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)

As patients with Systemic Lupus Erythematosus (SLE) live longer due to improved therapies and preventive measures, death and disability from cardiovascular events are increasing. Patients with SLE have an increased risk of atherosclerosis that persists even after accounting for traditional cardiac risk factors. Recent studies strongly suggest that the mechanism is due in part to a combination of inflammatory and immune mechanisms. Contributory factors include increased levels of oxidized lipids (such as oxidized LDL and pro-inflammatory HDL), upregulation of adhesion molecules, and upregulation of cytokines such as MCP-1, TNF-alpha, IFN-gamma, IL-1, and IL-12. Autoanitbodies to oxidized lipids and immune complexes may also play a role in the development of atherosclerosis in SLE. As in the pathogenesis of many lupus disease processes, the increased risk of atherosclerosis seen in SLE is likely due to the complex interplay of many of these inflammatory and immune mediators.
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PMID:Atherosclerosis and systemic lupus erythematosus: mechanistic basis of the association. 1808 18

Chemokines and cytokines play an important role in the inflammatory development and progression of autoimmune diseases. The aim of the present study was to evaluate the role of MCP-1, SDF-1, and RANTES polymorphisms as susceptibility markers for systemic lupus erythematosus (SLE) in a group of Mexican patients. MCP-1-2518, SDF-1 G801A, and RANTES-28 polymorphisms were determined in 242 patients with SLE and 220 ethnically matched healthy controls by the polymerase chain reaction-restriction fragment length polymorphism technique. The differences between patients and healthy controls were evaluated by chi(2), Fisher's exact test, and Woolf method for odds ratio. A moderately increased frequency of MCP-1-2518 A allele (p = 0.033, pC = NS) and AA genotype (p = 0.017, pC = NS) existed in SLE patients compared with healthy controls. There was a relationship between polymorphisms and some clinical and laboratory characteristics. SLE patients with and without antiphospholipid syndrome demonstrated different distribution of SDF-1 G801A genotype frequencies. On the other hand, patients with leukopenia, anti-dsDNA, and antiphospholipid autoantibodies demonstrated different MCP-1-2518 genotype distribution compared with patients without these features. Our results suggest that MCP-1 polymorphism is moderately associated with the genetic susceptibility to SLE in Mexican individuals. The polymorphisms could be related to specific clinical and laboratory characteristics in these patients.
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PMID:MCP-1, RANTES, and SDF-1 polymorphisms in Mexican patients with systemic lupus erythematosus. 1819 26

Cytokine blockade, a valid therapeutic concept, is not established in lupus nephritis as yet. In lupus nephritis CCL2/MCP-1 and its chemokine receptor CCR2 are of interest because CCL2/CCR2 mediate the recruitment of macrophages and T cells in the nephritic kidney. Lupus nephritis is markedly attenuated in CCL2- or CCR2-deficient autoimmune mice. Epidemiological studies addressing mutations in the CCL2 gene support the hypothesis that CCL2 mediates renal inflammation. Meanwhile experimental studies have shown that several classes of CCL2 antagonists can control established lupus nephritis. Interestingly, therapeutic CCL2 blockade does not affect the autoimmune lymphoproliferative syndrome and the production of lupus autoantibodies. This article briefly summarizes the potential role of therapeutic CCL2 blockade in lupus nephritis.
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PMID:[CCL2/MCP1: a novel target in systemic lupus erythematosus and lupus nephritis]. 1839 19

We sought to determine if the histone deacetylase inhibitor (HDI), trichostatin A (TSA), would alter systemic lupus erythematosus (SLE) in NZB/W mice. Fourteen to sixteen-week-old female NZB/W F1 mice were given TSA (1.0mg/kg body weight (BW)) intraperitonealy (i.p.) daily, TSA (1.0mg/kg BW) i.p.+anti-CD25 (250mg/mouse) i.p. every third day, only anti-CD25 (250mg/mouse) i.p., DMSO or isotype IgG. Disease progression was assessed as they aged. Mice were sacrificed at 26 or 38 weeks of age, tissues collected and evaluated. At 36 weeks, TSA-treated animals had decreased anti-double stranded DNA (dsDNA) autoantibodies and decreased protein excretion compared to controls. Spleen size and the percentage of CD4+CD69+ cells were decreased, with an increase in CD4+CD25+ T cells in the TSA-treated mice. Real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis of T cells showed a decrease in IL-6 production but an increase in TGF-beta1 and Foxp3 in the TSA-treated animals. Kidney analysis showed a decrease in IgG and C3 deposition, decrease in pathologic glomerular disease and renal MCP-1, MMP-9, and IL-6 mRNA expression. Anti-CD25-treated mice euthanized at 26 weeks of age showed decreased Foxp3+CD4+CD25+ T cells compared to TSA-treated mice. These data suggest TSA administration modulates lupus-like disease, in part, by increasing T regulatory cells.
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PMID:The histone deacetylase inhibitor trichostatin A upregulates regulatory T cells and modulates autoimmunity in NZB/W F1 mice. 1865 65

Lupus nephritis is one manifestation of systemic lupus erythematosus (SLE). Interleukin (IL)-10 is involved in the pathogenesis of SLE. To determine whether IL-20, a member of the IL-10 family, is associated with lupus nephritis, we analyzed the expression of IL-20 and its receptors in mesangial cells derived from SLE-prone, NZB/W, and DBA/W mice. IL-20 and its receptors were upregulated in mesangial cells from NZB/W mice. Incubating IL-20 with mesangial cells upregulated the transcripts of CCL2 (MCP-1), CCL5 (RANTES), CXCL10 (IP-10), IL-6, iNOS, and ROS, all of which are involved in the pathogenesis of lupus nephritis. IL-20 specifically activated the downstream signal ERK 1/2. We also detected human IL-20 protein in both mesangial cells and inflammatory cells in kidney biopsies of patients with lupus nephritis. Our results reveal the novel effects of IL-20 on mesangial cells and its association with lupus nephritis.
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PMID:Interleukin-20 targets renal mesangial cells and is associated with lupus nephritis. 1877 58

Cyclophosphamide (CYC) can control diffuse proliferative lupus nephritis (DPLN) by potent immunosuppression but remains associated with serious and life-threatening complications. Drugs that specifically target mediators of DPLN may help to reduce CYC dose and side effects. Monocyte chemoattractant protein (MCP-1)/CCL2 mediates monocyte and T cell recruitment in DPLN and Ccl2-specific l-enantiomeric RNA Spiegelmer mNOX-E36 neutralizes the biological effects of murine Ccl2 in vitro and in vivo. We injected MRL(lpr/lpr) mice with DPLN from 14 weeks of age with vehicle, weekly 30 mg/kg CYC (full dose), monthly 30 mg/kg CYC (one-fourth full dose), pegylated control Spiegelmer, pegylated anti-Ccl2 Spiegelmer (3/week), pegylated anti-Ccl2 Spiegelmer plus CYC one-fourth full dose and mycophenolate mofetil. At week 24, DPLN and autoimmune lung injury were virtually abolished with CYC full dose but not with CYC one-fourth full dose. The CYC one-fourth full dose/Spiegelmer combination was equipotent to CYC full dose on kidney and lung injury. CD3(+)CD4(-)CD8(-) and CD3(+)CD4(+)CD25(+) T cells and serum interleukin-12p40 and tumor necrosis factor-alpha levels were all markedly affected by CYC full dose but not by CYC one-fourth full dose. No additive effects of anti-Ccl2 Spiegelmer were noted on bone marrow colony-forming unit-granulocyte macrophage counts and 7/4(high) monocyte counts, lymphoproliferation, and spleen T cell depletion. In summary, anti-Ccl2 Spiegelmer permits 75% dose reduction of CYC for controlling DPLN and pneumonitis in MRL-Fas(lpr) mice, sparing suppressive effects of full-dose CYC on myelosuppression and T cell depletion. We propose anti-Ccl2 Spiegelmer therapy as a novel strategy to reduce CYC toxicity in the treatment of severe lupus.
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PMID:Anti-Ccl2 Spiegelmer permits 75% dose reduction of cyclophosphamide to control diffuse proliferative lupus nephritis and pneumonitis in MRL-Fas(lpr) mice. 1899 60

Neuropsychiatric disease in systemic lupus erythematosus (NPSLE) is a poorly understood, but potentially fatal, disease manifestation. A pathogenetic role for autoantibodies is suspected, but the mechanism is unclear. Since immune complexes in SLE can stimulate IFN-alpha and there is strong evidence in humans and in mice that IFN-alpha can cause neuropsychiatric manifestations, we asked whether NPSLE patient serum and/or cerebrospinal fluid (CSF) contain abnormally high IFN-alpha-inducing activity. In a bioassay containing plasmacytoid dendritic cells and a source of Ag, NPSLE CSF induced significantly higher IFN-alpha compared with CSF from patients with multiple sclerosis or other autoimmune disease controls. When normalized for IgG concentration, NPSLE CSF was 800-fold more potent at inducing IFN-alpha compared with paired serum due to inhibitors present in serum. Analysis of Ig-deficient patient serum, depletion of IgG from normal serum, as well as addition of purified IgG to NPSLE CSF and serum in the bioassays revealed that one inhibitor was contained within the IgG fraction itself. In addition to IFN-alpha, immune complexes formed by CSF autoantibodies produced significantly increased levels of IFN-gamma-inducible protein 10 (IP-10/CXCL), IL-8, and MCP-1, all of which have been reported to be elevated in CSF from NPSLE patients. Taken together, these findings are consistent with a two-step model of NPSLE whereby CSF autoantibodies bind to Ags released by neurocytotoxic Abs or other brain cell injury, and the resulting immune complexes stimulate IFN-alpha and proinflammatory cytokines and chemokines.
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PMID:Potent induction of IFN-alpha and chemokines by autoantibodies in the cerebrospinal fluid of patients with neuropsychiatric lupus. 1912 63

Patients with antiphospholipid syndrome (APS) have an increased risk for the development of thrombotic complications. Recent studies indicate that osteoprotegerin (OPG) acts as an important molecule in the development of vascular diseases. The aim of the present study was to examine the association between serum OPG levels and APS manifestations in patients with SLE. Seventy-nine patients with SLE and ninety-two healthy controls, matched for age and sex, were included in this study. Serum levels of OPG, monocyte chemoattractant protein(MCP)-1 and soluble E-selectin were determined by ELISA. At the time of serum sampling, various clinical and laboratory parameters were assessed. We found that serum levels of OPG were significantly higher in patients with SLE than in healthy controls (1236 +/- 82 vs 967 +/- 37 pg/mL, P = 0.003). Particularly, serum OPG levels were significantly higher in SLE patients with APS than those without (1615 +/- 191 vs 1171 +/- 91 pg/mL, P = 0.006). Serum OPG levels correlated with titres of IgG anti-cardiolipin antibody (P = 0.026) and anti-beta(2)-glycoprotein I antibody (P < 0.001). Moreover, serum OPG also correlated with serum levels of sE-selectin (P = 0.002), which is an endothelial cell activation marker, and MCP-1 (P = 0.003), a well known chemokine implicated in thrombogenesis. Collectively, serum OPG levels were increased in SLE patients with APS and correlated with titres of antiphospholipid antibodies, suggesting that OPG might be linked to the development of APS.
Lupus 2009 Feb
PMID:Circulating osteoprotegerin levels are elevated and correlated with antiphospholipid antibodies in patients with systemic lupus erythematosus. 1915 Nov 14

The development and progression of systemic lupus erythematosus (SLE) is strongly associated with complement activation and deposition. The anaphylatoxin C3a is a product of complement activation with immunomodulatory properties, and the receptor for C3a (C3aR) is not only expressed by granulocytes and antigen presenting cell populations, but it is also strongly up-regulated in lupus prone mice with active nephritis. In order to characterize the role of the C3aR in inflammatory nephritis, we bred C3aR knock out mice onto the MRL/lpr genetic background (C3aR KO MRL). Compared to control MRL/lpr mice, C3aR KO MRL mice had elevated auto-antibody titers and an earlier onset of renal injury. At 8 weeks, renal expression of a wide range of chemokines and chemokine receptors was increased in C3aR KO MRL kidneys compared to controls. Only the expression of MCP-1 was significantly decreased in the C3aR KO MRL mice. The increased chemokine and chemokine receptor expression seen in the C3aR KO MRL mice was associated with a more rapid rise in serum creatinine and the acceleration of renal fibrosis. However, loss of the C3aR had little impact on long-term kidney injury and did not alter survival. These findings suggest that activation of the C3aR plays a protective, not pathologic, role in the early phase of inflammatory nephritis in the MRL/lpr model of SLE.
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PMID:C3a receptor deficiency accelerates the onset of renal injury in the MRL/lpr mouse. 1916 60

Members of the TNF-ligand and receptor superfamilies are important in the pathogenesis of lupus nephritis, a major cause of mortality and morbidity in SLE. TWEAK, a member of the TNF-ligand superfamily, is markedly increased in urine from patients with active lupus nephritis, and urinary TWEAK levels significantly correlate with renal disease activity. To support a possible role of TWEAK in the pathogenesis of lupus nephritis and other inflammatory nephritides, we examined the effects of TWEAK in human kidney mesangial cells, podocytes and tubular cells, following our demonstration of the presence of the TWEAK receptor Fn14 on these cells. We found that TWEAK induces human kidney cells to express multiple inflammatory mediators, including RANTES, MCP-1, IP-10, MIP-1alpha, ICAM-1, and VCAM-1. Cytokine production is mediated through NF-kappaB activation, and is inhibited by anti-TWEAK monoclonal antibodies. TWEAK stimulated chemokines induced migration of human PBMC, particularly monocytes/macrophages. Furthermore, we found that TWEAK promotes kidney infiltration of inflammatory cells, and stimulates proliferation of kidney cells in vitro and in vivo. Thus, TWEAK may play an important pathogenic role in the development of glomerulonephritis by promoting a local inflammatory environment and inducing kidney cell proliferation. Blocking TWEAK/Fn14 interactions may be a promising therapeutic target in immune-mediated renal diseases.
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PMID:TNF-like weak inducer of apoptosis (TWEAK) induces inflammatory and proliferative effects in human kidney cells. 1923 85


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