Systemic lupus erythematosus (SLE) is characterized by chronic immune activation, enhanced type I interferon signaling, and epigenetic dysregulation, conditions that may promote the reactivation of human endogenous retroviruses (HERVs). Whether HERV activation in SLE is global or selective, however, remains unclear. We analyzed the expression of HERV-H, HERV-K, and HERV-W, along with the HERV-derived envelope genes Syncytin-1 and Syncytin-2, in samples from lupus patients and healthy controls. In parallel, we assessed the expression of the epigenetic repressors TRIM28 and SETDB1. HERV-H expression was comparable between groups, whereas HERV-K and HERV-W were significantly overexpressed in lupus patients. Syncytin-1 and HERV-W env transcripts were markedly increased in SLE, while Syncytin-2 expression was unchanged. Lupus patients showed reduced TRIM28 and increased SETDB1 expression, consistent with altered regulation of HERV repression pathways. Notably, HERV-H and HERV-W pol expression correlated with the type I interferon score, suggesting an association between interferon signaling and selective HERV activation. These findings indicate that SLE is associated with the selective activation of immunostimulatory HERV families, particularly HERV-W. The observed associations with interferon signaling suggest that HERV-W-related transcripts may represent disease-associated molecular signatures, warranting further mechanistic investigation.

Background/Objectives: Human endogenous retroviruses (HERVs) represent a substantial portion of the human genome and are increasingly recognized as active components of gene regulation and immune modulation. Aging has been associated with alterations in HERV expression; however, data in healthy populations remain limited. The aim of this study was to evaluate age-associated transcriptional patterns of selected HERV elements, and epigenetic regulators in a cohort of healthy individuals. Methods: A total of 269 subjects aged 0.13–89.48 years were enrolled. Transcriptional levels of HERV-H, HERV-K, and HERV-W pol genes, and of Syncytin-1, Syncytin-2, and HERV-W env genes, and the epigenetic regulators SETDB1 and TRIM28 were assessed by real-time PCR. Primary analyses used raw Ct values. Associations with age were evaluated separately in pediatric participants and adults using multivariable linear regression models including sex and the reference gene GAPDH Ct as covariates. Quadratic age terms and alternative approaches to GAPDH adjustment were also examined. Results: GADPH Ct values were positively correlated with age and all target genes. After Benjamini–Hochberg correction, HERV-H-pol, Syncytin-1, and Syncytin-2 showed increasing Ct values with age in pediatric participants, while HERV-K-pol, Syncytin-1, HERV-W-env, SETDB1, and TRIM28 showed increasing Ct values in adults. These associations are compatible with lower transcriptional signals of some HERVs and a few cellular genes over the years within each age group. Separate analyses in pediatric participants and adults provided no significant evidence of quadratic age associations after Benjamini–Hochberg correction for multiple testing. Conclusions: Several age associations depended on the analytical treatment of GAPDH. These findings identify target-specific age-associated transcriptional patterns in peripheral blood from apparently healthy individuals. They highlight the importance of distinguishing developmental from adult age associations and evaluating the reference gene suitability for normalization of target gene expressions. Longitudinal and mechanistic studies are needed to clarify the biological significance of these associations.

Background and Objectives: Type I interferon (IFN-I) transcriptional signatures are widely utilised as readouts of innate immunity. We evaluated whether age and sex affect single interferon-stimulated genes (ISGs) and the composite IFN-I score, with implications for control selection and assay calibration. Materials and Methods: Ninety-five healthy individuals (53 males, 42 females; 18 days to 89 years) were studied. Whole-blood expressions of IFI27, IFI44L, IFIT1, ISG15, RSAD2 and SIGLEC1 was quantified by RT-qPCR, normalised to GAPDH and calibrated to a paediatric reference. Age associations used Spearman’s rho; sex differences, two-sided Mann–Whitney U tests. Results: Age effects were modest and gene-specific: IFI44L declined and IFI27 increased with age (significant overall and in females), whereas in males only IFI44L decreased; other ISGs were null (|r| ≤ 0.36). The composite IFN-I score showed no association with age or sex, indicating that aggregation mitigates small gene-level variation and that demographic influences on baseline IFN-I readouts appear minimal within this six-gene whole-blood qPCR panel in our cohort. Conclusions: Methodologically, a single primary cut-off within homogeneous pipelines is appropriate. Although best practice favours age-, sex- and matrix-matched healthy controls, our data show no significant age- or sex-related differences in the composite IFN-I score; matching therefore primarily supports comparability and clinical governance rather than correction of demographic shifts.