The TLR7→BAFF Self-Sustaining Loop in Lupus: A Pan-Variant Transcriptomic Validation in Blood Across SLE, CLE, LN, and Primary APS

Background: Systemic lupus erythematosus (SLE), cutaneous lupus (CLE), lupus nephritis (LN), and primary antiphospholipid syndrome (APS) share a type I interferon (IFN) signature, B-cell hyperactivity, and toll-like receptor (TLR) involvement. The TLR7→MYD88→IRF7→BAFF (TNFSF13B) axis has been proposed as a self-sustaining pathogenic loop in SLE blood, but its universality across distinct lupus variants remains untested. Methods: Transcriptomic meta-analysis of 7 public GEO datasets encompassing SLE paediatric whole blood (GSE65391, n=924), SLE adult PBMC (GSE81622), CLE whole blood (GSE167923, n=62), LN whole blood (GSE72747), primary APS (GSE205465), and CLE skin biopsies (GSE109248/GSE112943) spanning >1,000 patients across 5 lupus variants. Results: In SLE blood, the loop was robustly correlated (IRF7→IFIT1 r=+0.86, BAFF→IRF7 r=+0.74) and identical across all 8 SLEDAI organ categories, race (4 groups), and sex. The correlation pattern was quantitatively indistinguishable in CLE blood, LN blood, and primary APS blood. In CLE skin, however, the loop was transcriptionally inactive (TLR7→BAFF r=-0.18, IRF7→CXCL10 r=+0.12) with an alternative UV→cGAS-STING→IFN-κ mechanism driving local inflammation. Conclusion: The TLR7→BAFF→IFN amplification loop is the transcriptomic common denominator of lupus in blood, active in all 5 tested variants regardless of organ involvement, race, or sex. This universality supports pan-lupus therapeutic strategies targeting multiple loop nodes simultaneously.