Fig. 7: Unrestricted mTORC1 activation drives the development of hemophagocytosis and macrophage activation syndrome.

a Hemoglobin levels (n = 5 per group), bone marrow cell count (n = 5 per group), plasma ferritin levels (Tsc2 ^fl/fl, n = 5, Tsc2 ikO, n = 6), spleen weight (n = 5 per group), and change in ankle joint thickness (n = 6 per group) and (b) representative ankle pathology (H&E stain) in Tsc2 iKO mice and control mice. c Wright-Giemsa staining of bone marrow leukocytes from Tsc2 iKO and control mice. d Confocal microscopy and e electron microscopy of hemophagocytes from the bone marrow of Tsc2 iKO mice. f Quantification of bone marrow hemophagocytes in Tsc2 iKO mice treated with rapamycin or vehicle control (3 slides analyzed for each mouse; n = 3 per group). Mice were 6–8 weeks of age and analyses in (a–f) were performed 3 weeks after poly I:C treatment to induce Tsc2 deletion. g Wright-Giemsa staining of human monocytes with targeted disruption of Tsc2 by CRISPR/Cas9 cultured with M-CSF for 14 days. h Pooled transcriptomic analysis of TSC1 and TSC2 expression in peripheral blood cells from patients with sJIA (n = 154) and healthy controls (n = 120). Data are compiled from GEO deposits GSE80325, GSE80060, GSE7753, GSE21521, GSE17590 and GSE112057. i Immunohistochemistry of phospho-S6 (S240/244) on bone marrow section from patients with Still’s disease and controls. Data in (a, f) were pooled from 2 to 3 independent experiments. Images in (b–e, g) are representative of 2 independent experiments. Images in (i) are derived from one experiment. Statistical analyses (all two-sided): Mann–Whitney U test (a, f, h). Median and error bars representing interquartile range are displayed in (a, f, h). Source data are provided as a Source Data file.