Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is shown in this study that the heparan sulfate proteoglycan agrin is overexpressed in T cells isolated from patients with the autoimmune disease systemic lupus erythematosus (SLE). Freshly isolated CD4(+) and CD8(+) subpopulations both exhibited higher expression over healthy controls, which however, gradually declined when cells were cultured in vitro. Agrin expression was induced following in vitro activation of cells via their Ag receptor, or after treatment with IFN-alpha, a cytokine shown to be pathogenic in lupus. Furthermore, serum from SLE patients with active disease was able to induce agrin expression when added to T cells from healthy donors, an increase that was partially blocked by neutralizing anti-IFN-alpha Abs. Cross-linking agrin with mAbs resulted in rapid reorganization of the actin cytoskeleton, activation of the ERK MAPK cascade, and augmentation of anti-CD3-induced proliferation and IL-10 production, indicating that agrin is a functional receptor in T cells. These results demonstrate that agrin expression in human T cells is regulated by cell activation and IFN-alpha, and may have an important function during cell activation with potential implications for autoimmunity.
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PMID:Agrin signalling contributes to cell activation and is overexpressed in T lymphocytes from lupus patients. 1802 46

The presence of autoantibodies specific for nucleic acid-associated antigens is the hallmark of systemic lupus erythematosus (SLE). We have recently developed a specific inhibitor of TLR7 and TLR9, called immunoregulatory sequence (IRS) 954, and showed that it inhibits the induction of IFN-alpha by human plasmacytoid dendritic cells in response to DNA and RNA viruses and isolated immune complexes from lupus patients. In this study, we show that IRS 954 can prevent progression of disease when injected in the lupus prone (NZBxNZW)F1 mice. Following treatment, we observed a significant reduction of serum levels of nucleic acid-specific autoantibodies as well as decreased proteinuria, reduced glomerulonephritis, end-organ damage and increased survival. These data demonstrate that in addition to its ability to block IFN-alpha, IRS 954 can reduce symptoms in a lupus model and thus represents a promising therapeutic agent for the treatment of SLE.
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PMID:Treatment of lupus-prone mice with a dual inhibitor of TLR7 and TLR9 leads to reduction of autoantibody production and amelioration of disease symptoms. 1803 31

Recently much attention was attracted to the importance of the type I interferon pathway in the initiation and development of the autoimmune disease systemic lupus erythematosus (SLE). Many SLE patients have increased serum levels of IFN-alpha and display an IFN gene expression "signature" characterized by strong overexpression of IFN-responsive genes in leukocytes and target tissues. Moreover, about 20% of cancer patients treated with IFN-alpha therapy manifest symptoms resembling SLE and some later develop the disease. One of the key genes of the IFN-alpha pathway, IRF5, was found to be strongly associated with SLE. Two functional SNPs lead to alternative splicing and altered steady-state level of IRF5 gene expression. Besides, the gene has a polymorphic inserion/deletion in exon 6, which contributes to the diversity in the isoform pattern of IRF5. Interestingly, recent studies have not found association of IRF5 with the other autoimmune diseases, such as rheumatoid arthritis or psoriasis, suggesting the unique role for IRF5 in the development of lupus. Here, we present the current knowledge on IRF5 genetics and its biological function and discuss the possible ways in which IRF5 contributes to susceptibility to SLE.
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PMID:The genetics and biology of Irf5-mediated signaling in lupus. 1807 93

Excess type I IFNs (IFN-I) have been linked to the pathogenesis of systemic lupus erythematosus (SLE). Therapeutic use of IFN-I can trigger the onset of SLE and most lupus patients display up-regulation of a group of IFN-stimulated genes (ISGs). Although this "IFN signature" has been linked with disease activity, kidney involvement, and autoantibody production, the source of IFN-I production in SLE remains unclear. 2,6,10,14-Tetramethylpentadecane-induced lupus is at present the only model of SLE associated with excess IFN-I production and ISG expression. In this study, we demonstrate that tetramethylpentadecane treatment induces an accumulation of immature Ly6C(high) monocytes, which are a major source of IFN-I in this lupus model. Importantly, they were distinct from IFN-producing dendritic cells (DCs). The expression of IFN-I and ISGs was rapidly abolished by monocyte depletion whereas systemic ablation of DCs had little effect. In addition, there was a striking correlation between the numbers of Ly6C(high) monocytes and the production of lupus autoantibodies. Therefore, immature monocytes rather than DCs appear to be the primary source of IFN-I in this model of IFN-I-dependent lupus.
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PMID:A novel type I IFN-producing cell subset in murine lupus. 1835 36

The term "interface dermatitis" (ID) involves a specific histological inflammatory pattern that is characterized by a cytotoxic lymphocytic infiltration and a hydropic degeneration of the basal epidermal layer. ID is typically seen in autoimmune skin disorders such as lichen planus (LP), cutaneous lupus erythematosus (CLE), and may also appear during immune reactions against drugs, viruses, and tumors. Recent studies have shown that the type-I IFN system is involved in cutaneous autoimmune diseases characterized by ID. IFNs induce the expression of proinflammatory cytokines and chemokines, which support the cellular immune response. The role of IFNs in ID is supported by a close morphological association between the expression pattern of IFN-inducible proteins and the distribution of CXCR3+ lymphocytes. The IFN-inducible chemokine CXCL10 is expressed in exactly those areas where cytotoxic lymphocytes invade the basal epidermis and cause keratinocyte death. A similar picture can be found in early herpes simplex viral skin lesions and viral warts, but also in "lichenoid" actinic keratosis and invasive squamous cell carcinoma. These data suggest that ID morphologically reflects a common IFN-driven cytotoxic attack affecting the basal keratinocytes under different conditions, which is important for antiviral and antitumor immune response, but is inappropriately activated in autoimmune skin disorders.
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PMID:An IFN-associated cytotoxic cellular immune response against viral, self-, or tumor antigens is a common pathogenetic feature in "interface dermatitis". 1841 11

Studies have identified IFN-inducible Ifi202 gene as a lupus susceptibility gene (encoding p202 protein) in mouse models of lupus disease. However, signaling pathways that regulate the Ifi202 expression in cells remain to be elucidated. We found that steady-state levels of Ifi202 mRNA and protein were high in mouse embryonic fibroblasts (MEFs) from E2F1 knockout (E2F1(-/-)) and E2F1 and E2F2 double knockout (E2F1(-/-)E2F2(-/-)) mice than isogenic wild-type MEFs. Moreover, overexpression of E2F1 in mouse fibroblasts decreased expression of p202. Furthermore, expression of E2F1, but not E2F4, transcription factor in mouse fibroblasts repressed the activity of 202-luc-reporter in promoter-reporter assays. Interestingly, the E2F1-mediated transcriptional repression of the 202-luc-reporter was independent of p53 and pRb expression. However, the repression was dependent on the ability of E2F1 to bind DNA. We have identified a potential E2F DNA-binding site in the 5'-regulatory region of the Ifi202 gene, and mutations in this E2F DNA-binding site reduced the E2F1-mediated transcriptional repression of 202-luc-reporter. Because p202 inhibits the E2F1-mediated transcriptional activation of genes, we compared the expression of E2F1 and its target genes in splenic cells from lupus-prone B6.Nba2 congenic mice, which express increased levels of p202, with age-matched C57BL/6 mice. We found that increased expression of Ifi202 in the congenic mice was associated with inhibition of E2F1-mediated transcription and decreased expression of E2F1 and its target genes that encode proapoptotic proteins. Our observations support the idea that increased Ifi202 expression in certain strains of mice contributes to lupus susceptibility in part by inhibiting E2F1-mediated functions.
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PMID:Disruption of mutually negative regulatory feedback loop between interferon-inducible p202 protein and the E2F family of transcription factors in lupus-prone mice. 1842 12

Although for decades sunlight was suspected to be involved in the development of cutaneous lupus erythematosus (CLE), only in recent years research on the effects of ultraviolet irradiation on the skin of patients with CLE has resulted in a more comprehensive model for the pathogenesis of the disease. In this model, exposure to UV light induces apoptosis of keratinocytes and the release of pro-inflammatory cytokines. In susceptible patients, the presence or even accumulation of apoptotic cells results in the induction of characteristic inflammatory skin lesions, which might be due to a delayed and pro-inflammatory clearance of these apoptotic cells. Many other factors, in part genetically determined, are involved in CLE resulting in a very heterogeneous clinical manifestation. Among these factors, presence of autoantibodies, a decreased number of regulatory T cells at the site of inflammation and increased expression of pro-inflammatory cytokines like TNFalpha and IFN-inducible protein myxovirus protein A have been shown to play a role in the pathogenesis of CLE.
Lupus 2008 May
PMID:Pathogenesis of cutaneous lupus erythematosus. 1849 Apr 14

The impact of IFN-alpha secretion on disease progression was assessed by comparing phenotypic changes in the lupus-prone B6.Sle1Sle2Sle3 (B6.Sle123) strain and the parental C57BL/6 (B6) congenic partner using an adenovirus (ADV) expression vector containing a recombinant IFN-alpha gene cassette (IFN-ADV). A comprehensive comparison of cell lineage composition and activation in young B6 and B6.Sle123 mice revealed a variety of cellular alterations in the presence and absence of systemic IFN-alpha. Most IFN-alpha-induced phenotypes were similar in B6 and B6.Sle123 mice; however, B6.Sle123 mice uniquely exhibited increased B1 and plasma cells after IFN-alpha exposure, although both strains had an overall loss of mature B cells in the bone marrow, spleen and periphery. Although most of the cellular effects of IFN-alpha were identical in both strains, severe glomerulonephritis occurred only in B6.Sle123 mice. Mice injected with IFN-ADV showed an increase in immune complex deposition in the kidney, together with an unexpected decrease in serum anti-nuclear antibody levels. In summary, the predominant impact of systemic IFN-alpha in this murine model is an exacerbation of mechanisms mediating end organ damage.
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PMID:Systemic IFN-alpha drives kidney nephritis in B6.Sle123 mice. 1858 36

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

Exacerbation of disease in systemic lupus erythematosus (SLE) is associated with bacterial infection. In conventional dendritic cells (cDCs), the TLR4 ligand bacterial LPS induces IFN-beta gene expression but does not induce IFN-alpha. We hypothesized that when cDCs are primed by cytokines, as may frequently be the case in SLE, LPS would then induce the production of IFN-alpha, a cytokine believed to be important in lupus pathogenesis. In this study we show that mouse cDCs and human monocytes produce abundant IFN-alpha following TLR4 engagement whether the cells have been pretreated either with IFN-beta or with a supernatant from DCs activated by RNA-containing immune complexes from lupus patients. This TLR4-induced IFN-alpha induction is mediated by both an initial TRIF-dependent pathway and a subsequent MyD88-dependent pathway, in contrast to TLR3-induced IFN-alpha production, which is entirely TRIF-dependent. There is also a distinct requirement for IFN regulatory factors (IRFs), with LPS-induced IFN-alpha induction being entirely IRF7- and partially IRF5-dependent, in contrast to LPS-induced IFN-beta gene induction which is known to be IRF3-dependent but largely IRF7-independent. This data demonstrates a novel pathway for IFN-alpha production by cDCs and provides one possible explanation for how bacterial infection might precipitate disease flares in SLE.
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PMID:TLR4 ligands induce IFN-alpha production by mouse conventional dendritic cells and human monocytes after IFN-beta priming. 1912 25


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