Role of the transcription factors Blimp-1/PRDI-BF1 and Pax-5 in B cell differentiation and in the pathogenesis of Common Variable Immunodeficiency
Project management at the University of Würzburg:
Patients with common variable immunodeficiency (CVID) are the predominant subgroup of primary antibody deficiency syndromes in children and young adults. In contrast to patients with X-linked severe hypogammaglobulinemia patients with CVID have mature B cells in peripheral blood. However, for reasons unknown, CVID B cells are unable to differentiate into immunoglobulin (Ig)-secreting plasma cells.
In this research project, we plan to study the role of the two transcription factors Pax-5 and Blimp-1 in the terminal stages of B cell differentiation. Starting with activated B cells from healthy donors, we plan to either enhance or suppress Blimp-1 and Pax-5 expression by retroviral gene transfer. The effects of enforced or suppressed gene expression on terminal B cell differentiation will be studied. We will then analyze the expression of both transcription factors in B cells from CVID patients with defects in terminal differentiation. We hope to correct defects of in vitro Ig-synthesis by retroviral gene transfer. The final aim ist to identify target genes of Blimp-1 and Pax-5 by using ATLAS expression libraries and by establishing subtraction libraries. To study the regulation of terminal B cell differentiation by Blimp-1 and Pax-5 similar experiments will be carried out in mouse models. We already know that retroviral gene transfer can be achieved in primary B cells. Murine B cells with qualitative or quantitative alterations in Blimp-1 or Pax-5 expression will be transferred in vivo, in order to study isotype switching, plasma cell differentiation and memory cell generation. We hope to establish animal models which are murine equivalents of CVID in man.
Projekt period: from 05.1999 to 04.2002
Landeshaushalt Wissenschaftsministerium ,Granting date: 28.04.1999