The TLR7→BAFF Self-Sustaining Loop in Systemic Lupus Erythematosus: Transcriptomic Validation Across 979 Patients and All Organ Domains (v2 — APS corrected)

Background: Systemic lupus erythematosus (SLE), lupus nephritis (LN, as SLE renal involvement), and cutaneous lupus (CLE) 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 types remains untested. Methods: Transcriptomic meta-analysis of 11 public GEO datasets encompassing SLE paediatric whole blood (GSE65391, n=611; GSE11909, n=22), SLE adult PBMC (GSE81622, n=28; GSE50772, n=34; GSE121239, n=65), LN whole blood (GSE72326, n=157), CLE whole blood (GSE167923, n=62), LN blood (GSE72747, n=30, for correlations only), and CLE skin biopsies (GSE109248/GSE112943, n=41) spanning 979 patients and 501 healthy controls across 4 racial groups and both sexes. 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 and LN 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. The loop is also detectable at the bone marrow haematopoietic stem/progenitor cell level (Banos 2021, Grigoriou 2023, Zervopoulou 2024), where TLR7 is upregulated 4.2-fold in SLE CD34+ HSPCs. Conclusion: The TLR7→BAFF→IFN amplification loop is the transcriptomic common denominator of lupus in blood, active in SLE and CLE regardless of organ involvement, race, or sex. This universality supports therapeutic strategies targeting multiple loop nodes simultaneously. v2 correction: This version removes primary antiphospholipid syndrome (APS) from the lupus framework — APS is a distinct thrombotic autoimmune disorder, not a lupus variant. Patient count corrected from 1,041 to 979; control count from 530 to 501.