Background In SLE, anti-dsDNA often exists together with autoantibodies against other chromatin components, like histones and nucleosomes. These antibodies can induce cytokines including interferon-alpha.
Methods We have measured ANA specificities and investigated their associations to inflammatory biomarkers. We included 93 Sudanese and 480 Swedish SLE patients. Serum levels of autoantibodies against dsDNA, Sm, the Sm/U1RNP complex, U1RNP, SSA/Ro52, SSA/Ro60, SSB/La, ribosomal P, PCNA and histones were quantified with a bead-based multiplex immunoassay. In the Swedish cohort also anti-nucleosome antibodies were investigated. Relative levels of 73 plasma biomarkers were determined with Proximity Extension Assay technique or ELISA. Adjusted p values were considered significant when <0.05.
Results Among Sudanese patients, levels of 5/73 biomarkers showed significant associations to ANA-associated antibodies. Anti-histone antibodies showed the strongest positive correlations with interferon-inducible factors MCP-1 and IP-10, and with MCP-3 and S100A12, and negative correlation with stem cell factor. Also anti-dsDNA antibodies associated with MCP-3, IP-10 and S100A12, but when combined in the same regression model, anti-dsDNA associations but not anti-histone lost significance.
Validation analyses among Swedish patients for MCP-1, IP-10, SA100A12 also demonstrated significantly stronger associations to anti-histone and anti-nucleosome antibodies respectively, compared to anti-dsDNA and other ANA specificities, and in combined regression models, anti-histone/nucleosome showed the strongest associations. When excluding anti-histone or anti-nucleosome positive patients, the associations between interferon-inducible factors MCP-1/IP-10 and anti-dsDNA and were lost. In contrary, when excluding anti-dsDNA positive patients, associations with anti-histone and anti-nucleosome respectively remained significant. SA100A12 associations with anti-dsDNA antibodies remained significant after exclusion of anti-histone positive patients but lost significance when excluding anti-nucleosome positive patients.
Conclusions Levels of mainly IFN-induced inflammatory biomarkers correlate stronger with anti-histone and anti-nucleosome antibodies compared to other ANA specificities including anti-dsDNA. Our results suggest that autoantibodies against DNA-complexes or DNA-associated proteins rather than anti-dsDNA induce the interferon signature in SLE.
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