NR4A Family as Markers and Mediators of B Cell Tolerance in SLE: From Antigen Discovery to Treatment

B cells play a key role in the pathogenesis of multiple autoimmune diseases by differentiating into autoantibody-secreting plasma cells and serving as antigen presenting cells for pathogenic T cells. Indeed, inhibition and/or depletion of B cells represent promising new treatments for systemic lupus erythematosus (SLE). Importantly, SLE exhibits considerable clinical heterogeneity for which clinicians lack adequate biomarkers. Discovery of novel autoantibodies (Abs) and autoantigens (Ags) holds the potential to subset patients according to clinical manifestations, to identify those at greatest risk for progression to end-organ damage, and to provide key insights into pathogenesis of disease. Moreover, selective targeting of pathogenic, self-reactive B cells would allow clinicians to maximize clinical benefit while minimizing off-target immunosuppression and infectious complications. However, although identifying self-reactive B cells and the antigens that they recognize is of critical importance, this task poses a major scientific and technical hurdle. The NR4A family of orphan nuclear hormone receptors (Nur77, Nurr, and Nor1, encoded by NR4A1-3) are upregulated by both acute and chronic antigen stimulation. They represent novel markers of self-reactive lymphocytes and have tolerogenic functions. This proposal harnesses the biology of the NR4A family of orphan nuclear hormone receptors to identify and manipulate self-reactive B cells, and couples this with our existing and well-validated phage-display pipeline for autoAb and autoAg discovery. Focus Area: Understand SLE disease heterogeneity, subtype patients, and understand lupus disease mechanisms Hypothesis: We hypothesize that the expression of NR4A family members may mark pathogenic B cells in SLE patients without a priori identification of self-antigens, and may also function to impose B cell tolerance.