Targeting the phosphatidylinositol 3-kinase signaling pathway to inhibit pathogenic B cells in systemic lupus erythematosus (SLE)

Abstract Systemic Lupus Erythematosus (SLE) is an autoimmune disease with high levels of autoreactive B cells and circulating anti-nuclear autoantibodies. Circulating antibody-antigen immune complexes deposit in tissues, including the kidney, causing chronic inflammation and irreparable tissue damage. The hematopoietic system expresses a unique isoform of the phosphatidylinositol 3 kinase (PI3K) catalytic subunit, termed delta (PI3Kδ). It is critical for B cell survival and function, and its inhibition results in impaired antibody production. We hypothesized that targeting PI3Kδ will decrease levels of circulating auto-antibodies in a mouse model of SLE and reduce disease pathology. This study shows that a clinically utilized small molecule inhibitor of PI3Kδ (GS-9820) significantly inhibits naïve B cell differentiation into antibody secreting plasma cells as well as B cell proliferation in vitro. Furthermore, in the (NZBxNZW)F1 mouse model of SLE, treatment with the PI3Kδ inhibitor reduced autoantibody levels to background and increased overall survival. Within 2 weeks of treatment animals showed a marked reduction of germinal center B cells and T follicular helper cells (Tfh). The decrease in autoantibody levels ultimately prevented kidney damage by reducing immune complex deposition and complement fixation. Current treatments for lupus predominantly utilize systemic immunosuppressive drugs which have severe side effects. Since PI3Kδ plays a predominant role in B cells, our data suggests a clinical PI3Kδ inhibitor can be a therapeutic for lupus, potentially reducing autoantibody levels and associated pathologies. This therapy can result in better disease management and quality of life for lupus patients.