers (LTa1/b2 or LTa2/b1). Conditional depletion of FDCs by a lymphotoxin b receptor (LTbR Ig) leads to resistance of mice towards prion inoculation (Montrasio et al., 2000). Therefore peripheral replication and conversion of PrPSC by FDCs is an important feature for the onset of prion disease in mice. The cytokines of the TNF/lymphotoxin (LT) family were shown to be essential for the establishment and maintenance of splenic and lymph nodal architecture. LTƒÑƒz LTb, TNFR-1 and TNFa knockout-mice show abnormalities in the development and organization of secondary lymphoid organs and are depleted for / or have strong reduction of FDCs. T-cell dependent expression of surface bound LTa /bƒnƒnheterotrimers is restricted to activated T-lymphocytes. We have generated transgenic mice overexpressing LTa and LTb or both on T-lymphocytes under the control of the lck-promoter. We observed a strong reduction of the thymus, disruption of splenic, thymic and lymph nodal architecture and hyperplasia of mesenteric (mln) and inguinal lymph nodes (iln). Moreover, we found FDC-M1+, CD21+ and BLC expressing cells in B lymphocyte-free zones that co-localize with or are located adjacent to T-lymphocytes of the spleen and thymus. Surprisingly, lck-LTa/LTb mice appear to lack normally developed Peyer`s patches. In addition, we have found by FACS analysis that in contrast to wild type mice (C57BL/6), transgenic mice expressing LTa an LTb on T-cells show hyperactivated peripheral lymphocytes evaluated by surface expression of the CD44 molecule. With this mouse model we plan to selectively examine the function of FDCs and B-cells within prion replication, by generating a mouse that lacks B-cells but harbors FDCs in T-cells zones of secondary lymphoid organs. |
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| Publications / Publikationen | Montrasio et al.; Impaired prion replication in spleens of mice lacking functional follicular dendritic cells. Science, 19, 288; 1257-1259, 2000. | ||||||||
| Keywords / Suchbegriffe | Lymphotoxin alpha and beta, neuroinvasion, ectopic FDCs, germinal centers, PrPSC | ||||||||
| Project leadership and contacts / Projektleitung und Kontakte |
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| Other links to external web pages | http://www.uzh.ch/pathol/neuropathologie/d/index.html | ||||||||
| Funding source(s) / Unterstützt durch |
Others Catello Family |
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| In collaboration with / In Zusammenarbeit mit |
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| Duration of Project / Projektdauer | Jan 2000 to Dec 2003 |