Endosomes and lysosomes (endo-lysosomes) play a central role in maintaining cellular homeostasis by degrading extracellular and obsolete intracellular waste through their ability to acidify and activate acid hydrolases. Our previous studies identified that lysosomal acidification is diminished in lupus-prone mice (NZM2410 and MRL/lpr), promoting the accumulation of undegraded IgG-immune complexes (IgG-ICs) in the endocytic pathway. This triggers exocytosis, a process where endo-lysosomes migrate to the plasma membrane and fuse, releasing their contents extracellularly and retaining receptor-associated cargo in the plasma membrane. In this cross-sectional study, we show that diminished endo-lysosome acidification is evident in blood monocytes, dendritic cells, B cells and T cells in systemic lupus erythematosus (SLE). We find that in active patients, acidification of endo-lysosomes is diminished; however, in inactive patients, acidification is comparable to HC. Further, the accumulation of exocytosed cargo on the plasma membrane, and the levels of circulating immune complexes (CIC), are elevated in active SLE patients (SLEDAI ≥6), but not inactive patients (SLEDAI ≤5). The highest accumulation of nuclear self-antigen occurs on the surface of activated naïve (aNAV) and DN2 B cells, cells previously implicate in active SLE. The greatest increase in CIC is seen in highly active SLE (SLEDAI ≥12). Clinically, non-acidic endo-lysosomes are evident in 67% of SLE patients and 90% of patients with active renal disease. Importantly, diminished endo- lysosomal acidification did not associate with Plaquenil prescription and was not evident in active rheumatoid arthritis patients. In summary, the human cross-sectional study implicates diminished lysosome acidification and exocytosis of IgG-ICs in active disease, finds a strong association between lysosome dysfunction and lupus nephritis, and reveals that a high proportion of SLE patients have lysosome defects. These findings raise the possibility that restoring lysosome function might be a strategy to maintain inactive disease.

This study is important because it advances our understanding of how cell death and diminished degradation of IgG-opsonized apoptotic debris impacts immune homeostasis and the progression of disease. It also expands the growing number of diseases with underlying lysosome defects to include SLE (Parkinson’s, Alzheimer’s, non-alcoholic fatty liver disease, Lysosomal Storage Diseases, SLE).