Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus

Christensen, Sean R.; Kashgarian, Michael; Alexopoulou, Lena; Flavell, Richard A.; Akira, Shizuo; Shlomchik, Mark J.

doi:10.1084/jem.20050338

Cited by 482 publications

(420 citation statements)

References 72 publications

(84 reference statements)

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“…A role for MyD88-dependent TLR signaling in the development of pathogenic ANA is supported by evidence from murine models and in vitro systems [18,19,[43][44][45]. Our results show that the generation of autoAb in Lyn-deficient mice is also dependent on MyD88-mediated signaling.…”

Section: Discussionsupporting

confidence: 69%

“…Thus, only chromatincontaining IC that engaged both autoreactive BCR and the dsDNA-specific TLR9 receptor were capable of initiating a full response of B cell proliferation and/or isotype class switching. In vivo evidence for dependence on dual receptor ligation was obtained with MRL-lpr/lpr mice: TLR9-deficient mice do not produce anti-dsDNA antibodies but still produce antibodies to small nuclear ribonucleoproteins (Sm antigens) and vice versa for TLR7-deficient mice [19,20]. Only MRL-lpr/gld mice that are MyD88-deficient and therefore unable to signal via both TLR9 or TLR7 have complete reduction of ANA and anti-Sm antibody production [19,45].…”

Section: Discussionmentioning

confidence: 99%

“…In vivo evidence for dependence on dual receptor ligation was obtained with MRL-lpr/lpr mice: TLR9-deficient mice do not produce anti-dsDNA antibodies but still produce antibodies to small nuclear ribonucleoproteins (Sm antigens) and vice versa for TLR7-deficient mice [19,20]. Only MRL-lpr/gld mice that are MyD88-deficient and therefore unable to signal via both TLR9 or TLR7 have complete reduction of ANA and anti-Sm antibody production [19,45]. This suggests that only B cells and T cells with specificity for nuclear antigens are stimulated by the nuclear components that are also endogenous TLR ligands.…”

Section: Discussionmentioning

confidence: 99%

“…Disease in the gp96 transgenic mice is dependent on MyD88, an adaptor molecule required for signaling by all TLR except TLR3, which binds dsRNA, and TLR4, which also signals by a MyD88-independent pathway. The association of TLR signaling with autoimmunity is strengthened by the findings that deficiency in TLR9, which recognizes bacterial CpG DNA and some mammalian DNA sequences, or TLR7, which binds ssRNA, reduces the number of antibodies against dsDNA or RNA-associated antigens, respectively, in lpr/lpr mice on MRL, C57BL/6 or mixed backgrounds [19,20]. Likewise, mice deficient in the inhibitory Fcc receptor, FccRIIb, also develop ANA, including anti-dsDNA antibodies, and fatal kidney disease unless deficient in TLR9 or MyD88 signaling [21].…”

Section: Introductionmentioning

confidence: 99%

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MyD88‐dependent autoimmune disease in Lyn‐deficient mice

et al. 2007

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Recent evidence suggests that systemic autoimmune disease depends on signals from TLR ligands, but little is known about how TLR-dependent pathways lead to the loss of self tolerance in vivo. To address this, we have examined the role of TLR signaling in Lyndeficient mice, which develop an autoimmune disease similar to SLE. We found that absence of the TLR signaling adaptor molecule MyD88 suppresses plasma cell differentiation of switched and unswitched B cells, and prevents the generation of antinuclear IgG antibodies and glomerulonephritis. In mixed chimeras the increased IgM and IgG antibody secretion in Lyn-deficient mice is at least partially due to B cellindependent effects of Lyn. We now show that MyD88 deficiency blocks the expansion and activation of DC in which Lyn is also normally expressed, and prevents the hypersecretion of proinflammatory cytokines IL-6 and IL-12 by Lyn-deficient DC. These findings further highlight the important role of TLR-dependent signals in both lymphocyte activation and autoimmune pathogenesis. IntroductionOur understanding of the pathways leading to autoantibody (autoAb) production in systemic lupus erythematosus (SLE) has been greatly enhanced by studies of murine SLE models, including mice with single targeted mutations to negative regulators of BCR signaling, e.g., the src-family protein tyrosine kinase Lyn [1][2][3], phosphatase SHP-1 [4] and coreceptor CD22 [5, 6]. Lyn deficiency manifests as the hypersecretion of IgM, IgA and IgG autoAb, which, by 17-20 weeks of age, develop specificity to nuclear components such as dsDNA, are deposited as immune complexes (IC) in the kidneys and lead to lethal proliferative glomerulonephritis [1][2][3]. Following BCR stimulation, Lyn-deficient B cells have greater and more prolonged intracellular calcium flux, more MAPK activation and hyperproliferate in comparison to WT B cells [1, 7, 8]. These findings, together with the fact that the expression of Lyn is limited to B, NK and myeloid cells [9], have led to the suggestion that B cell intrinsic effects are the main cause of SLE-like autoimmune disease. Growing support for the central role B cells play in the development of autoimmune disease (reviewed in [10]) and the discovery of lower levels of Lyn in B cells of human SLE patients have helped strengthen this idea [11].However, the development of high-affinity pathogenic autoAb, which are targeted at nuclear antigens and potentially damaging to organs including kidneys, depends on somatic hypermutation in the germinal center and collaboration between cells of the adaptive and innate immune systems. T cells play an important role in this process and autoantigen-specific T cells are required for secretion of IgG autoAb specific for nuclear components and end-organ damage in the spontaneous murine models, MRL-lpr/lpr and (NZBÂNZW)F 1 [18]. Disease in the gp96 transgenic mice is dependent on MyD88, an adaptor molecule required for signaling by all TLR except TLR3, which binds dsRNA, and TLR4, which also signals by a MyD88-independent pa...

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MyD88‐dependent autoimmune disease in Lyn‐deficient mice

et al. 2007

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“…This could be either because the D42 antibody does not belong to the group of "pathogenic" anti-DNA autoantibodies that induce glomerular deposition and proteinuria [37]; alternatively, there are likely to be additional genetic factors(s) which precipitate overt clinical disease and can be dissociated from the production of anti-DNA antibodies in lupus-prone mice, as recently suggested by several genetic and functional studies [6,38,39].…”

Section: Discussionmentioning

confidence: 99%

Peripheral B cell receptor editing may promote the production of high‐affinity autoantibodies in CD22‐deficient mice

et al. 2006

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CD22-deficient mice are characterized by B cell hyperactivity and autoimmunity. We have constructed knock-in CD22 -/-mice, expressing an anti-DNA heavy (H) chain (D42), alone or combined with Vj1-Jj1 or Vj8-Jj5 light (L) chains. The Ig-targeted mice produced a lupus-like serology that was age-and sex-dependent. High-affinity IgG autoantibodies were largely dependent on the selection of B cells with a particular H/L combination, in which a non-transgenic, endogenous L chain was assembled by secondary rearrangements through the mechanism of receptor editing. Moreover, we present evidence that these secondary rearrangements are very prominent in splenic peripheral B cells. Since CD22 is primarily expressed on the surface of peripheral B cells, we propose a model for the development of a lupus-like autoimmune disease by a combination of peripheral receptor editing and abnormal B cell activation. IntroductionSystemic lupus erythematosus (SLE) is a rheumatic disease of unknown etiology, usually occurring in young women of childbearing age. The presence of serum antibodies to a variety of self components and their possible involvement in the development of severe kidney disease (glomerulonephritis) has made SLE a prototype of systemic autoimmune diseases [1]. The autoantibodies in lupus sera react with a large variety of nuclear antigens, including DNA, RNA and nuclear proteins. The antibodies to dsDNA are mostly highaffinity IgG that appear almost exclusively in SLE and very rarely in other diseases [2, 3].Several mouse models which spontaneously develop a lupus-like disease have been studied extensively [4]. The NZB/NZW F1 mouse is considered to be the murine model most closely resembling human SLE [5]. The lupus-like disease in these mice is more severe in females and is accompanied by high-affinity IgG anti-dsDNA autoantibodies. Both NZB and NZW parents contribute multiple susceptibility genes to the immune abnormalities of the F1 hybrid mouse [6]. Additional mouse models of SLE include mouse strains with deficiencies in antigen disposal mechanisms and mice that are deficient in proteins regulating the thresholds for tolerance and activation of B and T lymphocytes [7].CD22 is a B cell-specific surface glycoprotein of the Ig superfamily expressed on mature B cells [8, 9]. It functions as an adhesion molecule, as a signal-transducing molecule and as a modulator of intracellular signaling through the B cell receptor (BCR) complex. Negative regulatory roles for CD22 in BCR signaling are proposed to be critical for normal B cell activation, since immunoreceptor tyrosine-based inhibitory motifs with- in CD22 recruit SHP-1, a potent intracellular phosphatase with inhibitory functions in BCR signaling [10,11]. CD22-deficient mice [12][13][14][15] were reported to have decreased numbers of circulating B cells and slightly increased numbers of peritoneal B-1 cells, as well as higher levels of serum IgM [12,14]. Significantly, mature B cells from CD22-deficient mice had decreased expression of cell surface IgM and augmented i...

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DNA Origami Nanorobots

Bachelet

2014

Encyclopedia of Molecular Cell Biology and Molecular Medicine

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Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus

Cited by 482 publications

References 72 publications

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

Peripheral B cell receptor editing may promote the production of high‐affinity autoantibodies in CD22‐deficient mice

DNA Origami Nanorobots

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