The role of FLT3L and BAFFin B cell development and homeostasis

• Main Author: Rauch, Melanie
• Other Authors: Rolink, Antonius G., Palmer, Ed
• Format: Thesis
• Language: English
• Published: 2009
• Subjects: Baffin
• Online Access: http://edoc.unibas.ch/diss/DissB_8751; https://edoc.unibas.ch/988/; https://edoc.unibas.ch/988/1/DISS-Melanie-Rauch.pdf; https://doi.org/10.5451/unibas-004953039

The maintenance of homeostasis in the immune system is a complex process. The control of B cell numbers occurs at many different stages in the developmental pathway, and numerous factors are involved. In this thesis, certain aspects of FLT3L, BAFF-R and BAFF on B cells were analyzed. In the first part (chapter 3), the effect of increased availability of FLT3L on EPLMs, which have been found previously to be B cell progenitors, was investigated. Upon FLT3L administration in mice, the number of EPLMs increased in a dose-dependent manner, but the number of B cells decreased. This decrease was reversible as B cell numbers recovered after cessation of FLT3L treatment. In vitro studies revealed, that EPLMs from FLT3L treated mice had a reduction of about 20-fold in B-lineage potential, while the potential for the T cell lineage was only slightly reduced and myeloid potential was unchanged. Transplantation of EPLMs from FLT3L treated mice into lymphopenic hosts showed, that these cells are able to give rise to B and T cells, but not to myeloid cells. From these experiments we concluded, that FLT3L is able to increase the number of EPLMs, and that these progenitor cells can reconstitute B and T cell compartments in vivo. In the second part (chapter 4), novel sets of monoclonal antibodies specific for mouse BAFF-R or human BAFF are described. Among the anti-mBAFF-R antibodies, several different clones that were able to block the binding of ligand to BAFF-R could be identified. With the anti-hBAFF antibodies, a sensitive ELISA for the detection of hBAFF in human sera was developed. In the third part (chapter 5), the role of BAFF-R signaling in the in vivo maintenance of mature B cells was investigated with the use of the new monoclonal anti-mBAFF-R antibodies. We showed that 14 days following a single injection of a monoclonal antimBAFF-R antibody that prevents BAFF binding, both follicular and marginal zone B cell numbers were drastically reduced, whereas B-1 cells were not affected. Injection of control, isotype-matched ...