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)

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

Toll-like receptor 9 (TLR9) promiscuously binds self- and microbial DNA, but only microbial DNA elicits an inflammatory response. How TLR9 discriminates between self- and foreign DNA is unclear, but inappropriate localization of TLR9 permits response to self-DNA, suggesting that TLR9 localization and trafficking are critical components. The molecular mechanisms controlling the movement of TLR9 may provide new insight into the recognition of DNA in normal and in pathological conditions such as autoimmune systemic lupus erythematosus. We have shown earlier that TLR9 is retained in the endoplasmic reticulum (ER) and it moves to endolysosomes to recognize CpG DNA. Other studies have suggested that TLR9 bypasses the Golgi complex to access endolysosomes. Here, we show that TLR9 translocates from ER to endolysosomes through the Golgi complex and that Golgi export is required for optimal TLR9 signaling. In all, 6-13% of TLR9 constitutively exits the ER, moves through the Golgi complex and resides in lysosomal-associated membrane protein-1-positive vesicles. TLR9 bound to CpG DNA had glycan modifications indicative of Golgi processing confirming that TLR9 travels through the Golgi complex to access CpG DNA in endolysosomes. Together, these data support a model where TLR9 uses traditional secretory pathways and does not bypass the Golgi complex.
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PMID:TLR9 traffics through the Golgi complex to localize to endolysosomes and respond to CpG DNA. 1907 58

Oligodeoxyribonucleotides containing unmethylated CpG motifs act as TLR9 agonists. In this study, we evaluated oligonucleotides containing an unmethylated CpG motif in which two nucleotides adjacent to the CpG dinucleotide were substituted with 2'-O-methylribonucleotides, resulting in TLR7 and TLR9 antagonists. In mouse and human cell cultures, antagonists did not stimulate immune activation but inhibited TLR7 and TLR9 agonist-induced activity. In mice, antagonists inhibited immune responses induced by TLR9 agonists for up to several days, and the inhibition was dose-dependent. Antagonists also inhibited immune responses induced by an RNA-based TLR7/8 agonist but not TLRs 2, 3, 4, or 5 agonists in mice. Additionally, antagonist inhibited TLR9 agonist-induced IL-6 in lupus-prone MRL/lpr mouse spleen cell cultures. These results indicate that antagonists described herein can suppress immune responses induced by TLR7 and TLR9 agonists. Antagonists may be suitable candidates for treating inflammatory and autoimmune diseases where inappropriate or uncontrolled TLR activation has been implicated.
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PMID:Oligodeoxyribonucleotide-based antagonists for Toll-like receptors 7 and 9. 1910 53

Toll-like receptor 9 (TLR9) plays an important role in the induction and regulation of the innate immune system or adaptive immune responses. Genetic variations within human TLR9 have been reported to be associated with a range of immune-related diseases, such as asthma, systemic lupus erythematosus (SLE) and so on. Family-based association analysis was performed to further investigate whether a single nucleotide polymorphism (rs352140) in the exon 2 region of TLR9 gene is associated with susceptibility to SLE in a Chinese population. A total of 77 patients with SLE from 74 nuclear families, aged from 12 to 63 years, were enrolled according to 1997 criteria of American College of Rheumatology (ACR), 211 family members of these patients were also included. Genotyping was performed by PCR-restriction fragment length polymorphism (PCR-RFLP) assay. Among 77 patients with SLE, the CC, CT and TT genetype frequencies of the SNP (rs352140) were 20.8, 61.0 and 18.2%, respectively. Single loci analysis suggested that the T allele at position of rs352140 was significantly associated with the susceptibility to SLE (Z = 2.357, P = 0.018402) in dominant model, but not in additive or recessive model. Genetype analysis showed that individuals with CT genetype had greater susceptibility to SLE than those without (Z = 2.004, P = 0.045067). Our study suggests that a single nucleotide polymorphism (rs352140) in the exon 2 region of TLR9 gene may be a susceptibility factor for SLE in Chinese population.
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PMID:Association study of a single nucleotide polymorphism in the exon 2 region of toll-like receptor 9 (TLR9) gene with susceptibility to systemic lupus erythematosus among Chinese. 1913 Feb 96

Toll-like receptor 9 (TLR9) plays a controversial role in the pathogenesis of systemic lupus erythematosus (SLE). T-bet may be involved in the processes between the initiation of TLR9 activation and the antibodies' production. To clarify the paradox of TLR9, we investigated the intracellular expressions of TLR9 and T-bet in B and T cells in peripheral blood samples from 35 newly diagnosed, untreated patients with SLE and 16 healthy subjects by flow cytometry (FCM). And we collected the clinic laboratory data obtained from the same individual blood sample tested by FCM each time. And the correlations among the expression levels of the two proteins and SLE laboratory data were calculated. We found the percentages of B cells expressing TLR9 and T-bet and of T cells expressing TLR9 were significantly elevated in SLE patients when compared with healthy controls. There was a significantly negative relationship between the proportion of B cells expressing TLR9 and SLE Disease Activity Index (SLEDAI) score. The serum levels of anti-dsDNA antibody reversely correlated with the mean fluorescence intensity (MFI) of B cells co-expressing T-bet and TLR9. The serum levels of anti-C1q antibody significantly associated with the proportion of B cells expressing T-bet. Also, the serum levels of IgM and IgA antibodies both significantly correlated with TLR9 and T-bet expressions in T and B cells. According to the immunological pathway knowledge and the mutually verified associations, the following conclusions are made. Expressions of TLR9 and T-bet were increased in patients with SLE. TLR9 may have a role to play in protecting against lupus. And the increase of the co-expression of TLR9 and T-bet may be of benefit to the protective antibodies' production and pathogenic antibodies' decline, and could be regarded as a good sign for lupus demission and/or treatment.
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PMID:The expressions of Toll-like receptor 9 and T-bet in circulating B and T cells in newly diagnosed, untreated systemic lupus erythematosus and correlations with disease activity and laboratory data in a Chinese population. 1936 85

High titers of autoantibodies reactive with DNA/RNA molecular complexes are characteristic of autoimmune disorders such as systemic lupus erythematosus (SLE). In vitro and in vivo studies have implicated Toll-like receptor 9 (TLR9) and Toll-like receptor 7 (TLR7) in the activation of the corresponding autoantibody producing B cells. Importantly, TLR9/TLR7-deficiency results in the inability of autoreactive B cells to proliferate in response to DNA/RNA-associated autoantigens in vitro, and in marked changes in the autoantibody repertoire of autoimmune-prone mice. Uptake of DNA/RNA-associated autoantigen immune complexes (ICs) also leads to activation of dendritic cells (DCs) through TLR9 and TLR7.The initial studies from our lab involved ICs formed by a mixture of autoantibodies and cell debris released from dying cells in culture. To better understand the nature of the mammalian ligands that can effectively activate TLR7 and TLR9, we have developed a methodology for preparing ICs containing defined DNA fragments that recapitulate the immunostimulatory activity of the previous "black box" ICs. These reagents reveal an important role for nucleic acid sequence, even when the ligand is mammalian DNA.
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PMID:Toll-like receptor-dependent immune complex activation of B cells and dendritic cells. 1937 22

Different immunological alterations may condition systemic lupus erythematosus (SLE) activity. However, it is not known whether alterations in the phenotype of circulating antigen-presenting cells (APCs) and in the response to CpG oligodeoxynucleotides (ODN-CpG) correlate with disease activity. APC expression of HLA-DR, costimulatory molecules, and TLR9 expression was determined in patients with SLE, other autoimmune diseases, and healthy controls. Monocyte and B cell response to synthetic ODN-CpG sequences was also evaluated. Monocytes from patients with moderate SLE activity had higher expression of CD40 and CD86. Decreased numbers of CD19+CD80+ and BDCA-3+CD40+ cells were found in patients with severe SLE activity. In patients with moderate SLE activity, non-adherent and enriched B cell response to ODN-CpG was similar to healthy controls. Adherent and enriched B cells from patients with severe SLE activity did not increase costimulatory molecule expression or cytokine production after ODN-CpG stimulation. APCs from patients with SLE, regardless of disease activity, displayed higher percentage of TLR9+ cells, as well as increased expression of TLR9, compared to healthy controls. Results suggest that the B cell response to ODN-CpG correlates with the SLE activity, independently of TLR9 expression, indicating that alterations in B cell response in severe activity SLE may be caused by events down-stream to TLR9.
Lupus 2009 Jul
PMID:Response to ODN-CpG by B Cells from patients with systemic lupus erythematosus correlates with disease activity. 1950 68

Inappropriate activation of TLR9 has been found to be involved in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus. TLR9 antagonists have been proposed to be therapeutic for some kinds of autoimmune diseases. In contrast, new negative regulators of TLR9 signal pathway need to be identified, and the mechanisms for the control of TLR9 response need to be fully investigated. It is well known that TLR9 will be finally transported to late endosome/lysosome once activated; however, the exact mechanism and the biological significance of the redistribution have not been fully elucidated. Ras related in brain (Rab)7b is a small guanosine triphosphatase, identified by us before, which is mainly localized in late endosome/lysosome. Our previous study shows that Rab7b can negatively regulate TLR4 signaling by promoting lysosomal degradation of TLR4. In this study, we show that TLR9 ligation can inhibit Rab7b expression in macrophages via ERK and p38 activation. In turn, the late endosome/lysosome-localized Rab7b can colocalize with TLR9 in lysosomal-associated membrane protein 1-positive compartment and down-regulate the expression of the TLR9 in macrophages by promoting TLR9 degradation once TLR9 is activated. Accordingly, Rab7b can negatively regulate TLR9-triggered production of TNF-alpha, IL-6, and IFN-beta in macrophages by impairing activation of MAPKs and NF-kappaB pathways. Our results suggest that the late endosome/lysosome-localized Rab7b can down-regulate TLR9-triggered proinflammatory cytokine and type I IFN production by impairing TLR9 signaling via promotion of TLR9 degradation.
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PMID:Late endosome/lysosome-localized Rab7b suppresses TLR9-initiated proinflammatory cytokine and type I IFN production in macrophages. 1958 7

Toll-like receptors (TLRs) play a central role in the response of both the innate and the adaptive immune system to microbial ligands. There is also evidence that they are stimulated by endogenous ligands. In this review, I discuss evidence that they are important in renal disease. This discussion considers the role of both endogenous and microbial ligands, and also the contribution of TLRs present on leucocytes and on intrinsic renal cells. There is strong evidence of a role for TLR2 and TLR4 in renal ischaemia-reperfusion injury, with the effects probably mediated by endogenous ligands. In systemic lupus erythematosus, stimulation of TLR7 and TLR9 by host-derived nucleic acids is important. TLR7 stimulation exacerbates disease, but the role of TLR9 is complex. I also discuss evidence that they are important in other forms of glomerulonephritis, with evidence derived mainly from experimental models in which exogenous ligands have been administered.
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PMID:Toll-like receptors and renal disease. 1959 Feb 36

Although TLR9 was originally thought to specifically recognize microbial DNA, it is now evident that mammalian DNA can be an effective TLR9 ligand. However, the DNA sequence required for TLR9 activation is controversial, as studies have shown conflicting results depending on the nature of the DNA backbone, the route of DNA uptake, and the cell type being studied. In systemic lupus erythematosus, a major route whereby DNA gains access to intracellular TLR9, and thereby activates dendritic cells (DCs), is through uptake as a DNA-containing immune complex. In this report, we used defined dsDNA fragments with a natural (phosphodiester) backbone and show that unmethylated CpG dinucleotides within dsDNA are required for murine DC TLR9 activation induced by a DNA-containing immune complex. The strongest activation is seen with dsDNA fragments containing optimal CpG motifs (purine-purine-CpG-pyrimidine-pyrimidine) that are common in microbial DNA but rare in mammalian DNA. Importantly, however, activation can also be induced by CpG-rich DNA fragments that lack these optimal CpG motifs and that we show are plentiful in CpG islands within mammalian DNA. No activation is induced by DNA fragments lacking CpG dinucleotides, although this CpG-free DNA can induce DC activation if internalized by liposomal transfection instead of as an immune complex. Overall, the data suggest that the release of CpG-rich DNA from mammalian DNA may contribute to the pathogenesis of autoimmune diseases such as systemic lupus erythematosus and psoriasis in which activation of TLR9 in DCs by self DNA has been implicated in disease pathogenesis.
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PMID:Requirement for DNA CpG content in TLR9-dependent dendritic cell activation induced by DNA-containing immune complexes. 1964 72


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