401 Type I interferon in NPSLE
Bibliographic record
Abstract
Background Neuropsychiatric symptoms are highly prevalent among systemic lupus erythematosus (SLE) patients, being clinically observed in up to 80% of adult and 95% of pediatric patients. Type 1 interferons, in particular interferon alpha (IFNα), have been implicated in the pathogenesis of SLE as well as its associated neuropsychiatric symptoms (NPSLE). The cellular components and molecular pathways affected within the central nervous system (CNS) in NPSLE remain unclear. Murine models of NPSLE with an elevated peripheral type 1 interferon signature are lacking, limiting studies of the mechanistic association between IFNα and behavioral phenotypes in this disease. Methods Male and female B6.Sle 1yaa mice were analyzed at varying ages from 10 days to 20 weeks. Both peripheral and CNS tissues were examined by RT-PCR for ISG expression. MERFISH, a spacial transcriptomic approach, was used to identify ISG expression in whole brain sections and results validated using RNA scope. To identify differentially expressed genes single nuclei were isolated from cells of hindbrain and hippocampus and analyzed by RNA sequencing. Behavior assays were used examine symptoms of anxiety and fatigue. Results We found using probe-based spatial transcriptomics that the type 1 interferon signature is present within the brain parenchyma of lupus mice as early as 3 weeks, with interferon stimulated genes (ISG) enriched in spatially distinct patches. ISG expression was validated by RT-PCR and RNA scope. Unbiased single nucleus sequencing of the murine hind brain and hippocampus revealed that ISGs as a group were the most highly differentially expressed genes. Sle 1 yaa male mice developed symptoms of anxiety as early as 4 weeks and fatigue by 8 weeks relative to WT controls. Behavior and ISG patch formation were not dependent on the yaa mutation as female mice at 20 weeks were also positive for focal patches and development behavior change. Conclusions We propose that the functional effects of interferon stimulated gene (ISG) patches play a mechanistic role in mediating behavioral phenotypes, and modulation of the type 1 interferon signaling pathway within the brain. Acknowledgement We thank NIAMS for support (R01AR072965) Lay summary A common problem in lupus is being tired and absent minded. The cause is not known. We think it is due to the same factors released by the body during a cold. We want to know how the factors get into the brain and how they affect the tissues. By using mutant mice that have lupus symptoms, we hope to find out how the factors work in the brain.
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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) | 0.002 | 0.001 |
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".