EVOLUTION OF AUTOREACTIVE GC AND EPITOPE SPREADING IN LUPUS Systemic lupus erythematosus (SLE) is an incurable autoimmune disease and represents a substantial health problem in the population. Longitudinal studies of patients and murine models of SLE identify development of autoantibodies against new epitopes over time that correlate with increased pathology. The phenomena is referred to as epitope spreading, i.e. development of autoantibodies against determinants other than the initiating self-antigen. While the mechanism underlying epitope spreading remains unclear, we propose that spontaneous autoreactive GC initiated by a single B cell clone along with T cell help can promote entry of multiple distinct clones of nave self-reactive B cells where they can be positively selected and undergo affinity maturation, compete and differentiate into effector cells leading to epitope spreading. In order to characterize the dynamics of spontaneous autoreactive GC in more depth, we developed a novel mixed bone marrow chimeric model in which bone marrow from a lupus strain is mixed with marrow from WT mice and transferred into irradiated recipients. In characterization of the chimeras, we found, unexpectedly, that the self-reactive WT B cells underwent clonal selection and affinity maturation resulting in one or two clones dominating the GC response much like that observed for foreign antigen. Furthermore, we identified epitope spreading by the WT B cells (Degn 2017). Thus, in contrast to the predicted negative selection of self- reactive clones in GC, we found robust positive selection with the generation of pathogenic antibodies specific for self-antigens distinct from the original nucleolar antigen. In the current proposal, we will characterize further the events initiating spontaneous autoreactive GC using both radiation chimeras and a parabiosis approach. Further, we will determine the role of T follicular helper cells in promoting epitope spreading.
Three aims are proposed:
Aim 1. Characterize the dynamics of autoreactive germinal centers leading to epitope spreading.
Aim 2. Characterize Tfh in epitope spreading of self-reactive GC B cells.
Aim 3. Test hypothesis that self-reactive memory B cells cycle through GCs and diversify.
EVOLUTION OF AUTOREACTIVE GC AND EPITOPE SPREADING IN LUPUS Narrative: Systemic lupus erythematosus (SLE) is an incurable autoimmune disease characterized by autoantibodies that continue to spread to new self-antigens over time resulting in increased pathogenesis and disease. We propose that this phenomena, referred to as epitope spreading, is promoted by spontaneous autoreactive GC. In the current proposal, we will characterize the dynamics of autoreactive GC leading to epitope spreading and dissect the interaction of autoreactive B cells with helper T cells.