High-mobility group box 1 represents a potential marker of disease activity and novel therapeutic target in systemic lupus erythematosus
Article first published online: 19 SEP 2011
© 2011 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine
Volume 270, Issue 4, pages 309–318, October 2011
How to Cite
Urbonaviciute, V. and Voll, R. E. (2011), High-mobility group box 1 represents a potential marker of disease activity and novel therapeutic target in systemic lupus erythematosus. Journal of Internal Medicine, 270: 309–318. doi: 10.1111/j.1365-2796.2011.02432.x
- Issue published online: 19 SEP 2011
- Article first published online: 19 SEP 2011
- Accepted manuscript online: 27 JUL 2011 11:45AM EST
- High-mobility group box 1;
- receptor for advanced glycation end products;
- systemic lupus erythematosus;
- Toll-like receptors
Abstract. Urbonaviciute V, Voll RE (Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen; and University Medical Centre Freiburg, Freiburg/Breisgau; Germany). High-mobility group box 1 represents a potential marker of disease activity and novel therapeutic target in systemic lupus erythematosus (Symposium). J Intern Med 2011; 270: 309–318.
High-mobility group box 1 (HMGB1) protein is a nuclear DNA-binding protein, which functions as an alarmin when released from cells. Recent studies implicate extracellular HMGB1 in the pathogenesis of systemic lupus erythematosus (SLE), a prototypical autoimmune disease characterized by the formation of multiple autoantibodies, especially those directed against nucleosomes and double-stranded (ds)DNA. Elevated concentrations of HMGB1 are observed in sera as well as in skin lesions of patients with lupus. Of importance, serum HMGB1 and anti-HMGB1 autoantibody levels correlate with disease activity. In the blood of patients with SLE, HMGB1 is complexed with nucleosomes, at least partially. Moreover, HMGB1–nucleosome complexes from apoptotic cells activate antigen-presenting cells. Injection of HMGB1–nucleosome complexes into nonautoimmune mice results in the formation of autoantibodies against dsDNA and histones in a Toll-like receptor (TLR) 2-dependent manner. Additionally, HMGB1, as a part of DNA–anti-DNA immune complexes, can interact with receptor for advanced glycation end products (RAGE) on the surface of plasmacytoid dendritic cells and B cells leading to TLR9-dependent interferon (IFN)α release and activation of autoreactive B cells, respectively. HMGB1 attached to neutrophil extracellular traps may contribute to IFNα production by facilitating the recognition of self-nucleic acids. Furthermore, HMGB1, complexed with DNA and pathogenic anti-DNA autoantibodies, activates its receptors, TLR2, TLR4 and RAGE, and may thereby be involved in anti-DNA autoantibody-induced kidney damage in lupus nephritis. Collectively, these findings suggest that HMGB1 is a potential marker of disease activity and, because of its probable involvement in the pathogenesis, a novel therapeutic target in SLE.