Activation of Autoreactive B Cells by CpG dsDNA

Viglianti, Gregory A.; Lau, Christina M.; Hanley, Timothy M.; Miko, Benjamin A.; Shlomchik, Mark J.; Marshak‐Rothstein, Ann

doi:10.1016/s1074-7613(03)00323-6

Cited by 481 publications

(477 citation statements)

References 41 publications

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Section: Introductionmentioning

confidence: 69%

“…These in vivo results provide a strong basis for the hypothesis that pathogenic antibodies in SLE become targeted to nuclear antigens because the nuclear antigens are themselves stimulators of the immune system via TLR [24,25]. This is further supported by evidence in vitro that chromatin-containing IC directly stimulate autoreactive B cell proliferation via TLR9 [26,27], and that RNA-associated proteins cause DC and monocyte secretion of type I IFN, TNF-a and IL-12 via TLR7 and TLR8 [28]-The evidence for involvement of TLR in autoimmunity and the fact that transgenic Lyn-deficient B cells are able to class switch to IgG isotypes by a mechanism that does not obviously require the presence of self antigen [29] has now led us to explore the requirement for TLR signaling in the Lyn-deficient lupus model. To do this, we generated Lyn-deficient (lyn -/-) mice that were also deficient in MyD88 on a uniform C57BL/6 (B6) genetic background and analyzed these mice alongside lyn -/-and WT littermates.…”

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confidence: 69%

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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: Introductionmentioning

confidence: 69%

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confidence: 69%

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

et al. 2007

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“…Toll-like receptor 9 (TLR-9) has recently been implicated in the activation of autoreactive B cells in murine models of systemic lupus erythematosus (SLE) (1)(2)(3). Its recognition of CpG nucleotide sequences appears to enhance the activation of B cells via the B cell receptor (1)(2)(3).…”

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confidence: 99%

“…Its recognition of CpG nucleotide sequences appears to enhance the activation of B cells via the B cell receptor (1)(2)(3). Subsequent studies in humans have shown that dendritic cells are activated by chromatin immune complexes and that this effect is mediated by a cooperation between TLR-9 and Fc␥ receptors (4,5).…”

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confidence: 99%

Genetic variation in toll‐like receptor 9 and susceptibility to systemic lupus erythematosus

Jager¹,

Richardson²,

Vyse³

et al. 2006

Arthritis & Rheumatism

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Objective. Autoantibodies produced by differentiated B cells play an important role in the pathogenesis of systemic lupus erythematosus (SLE). The Toll-like receptor 9 (TLR-9) gene has recently emerged as an important costimulatory molecule for both B cells and dendritic cells that respond to chromatin immune complexes. Genetic variation affecting the function of TLR-9 may therefore increase or decrease the threshold of B cell or dendritic cell activation. This variability in activation threshold may, in turn, affect an individual's susceptibility to SLE. This study assessed the role of genetic variation within the TLR-9 gene in susceptibility to SLE.Methods. We genotyped 362 SLE-affected subject/ parent trios for 10 single-nucleotide polymorphisms (SNPs) covering a 68,742-bp genomic segment that contains the TLR-9 gene and ϳ60 kb of flanking sequence. We analyzed the data using the transmission disequilibrium test.Results. There was no association of susceptibility to SLE with any of the 9 SNPs that generated usable data or the 8 haplotypes found at a frequency of >0.05 in this population. When analyzing the subset of 143 subjects with lupus nephritis, there was also no evidence of association between disease susceptibility and any SNP or haplotype. Conclusion. These results indicate that there is no evidence that common (frequency higher than 5%) alleles of the TLR-9 gene contribute significantly to the genetic risk involved in susceptibility to SLE or lupus nephritis.Toll-like receptor 9 (TLR-9) has recently been implicated in the activation of autoreactive B cells in murine models of systemic lupus erythematosus (SLE) (1-3). Its recognition of CpG nucleotide sequences appears to enhance the activation of B cells via the B cell receptor (1-3). Subsequent studies in humans have shown that dendritic cells are activated by chromatin immune complexes and that this effect is mediated by a cooperation between TLR-9 and Fc␥ receptors (4,5). These observations suggest that genetic variation affecting the costimulatory function of TLR-9 could lead to differences in B cell response to autoantigens and dendritic cell response to chromatin immune complexes. Such genetic variation may have an effect on susceptibility to SLE.At the time of completion of our current experiment, another group presented their observation that 4 polymorphisms within a 4,334-bp segment of the TLR-9 gene demonstrated no significant association with susceptibility to SLE in a Korean population (6). We pursued a more comprehensive approach to assessing the role of genetic variation in the vicinity of TLR-9 by genotyping our collection of 362 SLE-affected subject/parent trios from the United Kingdom with single-nucleotide polymorphisms (SNPs) that tag all haplotypes with Ͼ0.05 frequency within a genomic segment, starting 30 kb upstream and ending 30 kb downDr. De Jager is the William C.

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“…Reductions in self-reactivity at this first checkpoint are biased strongly toward B cells that are polyreactive and/or reactive with nuclear antigens (10,18). This bias suggests the action of antigen-or stage-specific tolerance mechanisms, perhaps something similar to the Toll-like receptor/BCR synergy exhibited by B cells reactive with DNA (23). Emigration of vetted transitional B cells into the periphery as new emigrant B cells, and their subsequent maturation, defines the second, peripheral checkpoint of B cell tolerance ( Figure 1).…”

Section: Garnett Kelsoementioning

confidence: 99%

B cell tolerance: Putting the horse before the cart

Kelsoe¹

2011

Arthritis & Rheumatism

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Activation of Autoreactive B Cells by CpG dsDNA

Cited by 481 publications

References 41 publications

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

Genetic variation in toll‐like receptor 9 and susceptibility to systemic lupus erythematosus

B cell tolerance: Putting the horse before the cart

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