Autoantibodies to box A of high mobility group box 1 in systemic lupus erythematosus

Abstract

Autoantibodies to nuclear structures are a hallmark of systemic lupus erythematosus (SLE), including autoantibodies to nuclear protein high mobility group box 1 (HMGB1). HMGB1 consists of three separate domains: box A, box B and an acidic tail. Recombinant box A acts as a competitive antagonist for HMGB1 and might be an interesting treatment option in SLE. However, antibodies to box A might interfere. Therefore, levels of anti-box A were examined in SLE patients in association with disease activity and clinical parameters. Serum anti-box A was measured in 86 SLE patients and 44 age- and sex-matched healthy controls (HC). Serum samples of 28 patients with primary Sjögren's syndrome and 32 patients with rheumatoid arthritis were included as disease controls. Anti-HMGB1 and anti-box B levels were also measured by enzyme-linked immunosorbent assay during quiescent disease [SLE Disease Activity Index (SLEDAI) ≤ 4, n = 47] and active disease (SLEDAI ≥ 5, n = 39). Anti-box A levels in active SLE patients were higher compared to quiescent patients, and were increased significantly compared to HC and disease controls. Anti-box A levels correlated positively with SLEDAI and anti-dsDNA levels and negatively with complement C3 levels. Increased levels of anti-box A antibodies were present in the majority of patients with nephritic (73%) and non-nephritic exacerbations (71%). Antibodies to the box A domain of HMGB1 might be an interesting new biomarker, as these had a high specificity for SLE and were associated with disease activity. Longitudinal studies should be performed to evaluate whether these antibodies perform better in predicting an exacerbation, especially non-nephritic exacerbations.

C1q and HMGB1 reciprocally regulate human macrophage polarization

“…35 The amount of HMGB1 in SLE serum is increased compared with healthy controls 36 ; however, the HMGB1 enzyme-linked immunosorbent assay is an inadequate instrument for measuring HMGB1 levels in active SLE patients. 17 Therefore, we chose to use a saturating concentration of HMGB1 (3 mg/mL) and C1q levels up to 50 ug/mL. As anticipated, the addition of HMGB1 dramatically increased the transcription and secretion of type 1 IFN, IFN-inducible genes, and NFkB-dependent proinflammatory cytokines, as previously reported 7 ( Figure 1A-B).…”

“…11,17 Because C1q inhibited HMGB1-induced cytokine secretion, we asked whether this might result from a C1q-mediated inhibition of the internalization of HMGB1. We incubated AF555-HMGB1-labeled HMGB1 with freshly isolated monocytes in the presence or absence of C1q and performed imaging flow cytometry.…”

“…10,11 When bound to the Receptor for Advanced Glycation Endproducts (RAGE), it facilitates the transport of RNA and DNA to endosomal TLRs, leading to the production of type 1 interferon (IFN), IFN-inducible genes, and proinflammatory cytokines, which skew the differentiation of monocytes toward proinflammatory macrophages. 9,[12][13][14][15] Significantly elevated serum levels of HMGB1 have been demonstrated in SLE patients, 16,17 and administration of antibodies against HMGB1 confer protection against tissue injury in some experimental models of autoimmune disease and inflammation. 18 HMGB1 has also been shown to suppress inflammation.…”

Neutrophil extracellular traps are a source of extracellular HMGB1 in lupus nephritis: associations with clinical and histopathological features

“…Although serum levels of HMGB1 have been associated with disease activity and LN features, 15,17 previous studies using ELISA to determine the serum levels of HMGB1, 24 have demonstrated that the performance of this method is limited 10 because of the union of extracellular HMGB1 to free DNA 37 and the high prevalence of anti-HMGB1 autoantibodies in SLE patients. 22,38 In contrast, when HMGB1 was quantified by Western blot, the serum levels were higher in patients with renal involvement. 16,24,39 The discordant results are explained by the union of extracellular HMGB1 to free DNA 37 and anti-HMGB1 autoantibodies, frequently present in SLE patients, 22,38 which affect the ELISA performance.…”

Biomarkers of disease activity and organ damage in systemic lupus erythematosus

“…HMGB1 is a nuclear protein capable of binding to DNA, thereby regulating gene transcription, chromatin replication and DNA repair [40]. HMGB1 consists of three domains; A box, B box, and an acidic tail.…”