Abstract
Degradation of cellular waste from phagocytosis, endocytosis and autophagy occurs through hydrolases that become activated during acidification of late endosomes and lysosomes (LELs). In a cross-sectional study we show diminished LEL acidification and the accumulation of surface-bound nucleosome on monocytes, dendritic cells, and B cells from SLE patients. Diminished acidification and exocytosis of undegraded IgG-ICs is evident in active, but not inactive disease. This is supported by our murine study where LEL acidification is diminished, promoting exocytosis and the accumulation of cell surface IgG-immune complexes. Mechanistically, LEL dysfunction is induced by chronic PI3k activation in lupus-prone MRL/lpr mice. We also show that on a non-autoimmune C57BL/6 background, deficiency in SHP-1 and inhibition of SHIP-1 activity is sufficient to recapitulate LEL dysfunction found in MRL/lpr mice. Non-acidic LELs are evident in 67% of patients, and associate with SLEDAI arthritis, rash, and nephritis. The high frequency of LEL dysfunction in SLE suggests it could serve as a biomarker identifying a specific disease endotype.
Authors
SunAh Kang, Andrew J. Monteith, Liubov Arbeeva, Karissa Grier, Shruti Saxena Beem, Anthony C. Trujillo, Xinyun Bi, Kai Sun, Rebecca E. Sadun, Mithu Maheswaranathan, Megan E.B. Clowse, Saira Z. Sheikh, Jennifer L. Rogers, Barbara J. Vilen
