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)

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

The mammalian immune system senses pathogens through pattern recognition receptors (PRR) and responds with activation. Toll-like receptors (TLRs) that are expressed on immune and non-immune cells play a critical role in this process. As part of the innate immune response, TLRs lead to cellular activation and cytokine production with subsequent initiation of an adaptive immune response. TLR7-9 recognize single-stranded RNA, nucleoside analogs and single-stranded CpG-DNA, respectively, and their activation initiates the immune response against viruses and bacteria. Furthermore, the stimulation of these TLRs may be exploited for adjuvant therapy, vaccination and anti-tumor responses. However, a role in the generation or perpetuation of autoimmune diseases such as systemic lupus erythematosus (SLE) has also been suggested.
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PMID:Recognition of nucleic acid and nucleic acid analogs by Toll-like receptors 7, 8 and 9. 1840 77

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

Toll-like receptors (TLR), such as TLR7, were first described as innate pathogen recognition receptors that trigger appropriate antimicrobial immune responses upon exposure to pathogen-associated molecules, e.g. viral ssRNA. In parallel to ongoing studies on TLR-biology, mounting experimental evidence suggests that endogenous RNA-related autoantigens may also activate dendritic cells (DC) and B cells through TLR7. TLR7-mediated DC activation, autoantibody secretion, lymphoproliferation, and autoimmune tissue injury, are frequently observed in various murine models of systemic lupus and lupus nephritis. A paper in the current issue of the European Journal of Immunology, provide striking experimental evidence for this concept; the authors show that the Y chromosome-linked autoimmune accelerating (Yaa) translocation from the X-chromosome, consisting of 16 genes including Tlr7, largely mediates the autoimmune phenotype via the duplication of Tlr7. This finding highlights the need to address the significance of TLR7 in human lupus in terms of both genetic risk and as a therapeutic option.
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PMID:Molecular mimicry in innate immunity? The viral RNA recognition receptor TLR7 accelerates murine lupus. 1850 82

The accelerated development of systemic lupus erythematosus (SLE) in male BXSB mice is associated with the genetic abnormality in its Y chromosome, designated Yaa (Y-linked autoimmune acceleration). Recently, the Yaa mutation was identified to be a translocation from the telomeric end of the X chromosome (containing the gene encoding TLR7) onto the Y chromosome. In the present study, we determined whether the Tlr7 gene duplication is indeed responsible for the Yaa-mediated acceleration of SLE. Analysis of C57BL/6 mice congenic for the Nba2 (NZB autoimmunity 2) locus (B6.Nba2) bearing the Yaa mutation revealed that introduction of the Tlr7 null mutation on the X chromosome significantly reduced serum levels of IgG autoantibodies against DNA and ribonucleoproteins, as well as the incidence of lupus nephritis. However, the protection was not complete, because these mice still developed high titers of anti-chromatin autoantibodies and retroviral gp70-anti-gp70 immune complexes, and severe lupus nephritis, which was not the case in male B6.Nba2 mice lacking the Yaa mutation. Moreover, we found that the Tlr7 gene duplication contributed to the development of monocytosis, but not to the reduction of marginal zone B cells, which both are cellular abnormalities causally linked to the Yaa mutation. Our results indicate that the Yaa-mediated acceleration of SLE as well as various Yaa-linked cellular traits cannot be explained by the Tlr7 gene duplication alone, and suggest additional contributions from other duplicated genes in the translocated X chromosome.
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PMID:Evidence for genes in addition to Tlr7 in the Yaa translocation linked with acceleration of systemic lupus erythematosus. 1860 11

Plasmacytoid dendritic cells (pDCs) can produce a large amount of interferon-alpha (IFN-alpha) upon exposure to TLR9 or TLR7 agonists. Human pDCs have been shown to play an important role in the pathogenesis of systemic lupus erythematosus (SLE) through increased production of IFN-alpha. So, how to negatively regulate activation of pDCs and how to evaluate the activation of pDC in SLE patients attract much attention. BDCA2 is selectively expressed on human pDCs, acting as a hallmark of human pDCs. In this study, we showed that BDCA2 expression on pDCs decreased along maturation of pDCs, and TLR7 or TLR9 agonists could further significantly downregulate pDCs to express BDCA2, suggesting that the activated pDCs exhibit decreased expression of BDCA2. Functionally, BDCA2 ligation significantly inhibited upregulation of CD40, CD86 and CCR7 expression, IFN-alpha, IFN-beta and IL-6 production by pDCs stimulated with CpG ODN. Moreover, BDCA2 ligation suppressed CpG ODN-activated pDCs to mediate Th1 response, including T cell proliferation, IFN-gamma production, and CD4(+)CCR5(+)Th1 development, confirming that BDCA2 is a negative regulator of TLR9-dependent activation of human pDCs. BDCA2 expression on pDCs from SLE patients decreased significantly but IFN-alpha production of these patients increased markedly as compared to that from healthy donors. Therefore, these results suggest that downregulation of BDCA2 expression on pDCs may reflect the activation of pDCs accumulated in SLE patients, and may be one marker for indication of the disease activity of SLE patients.
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PMID:TLR9/TLR7-triggered downregulation of BDCA2 expression on human plasmacytoid dendritic cells from healthy individuals and lupus patients. 1868 74

On the lupus-prone MRL-lpr/lpr (MRL-lpr) background, AM14 rheumatoid factor (RF) B cells are activated, differentiate into plasmablasts, and undergo somatic hypermutation outside of follicles. Using multiple strategies to impair T cells, we found that such AM14 B cell activation did not require T cells but could be modulated by them. In vitro, the signaling adaptor MyD88 is required for IgG anti-chromatin to stimulate AM14 B cell proliferation when T cells are absent. However, the roles of Toll-like receptors (TLRs) in AM14 B cell activation in vivo have not been investigated. We found that activation, expansion, and differentiation of AM14 B cells depended on MyD88; however, mice lacking either TLR7 or TLR9 displayed partial defects, indicating complex roles for these receptors. T cell-independent activation of certain autoreactive B cells, which gain stimuli via endogenous TLR ligands instead of T cells, may be the initial step in the generation of canonical autoantibodies.
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PMID:T cell-independent and toll-like receptor-dependent antigen-driven activation of autoreactive B cells. 1869 14

The autoimmune disease systemic lupus erythematosus (SLE) is characterized by loss of tolerance to nuclear antigens such as chromatin, DNA, and RNA. This focused autoreactivity is thought to arise from the ability of DNA or RNA specific B cells to receive dual signals from the BCR and TLR9 or TLR7, respectively. The Tec kinase Btk is necessary for the production of anti-DNA antibodies in several murine models of SLE. To assess the role of Btk in the fate of DNA reactive B cells, we generated Btk-/- mice carrying the 56R anti-DNA Ig transgene on the C57BL/6 background. dsDNA specific B cells were present in 56R.Btk-/- mice, although they were not preferentially localized to the marginal zone. These cells were able to proliferate in response to large CpG DNA containing fragments that require BCR-induced internalization to access TLR9. However, anti-DNA antibodies were not observed in the serum of 56R.Btk-/- mice. A transgene expressing a low level of Btk in B cells (Btk(lo)) restored anti-DNA IgM in these mice. This correlated with partial rescue of proliferative response to BCR engagement and TLR9-induced IL-10 secretion in Btk(lo) B cells. anti-DNA IgG was not observed in 56R.Btk(lo) mice, however. This was likely due, at least in part, to a role for Btk in controlling the expression of T-bet and AID in cells stimulated with CpG DNA. Thus, Btk is required for the initial loss of tolerance to DNA and the subsequent production of pathogenic autoantibodies once tolerance is breached.
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PMID:Btk regulates localization, in vivo activation, and class switching of anti-DNA B cells. 1884 77

Increased type I interferon (IFN-I) production and IFN-stimulated gene (ISG) expression are linked to the pathogenesis of systemic lupus erythematosus (SLE). Although the mechanisms responsible for dysregulated IFN-I production in SLE remain unclear, autoantibody-mediated uptake of endogenous nucleic acids is thought to play a role. 2,6,10,14-tetramethylpentadecane (TMPD; also known as pristane) induces a lupus-like disease in mice characterized by immune complex nephritis with autoantibodies to DNA and ribonucleoproteins. We recently reported that TMPD also causes increased ISG expression and that the development of the lupus is completely dependent on IFN-I signaling (Nacionales, D.C., K.M. Kelly-Scumpia, P.Y. Lee, J.S. Weinstein, R. Lyons, E. Sobel, M. Satoh, and W.H. Reeves. 2007. Arthritis Rheum. 56:3770-3783). We show that TMPD elicits IFN-I production, monocyte recruitment, and autoantibody production exclusively through a Toll-like receptor (TLR) 7- and myeloid differentiation factor 88 (MyD88)-dependent pathway. In vitro studies revealed that TMPD augments the effect of TLR7 ligands but does not directly activate TLR7 itself. The effects of TMPD were amplified by the Y-linked autoimmune acceleration cluster, which carries a duplication of the TLR7 gene. In contrast, deficiency of Fcgamma receptors (FcgammaRs) did not affect the production of IFN-I. Collectively, the data demonstrate that TMPD-stimulated IFN-I production requires TLR7/MyD88 signaling and is independent of autoantibody-mediated uptake of ribonucleoproteins by FcgammaRs.
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PMID:TLR7-dependent and FcgammaR-independent production of type I interferon in experimental mouse lupus. 1904 36


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