Anti-histone and anti-nucleosome rather than anti-dsDNA antibodies associate with IFN-induced biomarkers in Sudanese and Swedish SLE patients

• Published in: Rheumatology (Oxford, England) Vol. 64; no. 3; pp. 1170 - 1178
• Main Authors: Elbagir, Sahwa, Mohammed, NasrEldeen A, Oke, Vilija, Larsson, Anders, Nilsson, Jan, Elshafie, Amir, Elagib, Elnour M, Nur, Musa A M, Gunnarsson, Iva, Svenungsson, Elisabet, Rönnelid, Johan
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.03.2025
• Subjects: Adult; Antibodies, Antinuclear - blood; Antibodies, Antinuclear - immunology; Autoantibodies; Biomarkers - blood; Case-Control Studies; Clinical Medicine; Clinical Science; Female; Histones - immunology; Humans; Klinisk medicin; Lupus Erythematosus, Systemic - blood; Lupus Erythematosus, Systemic - immunology; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Middle Aged; Nucleosomes - immunology; Reumatologi; Rheumatology; Sudan; Sweden; Young Adult; Sweden; Sudan; anti-chromatin antibodies; proteome analysis; interferon; SLE; Africa; anti-dsDNA
• ISSN: 1462-0324; 1462-0332; 1462-0332
• DOI: 10.1093/rheumatology/keae134

In SLE, anti-dsDNA can co-occur with autoantibodies against other chromatin components, like histones and nucleosomes. These antibodies induce type-1 interferon production, a hallmark of SLE. We measured ANA sub-specificities and investigated their associations to inflammatory biomarkers including interferon-regulated chemokines. We included 93 Sudanese and 480 Swedish SLE patients and matched controls (N = 104 + 192). Autoantibodies targeting ANA sub-specificities: dsDNA, Sm, Sm/U1RNPcomplex, U1RNP, SSA/Ro52, SSA/Ro60, SSB/La, ribosomal P, PCNA and histones were quantified in all subjects, anti-nucleosome only in the Swedish patients, with a bead-based multiplex immunoassay. Levels of 72 plasma biomarkers were determined with the Proximity Extension Assay technique or ELISA. Among Sudanese patients, the investigated antibodies were significantly associated with 9/72 biomarkers. Anti-histone antibodies showed the strongest positive correlations with MCP-3 and S100A12 as well as with interferon I-inducible factors MCP-1 and CXCL10. Anti-dsDNA antibodies were associated with CXCL10 and S100A12, but in multivariate analyses, unlike anti-histone, associations lost significance.Among Swedish patients, MCP-1, CXCL10, and SA100A12 also demonstrated stronger associations to anti-histone and anti-nucleosome antibodies, compared with anti-dsDNA and other ANA sub-specificities. In multiple regression models, anti-histone/nucleosome retained the strongest associations. When excluding anti-histone or anti-nucleosome positive patients, the associations between MCP-1/CXCL10 and anti-dsDNA were lost. In contrast, when excluding anti-dsDNA positive patients, associations with anti-histone and anti-nucleosome remained significant. In two cohorts of different ethnical origins, autoantibodies targeting chromatin correlate stronger with IFN-induced inflammatory biomarkers than anti-dsDNA or other ANA sub-specificities. Our results suggest that anti-histone/nucleosome autoantibodies may be the main drivers of type-1 interferon activity in SLE.