MECHANISMS PROTECTING MALES FROM DEVELOPMENT OF SLE
Bibliographic record
Abstract
PV108 / #408 Poster Topic: AS12 - Genetics, Epigenetics, Transcriptomics Background/Purpose Among the autoimmune rheumatic diseases, the highest female prevalence is observed in SLE, suggesting that sex-related pathways are important contributors to disease pathogenesis. Several hypotheses have been presented to explain the extreme 9-10:1 female:male skewing of SLE, with a role for sex hormones, X chromosome dose, and incomplete X chromosome inactivation (XCI) currently dominating this field of research. We have taken a novel experimental approach by investigating the cellular and molecular factors that protect males from development of SLE. Our goal is to gain new understanding of the skewed sex-related occurrence of SLE, thereby identifying new therapeutic approaches. Methods The study groups included 15 females with SLE, 15 males with SLE, all from our longitudinal SLE cohort established at Hospital for Special Surgery, and 15 female and 15 male healthy donor subjects, well matched for age and ancestry with the SLE patients. RNA sequencing of PBMC was performed and data analyzed using principal component analysis (PCA) and determination of differentially expressed gene transcripts. Results PCA showed a larger difference in RNA transcripts between SLE males and healthy males than between SLE females and healthy females. Weighted gene co-expression analysis identified 24 groups of co-expressed and functionally related transcripts, with female and male SLE patients demonstrating considerable overlap of common disease-associated genes, including type I interferon-stimulated genes, neutrophil-related genes, and B cell/plasmablast transcripts. However, transcripts associated with the NF-kB and epidermal growth factor receptor pathways were expressed at a significantly higher level in SLE males than in healthy males, while those pathways were expressed at comparable levels between SLE and healthy donor females. In contrast, gene transcripts typically expressed in natural killer (NK) cells, including KLRK1, KLRC3, KLRC4 and CADM1 , were expressed at a significantly lower level in SLE males than in healthy males. In addition, several Y chromosome-encoded genes, namely KDMD5D , encoding a histone demethylase that is expressed in NK cells, and TXLNGY were expressed at a significantly lower level in SLE males than in healthy males (adjusted p < 0.01 for comparison with healthy males for both genes). Conclusions Our data suggest that NK cells may represent an important protective cell type that limits development of SLE in most males. Moreover, our data point to several Y chromosome-encoded genes that are decreased in expression in SLE males and may contribute to altered epigenetic regulation of immune system cells, including NK cells, leading to impaired control of autoimmunity and development of SLE in some males. Further characterization of these alterations in SLE males may identify novel approaches for limiting development or severity of SLE in both males and females.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.004 | 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".