Article Text
Abstract
Objective 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 antinuclear antibody (ANA) sub-specificities and investigated their associations to inflammatory biomarkers including interferon-regulated chemokines.
Methods We included 93 Sudanese and 480 Swedish SLE patients and matched controls (N=104+192). Autoantibodies targeting ANA-subspecificites: 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 Proximity Extension Assay technique or ELISA.
Results Among Sudanese patients, the investigated antibodies 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 associated with CXCL10 and S100A12, but in multivariate analyses, unlike anti-histone, associations lost significance.
Among Swedish patients for MCP-1, CXCL10, SA100A12 also demonstrated stronger associations to anti-histone and anti-nucleosome antibodies, compared to 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.
Conclusions In two cohorts of different ethnical origin, 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 main drivers of type-1 interferon activity in SLE.
Acknowledgments This work was supported by the Swedish Rheumatism Association (R-932093, to JR, R-840401 to ES); King Gustav Vth 80-year foundation (FAI-2019–0577, to JR, FAI-2019–0628 to ES); the Agnes and Mac Rudberg Foundation; the Signe and Reinhold Sund’s Foundation for Rheumatological Research; the Swedish Society of Medicine and the Ingegerd Johansson Donation (SLS-713911 to ES); the Swedish Research Council (2019–01632, to JR, 2018–02535 to ES); the Uppsala County Council (ALF); the Stockholm County Council (ALF) and the Swedish Heart-Lung Foundation (20170257 and 20190510 to ES).
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