Research Project
9736611
ABSTRACT B cells play an important role in the immune response to foreign pathogens via secretion of immunoglobulin (Ig) and inflammatory cytokines. Although significant advances have been made in our understanding of the mechanisms regulating inflammatory and Ig-mediated responses, many of the signaling events regulating these responses remain elusive. Of particular interest is the dysregulation of Ig-responses that is observed in several malignant and autoimmune disorders, where aberrant Ig production is associated with these diseases and are often associated with a worse prognosis. Furthermore, increased levels of inflammatory cytokines have been reported in autoimmune and malignant diseases. Therefore, the identification of novel mechanisms that modulate inflammatory and immunoglobulin responses in normal B cell functions is important for our understanding of these responses in disease states. In previous work, we have demonstrated a novel role for the transcription factor GLI2 in the regulation of immunoglobulin secretion using human IgM-secreting B cells and mouse B-1 cells. Furthermore, we have found that GLI2 can directly regulate several inflammatory cytokine genes. These studies suggest that in addition to its role in development, GLI2 may play a role in the innate immune response to pathogens. To better characterize the role of GLI2 in regulating Ig and inflammatory responses, we are proposing to address the following CENTRAL HYPOTHESIS: that the transcription factor GLI2 modulates inflammatory responses by B cells and is required for the generation of immunoglobulin in response to pathogens. To address this hypothesis, we propose two specific aims: AIM 1: To determine the biological significance of GLI2 in B cell inflammatory responses to pathogens and AIM 2: To define the role of GLI2 on the ability of B cell populations to respond during pathogen-induced inflammation.
