High systemic levels of the cytokine-inducing HMGB1 isoform secreted in severe macrophage activation syndrome.

Karin Palmblad,Erik Sundberg,Daniel J Antoine,Hanna Schierbeck,Anna-Carin Horne,Ulf Andersson,Helena Erlandsson Harris,Jan-Inge Henter

doi:10.2119/molmed.2014.00183

Abstract

Macrophage activation syndrome (MAS) is a potentially fatal complication of systemic inflammation. High mobility group box 1 (HMGB1) is a nuclear protein extensively leaked extracellularly during necrotic cell death or actively secreted by natural killer (NK) cells, macrophages and additional cells during infection or sterile injury. Extracellular HMGB1 orchestrates key events in inflammation as a prototypic alarmin. The redox states of its three cysteines render the molecule mutually exclusive functions: fully reduced "all-thiol HMGB1" exerts chemotactic activity; "disulfide HMGB1" has cytokine-inducing, toll-like receptor 4 (TLR4)-mediated effects—while terminally oxidized "sulfonyl HMGB1" lacks inflammatory activity. This study examines the kinetic pattern of systemic HMGB1 isoform expression during therapy in four children with severe MAS. Three of the four patients with underlying systemic rheumatic diseases were treated with biologics and two suffered from triggering herpes virus infections at the onset of MAS. All patients required intensive care unit therapy due to life-threatening illness. Tandem mass-spectrometric analysis revealed dramatically increased systemic levels of the cytokine-inducing HMGB1 isoform during early MAS. Disease control coincided with supplementary etoposide therapy initiated to boost apoptotic cell death, when systemic HMGB1 levels drastically declined and the molecule emerged mainly in its oxidized, noninflammatory isoform. Systemic interferon (IFN)-γ and ferritin peaked concomitantly with HMGB1, whereas interleukin (IL)-18 and monocyte chemotactic protein (MCP)-1 levels developed differently. In conclusion, this work provides new insights in HMGB1 biology, suggesting that the molecule is not merely a biomarker of inflammation, but most likely also contributes to the pathogenesis of MAS. These observations encourage further studies of disulfide HMGB1 antagonists to improve outcome of MAS.

Highlights

Macrophage activation syndrome (MAS) is a severe and potentially lifethreatening complication of systemic inflammatory disorders
MAS typically appears in patients with systemic onset juvenile idiopathic arthritis (SoJIA) and its adult equivalent, adult-onset Still disease [1]; it is reported in other pediatric inflammatory disorders including juvenile systemic lupus erythematosus (SLE) [2] and
MAS were studied retrospectively regarding systemic overall High mobility group box 1 (HMGB1) levels and the kinetic expression of systemic HMGB1 isoforms generated by posttranslational modifications in particular

Summary

Introduction

Macrophage activation syndrome (MAS) is a severe and potentially lifethreatening complication of systemic inflammatory disorders. MAS typically appears in patients with systemic onset juvenile idiopathic arthritis (SoJIA) and its adult equivalent, adult-onset Still disease [1]; it is reported in other pediatric inflammatory disorders including juvenile systemic lupus erythematosus (SLE) [2] and Kawasaki disease [3]. MAS expresses a close clinical resemblance to a group of histiocytic cell disorders collectively known as hemophagocytic lymphohistiocytosis (HLH). MAS is classified among the secondary, or acquired forms of HLH [4,5]. Primary HLH is a genetic disorder of immune regulation caused by mutations in genes encoding proteins required for the cytolytic activity exerted by NK cells and cytotoxic T cells [6]. Impaired cytolytic capacity is postulated as a key event in the RESEARCH ARTICLE

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