# Reduced late endosome/lysosome function promotes SLE through chronic PI3K activity and SHP-1/SHIP-1 defects

## TL;DR

This study finds that malfunctioning late endosomes and lysosomes in immune cells contribute to lupus symptoms like arthritis and kidney disease.

## Contribution

The study identifies LEL dysfunction as a novel biomarker for a specific lupus endotype linked to disease activity.

## Key findings

- LEL dysfunction is associated with active lupus and symptoms like nephritis and arthritis.
- Chronic PI3K activation and SHP-1/SHIP-1 defects cause LEL dysfunction in lupus-prone mice.
- Non-acidic LELs are common in SLE patients and correlate with disease severity.

## 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 our cross-sectional study, we showed diminished LEL acidification and the accumulation of surface-bound nucleosome on monocytes, dendritic cells, B cells, neutrophils, and T cells from patients with systemic lupus erythematosus (SLE). Diminished acidification and exocytosis of undegraded IgG-immune complexes were evident in active, but not inactive, disease. This was supported by our murine study in which LEL acidification was diminished, promoting exocytosis and the accumulation of cell surface IgG-immune complexes. Mechanistically, LEL dysfunction was induced by chronic PI3K activation in lupus-prone MRL/lpr mice. We also showed that on a non-autoimmune C57BL/6 background, deficiency in SHP-1 and inhibition of SHIP-1 activity were sufficient to recapitulate LEL dysfunction found in MRL/lpr mice. Non-acidic LELs were evident in the majority of patients and associated with SLEDAI arthritis, rash, and nephritis. The high frequency of LEL dysfunction in SLE suggests that it could serve as a biomarker identifying a specific disease endotype.

This study identifies defective late endosomes/lysosomes (LELs) in patients with active lupus and shows defective LELs associated with lupus related nephritis, rash, and arthritis.