Objective: To define mechanisms responsible for spontaneous B cell hyperactivity in autoimmune mice.
Specific aims of the original application included defining mechanisms involved in the resistance of NZB mice to antibody mediated suppression. A major feature of this proposal was development of the splenic fragment assay for precursor enumeration. After successfully adapting this technique in our laboratory, we applied it to antibody mediated suppression and found that passive antibody had no impact on precursor frequency. By using the splenic fragment assay we were able to evaluate the tolerance in immature B cells, and ours is the first description of defective clonal deletion in autoimmune mice. We propose to pursue the mechanisms responsible for the tolerance resistance of NZB pre-B cells.
Specific aims i nclude the following: 1: Determination whether the pre-B cell tolerance defects observed in NZB mice are an intrinsic property of the pre-B cell pool. 2: Exploration of the role of cells distinct from the B cell lineage in NZB tolerance resistance. Specifically, the role of T cells and accessory cells will be examined. 3: Guided by the results obtained in Aims 1 and 2, we will evaluate the role of soluble mediators (such as IL-1, IL-2, and prostaglandin E2), in conferring tolerance resistance. By improving our insight into mechanisms responsible for autoimmunity, we can more rationally pursue effective therapy.
