Preferential Isoform Usage and Isoform Switching in Systemic Lupus Erythematosus Patients with Distinct Autoantibody Profile

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--induced cell death, switched toward its protein-coding transcript. In the anti-dsDNA+ENA+ subgroup, TNFAIP2, a TNF--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.