The mechanisms underlying the negative regulation of self-reactive B cells that arise during antigen-driven B cell responses remain obscure. The project described in this fellowship application centers on understanding the role of the cytokine BAFF in the regulation of DNA-reactive B cells that enter the germinal center B cell response. Through the use of unique transgenic mouse lines, the influence of BAFF on the fate of self-reactive B cells will be determined.
The specific aims are: 1) determine whether BAFF expression by follicular helper T cells alters counter-selection of self-reactive germinal center B cells;and 2) determine whether changes in germinal center B cell TACI receptor expression disturb the counter-selection of self-reactive germinal center B cells. These studies will provide fundamental information on the regulation of self-reactive B cells, which are the source of pathogenic antibodies in a variety of autoimmune disorders including Lupus, and will therefore fulfill the mission of the Transfusion Medicine and Cellular Therapeutics program of the NIHLB.
The proposed studies will test whether exposure of activated DNA-reactive B cells to BAFF, a soluble protein produced by a variety of immune system cells, increases the likelihood that such cells will produce pathogenic antibodies. This work will increase understanding of the mechanisms underlying lupus and related autoimmune disorders.
|Nikbakht, Neda; Shen, Shixue; Manser, Tim (2013) Cutting edge: Macrophages are required for localization of antigen-activated B cells to the follicular perimeter and the subsequent germinal center response. J Immunol 190:4923-7|