The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20081165
The Journal of Experimental Medicine, Vol. 205, No. 13, 3007-3018
The Rockefeller University Press, 0022-1007 $30.00
© Urbonaviciute et al.
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ARTICLE

 Induction of inflammatory and immune responses by HMGB1–nucleosome complexes: implications for the pathogenesis of SLE

Vilma Urbonaviciute1, Barbara G. Fürnrohr1, Silke Meister1, Luis Munoz2, Petra Heyder1, Francesco De Marchis3, Marco E. Bianchi3, Carsten Kirschning4, Hermann Wagner4, Angelo A. Manfredi3, Joachim R. Kalden2, Georg Schett2, Patrizia Rovere-Querini3, Martin Herrmann2, and Reinhard E. Voll1,2

1 Interdisciplinary Center of Clinical Research (IZKF), Research Group N2, Nikolaus Fiebiger Center of Molecular Medicine, and 2 Department of Internal Medicine 3, Rheumatology and Immunology, University Hospital Erlangen, University of Erlangen-Nuremberg, 91054 Erlangen, Germany
3 Istituto Scientifico San Raffaele and Università Vita-Salute San Raffaele, 20132 Milano, Italy
4 Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, 80333 Munich, Germany

CORRESPONDENCE Reinhard Voll: rvoll{at}molmed.uni-erlangen.de

Autoantibodies against double-stranded DNA (dsDNA) and nucleosomes represent a hallmark of systemic lupus erythematosus (SLE). However, the mechanisms involved in breaking the immunological tolerance against these poorly immunogenic nuclear components are not fully understood. Impaired phagocytosis of apoptotic cells with consecutive release of nuclear antigens may contribute to the immune pathogenesis. The architectural chromosomal protein and proinflammatory mediator high mobility group box protein 1 (HMGB1) is tightly attached to the chromatin of apoptotic cells. We demonstrate that HMGB1 remains bound to nucleosomes released from late apoptotic cells in vitro. HMGB1–nucleosome complexes were also detected in plasma from SLE patients. HMGB1-containing nucleosomes from apoptotic cells induced secretion of interleukin (IL) 1β, IL-6, IL-10, and tumor necrosis factor (TNF) {alpha} and expression of costimulatory molecules in macrophages and dendritic cells (DC), respectively. Neither HMGB1-free nucleosomes from viable cells nor nucleosomes from apoptotic cells lacking HMGB1 induced cytokine production or DC activation. HMGB1-containing nucleosomes from apoptotic cells induced anti-dsDNA and antihistone IgG responses in a Toll-like receptor (TLR) 2–dependent manner, whereas nucleosomes from living cells did not. In conclusion, HMGB1–nucleosome complexes activate antigen presenting cells and, thereby, may crucially contribute to the pathogenesis of SLE via breaking the immunological tolerance against nucleosomes/dsDNA.

Abbreviations used: dsDNA, double-stranded DNA; HMGB1, high mobility group box protein 1; MEF, mouse embryonic fibroblast; pDC, plasmacytoid DC; PEG, polyethylene glycol; RAGE, receptor for advanced glycation end products; SLE, systemic lupus erythematosus; ssDNA, single-stranded DNA; TLR, Toll-like receptor.

© 2008 Urbonaviciute et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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