Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human toll-like receptors (TLRs) participate in the innate response and signal the activation of adaptive immunity. Therefore, these TLRs may be important in autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We investigated, by using a polymerase chain reaction restriction-fragment length polymorphism method, the possible association between the polymorphisms of TLR2 (Arg677Trp and Arg753Gln) and TLR4 (Asp299Gly and Thr399Ile) genes with the susceptibility or severity of RA and SLE. Our study population consisted of 122 patients with SLE, 224 patients with RA, and a control group of 199 healthy individuals. The TLR2 polymorphisms were very rare in our population; no individual carrying the TLR2-Arg677Trp polymorphism was observed, whereas the TLR2-Arg753Gln polymorphism was present in only 1% of the total population. We found no statistically significant differences in the TLR4-Asp299Gly and the TLR4-Thr399Ile genotype or allele distribution between SLE patients, RA patients, and control individuals. Similarly, no association was found with any of the demographic and clinical parameters tested either in RA or in SLE patients. In conclusion, a case-control study was used to analyze, for the first time, the influence of TLR2 and TLR4 gene polymorphism on the predisposition and clinical characteristics of SLE and RA but provided no evidence for association of TLR2 or TLR4 gene polymorphism with either disease in the population under study.
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PMID:Polymorphisms of toll-like receptor 2 and 4 genes in rheumatoid arthritis and systemic lupus erythematosus. 1465 24

Toll-like receptors (TLR) recognize bacterial and viral components, but direct interaction of receptor and ligand is unclear. Here, we demonstrate that TLR9 binds directly and sequence-specifically to single-stranded unmethylated CpG-DNA containing a phosphodiester backbone. TLR9-CpG-DNA interaction occurs at the acidic pH (6.5-5.0) found in endosomes and lysosomes. By sequence comparison we identified a potential CpG-DNA binding domain homologous to that described for methyl-CpG-DNA binding proteins. Amino acid substitutions in this region abrogated CpG-DNA binding and led to loss of NF-kappaB activation. Furthermore, chloroquine and quinacrine, therapeutic agents for autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus, directly blocked TLR9-CpG-DNA interaction but not TLR2-Pam3Cys binding. Our results demonstrate direct binding of TLR9 to CpG-DNA and suggest that the therapeutic activity of chloroquine and quinacrine in autoimmune diseases may be due to its activity as a TLR9 antagonist and inhibitor of endosomal acidification.
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PMID:Toll-like receptor 9 binds single-stranded CpG-DNA in a sequence- and pH-dependent manner. 1530 86

The nucleosome is a major autoantigen in systemic lupus erythematosus (SLE); it can be detected as a circulating complex in the serum, and nucleosomes have been suggested to play a key role in disease development. In the present study, we show for the first time that physiological concentrations of purified nucleosomes trigger innate immunity. The nucleosomes are endocytosed and induce the direct activation of human neutrophils (polymorphonuclear leukocytes (PMN)) as revealed by CD11b/CD66b up-regulation, IL-8 secretion, and increased phagocytic activity. IL-8 is a neutrophil chemoattractant detected in high concentrations in the sera of patients, and IL-8 secretion might thus result in enhanced inflammation, as observed in lupus patients, via an amplification loop. Nucleosomes act as free complexes requiring no immune complex formation and independently of the presence of unmethylated CpG DNA motifs. Both normal and lupus neutrophils are sensitive to nucleosome-induced activation, and activation is not due to endotoxin or high-mobility group box 1 contamination. In mice, i.p. injection of purified nucleosomes induces neutrophil activation and recruitment in a TLR2/TLR4-independent manner. Importantly, neutrophils have been suggested to link innate and adaptive immunity. Thus, nucleosomes trigger a previously unknown pathway of innate immunity, which may partially explain why peripheral tolerance is broken in SLE patients.
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PMID:TLR2/TLR4-independent neutrophil activation and recruitment upon endocytosis of nucleosomes reveals a new pathway of innate immunity in systemic lupus erythematosus. 1711 45

Recent studies in animal models for systemic lupus erythematosus (SLE) have shown that Toll-like receptors (TLR-7 and TLR-9) and interferon (IFN)-alpha are involved in the pathogenesis of murine lupus. Recent studies using flow cytometry have also shown increased expression of TLR-9 in peripheral blood mononuclear cells (PBMCs) from SLE patients. In this study, we performed quantitative real-time reverse transcription-polymerase chain reaction analyses of PBMCs from 21 SLE patients and 21 healthy subjects, to estimate TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, TLR9, IFN-alpha and LY6E (a type I IFN-inducible gene) mRNA expression levels. Expression levels of TLR2, TLR7, TLR9, IFN-alpha and LY6E mRNAs in SLE patients were significantly higher than those in healthy controls. Expression levels of TLR7 and TLR9 mRNAs correlated with that of IFN-alpha mRNA in SLE patients. These results suggest that up-regulated expression of TLR7 and TLR9 mRNAs together with increased expression of IFN-alpha mRNA in PBMCs may also contribute to the pathogenesis of human lupus.
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PMID:Up-regulated expression of Toll-like receptors mRNAs in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. 1837 99

Toll-like receptors (TLRs) have caught the attention of rheumatologists searching for additional therapeutic targets for diseases such as rheumatoid arthritis and systemic lupus erythematosus. Signaling from these molecules can induce the expression of cytokines such as tumor necrosis factor and interferon alpha. Strategies that target TLRs and their co-receptors (such as MD2 for TLR4 or CD36 for TLR2) might be a more-selective approach than inhibition of global signals such as nuclear factor kappaB or p38 mitogen-activated protein kinase. TLR signaling requires adaptor proteins, including MyD88, Mal, TRIF and TRAM, which are recruited to specific receptors: Mal is used only by TLR2 and TLR4, TRIF is used by TLR3 and TLR4, and TRAM is recruited by TLR4 alone. Mal and TRAM are subject to complex biochemical regulation. Inhibition of Mal or MyD88 blocks the production of inflammatory mediators in synovial tissue. Another possible intracellular target is Unc93b, a protein involved in signaling from TLR3, TLR7 and TLR9. Inhibition of TLR4, TLR7 and TLR9 has produced intriguing results, which indicate that TLRs and their signaling pathways might indeed have great potential as novel targets for the treatment of inflammatory joint disease.
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PMID:Primer: Toll-like receptor signaling pathways--what do rheumatologists need to know? 1844 39

Toll-like receptors (TLRs) have a crucial role in sensing microbial products and triggering immune responses. Recent reports have indicated that TLR7 and TLR9 have an important role in activating autoreactive B cells. In addition to TLR7 and TLR9, mouse B cells express TLR2, TLR4 and structurally related Radioprotective105 (RP105). We have previously shown that RP105 works in concert with TLR2/4 in antibody response to TLR2/4 ligands. We here report that B cells are constitutively activated by TLR2/4 and RP105. Such B cell activation was revealed by the gamma3 germ line transcript and serum IgG3 production, both of which were impaired by the lack of RP105 or TLR2/4. Serum IgG3 was not altered in germ-free or antibiotics-treated mice, suggesting that the microbial flora hardly contributes to the continuous activation of B cells. The lack of RP105-dependent B cell activation ameliorated disease progression in lupus-prone MRL/lpr mice. RP105(-/-) MRL/lpr mice showed less lymphoadenopathy/splenomegaly and longer survival than MRL/lpr mice. Whereas glomerulonephritis and auto-antibody production were not altered, improvement in blood urea nitrogen and lower incidence of renal arteritis indicated that renal function was ameliorated in the absence of RP105. Our results suggest that RP105-dependent tonic B cell activation has a pathogenic role in MRL/lpr mice.
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PMID:Tonic B cell activation by Radioprotective105/MD-1 promotes disease progression in MRL/lpr mice. 1849 57

Although anti-DNA antibodies have been decisively linked to the pathogenesis of lupus nephritis, the mechanisms have not been conclusively determined. Recently, we reported that anti-DNA antibodies may contribute to kidney damage by upregulation of proinflammatory genes in mesangial cells (MC), a process involving both Fc receptor-dependent and independent pathways. In investigating the mechanism by which pathogenic anti-DNA antibodies modulate gene expression in MC, we found that the pathogenic anti-DNA antibody 1A3F bound to high mobility group binding protein 1 (HMGB1), an endogenous ligand for TLR2/4 and RAGE (receptor for advanced glycation end products). Interestingly, HMGB1 treatment of MC induced a similar pattern of genes as stimulation with 1A3F. Furthermore, HMGB1 and 1A3F exhibited a synergistic proinflammatory effect in the kidney, where increased expression of HMGB1 was found in lupus patients but not in patients with other types of renal disease. TLR2/Fc and RAGE/Fc inhibited the proinflammatory effects of 1A3F on MC. Finally, we found enhanced susceptibility of lupus prone MRL-lpr/lpr (MRL/lpr) as compared to normal BALB/c derived MC to pathogenic anti-DNA antibody and LPS stimulation (in particular enhanced chemokine synthesis), in addition to significantly increased expression of TLR4. Our results suggest that gene upregulation in MC induced by nephritogenic anti-DNA antibodies is TLR2/4 and RAGE-dependent. Finally, HMGB1 may act as a proinflammatory mediator in antibody-induced kidney damage in systemic lupus erythematosus (SLE).
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PMID:Pathogenic anti-DNA antibodies modulate gene expression in mesangial cells: involvement of HMGB1 in anti-DNA antibody-induced renal injury. 1882 17

The author provides a critical analysis of systemic lupus erythematosus associated with tuberculosis. A brief review of the lupus-tuberculosis association is also given, and stresses that extra-pulmonary TB is the most usual form of TB in these cases. Other issues considered are the heat shock proteins of Mycobacterium tuberculosis HSP70KDa and HSP65KDa families and TLR2, TLR4, TLR9 that can be involved in interaction between bacilli antigen and host tissue causing autoimmune induction by lupus. The author concludes that early diagnosis and appropriate management are mandatory in SLE associated with TB, in areas where TB is endemic.
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PMID:[Systemic lupus erythematosus association with tuberculosis - critical review]. 1902 98

Detection of bacterial CpG-containing DNA (CpG DNA) by innate immune cells is dependent on toll-like receptor 9 (TLR9). Here we show that the expression of tlr9 mRNA was induced in mouse bone marrow-derived macrophages (BMMs) upon infection with the facultative Gram-negative intracellular bacterium Salmonella enterica serovar Typhimurium (S. typhimurium). Treatment of BMM with the inhibitory oligonucleotide (ODN) 2114, an antagonist of TLR9 signalling, enhanced intracellular S. typhimurium numbers approximately fivefold, whereas a control ODN (2310) had no significant effect. Surprisingly, 2114 also amplified S. typhimurium bacterial loads in TLR9-deficient BMM. Indeed, 2114 suppressed responses (nuclear factor-kappaB-dependent reporter gene expression and interleukin-12p40 secretion) to not only CpG DNA, but also the TLR2 ligand Pam(3)Cys, in BMM and RAW264 cells in a sequence-specific manner. Inhibitory ODNs, which have been proposed as therapeutic agents for the treatment of systemic lupus erythematosus because of their inhibitory effects on TLR9 signalling, may thus compromise the host response to bacterial pathogens through TLR9-independent mechanisms.
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PMID:TLR9-independent effects of inhibitory oligonucleotides on macrophage responses to S. typhimurium. 1904 19

What are the molecular mechanisms of bacterial infections triggering or modulating lupus nephritis? In nephritic MRL(lpr/lpr) mice, transient exposure to bacterial cell wall components such as lipopeptide or lipopolysaccharide (LPS) increased splenomegaly, the production of DNA autoantibodies, and serum interleukin (IL)-6, IL-12 and tumour necrosis factor (TNF) levels, and aggravated lupus nephritis. Remarkably, bacterial lipopeptide induced massive albuminuria in nephritic but not in non-nephritic mice. This was associated with down-regulation of renal nephrin mRNA and redistribution from its normal localization at foot processes to the perinuclear podocyte area in nephritic MRL(lpr/lpr) mice. Bacterial lipopeptide activates Toll-like receptor 2 (TLR2), which we found to be expressed on cultured podocytes and glomerular endothelial cells. TNF and interferon (IFN)-gamma induced TLR2 mRNA and receptor expression in both cell types. Albumin permeability was significantly increased in cultured podocytes and glomerular endothelial cells upon stimulation by bacterial lipopeptide. LPS also induced moderate albuminuria. In summary, bacterial lipopeptide and LPS can aggravate glomerulonephritis but only lipopeptide potently induces severe albuminuria in MRL(lpr/lpr) mice.
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PMID:Bacterial lipopeptide triggers massive albuminuria in murine lupus nephritis by activating Toll-like receptor 2 at the glomerular filtration barrier. 1917 1


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