PROJECT SUMMARY Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. 90% of patients with SLE are women between the ages of 15 and 44. SLE is characterized by a hyperactive, dysfunctional immune system, the presence of autoantibodies, and widespread inflammation in multiple organ systems, including the skin, joints, heart, lungs, kidneys, and brain. In SLE, dysregulated plasma cells, a terminally differentiated subset of B cells, produce autoantibodies which attack DNA, RNA, and self-proteins, including histones. SLE is currently managed with anti-inflammatory and immunosuppressive approaches including pan B-cell depleting regimens that alleviate symptoms and slow tissue damage. However, sustained remission of SLE remains a clinical challenge for several reasons. First, many therapies cause significant side effects as they globally affect the immune system. Second, there is a lack of targeted therapies that simultaneously eradicate autoantibody-producing short-lived plasmablasts and long-lived plasma cells (LLPCs), as well as their B-cell precursors. To eradicate all pathogenic B-cell subsets concurrently and specifically in patients with SLE, we propose to determine whether a patented, non-toxic splice-modulating oligomer (SMO), that prevents synthesis of the long isoform of the prolactin receptor (LFPRLR), is a viable approach. Increased circulating levels of the hormone, prolactin (PRL), are known to be associated with the exacerbation of symptoms of adult and pediatric SLE. Consistent with this, our preliminary findings suggest abnormally elevated expression of PRLRs in immune cells of female mice and patients with SLE. However, whether PRL and its receptors are causal in immunomodulation in SLE is less understood. Recently, we and others published that the LFPRLR specifically promotes the retention of potentially autoreactive B cells in a mouse model of SLE. We found that knockdown of the LFPRLR reduces the numbers of short-lived plasmablasts and LLPCs and their B-cell precursors in female SLE-prone mice. How the LFPRLR maintains pathogenic plasma cells and their precursor B cells in SLE remains to be delineated. This forms the focus of our current R21. We propose two Aims. In Aim 1, we will determine the effect of LFPRLR knockdown on pathogenic B-cell subsets including their terminally differentiated derivatives, plasma cells, in murine SLE. In Aim 2, we will determine the ability of LFPRLR knockdown to reduce pathologic plasma cells in human SLE. In both Aims, we will employ complimentary high-dimensional single-cell immune profiling approaches. We will correlate these findings with measurements of standard indicators of autoimmune disease pathology in SLE- prone mice and in samples from patients with SLE. Our studies will solidify knockdown of the LFPRLR as a novel, effective, non-toxic, and isoform-specific strategy to eradicate abnormal autoantibody-producing plasma cells in patients with SLE. In the long-term, these stud...