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

被引：443

作者：

Urbonaviciute, Vilma ^{[1
]}

Fuernrohr, Barbara G. ^{[1
]}

Meister, Silke ^{[1
]}

Munoz, Luis ^{[2
]}

Heyder, Petra ^{[1
]}

De Marchis, Francesco ^{[3
,4
]}

Bianchi, Marco E. ^{[3
,4
]}

Kirschning, Carsten ^{[5
]}

Wagner, Hermann ^{[5
]}

Manfredi, Angelo A. ^{[3
,4
]}

Kalden, Joachim R. ^{[2
]}

Schett, Georg ^{[2
]}

Rovere-Querini, Patrizia ^{[3
,4
]}

Herrmann, Martin ^{[2
]}

Voll, Reinhard E. ^{[1
,2
]}

机构：

[1] Univ Erlangen Nurnberg, Nikolaus Fiebiger Ctr Mol Med, Res Grp N2, Interdisciplinary Ctr Clin Res IZKF, D-91054 Erlangen, Germany

[2] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Internal Med Rheumatol & Immunol 3, D-91054 Erlangen, Germany

[3] Ist Sci San Raffaele, I-20132 Milan, Italy

[4] Univ Vita Salute San Raffaele, I-20132 Milan, Italy

[5] Tech Univ Munich, Inst Med Microbiol Immunol & Hyg, D-80333 Munich, Germany

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2008年 / 205卷 / 13期

关键词：

D O I：

10.1084/jem.20081165

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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) 1 beta, 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.

引用

页码：3007 / 3018

页数：12

共 79 条

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