Chromatin–IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors

Abstract

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.

Induction of interferon‐α production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG

“…TLR-9 is involved in recognition of CpG-containing DNA and induction of IFN␣ (65). Furthermore, activation of B lymphocytes by complexes of chromatin and IgG involved both the B cell receptor and TLR-9 (66). We therefore propose that the activation of NIPC/PDCs by DNA-containing IICs is due to a dual engagement of TLR-9 and Fc␥RIIa.…”

An intrinsic B‐cell defect supports autoimmunity in New Zealand black chromosome 13 congenic mice

“…BCR-mediated endocytosis is required to transfer endogenous TLR ligands to RNA-and DNA-sensing TLRs (including, TLR3, -7, and -9) sequestered in the endosome and initiate effective autoreactive B-cell activation [22][23][24]. As a result, synergistic BCR-TLR signalling could explain why increased titres of anti-Sm/RNP (or snRNP) antibodies are present in B6.NZBc13.dTg (of the nonTg isotype) and older B6.NZBc13 mice (our unpublished observations).…”

“…Recently it has been shown that TLR7 overexpression in mice bearing the Y autoimmune accelerator (Yaa) or a TLR7 Tg leads to increased B-cell proliferation in response to TLR7 ligands in vitro and promotes the differentiation of B cells into anti-RNA antibody-producing cells that augments lupus-like autoimmunity in vivo [20,21]. Our findings demonstrate an association between B-cell TLR3 hyper-responsiveness and antinuclear antibody production in B6.NZBc13 mice, and raise the possibility that genetic polymorphisms leading to altered TLR3 signalling may also produce the lupus phenotype.BCR-mediated endocytosis is required to transfer endogenous TLR ligands to RNA-and DNA-sensing TLRs (including, TLR3, -7, and -9) sequestered in the endosome and initiate effective autoreactive B-cell activation [22][23][24]. As a result, synergistic BCR-TLR signalling could explain why increased titres of anti-Sm/RNP (or snRNP) antibodies are present in B6.NZBc13.dTg (of the nonTg isotype) and older B6.NZBc13 mice (our unpublished observations).…”

Antibody response in MOG35–55 induced EAE

“…SLE is a prototypic autoimmune disease characterized by the production of antibodies to a diverse array of nuclear antigens. While a role for anti-nuclear antibodies in the pathogenesis of SLE is well established, recent data show that anti-DNA and anti-RNA antibodies can activate autoreactive B cells by dual engagement of the B cells receptor (BCR) and TLR9 or TLR7, respectively (Leadbetter et al, 2002;Lau et al, 2005).…”