Preferential Isoform Usage and Isoform Switching in Systemic Lupus Erythematosus Patients with Distinct Autoantibody Profile
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: RNA sequencing has advanced our understanding of molecular heterogeneity in systemic lupus erythematosus (SLE), yet most studies have focused on differential gene expression (DGE), which overlooks transcript-level complexity. Alternative splicing and polyadenylation generate multiple isoforms from a single gene, and their dysregulation may contribute to autoimmune pathogenesis, including through the production of non-canonical isoforms with potential autoantigenic properties. To explore this underexamined dimension, we analysed differential isoform usage (DIU) and major isoform switching (MIS) across SLE subgroups stratified by autoantibody profile: anti-dsDNA+, anti-ENA+ and anti-dsDNA+ENA+. Subgroup-specific DIU and MIS events were enriched in RNA-binding and transcription-related functions. In the anti-dsDNA+ subgroup, the T-cell receptor adaptor GRAP2 showed isoform switching accompanied by expansion of a non-coding retained-intron transcript. In the anti-ENA+ subgroup, IGHM switched from the membrane-bound to the secretory form, consistent with an antibody-secreting cell signature; NACA, a reported IgE autoantigen, showed isoform switching; and BRI3, linked to TNF-α-induced cell death, switched toward its protein-coding transcript. In the anti-dsDNA+ENA+ subgroup, TNFAIP2, a TNF-α-induced gene, showed isoform redistribution with loss of a uORF-containing transcript. These findings highlight isoform regulation as a distinct, subgroup-specific and functionally relevant layer of transcriptomic dysregulation in SLE.
Institutions: Banaras Hindu University, Institute of Medical Sciences
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7225428825