Defects in lysosome acidification are evident in active, but not inactive, systemic lupus erythematosus (SLE)

Abstract

Abstract Better strategies are needed in SLE to identify the receptors and molecular events that promote inflammation. We identified a defect in lysosomal acidification in multiple hematopoietic cell types in the MRL/lpr, NZM2410, and sle123 murine models of lupus. On myeloid cells, lysosome dysfunction is induced by chronic Fcgamma receptor (FcγR) signal transduction and results in the recycling of internalized IgG-immune complexes, and their accumulation on the cell surface. This perpetuates FcγR activation, promoting BAFF and IFNα/β secretion upstream of autoantibody production, lupus nephritis, and tertiary lymphoid organogenesis. Here, we define whether lysosomal defects and accumulation of nuclear antigens (Ags) are evident on human blood cells in SLE. Our data show that diminished lysosome function and the accumulation of nuclear Ags on patients’ blood cells are more evident in active, compared to inactive disease. On monocytes, 78% of active (n=18), but only 38% of inactive (n=16) patients showed diminished lysosomal acidification. On B cells, 47% of active, while only 9% of inactive patients, showed defects in lysosomal acidification. To assess whether lysosomal defects were coincident with the accumulation of nuclear Ags, we measured surface DNA levels (n = 57 active, 51 inactive patients, 109 HCs). In active patients, surface DNA levels were also elevated on blood B cells (7-fold; p = <0.002), DCs (3.7 fold; p = 0.06), T cells (2.4-fold; p = 0.03), and monocytes (1.8-fold; p = 0.09). Because monocytes exhibited lysosome defects, the low levels of surface DNA on monocytes was unexpected. However, it raises the possibility that monocytes activated by lysosome dysfunction and chronic FcγR signaling leave the blood.