mTOR activation triggers proinflammatory expansion of IL-4-producing and necrosis-prone double-negative T cells, precedes flares, and serves as target for treatment in patients with systemic lupus erythematosus
Bibliographic record
Abstract
Oxidative stress is increased in systemic lupus erythematosus (SLE), and it contributes to immune system dysregulation and fatal comorbidities. Mitochondrial dysfunction in T cells promotes the release of highly diffusible inflammatory lipid hydroperoxides, which spread oxidative stress to other intracellular organelles and through the bloodstream. In T cells from patients with SLE and animal models of the disease, glutathione, the main intracellular antioxidant, is depleted and the mechanistic target of rapamycin (mTOR), serine/threonine protein kinase, undergoes redox-dependent activation. In turn, reversal of glutathione depletion by application of its amino acid precursor, N -acetylcysteine, blocks mTOR activation and improves disease activity in lupus-prone mice and patients with SLE. While mTOR has been also recognized as an effector of T-cell lineage development, its role in autoimmunity and disease activation remain unclear. Here, we prospectively examined mitochondrial dysfunction and mTOR in PBL relative to SLEDAI and BILAG disease activity indices during 274 visits of 59 patients and 54 healthy subjects matched for each patient blood donation. A total of 212 metabolic biomarkers and traditional biomarkers, anti-DNA, C3, and C4, were evaluated by partial least-square discriminant analysis (PLS-DA). False discovery rate (FDR) P values were determined for each contributing biomarker and considered significant at P < 0.000236 with correction for multiple comparisons (0.05/212). Medication use was compared between patient groups exhibiting flare and remission with chi-square and Fischer's exact tests. PLS-DA identified 15 of 212 parameters that accounted for 70.2% of the total variance and discriminated lupus and control samples ( P < 0.0005); increased mitochondrial mass of CD3 /CD4 /CD8 double-negative (DN) T cells ( P = 1.1 × 10 ) and FoxP3 depletion in CD4 /CD25 T cells were top contributors ( P = 6.7 × 10 ). Prominent necrosis and mTOR activation were noted in DN T cells during 15 visits characterized by flares (SLEDAI increase ≥4) relative to 61 visits of remission (SLEDAI decrease ≥4). mTOR activation in DN T cells was also noted at preflare visits of SLE patients relative to those of stable disease or healthy controls. DN lupus T cells showed increased production of IL-4, which correlated with depletion of CD25 /CD19 B cells. Rapamycin treatment in vivo reduced SLEDAI and BILAG, blocked the IL-4 production and necrosis of DN T cells, increased the expression of FoxP3 in CD25 /CD4 T cells, and expanded CD25 /CD19 B cells. These results identify mTOR activation to be a trigger of IL-4 production and necrotic death of DN T cells, predictor of disease flares, and effective target for treatment in patients with SLE.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".