| RAGE-independent autoreactive B cell activation in response to chromatin and HMGB1/DNA immune complexes. | |
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MedLine Citation:
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PMID: 20014975 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Increasing evidence suggests that the excessive accumulation of apoptotic or necrotic cellular debris may contribute to the pathology of systemic autoimmune disease. HMGB1 is a nuclear DNA-associated protein, which can be released from dying cells thereby triggering inflammatory processes. We have previously shown that IgG2a-reactive B cell receptor (BCR) transgenic AM14 B cells proliferate in response to endogenous chromatin immune complexes (ICs), in the form of the anti-nucleosome antibody PL2-3 and cell debris, in a TLR9-dependent manner, and that these ICs contain HMGB1. Activation of AM14 B cells by these chromatin ICs was inhibited by a soluble form of the HMGB1 receptor, RAGE-Fc, suggesting HMGB1-RAGE interaction was important for this response. To further explore the role of HMGB1 in autoreactive B cell activation, we assessed the capacity of purified calf thymus HMGB1 to bind dsDNA fragments and found that HMGB1 bound both CG-rich and CG-poor DNA. However, HMGB1-DNA complexes could not activate AM14 B cells unless HMGB1 was bound by IgG2a and thereby able to engage the BCR. To ascertain the role of RAGE in autoreactive B cell responses to chromatin ICs, we intercrossed AM14 and RAGE-deficient mice. We found that spontaneous and defined DNA ICs activated RAGE+ and RAGE(- ) AM14 B cells to a comparable extent. These results suggest that HMGB1 promotes B cell responses to endogenous TLR9 ligands through a RAGE-independent mechanism. |
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Authors:
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Ana M Avalos; Kerstin Kiefer; Jane Tian; Sean Christensen; Mark Shlomchik; Anthony J Coyle; Ann Marshak-Rothstein |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Autoimmunity Volume: 43 ISSN: 1607-842X ISO Abbreviation: Autoimmunity Publication Date: 2010 Feb |
Date Detail:
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Created Date: 2010-01-20 Completed Date: 2010-03-18 Revised Date: 2012-10-09 |
Medline Journal Info:
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Nlm Unique ID: 8900070 Medline TA: Autoimmunity Country: England |
Other Details:
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Languages: eng Pagination: 103-10 Citation Subset: IM |
Affiliation:
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Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antigen-Antibody Complex / immunology Autoimmune Diseases / immunology* B-Lymphocytes / immunology* Cell Proliferation Chromatin / immunology DNA / immunology* Flow Cytometry HMGB1 Protein / immunology* Lymphocyte Activation / immunology* Mice Mice, Knockout Mice, Transgenic Mitogen-Activated Protein Kinases / deficiency, immunology* Receptors, Antigen, B-Cell / immunology* Toll-Like Receptor 9 / immunology |
| Grant Support | |
ID/Acronym/Agency:
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P01 AR050256/AR/NIAMS NIH HHS; P01 AR050256-06/AR/NIAMS NIH HHS; R01 AI073722-04/AI/NIAID NIH HHS; R01 AR035230/AR/NIAMS NIH HHS; R01 AR035230-24/AR/NIAMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antigen-Antibody Complex; 0/Chromatin; 0/HMGB1 Protein; 0/Receptors, Antigen, B-Cell; 0/Tlr9 protein, mouse; 0/Toll-Like Receptor 9; 9007-49-2/DNA; EC 2.7.1.-/Stk30 protein, mouse; EC 2.7.11.24/Mitogen-Activated Protein Kinases |
| Comments/Corrections | |
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