Whole-Blood Transcriptomic Profiling Unveils An HERV-Interferon Axis as A Novel Immunological Signature in Latent Autoimmune Diabetes in Adults (LADA)
DOI:
https://doi.org/10.54097/vr5y8484Keywords:
LADA, ERV, Type 1 Interferon, Autoimmune, Transcriptome.Abstract
Latent Autoimmune Diabetes in Adults (LADA) is characterized by progressive autoimmune beta-cell destruction, yet its upstream molecular triggers remain elusive. In this study, we utilized whole-blood RNA sequencing to investigate the global transcriptomic and endogenous virome landscapes of LADA patients. Principal Component Analysis revealed a robust systemic separation driven by both host immune gene remodeling and a distinct human endogenous retrovirus (HERV) expression signature. Differential expression profiling uncovered widespread host immune dysregulation coupled with a highly targeted and bidirectional modulation of specific HERV loci, including the profound upregulation of distinct viral elements alongside the significant downregulation of others. Crucially, functional enrichment demonstrated a profound "viral mimicry" state, characterized by overwhelming antiviral innate immune activation and Type I interferon (IFN) signaling, despite the absence of exogenous viral infection. Gene Set Variation Analysis (GSVA) further confirmed the Type I IFN storm as the singular, significantly upregulated systemic module in peripheral circulation. Finally, a highly stringent Spearman co-expression network and node degree analysis directly linked specific upregulated HERV hubs (e.g., loci 1371) to core IFN pathway integrators and molecular switches (e.g., IFI27, USP18, ISG15, IFITM3). Together, our findings provide compelling bioinformatic evidence that specific HERV activation serves as a crucial upstream trigger orchestrating the pathogenic interferon cascade in LADA.
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