Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors.
Autoreactive B cells are present in the lymphoid tissues of healthy individuals, but typically remain quiescent. When this homeostasis is perturbed, the formation of self-reactive antibodies can have serious pathological consequences. B cells expressing an antigen receptor specific for self-immunoglobulin-gamma (IgG) make a class of autoantibodies known as rheumatoid factor (RF). Here we show that effective activation of RF+ B cells is mediated by IgG2a-chromatin immune complexes and requires the synergistic engagement of the antigen receptor and a member of the MyD88-dependent Toll-like receptor (TLR) family. Inhibitor studies implicate TLR9. These data establish a critical link between the innate and adaptive immune systems in the development of systemic autoimmune disease and explain the preponderance of autoantibodies reactive with nucleic acid-protein particles. The unique features of this dual-engagement pathway should facilitate the development of therapies that specifically target autoreactive B cells.
Leadbetter
Elizabeth A
EA
Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Rifkin
Ian R
IR
Hohlbaum
Andreas M
AM
Beaudette
Britte C
BC
Shlomchik
Mark J
MJ
Marshak-Rothstein
Ann
A
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000936:Antigen-Antibody Complex; D000943:Antigens, Differentiation / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology*; D002843:Chromatin / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D003850:Deoxyribonuclease I / Q000378:metabolism; D029721:Drosophila Proteins; D007074:Immunoglobulin G / Q000276:immunology*; D007075:Immunoglobulin M / Q000276:immunology*; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017463:Receptors, Complement 3b / Q000172:deficiency / Q000276:immunology; D017464:Receptors, Complement 3d / Q000172:deficiency / Q000276:immunology; D011971:Receptors, Immunologic / Q000378:metabolism; D012217:Rheumatoid Factor / Q000276:immunology*; D015398:Signal Transduction; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors
D048868:Adaptor Proteins, Signal Transducing; D000936:Antigen-Antibody Complex; D000943:Antigens, Differentiation; D002843:Chromatin; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D017463:Receptors, Complement 3b; D017464:Receptors, Complement 3d; D011971:Receptors, Immunologic; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D012217:Rheumatoid Factor; D003850:Deoxyribonuclease I