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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CpG sequences in self-DNA are an important potential trigger for autoantibody secretion in systemic lupus and other systemic autoimmune disorders. It is not known how this ubiquitous threat may be controlled by active mechanisms for maintaining self tolerance. Here we show that two distinct mechanisms oppose autoantibody secretion induced by CpG DNA in anergic B cells that are constantly binding self-antigen. Uncoupling of the antigen receptor (BCR) from a calcineurin-dependent pathway prevents signals that synergize with CpG DNA for proliferation. The BCR does not become desensitized by activating the extracellular response kinase (ERK) MAP kinase pathway, however, and continuous self-antigen signaling to ERK inhibits CpG DNA-induced plasma cell differentiation. These two mechanisms seem to act as a general control against autoantibody production elicited by Toll-like receptors, and their regulation of T cell-independent responses to Toll-like receptor 9 (TLR9) is probably crucial for resistance to systemic autoimmunity.
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PMID:Resistance to CpG DNA-induced autoimmunity through tolerogenic B cell antigen receptor ERK signaling. 1274 May 74

Inadequate immune response to infectious danger may contribute to the pathogenesis of systemic autoimmune diseases, e.g., systemic lupus erythematosus. To test this hypothesis, we studied innate responses of prediseased lupus-prone Palmerston North (PN) mice to lipopolysaccharide (LPS), bacterial DNA, and synthetic CpG oligonucleotides. LPS and bacterial DNA/CpG oligodeoxyribonucleotides (ODNs) drove PN splenocytes into the cell cycle and protected B cells against spontaneous apoptosis, as in control lupus-free DBA-1 mice. LPS induced significantly higher IL-6 production in PN than in control splenocytes. In contrast, in PN splenocytes bacterial DNA and CpG ODNs induced approximately four- to sixfold lower IL-12p40 and approximately twofold lower IL-6 secretion than controls. This reduction in cytokine secretion in PN mice was not due to delayed kinetics but was related to significantly higher constitutive and CpG-inducible IL-10 secretion. Neutralizing anti-IL-10 antibodies almost completely restored PN IL-6 and IL-12p40 secretion to DBA-1 levels, whereas exogenous IL-10 inhibited in vitro IL-6 and IL-12p40 production in DBA-1 mice. Importantly, treatment with either IL-10 or anti-IL-10 antibody did not modulate CpG-induced cell cycle entry and apoptosis protection in either strain. In conclusion, lupus-prone PN mice show abnormal innate responses through their pattern-recognition TLR9 receptors, characterized by higher inducible IL-10 and lower IL-12p40 and IL-6 secretion, thus implying that response to infectious danger in PN mice is inappropriate and may be linked to lupus pathogenesis.
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PMID:Innate immune responses in lupus-prone Palmerston North mice: differential responses to LPS and bacterial DNA/CpG oligonucleotides. 1279 42

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathogenic autoantibodies against nucleoproteins and DNA. Here we show that DNA-containing immune complexes (ICs) within lupus serum (SLE-ICs), but not protein-containing ICs from other autoimmune rheumatic diseases, stimulates plasmacytoid DCs (PDCs) to produce cytokines and chemokines via a cooperative interaction between Toll-like receptor 9 (TLR9) and FcgammaRIIa (CD32). SLE-ICs transiently colocalized to a subcellular compartment containing CD32 and TLR9, and CD32+, but not CD32-, PDCs internalized and responded to SLE-ICs. Our findings demonstrate a novel functional interaction between Fc receptors and TLRs, defining a pathway in which CD32 delivers SLE-ICs to intracellular lysosomes containing TLR9, inducing a signaling cascade leading to PDC activation. These data demonstrate that endogenous DNA-containing autoantibody complexes found in the serum of patients with SLE activate the innate immune system and suggest a novel mechanism whereby these ICs contribute to the pathogenesis of this autoimmune disease.
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PMID:Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. 1566 40

Several types of CpG-oligodeoxynucleotides (ODN) have been recently characterized. In mice, type A(D) CpG-ODNs primarily stimulate macrophages and dendritic cells, but fail to stimulate B cells. On the contrary, type B(K) CpG-ODNs are excellent B cell activators. Type C CpG-ODNs combine features of both types A(D) and B(K) CpG-ODNs. Despite cell type preferences, all CpG-ODNs require the presence of TLR9 for activation. In this study, we show that a subset of B cells from lupus mice responds to type A(D) CpG-ODN stimulation vigorously and directly with increased CD25 and CD86 expression and IL-10 secretion. Furthermore, these CpG-ODNs induce high surface IgM expression and promote 50- to 100-fold higher IgM and IgG3 secretion in lupus B cells than in controls. This response is similar to that seen with bacterial DNA stimulation of B cells. Type A(D)-responsive cells are enriched within lupus B cells with the marginal zone (MZ) phenotype. These cells are at least twice more numerous in lupus mice than in controls. The ability of lupus B cells to respond to type A(D) CpG-ODN stimulation is not due to differential TLR9 expression. Therefore, type A(D) CpG-ODNs may contribute to the lupus pathogenesis by inducing MZ-B cell activation, costimulatory molecule expression, and polyclonal Ig secretion. Through increased IL-10 secretion, MZ-B cells may also modify the activity of other cell types, particularly dendritic cells and macrophages.
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PMID:Activation of marginal zone B cells from lupus mice with type A(D) CpG-oligodeoxynucleotides. 1569 80

Recent studies have shed new light on a possible link between the innate activation of plasmocytoid dendritic cells and marginal zone B cells and the pathogenesis of systemic lupus erythematosus. Animal studies have identified that this response requires the Toll-like receptor 9 (TLR9). Engagement of the TLR9 by various ligands, including non-canonical CpG-motifs, can cause or aggravate pathogenic autoantibody production and cytokine secretion in lupus. Attempts to neutralize this activity either by blocking the acidification of the endosomal compartment with chloroquine and related compounds, or by preventing the interaction between the CpG-DNA sequences and TLR9 using inhibitory oligonucleotides could be a promising therapeutic option for lupus.
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PMID:Inhibitory oligodeoxynucleotides - therapeutic promise for systemic autoimmune diseases? 1576 69

Systemic autoimmune disease in humans and mice is characterized by loss of immunologic tolerance to a restricted set of self-nuclear antigens. Autoantigens, such as double-stranded (ds) DNA and the RNA-containing Smith antigen (Sm), may be selectively targeted in systemic lupus erythematosus because of their ability to activate a putative common receptor. Toll-like receptor 9 (TLR9), a receptor for CpG DNA, has been implicated in the activation of autoreactive B cells in vitro, but its role in promoting autoantibody production and disease in vivo has not been determined. We show that in TLR9-deficient lupus-prone mice, the generation of anti-dsDNA and antichromatin autoantibodies is specifically inhibited. Other autoantibodies, such as anti-Sm, are maintained and even increased in TLR9-deficient mice. In contrast, ablation of TLR3, a receptor for dsRNA, did not inhibit the formation of autoantibodies to either RNA- or DNA-containing antigens. Surprisingly, we found that despite the lack of anti-dsDNA autoantibodies in TLR9-deficient mice, there was no effect on the development of clinical autoimmune disease or nephritis. These results demonstrate a specific requirement for TLR9 in autoantibody formation in vivo and indicate a critical role for innate immune activation in autoimmunity.
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PMID:Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus. 1602 40

Toll-like receptor (TLR)-9 recognizes CpG motifs in microbial DNA. TLR9 signalling stimulates innate antimicrobial immunity and modulates adaptive immune responses including autoimmunity against chromatin, e.g., in systemic lupus erythematosus (SLE). This review summarizes the available data for a role of TLR9 signalling in lupus and discusses the following questions that arise from these observations: 1) Is CpG-DNA/TLR9 interaction involved in infection-induced disease activity of lupus? 2) What are the risks of CpG motifs in vaccine adjuvants for lupus patients? 3) Is TLR9 signalling involved in the pathogenesis of lupus by recognizing self DNA?
Lupus 2005
PMID:A Toll for lupus. 1603 3

Raised serum levels of interferon (IFN)-alpha have been observed in systemic lupus erythematosus (SLE) patients, and these levels are correlated with both disease activity and severity. The origin of this IFN-alpha is still unclear, but increasing evidence suggests the critical involvement of activated plasmacytoid predendritic cells (PDCs). In SLE patients, DNA and RNA viruses, as well as immune complexes (ICs), that consist of autoantibodies specific to self-DNA and RNA protein particles can stimulate production of IFN-alpha. We have developed three series of oligonucleotide (ODN)-based inhibitors of Toll-like receptor (TLR) signaling. These ODNs include inhibitors of TLR9, inhibitors of TLR7 but not TLR9, and sequences that inhibit both TLR7 and TLR9. Specificity of these inhibitors is confirmed by inhibition of IFN-alpha production by PDCs in response to DNA or RNA viruses. We show that mammalian DNA and RNA, in the form of ICs, are potent self-antigens for TLR9 and TLR7, respectively, and induce IFN-alpha production by PDCs. This work suggests that TLRs may have a critical role in the promotion of lupus through the induction of IFN-alpha by PDCs. These inhibitors of TLR signaling thus represent novel therapeutic agents with potential for the treatment of lupus.
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PMID:Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. 1623 Apr 78

This review focuses on the role of Toll-like receptors (TLRs) in lupus and on possibilities to treat lupus using TLR modulating inhibitory oligodeoxynucleotides (INH-ODNs). TLRs bridge innate and adaptive immune responses and may play an important role in the pathogenesis of systemic lupus erythematosus. Of particular interest are TLR3, -7, -8, and -9, which are localized intracellularly. These TLRs recognize single-stranded or double-stranded RNA or hypomethylated CpG-DNA. Exposure to higher order CpG-DNA ligands or to immune complexed self-RNA triggers activation of autoreactive B cells and plasmacytoid dendritic cells. INH-ODNs were recently developed that block all downstream signaling events in TLR9-responsive cells. Some of these INH-ODNs can also target TLR7 signaling pathways. Based on their preferential cell reactivity, we classify INH-ODNs into class B and class R. Class B ('broadly reactive') INH-ODNs target a broad range of TLR-expressing cells. Class R ('restricted') INH-ODNs easily form DNA duplexes or higher order structures, and are preferentially recognized by autoreactive B cells and plasmacytoid dendritic cells, rather than by non-DNA specific follicular B cells. Both classes of INH-ODNs can block animal lupus. Hence, therapeutic application of these novel INH-ODNs in human lupus, particularly class R INH-ODNs, may result in more selective and disease-specific immunosuppression.
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PMID:Targeting Toll-like receptor signaling in plasmacytoid dendritic cells and autoreactive B cells as a therapy for lupus. 1654 67

Mouse follicular B cells express TLR9 and respond vigorously to stimulation with single-stranded CpG-oligodeoxynucleotides (ODN). Surprisingly, follicular B cells do not respond to direct stimulation with other TLR9 ligands, such as bacterial DNA or class A(D) CpG-ODN capable of forming higher-order structures, unless other cell types are present. Here, we show that priming with interferons or with B cell-activating factor, or simultaneous co-engagement of the B cell receptor for antigen (BCR), can overcome this unresponsiveness. The effect of interferons occurs at the transcriptional level and is mediated through an autocrine/paracrine loop, which is dependent on IRF-1, IL-6 and IL-12 p40. We hypothesize that the lack of bystander activation of follicular B cells with more complex CpG ligands may be an important safety mechanism for avoiding autoimmunity. This will prevent resting B cells from responding to foreign or self-derived hypomethylated double-stranded CpG ligands unless these ligands are either delivered through the B cell receptor or under conditions where B cells are simultaneously co-engaged by activated plasmacytoid dendritic cells or TH1 cells. A corollary is that the heightened responsiveness of lupus B cells to TLR9-induced stimulation cannot be ascribed to unprimed follicular B cells, but is rather mediated by hypersensitive marginal zone B cells.
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PMID:Higher-order CpG-DNA stimulation reveals distinct activation requirements for marginal zone and follicular B cells in lupus mice. 1679 98


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