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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\/\n                    <jats:italic>lpr<\/jats:italic>\n                    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\/\n                    <jats:italic>lpr<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.191767","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T14:19:42Z","timestamp":1771337982000},"source":"Crossref","is-referenced-by-count":1,"title":["Reduced late endosome\/lysosome function promotes SLE through chronic PI3K activity and SHP-1\/SHIP-1 defects"],"prefix":"10.1172","volume":"11","author":[{"given":"SunAh","family":"Kang","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew J.","family":"Monteith","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liubov","family":"Arbeeva","sequence":"additional","affiliation":[{"name":"Division of 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