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)

Roquinimex is an immunomodulator that can effectively inhibit the development of several autoimmune diseases in animal models, but the mechanism is still unknown. In this study, we investigated the effect of roquinimex on chronic graft-versus-host disease (GVHD) in mice, a well-established model for human systemic lupus erythematosus (SLE). Oral administration of roquinimex significantly suppressed the development of proteinuria and ameliorated nephritis symptoms in chronic GVHD mice. In addition, renal histopathology and immunohistochemistry studies revealed reduced glomerulonephritis and decreased IgG deposition in chronic GVHD mice treated with roquinimex. Chronic GVHD is characterized by a predominance of Th2 cytokines, and proinflammatory cytokines that also play an important role in the pathology of tissue damage. Therefore, we focused on the effect of roquinimex on cytokine production. Chronic GVHD mouse splenocytes exhibited severely reduced interferon (IFN)-gamma production in response to Concanavalin (Con A) stimulation and an overt Th2 skewness. Roquinimex treatment, however, induced IFN-gamma production and restored the Th1/Th2 cytokine balance, although only a minimal effect of roquinimex on interleukin (IL)-4 secretion was observed. The production of the proinflammatory cytokines TNF-alpha and IL-1 beta by peritoneal macrophages from lipopolysaccharide (LPS)-treated GVHD mice was significantly inhibited by roquinimex treatment. These data suggested that the beneficial effect of roquinimex on lupus might, at least in part, result from a restoration of Th1/Th2 cytokine balance and inhibition of inflammatory cytokine production.
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PMID:Roquinimex-mediated protection effect on the development of chronic graft-versus-host disease in mice is associated with induction of Th1 cytokine production and inhibition of proinflammatory cytokine production. 1795 Mar 63

A global expression profile of peripheral blood from patients with immune thrombocytopenic purpura (ITP) was performed that identified an ITP-specific signature, which also included interferon (IFN)-induced genes. Several genes correlated with ITP have been shown to be associated with expression signatures in systemic lupus erythematosis and rheumatoid arthritis, indicating an overlap with other autoimmune disorders. Pathway analysis demonstrated that IFN signalling, death receptor and protein ubiquitination pathways were associated with ITP. These results provide the first glimpse of the genes and pathways consistently aberrant in ITP, identifying new targets for investigations of pathogenesis and treatment of ITP.
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PMID:Gene expression and pathway analysis of immune thrombocytopenic purpura. 1800 67

Dynamic changes in chromatin structure through ATP-dependent remodeling and covalent modifications on histones play important roles in transcription regulation. Among the many chromatin modifiers identified, the NuRD (nucleosome remodeling histone deacetylase) complex is unique because it possesses both nucleosome remodeling and histone deacetylase activities. To understand the biological function of the NuRD complex, we generated a knock-out mouse model of the Mta2 (metastasis-associated protein 2) gene, which encodes a NuRD-specific component. Mta2 null mice exhibited partial embryonic lethality. The surviving mice developed lupus-like autoimmune symptoms including skin lesions, bodyweight loss, glomerulonephritis, liver inflammation, and production of autoantibodies. Transplantation of bone marrow cells from Mta2 null mice recapitulated some of the symptoms including skin lesion and bodyweight loss in the recipient mice. Mta2 null T lymphocytes showed normal development but hyperproliferation upon stimulation, which correlates with hyperinduction of interleukin (IL)-2, IL-4, and interferon (IFN)-gamma. T cell hyperproliferation, but not other autoimmune symptoms, was observed in T cell-specific Mta2 knock-out mice. Mta2 null T cells produced more IL-4 and IFN-gamma under Th2 activation conditions, but normal levels of IL-4 and IFN-gamma under Th1 activation conditions. Furthermore, we found that IL-4 is a direct target gene of Mta2. Our study suggests that Mta2/NuRD is involved in modulating IL-4 and IFN-gamma expression in T cell immune responses, and gene expression in non-T cells plays an important role in controlling autoimmunity.
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PMID:Inactivation of NuRD component Mta2 causes abnormal T cell activation and lupus-like autoimmune disease in mice. 1835 70

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

Studies have revealed that increased expression of interferon (IFN)-inducible Ifi202 gene (encoding p202 protein) in splenic B and T cells from B6.Nba2 congenic (congenic for Nb2 locus derived from NZB mice) female mice is associated with lupus susceptibility. However, signaling pathways that regulate Ifi202 expression in immune cells remain to be elucidated. Here we report that stimulation of T cells up-regulates the Ifi202 expression. We found that steady-state levels of Ifi202 mRNA and protein were detectable in splenic T cells from NZB mice and stimulation of T cells with anti-CD3 and anti-CD28 up-regulated expression of the Ifi202 gene. Similarly, stimulation of cells of a mouse T cell hybridoma cell line (2B4.11) also activated transcription of the Ifi202 gene. Significantly, up-regulation of Ifi202 expression in stimulated T cells was inhibited by treatment of cells with SP600125, a specific inhibitor of c-Jun N-terminal kinase (JNK). Conversely, treatment of cells with anisomycin, a potent activator of the JNK and c-Jun, up-regulated Ifi202 expression. Consistent with the activation of JNK/c-Jun pathway by T cell stimulation, forced expression of c-Jun in 2B4 T cells and in mouse embryonic fibroblasts (MEFs) also up-regulated the Ifi202 expression. Furthermore, we found that stimulation of T cells increased association of the activated c-Jun to the 5'-regulatory region of the Ifi202 gene in chromatin immunoprecipitation assays (ChIPs). Together, our observations demonstrate that stimulation of T cells up-regulates the Ifi202 expression in part through the JNK/c-Jun pathway.
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PMID:Stimulation of T cells up-regulates expression of Ifi202, an interferon-inducible lupus susceptibility gene, through activation of JNK/c-Jun pathway. 1837 89

In recent years, DNA microarray technology has been used for the analysis of gene expression patterns in a variety of skin diseases, including malignant melanoma, psoriasis, lupus erythematosus, and systemic sclerosis. Many of the studies described herein confirmed earlier results on individual genes or functional groups of genes. However, a plethora of new candidate genes, gene patterns, and regulatory pathways have been identified. Major progresses were reached by the identification of a prognostic gene pattern in malignant melanoma, an immune signaling cluster in psoriasis, and a so-called interferon signature in systemic lupus erythematosus. In future, interference with genes or regulatory pathways with the use of different RNA interference technologies or targeted therapy may not only underscore the functional significance of microarray data but also may open interesting therapeutic perspectives. Large-scale gene expression analyses may also help to design more individualized treatment approaches of cutaneous diseases.
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PMID:DNA microarray technology in dermatology. 1848 20

Patients with systemic lupus erythematosus (SLE) have an increased expression of type I interferon (IFN) regulated genes because of a continuous production of IFN-alpha. The cellular and molecular background to this IFN-alpha production has started to be elucidated during the last years, as well as the consequences for the innate and adaptive immune systems. Plasmacytoid dendritic cells (pDC) activated by immune complexes containing nucleic acids secrete type I IFN in SLE. Type I IFN causes differentiation of monocytes to myeloid-derived dendritic cell (mDC) and activation of autoreactive T and B cells. A new therapeutic option in patients with SLE is, therefore, inhibition of IFN-alpha, and recent data from a phase I clinical trial suggests that administration of neutralizing monoclonal antibodies against anti-IFN-alpha can ameliorate disease activity.
Lupus 2008 May
PMID:The innate immune system in SLE: type I interferons and dendritic cells. 1849 Apr 15

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies against a host of nuclear antigens. The pathogenesis of lupus is incompletely understood. Environmental factors may play a role via altering DNA methylation, a mechanism regulating gene expression. In lupus, genes including CD11a and CD70 are overexpressed in T cells as a result of promoter hypomethylation. T-cell DNA methyltransferase expression is regulated in part by the extracellular signal-regulated kinase (ERK) signaling pathway. In this study, we investigate the effects of decreased ERK pathway signaling in T cells using transgenic animals. We generated a transgenic mouse that inducibly expresses a dominant-negative MEK in T cells in the presence of doxycycline. We show that decreased ERK pathway signaling in T cells results in decreased expression of DNA methyltransferase 1 and overexpression of the methylation-sensitive genes CD11a and CD70, similar to T cells in human lupus. Our transgenic animal model also develops anti-dsDNA antibodies. Interestingly, microarray expression assays revealed overexpression of several interferon-regulated genes in the spleen similar to peripheral blood cells of lupus patients. This model supports the contention that ERK pathway signaling defects in T cells contribute to the development of autoimmunity.
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PMID:Defective T-cell ERK signaling induces interferon-regulated gene expression and overexpression of methylation-sensitive genes similar to lupus patients. 1852 34

We report the case of a 43-year-old man who developed systemic lupus erythematosus (SLE) after receiving pegylated alpha-interferon and ribavirin for chronic hepatitis C. He displayed 8 features of the American College of Rheumatology criteria for SLE: glomerulonephritis, arthritis, serositis, a florid discoid rash, lymphopenia, oral ulcers, the development of high titers of antinuclear antibodies, and antidouble stranded DNA antibodies. Furthermore, his admission was complicated by the development of life threatening myopericarditis and vasculitis. This case is notable for the clinical severity and nature of multiorgan lupus involvement from hepatitis C antiviral therapy. Clinical signs of SLE have resolved and anti DS DNA has normalized.
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PMID:Severe systemic lupus erythematosus induced by antiviral treatment for hepatitis C. 1852 29

In order to identify a novel candidate gene in systemic lupus erythematosus (SLE), we analysed a panel of six genes encoding molecules involved in the type I interferon (IFN) system. We first identified variants in the five genes related to type I IFN pathway by sequencing. Genotyping of a panel of eight selected single-nucleotide polymorphisms (SNPs) in six candidate genes (TLR9, MYD88, IRF3, IRF7, IFNB1, IFNA17) was performed in 137 patients with SLE and matched with 152 healthy controls using polymerase chain reaction-restriction fragment length polymorphism analysis. In functional assay, quantitative real-time polymerase chain reaction was performed to assess constitutive IRF3 mRNA expression in peripheral blood mononuclear cells from healthy subjects with different IRF3 promoter haplotypes. Among eight SNPs genotyped, an IRF3 SNP at -925 was found to be associated with SLE after correction for multiple tests (corrected P=0.016). Of total five IRF3 SNPs genotyped, the promoter IRF3 SNPs -925A/G and -776C/T showed the most significant association with SLE. With regard to -925A/G, the frequency of GG genotype was significantly decreased among SLE patients compared with the control group (1.5% vs. 9.9%; chi(2)=10.0, P=0.0015, odds ratio 0.12, 95% confidence interval 0.027-0.554). Our experimental data indicated that constitutive IRF3 mRNA expression was significantly lower in cells carrying the minor G-T/G-T haplotype pair compared with those carrying the major A-C haplotype. In conclusion, we showed that the promoter SNPs of the IRF3 gene were significantly associated with resistance against SLE.
Lupus 2008 Jun
PMID:Promoter polymorphisms in the IRF3 gene confer protection against systemic lupus erythematosus. 1853 11


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