Department of Medicine, Unit of Rheumatology, D2:00 Solna, Karolinska University Hospital, Karolinska Institute, S-171 76 Stockholm, Sweden.
Arthritis Res Ther. 2012 Feb 20;14(1):R36. doi: 10.1186/ar3747.
High 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.
Thirty-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.
Baseline 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.
Renal 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.
高迁移率族蛋白 B1（HMGB1）是一种核 DNA 结合蛋白，在细胞外释放后作为促炎介质发挥作用。HMGB1 已被越来越多地认为是几种炎症性疾病的致病介质。自身免疫性疾病包括系统性红斑狼疮（SLE）患者的血清 HMGB1 水平升高。然而，活动期狼疮性肾炎（LN）中 HMGB1 的局部表达尚不清楚。本研究旨在研究活动期 LN 患者血清和组织中 HMGB1 的表达。
纳入 35 例活动期 LN 患者。在基线和标准诱导治疗后（皮质类固醇联合免疫抑制剂）进行肾活检；。根据世界卫生组织（WHO）分类评估肾活检，采用不列颠群岛狼疮评估组（BILAG）指数评估肾脏疾病活动度。采用 Western blot 分析血清 HMGB1 水平。在 25 例患者的基线和随访活检中，通过免疫组化评估肾组织中 HMGB1 的表达。
基线活检显示 WHO Ⅲ、Ⅳ或Ⅴ级，所有患者均有高肾脏疾病活动度（BILAG A/B）。随访活检显示 WHO Ⅰ至Ⅱ级（n=14）、Ⅲ级（n=6）、Ⅳ级（n=3）或Ⅴ级（n=12），35 例患者中有 15 例被认为是肾脏应答者（BILAG C/D）。与健康对照组相比，基线时血清 HMGB1 明显升高（P＜0.0001）。所有患者的血清水平仅略有下降；然而，基线时 WHO Ⅳ级患者的血清水平显著下降（P=0.03）。免疫组化显示，HMGB1 呈明显的核外表达，主要围绕肾小球内皮细胞和系膜。与基线活检相比，HMGB1 的表达在随访活检中没有明显差异，与组织病理学分类或临床结局也没有明显的相关性。
LN 患者肾组织表达和血清 HMGB1 水平升高。本研究中免疫抑制治疗后血清和组织中 HMGB1 无明显下降，可能反映持续的炎症活性。本研究清楚地表明 HMGB1 在 LN 中起作用。
