Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus (original) (raw)
NASA/ADS
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- Kang, SunAh ;
- Scott, Eric ;
- Hillman, Kai ;
- Rajfur, Zenon ;
- Jacobson, Ken ;
- Costello, M. Joseph ;
- Vilen, Barbara J.
Abstract
Activation of innate sensors by self-antigen contributes to autoimmunity, although how intracellular sensors are chronically exposed to self-antigen has remained unknown. Here, we identify a previously unidentified defect in which lupus-prone macrophages fail to mature the lysosome, promoting the accumulation of apoptotic debris-containing IgG-immune complexes (IgG-ICs). Interestingly, macrophages from other autoimmune diseases accumulate IgG-ICs, indicating that lysosomal defects may underlie multiple autoimmune diseases. Furthermore, the prolonged intracellular residency chronically activates Toll-like receptors and permeabilizes the phagolysosomal membrane, allowing activation of cytosolic sensors. These findings identify lysosomal maturation as a unique defect in MRL/lpr mice that impacts multiple events known to underlie SLE, including pathogenic cytokine secretion.
Publication:
Proceedings of the National Academy of Science
Pub Date:
April 2016
DOI:
Bibcode: