Abstract
BackgroundOur previous study found that circulating and urinary levels of high mobility group box-1 (HMGB1) were closely associated with disease activity in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Moreover, HMGB1 participates in ANCA-induced neutrophil activation. Cross-reactivity between moesin and anti-myeloperoxidase (MPO) antibody has been reported in both human and mouse. The current study investigated whether HMGB1 participated in MPO-ANCA-induced glomerular endothelial cell (GEnC) injury, which is one of the most important aspects in the pathogenesis of AAV.MethodsThe effects of HMGB1 on expression of moesin on GEnCs and anti-MPO antibody binding to GEnCs were measured. MPO expression on GEnCs was explored. The effects of HMGB1 in MPO-ANCA induced GEnC injury were measured, during which the role of moesin was explored. Antagonists for various relevant receptors were employed.ResultsSera from AAV patients at the active stage could mediate GEnC injury, while this effect could be attenuated by preblocking HMGB1. HMGB1 could increase the expression of moesin on GEnCs and the binding of anti-MPO antibody to moesin. The colocalization of moesin expression and anti-MPO antibody binding can be detected. Little, if any, MPO was expressed in GEnCs. HMGB1 increased GEnC activation and injury in the presence of patient-derived MPO-ANCA-positive IgGs through moesin. The effects of HMGB1 on expression of moesin on GEnCs, anti-MPO antibody binding to GEnCs, GEnC activation and injury were mainly toll like receptor 4 (TLR4) dependent.ConclusionsHMGB1 can increase the expression of moesin but not MPO on GEnCs, and can further participate in MPO-ANCA-induced GEnC activation and injury by cross-reactivity between moesin and anti-MPO antibody.
Highlights
Our previous study found that circulating and urinary levels of high mobility group box-1 (HMGB1) were closely associated with disease activity in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)
HMGB1 participated in glomerular endothelial cell (GEnC) injury mediated by sera from AAV patients Compared with GEnCs incubated with endothelial cell basal medium (ECM) with additional 10% sera from healthy controls, the levels of lactate dehydrogenase (LDH) release increased significantly in GEnCs incubated with ECM with additional 10% sera from AAV patients (1.44 ± 0.16 vs 1.18 ± 0.11, p < 0.01)
By preincubating antiHMGB1 IgY, the levels of LDH release decreased significantly in GEnCs incubated with ECM with additional 10% sera from AAV patients (1.44 ± 0.16 vs 1.30 ± 0.21, p = 0.02) (Fig. 1)
Summary
Our previous study found that circulating and urinary levels of high mobility group box-1 (HMGB1) were closely associated with disease activity in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The current study investigated whether HMGB1 participated in MPO-ANCA-induced glomerular endothelial cell (GEnC) injury, which is one of the most important aspects in the pathogenesis of AAV. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) consists of granulomatosis with polyangiitis (GPA, previously named Wegener’s granulomatosis), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA) [1]. It is worth noting that Chinese patients with AAV are predominantly MPO-ANCA-positive, as demonstrated by our previous studies [2, 3]. ANCAs are proved to be involved in inducing and amplifying neutrophil-mediated endothelial injury in AAV [4, 5]. There is evidence supporting the direct ability of MPO-ANCA to produce vessel damage [6,7,8]
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