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)

Studies reported during the past year have added new knowledge to our understanding of cellular abnormalities in systemic lupus erythematosus: 1) Antigen-specific and "pathogenic" T cells display a limited T cell receptor repertoire in lupus. 2) The ratio of interleukin-10 to interferon gamma-secreting cells in the peripheral blood of patients with lupus is increased in patients with active disease. 3) CD3-mediated increases in free intracytoplasmic calcium occur specifically in lupus T cells and lines; this finding provides additional evidence that cell-signaling events are defective in patients with lupus. 4) Aberrant expression of adhesion molecules on the surface membrane of leukocytes and endothelial cells was shown, a finding with important mechanistic and therapeutic implications. 5) Lupus antigen-presenting cells fail to upregulate the expression of B7-1 (CD80) in response to interferon gamma; defective expression of B7-1 is responsible for the decreased response of lupus cells to recall antigens.
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PMID:Lymphocytes, cytokines, inflammation, and immune trafficking. 894 41

During the past year several novel reports have added new knowledge to our understanding of the pathogenesis of system lupus erythematosus (a) a novel pathway for the presentation of autoantigens to autoreactive T cells was revealed. Universally binding nucleosomal epitopes are productively recognized by autoreactive T cells by binding to the T-cell receptor-alpha chain; (b) circulating T cells from patients with lupus commonly display a deficiency of the T-cell receptor zeta chain, and upon ligation of their cell-surface antigen receptor overproduce tyrosine phosphorylated proteins; (c) lupus and lupus nephritis are associated with a low-binding FcgammaRIIIA (CD16) polymorphism that crosses ethnic barriers; (d) the pathogenetic role of the cytokine interleukin-10 is expanding, because it is reportedly overproduced not only by cells from lupus patients but also by cells from their healthy relatives, and its overproduction in vitro is correlated with increased apoptotic cell death and with lymphopenia.
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PMID:Lymphocytes, cytokines, inflammation, and immune trafficking. 974 56

It is controversial whether mixed connective tissue disease (MCTD) should be regarded as a distinct disease entity. In the present study, we investigated immunological parameters in patients with MCTD by studying serum levels of immunoglobulins, C-reactive protein (CRP) and cytokines and compared the results to the corresponding values in systemic lupus erythematosus (SLE), in rheumatoid arthritis (RA) patients and in healthy controls. Using the ELISA technique, serum levels of the cytokines interferon-gamma (IFN-gamma), interleukin-10 (IL-10) and tumour necrosis factor-alpha (TNF-alpha) were investigated. Cytokine levels in SLE and MCTD were correlated to disease activity as assessed by systemic lupus activity measure (SLAM). They were also correlated to serum levels of CRP, IgG, IgA and IgM in the three patient groups. The MCTD patients had the highest levels of immunoglobulins, followed by the SLE patients. In contrast, the highest CRP levels were observed in RA patients, followed by the MCTD patients. The MCTD patients had the highest serum levels of IL-10, but also had elevated IFN-gamma and TNF-alpha levels similar to the RA patients. There was no correlation between the investigated cytokine levels and disease activity, as assessed by SLAM. We conclude that MCTD patients have high immunoglobulin levels as well as high CRP levels and that this situation is compatible with the observed increase in both type 1 and type 2 cytokine levels. The findings imply that MCTD shares some distinct immunological properties with both RA and SLE and that MCTD may also be considered as a separate disease entity according to these properties.
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PMID:Increased serum levels of immunoglobulins, C-reactive protein, type 1 and type 2 cytokines in patients with mixed connective tissue disease. 980 36

Lupus nephritis can be managed successfully in the majority of cases; most therapies, however, are associated with significant side-effects. Several new agents aiming at specific stages in the pathogenesis of lupus are in different phases of clinical trials. The central role of lymphocytes makes them targets of various therapeutic approaches. Lymphocyte depletion can be achieved by high-dose chemotherapy with or without bone marrow transplantation. Nucleoside analogs selectively deplete mononuclear cells; antibodies against T or B cell surface antigens target specific subsets of lymphocytes. Synchronized plasmapheresis has been used in an attempt to delete pathogenic lymphocyte clones activated by plasmapheresis. Treating patients with DNase or neutralizing pathogenic antibodies by administering specific binding peptides or inducing specific anti-idiotype antibodies may prevent immune complex formation and/or deposition. Blocking the complement cascade or some of the inflammatory mediators like thromboxane A2 may be efficacious even if immune complex deposition could not be prevented. Inducing antigen-specific tolerance or interfering with important interactions between T-lymphocytes and other cells by blocking CD40 ligand or decreasing the level of interleukin-10 are some of the other approaches currently under clinical investigation.
Lupus 1998
PMID:Novel approaches in the treatment of lupus nephritis. 988 4

Early onset periodontitis (EOP) is considered to have a substantial genetic basis, although the gene or genes involved have not been elucidated. The aim of the present study was to investigate possible links between generalized EOP (GEOP) and genes regulating expression of the cytokines tumour necrosis factor (TNF) and interleukin-10 (IL-10). Microsatellite marker DNA sequences corresponding to phenotypic variations in cytokine response were analysed. Genotypic variations in cytokine response have been shown in vitro for TNF and IL-10, and specific alleles are implicated in diseases such as systemic lupus erythmatosus (SLE) and rheumatoid arthritis (RA). Two microsatellites at the IL-10 locus, IL10.R and IL10.G, and 1 microsatellite at the TNF locus, TNFa, were typed for 77 GEOP patients in the West of Scotland. Due to the highly polymorphic nature of the microsatellite loci, a statistical comparison with ethnically matched healthy controls (TNFa, n = 91, IL10.R, n = 94, IL10.G, n = 102) was conducted using a Monte Carlo simulation for each marker. No significant differences were observed for any of the 3 markers, although there were possible indications of trends similar to those observed in SLE for the IL10.G marker. In conclusion, no links were found between GEOP and microsatellites at TNFa, IL10.R or IL10.G loci.
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PMID:Analysis of genetic polymorphisms at the interleukin-10 and tumour necrosis factor loci in early-onset periodontitis. 1068 65

To investigate the effects of the estrogen receptor-binding molecule bisphenol A (BPA) on murine immune function in vivo, we fed a low dose of 2.5 micro g BPA/kg body weight/day to both normal C57BL/6 and lupus-prone NZB X NZW F(1) (NZB/NZW) 5-week-old mice for 1 week. Analysis of concanavalin A (ConA)-stimulated splenic mononuclear cells by ELISA demonstrated that BPA-fed C57BL/6 males produced, on average, 40% less interferon-gamma (IFN-gamma; p < 0.01) and C57BL/6 females 28% less IFN-gamma (p < 0.05) compared with controls. Treated female NZB/NZW mice were monitored for lupus disease symptoms, defined as proteinuria (> 100 mg/dL albumin in urine for 2 consecutive weeks). Before the development of proteinuria, BPA-fed NZB/NZW mice produced significantly less ConA-stimulated IFN-gamma than did controls and displayed an average reduction of 50% in immunoglobulin G2a (IgG2a) antibody production from lipopolysaccharide (LPS)-stimulated splenocytes (p < 0.05). It is striking that 5-week-old female NZB/NZW mice fed a 7-day low-dose course of BPA developed proteinuria an average of 7 weeks later than did controls. Once proteinuria developed, splenocytes were stimulated with ConA for cytokine analysis. The BPA-fed mice showed a dramatic reduction of 64% in IFN-gamma production and a 32% reduction in ConA-stimulated interleukin-10 (p < 0.05). The long-lasting effects of BPA on IFN-gamma and IgG2a production likely contributed to the increased symptom-free period of the NZB/NZW mice.
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PMID:Effect of bisphenol A on murine immune function: modulation of interferon-gamma, IgG2a, and disease symptoms in NZB X NZW F1 mice. 1464 61

Although systemic lupus erythematosus (SLE) is indeed a complex autoimmune disease, recent advances in our understanding of lupus pathogenesis have suggested new, targeted approaches to therapy. The purpose of this review is to discuss the underlying scientific rationale and results of first clinical studies of new treatment approaches to SLE, with a focus on cell-depleting therapies and cytokine blockade. It has become clear that the B lymphocyte plays a key role in disease pathogenesis by both autoantibody-dependent and autoantibody-independent mechanisms. Additionally, aberrant interactions between B and T cells are critical to disease emergence and progression. New agents that directly target immune cells abnormal in SLE include the B-cell depleting or modulating antibodies, rituximab (anti-CD20) and epratuzumab (anti-CD22) and the anti-dsDNA tolerogen LJP394. Another promising approach has been to block co-stimulatory interactions between T and B cells, for example by inhibiting the CD40-CD40 ligand pathway with anti-CD40 ligand monoclonal antibody or the B7 pathway with CTLA-4Ig. Immune cells can also be manipulated indirectly through cytokine effects. For B cells, anti-BAFF (B-cell activation factor of the tumor necrosis family) provides an example of this approach. Other, more pleiotropic cytokines can likewise be blocked in SLE. In addition to the blockade of interleukin-10 (IL-10), the first anti-cytokine approach examined, it is mainly anti-tumor necrosis factor therapy that has come into focus, holding promise for some patients with lupus nephritis. The majority of the available data on these new treatment approaches stems from open-label trials, but controlled trials are under way. Moreover, many additional cytokines, such as interleukin (IL)-6, IL-18, and the type I interferons, represent interesting future targets.
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PMID:New treatments for SLE: cell-depleting and anti-cytokine therapies. 1615 Apr 7

The objective of the study is to examine whether interleukin-10 (IL-10) promoter polymorphism is a marker of susceptibility of systemic lupus erythematosus (SLE) in Chinese patients in Taiwan. The study included 119 Chinese patients with SLE. One hundred unrelated healthy individuals living in central Taiwan served as control subjects. Each polymorphism was detected as a result of a polymerase chain reaction (PCR)-based restriction analysis. The PCR product length was determined to be 412 bp (CC) whereas two fragments of 236 and 176 bp were determined to be excisable lengths (AA). The relationship between the IL-10 gene polymorphism and clinical manifestations of SLE was evaluated. For the genotype and allelic frequency, there were statistically significant differences between the SLE patients and the normal control subjects (p=0.007 and 0.003, respectively). But we did not detect any association of carriage rate of the IL-10 polymorphism and the normal control subjects (p=0.077). Furthermore, we did not detect any association of IL-10 genotype with antinuclear antibody, malar rash, photosensitivity, discoid lupus, mucosal ulcer, arthritis, serositis, hematology, immunology, involvement of central nervous system, and renal disease involvement in the SLE patients. The significant relation of -627 IL-10 genotype and allelic frequency with SLE implies that the IL-10 gene polymorphism can serve as a candidate gene marker for further study in patients with SLE in Taiwan.
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PMID:The association of -627 interleukin-10 promoter polymorphism in Chinese patients with systemic lupus erythematosus. 1682 68

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibodies and systemic clinical manifestations. In this study we investigated the beneficial effects on murine lupus accomplished by a peptide based on the sequence of the complementarity-determining region 1 of an anti-DNA autoantibody (hCDR1) when given alone or in combination with cyclophosphamide (CYC), and determined the mechanisms underlying those effects. SLE-afflicted (NZB x NZW) F(1) mice were treated for 12 weeks with injections of hCDR1, CYC or a combination of both drugs. We found that hCDR1 and CYC ameliorated serological and renal manifestations of the diseased mice, down-regulated interferon-gamma and interleukin-10, and up-regulated transforming growth factor-beta. These effects were associated with an increment of naive CD4(+) cells at the expense of the number of CD4(+) cells with the memory/activated phenotype. Further, the number of CD8(+) cells in the diseased mice was increased by the two drugs, resulting in a significant decrease in the CD4 : CD8 ratio. However, whereas the frequency and activity of CD4(+) CD25(+) CD45RB(low) regulatory T cells and the expression of cytotoxic T-lymphocyte antigen 4 (CTLA-4) in CD4(+) cells were up-regulated by hCDR1 treatment, they were minimally affected following treatment with CYC. CTLA-4 played an important role in the activity of the hCDR1-induced CD4(+) CD25(+) cells as manifested by down-regulation of CD28 expression, decrease of activation-induced apoptosis, and modulation of the cytokine profile in CD4(+) CD25(-) cells derived from SLE-afflicted mice. Thus, although the two drugs have similar ameliorative effects, hCDR1 but not CYC elicits regulatory pathways that are of importance for tolerance induction in SLE.
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PMID:Clinical amelioration of murine lupus by a peptide based on the complementarity determining region-1 of an autoantibody and by cyclophosphamide: similarities and differences in the mechanisms of action. 1734 82

The outcome of pregnancy in systemic lupus erythematosus is still controversial. The authors recently reported the disappearance of the manifestation of the skin disease but a diminished survival rate in lupus-prone animals undergoing several pregnancies. It was postulated that lupus-prone animals must have subclinical renal symptoms at an early age and that immune and hormonal changes during pregnancy exacerbate immune reactions in the kidneys, leading to a shortened life span. Here, the authors analysed changes at day 14 of pregnancy in lupus-prone LPR (MRL/lpr) mice and MRL controls regarding cytokines, regulatory T (Treg) cells and deposition of immunocomplexes. Worsened kidney function was observed during pregnancy, even in the absence of lupus signs. This was accompanied by renal inflammation and higher interferon-gamma and interleukin-10 levels. C3 and immunoglobulin G deposition was enhanced in kidney and placenta from lupus-prone pregnant animals. Pregnancy enhanced the levels of Treg cells in control animals but not in lupus-prone animals. As pregnancy-induced Treg cells were shown to be specific for paternal antigens it is not to be expected that these Treg cells can help to destroy autoreactive cells. The authors conclude that early subclinical kidney disease in lupus-prone animals exacerbates during pregnancy. Albeit obtained with an experimental animal model, their data are potentially of importance for lupus patients of reproductive age.
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PMID:Mechanisms behind flare of renal lupus during murine pregnancy. 1861 99


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