The role of neutrophils in B cell dysregulation in systemic lupus erythematosus (BA7P.146)

Abstract

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease involving dysregulation of both innate and adaptive immune compartments. The hallmark of SLE is loss of B cell tolerance and production of auto-antibodies, which results in tissue damage and inflammation. Factors driving loss of B cell tolerance are incompletely characterized, but include failure of central tolerance mechanisms, inadequate clearance of cell debris, and alterations in the cytokine milieu, including elevated interferon alpha (IFNα). Our lab and others have shown that SLE neutrophils are a significant source of IFNα as well as self-antigen in the form of apoptotic debris and neutrophil extracellular traps (NETs). However, it is unknown whether neutrophils contribute to B cell activation and tolerance loss in lupus. To address this, we examined both splenic and bone marrow (BM) tissues from lupus prone mice to determine whether neutrophils secrete cytokines that alter the inflammatory milieu. Our data shows that neutrophil numbers and apoptosis are increased in lupus BM. BM neutrophils from lupus prone mice have elevated production of the B cell survival cytokines BAFF and APRIL, as well as IFNα. There was an enrichment of IFNα-producing neutrophils in the spleen in close proximity to both B and T cells. These data suggests that neutrophils likely participate in the creation of an inflammatory microenvironment that sustains auto-reactive B cells and exacerbates SLE pathogenesis in the spleen and the BM.