UC San Diego

The main focus of this dissertation is examining the mechanisms of peripheral B cell tolerance (Chapter 2). Generating a diverse repertoire of B cells reactive against foreign pathogens, yet tolerant to self-tissue, is imperative for an effective immune system. Random gene rearrangement at the immunoglobulin loci results in the majority of newly formed B cells being self-reactive. At an initial checkpoint in the bone marrow, a large portion of self-reactive B cells are rendered unresponsive or are eliminated through apoptosis. A second, less well-defined checkpoint in B cell tolerance occurs in the periphery as developing transitional B cells mature in the spleen. Indeed, studies have shown that rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) patients have a defect at this second crucial checkpoint. Within the follicle, follicular dendritic cells (FDCs) retain immune complexes and opsonized foreign antigens by Fc and complement receptors, respectively, important for B cell selection during the germinal center response. However, the selection of self-reactive B cells by self-antigen on FDCs has not been addressed. To this end, a mouse model (Cd21cremDELloxp mice) that expresses self-antigen membrane-bound Duck Egg Lysozyme (mDEL) on FDCs to study the fate of mDEL-binding B cells was generated. The results from this model show that self-antigen displayed on FDCs mediates effective elimination of self-reactive B cells at the transitional stage. A portion of Chapter 2 will be on the design and generation of the appropriate mouse model to address the question of peripheral B cell tolerance in late-stage transitional and follicular B cells in the spleen. The remaining half of the chapter will present the results of peripheral B cell tolerance studies in Cd21cremDELloxp mice. Chapter 3 presents work on various aspects of the germinal center reaction including the tools used to study GC B cells, the proteins involved in forming a GC reaction, and exploring mechanisms of eliminating self-reactive B cells that may arise in a GC reaction