Abstract
IntroductionHigh mobility group box 1 protein (HMGB1) is a nuclear DNA binding protein acting as a pro-inflammatory mediator following extracellular release. HMGB1 has been increasingly recognized as a pathogenic mediator in several inflammatory diseases. Elevated serum levels of HMGB1 have been detected in autoimmune diseases including Systemic lupus erythematosus (SLE). However, the local expression of HMGB1 in active lupus nephritis (LN) is not known. Here we aimed to study both tissue expression and serum levels of HMGB1 in LN patients with active disease and after induction therapy.MethodsThirty-five patients with active LN were included. Renal biopsies were performed at baseline and after standard induction therapy; corticosteroids combined with immunosuppressive drugs. The biopsies were evaluated according to the World Health Organization (WHO) classification and renal disease activity was estimated using the British Isles lupus assessment group (BILAG) index. Serum levels of HMGB1 were analysed by western blot. HMGB1 expression in renal tissue was assessed by immunohistochemistry at baseline and follow-up biopsies in 25 patients.ResultsBaseline biopsies showed WHO class III, IV or V and all patients had high renal disease activity (BILAG A/B). Follow-up biopsies showed WHO I to II (n = 14), III (n = 6), IV (n = 3) or V (n = 12), and 15/35 patients were regarded as renal responders (BILAG C/D).At baseline HMGB1 was significantly elevated in serum compared to healthy controls (P < 0.0001). In all patients, serum levels decreased only slightly; however, in patients with baseline WHO class IV a significant decrease was observed (P = 0.03). Immunostaining revealed a pronounced extranuclear HMGB1 expression predominantly outlining the glomerular endothelium and in the mesangium. There was no clear difference in HMGB1 expression comparing baseline and follow-up biopsies or any apparent association to histopathological classification or clinical outcome.ConclusionsRenal tissue expression and serum levels of HMGB1 were increased in LN. The lack of decrease of HMGB1 in serum and tissue after immunosuppressive therapy in the current study may reflect persistent inflammatory activity. This study clearly indicates a role for HMGB1 in LN.
Highlights
High mobility group box 1 protein (HMGB1) is a nuclear DNA binding protein acting as a proinflammatory mediator following extracellular release
Renal tissue expression and serum levels of HMGB1 were increased in lupus nephritis (LN)
This study clearly indicates a role for HMGB1 in LN
Summary
High mobility group box 1 protein (HMGB1) is a nuclear DNA binding protein acting as a proinflammatory mediator following extracellular release. Elevated serum levels of HMGB1 have been detected in autoimmune diseases including Systemic lupus erythematosus (SLE). Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease characterized by multiple organ involvement, production of autoantibodies to nuclear components, and immune complex deposition [1]. High-mobility group box 1 protein (HMGB1), a nuclear protein found in all mammalian cells, is known as a DNA-binding protein participating in chromatin structure and transcriptional regulation [3,4]. Extracellular HMGB1 has been identified as a proinflammatory mediator and, owing to its proinflammatory and immunostimulatory properties, has been proposed to contribute to the pathogenesis of multiple chronic inflammatory and autoimmune diseases [5,6,7,8]. HMGB1 induces other cytokines such as tumor necrosis factor and interleukin-1 (IL-1), IL-6, and IL-8 and is an activator of endothelial cells leading to the upregulation of adhesion molecules [11,12]
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