Role of the transcription factor Blimp-1/PRDI-BF1 in terminal differentiation of B lymphocytes and in the pathogenesis of the Common Variable Immunodeficiency syndrome
Project management at the University of Würzburg:
Terminal stages of plasma cell generation are regulated by the transcription factor Blimp-1 which is necessary for immunoglobulin secretion and, at the same time, arrests cell cycle progression and induces apoptosis. High levels of A1, an antiapoptotic member of the bcl-2 family, rescue cells from Blimp-1 induced cell death. Blimp-1 expression and secretion of all isotypes investigated are negatively regulated by ligation of the B cell antigen receptor and by T helper cell derived signals such as CD40L and IL-4. On the other hand, the T helper cytokines IL-2 and IL-5 induce Blimp-1 expression. Enforced Blimp-1 expression early after B cell activation (achieved through retroviral transduction of Blimp-1) lead to terminal B cell differentiation accompanied by suppression of immunoglobulin class switching. Using retroviral gene transfer, the functional properties of the Blimp-1 interaction partner IRF-4 and the downstream target of Blimp-1, mad-4, will be studied in vitro in murine B-lymphoma and primary B cell cultures. At the same time we plan to establish mouse models of altered Blimp-1 expression.
Common variable immunodeficiency, at an incidence of 1:5000, is the second most frequent congenital immunodeficiency. A subgroup of CVID patients still has mature peripheral B cells which, however, fail to differentiate into Ig secreting plasma cells. In some cases all Ig isotypes are affected, while other patients only fail to produce secondary isotypes. It is to be expected that many different molecular mechanisms underly CVID in its various manifestations. In view of the central importance of Blimp-1 in terminal B cell differentiation, it is, however, to be expected that qualitative or quantitative alterations in Blimp-1 expression may contribute to some forms of the disease.
Projekt period: from 05.1999 to 04.2004
Sondermittel Land Bayern