RAGE-independent autoreactive B cell activation in response to chromatin and HMGB1/DNA immune complexes.
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.
Avalos
Ana M
AM
Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA.
Kiefer
Kerstin
K
Tian
Jane
J
Christensen
Sean
S
Shlomchik
Mark
M
Coyle
Anthony J
AJ
Marshak-Rothstein
Ann
A
D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002843:Chromatin / Q000276:immunology; D004247:DNA / Q000276:immunology*; D005434:Flow Cytometry; D024243:HMGB1 Protein / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000172:deficiency / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000276:immunology
D000936:Antigen-Antibody Complex; D002843:Chromatin; D024243:HMGB1 Protein; D011947:Receptors, Antigen, B-Cell; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D004247:DNA; C498977:Mok protein, mouse; D020928:Mitogen-Activated Protein Kinases