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Function and regulation of ZAP-70 expression in human B cells

Our research interest lies in understanding the role of infection in the physiological and pathological immune response. The ongoing projects focus on the stimulatory requirements for activation of human plasmacytoid dendritic cells and B cells in response to bacteria or bacterial-derived substances such as lipopeptides or nucleic acids. We are especially interested in molecular mechanisms involved in sensitizing these cells for microbial stimuli since we have found that costimulatory signals via cytokine receptors or other cell surface molecules often modulate the qualitative outcome of the immune response to pathogen-associated molecular patterns (PAMPs).

Our recent work has identified protein kinase B (PKB/Akt) signaling as an important player in Toll-like receptor (TLR)-induced B cell activation since PKB activation sensitizes B cells for microbial stimuli. Since mutations resulting in PKB activation are frequently found in B-CLL and infections are thought to drive the development of chronic lymphatic leukaemia of the B cell type (B-CLL) we believe that these findings could be relevant for the understanding of the pathogenesis of B-CLL: Since B-CLL cells like normal B cells express TLR these receptors are likely to be involved in B-CLL recognition of microbial agents. 

Our data indicate that human peripheral blood B cells from healthy donors resemble B-CLL cells when stimulated with Toll-like receptor-9 ligand CpG DNA. Among the typical B-CLL features we found upon TLR9 activation expression of the syk kinase ZAP-70 correlates with B cell proliferation and depends on the PKB signaling pathway. ZAP-70 expression has been shown to correlate with aggressive course of disease and is believed to be involved in the modulation of signals transduced by the B cell receptor. The PhD project proposed will focus on two main issues: 1. the molecular mechanisms regulating ZAP-70 expression in normal human B cells and 2. the analysis of the role of ZAP-70 in the modulation of BCR signaling and its impact on B cell survival and functions in conjunction with TLR-mediated B cell activation.

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Dr. Isabelle Bekeredjian-Ding

Dept. of Medical Microbiology and Hygiene

UniversityHospital Heidelberg

Im Neuenheimer Feld 324

D-69120 Heidelberg