Type I interferon and mitochondrial dysfunction are associated with dysregulated cytotoxic CD8+ T cell responses in juvenile systemic lupus erythematosus
Bibliographic record
Abstract
Juvenile systemic lupus erythematosus (JSLE) is an autoimmune condition which causes significant morbidity in children and young adults and is more severe in its presentation than adult-onset SLE. While many aspects of immune dysfunction have been studied extensively in adult-onset SLE, there is limited and contradictory evidence of how cytotoxic CD8+ T cells contribute to disease pathogenesis and studies exploring cytotoxicity in JSLE are virtually non-existent. Here, we report that CD8+ T cell cytotoxic capacity is reduced in JSLE versus healthy controls, irrespective of treatment or disease activity. Transcriptomic and serum metabolomic analysis identified that this reduction in cytotoxic CD8+ T cells in JSLE was associated with upregulated type I interferon (IFN) signalling, mitochondrial dysfunction, and metabolic disturbances when compared to controls. Greater interrogation of the influence of these pathways on altered cytotoxic CD8+ T cell function demonstrated that JSLE CD8+ T cells had enlarged mitochondria and enhanced sensitivity to IFN-α leading to selective apoptosis of effector memory (EM) CD8+ T cells, which are enriched for cytotoxic mediator-expressing cells. This process ultimately contributes to the observed reduction in CD8+ T cell cytotoxicity in JSLE, reinforcing the growing evidence that mitochondrial dysfunction is a key pathogenic factor affecting multiple immune cell populations in type I IFN-driven rheumatic diseases.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".