Background Systemic lupus erythematosus (SLE) is a systemic autoimmune condition characterized by reduced ability to degrade and eliminate apoptotic cells. This probably contributes to the excessive production of antinuclear autoantibodies (ANA), including anti-double-stranded (ds) DNA, which is a hallmark of SLE. The non-histone nuclear protein high mobility group box protein-1 (HMGB1) can act as a pro-inflammatory mediator in many inflammatory diseases when released extracellularly. In SLE, HMGB1 may leak out from inefficiently degraded apoptotic cells and be involved in the pathogenesis . Serum levels of HMGB1 correlate with SLE disease activity , and HMGB1 has also been shown to contribute to anti-dsDNA antibody production . Anti-HMGB1 antibodies have been reported in SLE [2, 4], although their pathogenetic role remains elusive.
Objectives We aimed to detect and evaluate anti-HMGB1 antibodies in relation to other autoantibodies and to disease activity, phenotypes and organ damage in a well-characterized cohort of Swedish SLE patients.
Methods Sera from 188 SLE patients meeting the 1982 ACR and/or the 2012 SLICC classification criteria (89% female; mean age 49 years/range 18-88; mean duration 11 years/range 0-45) and 112 healthy controls (91% female; mean age 47 years/range 19-84) were included. Anti-HMGB1 antibody levels were analyzed by an in-house ELISA using recombinant HIS-tagged HMGB1. The cut-off value (300 AU) was set 2 standard deviations above the mean value among healthy controls. SLE sera were also analyzed by immunofluorescence microscopy with regard to ANA (IF-ANA) using fixed HEp-2 cells (ImmunoConcepts, Sacramento, US). Fluoroenzyme-immunoassay was used to evaluate anti-dsDNA antibodies (EliA, ThermoFischer, Uppsala, Sweden), and line-blot technique (ANA profile-5, Euroimmun, Lübeck, Germany) was used for other ANA fine specificities.
Results 23% (43/188) of the SLE patients were judged anti-HMGB1 antibody positive versus 4% (5/112) of the controls. The levels of anti-HMGB1 were significantly higher in patients compared to controls. Anti-HMGB1 antibodies were associated with anti-dsDNA antibody (EliA) levels (r=0.49; p<0.001), whereas correlations were less pronounced regarding SLEDAI-2K (r=0.15; p=0.04) and albuminuria (r=-0.18; p=0.02), classical complement function (r=-0.24; p=0.002) and complement protein C4 (r=-0.23; p=0.002). The presence of anti-HMGB1 was not associated with organ damage or distinct disease manifestations. Sera containing anti-HMGB1 antibodies were more likely to contain IF-ANA yielding chromatin staining (homogenous) on HEp-2 cells, compared to anti-HMGB1 negative samples (p=0.009).
Conclusions We confirm that anti-HMGB1 antibodies occur in SLE and that they predominantly associate with a homogenous IF-ANA staining pattern. We did not find association with renal disease. Anti-HMGB1 levels were correlated with both clinical and serological signs of disease activity.
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Disclosure of Interest : None declared
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