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)

The initial novel observation of this study was that most B cells of male BXSB lupus mice bear surface IgG2a(b) of extrinsic origin. To define the surface antigen, we here examine three (NZBxBXSB)F1-derived IgG2a(b) monoclonal antibodies (mAbs) selected for binding to cell surfaces. Surprisingly, all three mAbs bound the nucleosome (nuc) particle, the fundamental unit of chromatin and an early target of autoimmunity in systemic lupus erythematosus. Their tentative dissociation constant (K(d)) for soluble nuc particles was approximately 7 x 10(-10) m. The mAbs bound more weakly to both H2A-H2B-DNA and H3-H4-DNA complexes, and in immunoblot they stained all four core histones. The mAbs detected a surface antigen on all cell lines examined, present on viable cells. When stripped of nuc, and in the presence of DNase I, their binding to cell lines improved. Heparin displaced the antigen from the cell surface. In vivo, the three mAbs stained B cells of several BALB/c mice clearly stronger than the isotype control; this differential staining was significantly reduced in FcgammaRIIB-deficient mice. The results indicate that the three mAbs recognize (a) planted antigen on viable cultured cells and (b) soluble autoantigen in vivo, leading to immune complexes that bind to FcgammaRIIB. Further experiments demonstrated that antinuc IgG2a could be eluted from splenocytes of a male BXSB lupus mouse. Hence, at least part of the extrinsic IgG2a(b) found on BXSB B cells may represent FcgammaRIIB-bound nuc-IgG2a(b) complexes.
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PMID:Antinucleosome autoantibodies bind directly to cell lines in vitro and via the FcgammaRIIB receptor to B lymphocytes in vivo: a role for immune complexes in interactions between antinucleosome IgG2a and B cells of BXSB lupus mice. 1523 81

DNase I could be the most important nuclease for the removal of DNA from nuclear antigens at sites of high cell turnover, and thus may also prevent systemic lupus erythematosus (SLE). Sixteen SNPs were identified by direct DNA sequencing, among which six were selected for genotyping in a larger investigation on the basis of linkage disequilibria among SNPs, their frequency, location and haplotype tagging status. Genetic associations of polymorphisms in DNase I with the risk of SLE and the production of common autoantibodies were examined in a Korean population (350 SLE patients and 330 controls). Although no significant associations with the risk of SLE were found, logistic regression analyses revealed that one non-synonymous SNPs in exon 8, +2373A>G(Gln244Arg), was significantly associated with an increased risk of the production of anti-RNP and anti-dsDNA antibodies among SLE patients. The frequency of the homozygous minor allele (Arg/Arg) was much higher in patients who had the anti-RNP antibody (31.3%) than in patients who did not have this antibody (14.4%) (P=0.0006, OR=2.86). In addition, the A/T mutation in exon 2 of DNase reported in two Japanese SLE patients was not present in SLE patients (n=350) or controls (n=330) in our Korean population, which combined with the results of previous reports strongly suggests that the mutation is not present in three major ethnic groups: Caucasian, African and Asian.
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PMID:Common DNase I polymorphism associated with autoantibody production among systemic lupus erythematosus patients. 1533 86

Nucleosomes are the dominant autoantigens in patients with systemic lupus erythematosus (SLE), and immune complexes involving nucleosomes are the major cause of tissue damage. The activity of DNase I, the enzyme responsible for nucleosome degradation, has been found to be decreased in patients with SLE. However, it is not known whether DNase activity is a clinically useful parameter. The aim of our study was to assess DNase activity in a prospective study of 113 patients with SLE in relation to disease activity and organ involvement. We included two control groups: 9 patients with undifferentiated connective tissue disease (UCTD) and 14 healthy individuals. DNase activity was found to be lower in patients with SLE (63.75%+/-12.1%) than in the controls (81.3%+/-9.25%) (P<0.001). DNase activity in patients with UCTD (64.9%+/-18.2%; P=0.854) did not differ from that in patients with SLE. Patients with SLE had higher antinucleosome antibody titers (356.3+/-851) than the controls (1.44+/-2.77; P<0.01) or UCTD patients (39.9+/-57.7; P<0.01). In addition, samples positive for antinucleosome antibodies displayed low levels of DNase activity. Within the SLE group, the presence of renal disease had no impact on DNase activity or antinucleosome antibody titers. Also, the SLE disease activity index showed no correlation with DNase activity. In a longitudinal study of six SLE patients, DNase activity did not follow disease activity or autoantibody titers. Our results confirm that serum DNase activity is decreased in patients with SLE, but we conclude that it is not a clinically useful parameter for the prediction of flare-ups of disease or renal involvement.
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PMID:Antinucleosome antibodies and decreased deoxyribonuclease activity in sera of patients with systemic lupus erythematosus. 1564 85

The pathogenetic mechanisms of lupus nephritis (LN) remain to be elucidated. In our previous study, autoantibodies against human glomerular mesangial cells (HMC) were identified in sera of most patients with lupus nephritis. The current study is to investigate the binding characteristics of anti-mesangial cell antibodies to human mesangial cell membrane. Serum samples were collected from 54 patients with renal biopsy proven lupus nephritis, 12 patients with systemic lupus erythematosus without clinical renal involvement, and 15 healthy subjects. Membrane proteins were obtained from in vitro cultured HMC by sonication and sequential centrifugation. DNase I were employed to remove DNA fragments in sera and membrane protein preperation and IgG F(ab')2 was obtained by pepsin digestion. Western Blot analysis was used to characterize the antibody and antigen interaction. In results, 25 of 54 (46.3%) sera from patients with lupus nephritis had anti-mesangial cell antibodies targeted at 74 kDa, 63 kDa, 52 kDa and 42 kDa protein bands of HMC membrane. Only four of 12 (33.3%) sera from patients without renal involovement recognized the protein bands at 74 kDa and 63 kDa, but not 52 kDa and 42 kDa. DNase treatment of the HMC membrane and the sera did not affect the binding. IgG F(ab')2 from sera of 10 patients with positive anti-mesangial cell antibodies could still bind the 63 kDa protein. In conclusion, anti-mesangial cell antibodies from sera of patients with lupus nephritis could bind membrane proteins of HMC directly without a DNA bridge and the binding was through antigen-antibody interation. Anti-mesangial cell antibodies might play some role in the pathogenesis of lupus nephritis(LN).
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PMID:Characterization of anti-mesangial cell antibodies and their target antigens in patients with lupus nephritis. 1598 Oct 94

Not properly cleared dead cells are dangerous for the body. The dead cells accumulate, lose their membrane integrity, danger signals are released, and nuclear antigens get accessible in an inflammatory context. In times of increased apoptosis, tolerance can be broken, a chronic inflammation results which then can lead to an autoimmune reaction against nuclear constituents. An impaired clearance of dying cells represents a central pathogenic process in the development of chronic autoimmune diseases like in systemic lupus erythematosus (SLE). Many adaptor molecules and receptors are involved in the clearance of dying cells. Complement components, serum DNase I, phosphatidylserine, and modified glycoproteins participate crucially in the clearance of apoptotic and necrotic cells. We further observed intrinsic defects of macrophages of some SLE patients. Macrophages as well as granulocytes of some SLE patients showed heterogeneous clearance defects. Furthermore, we observed an accumulation of nuclear material in germinal centres of lymph nodes of some SLE patients. The non-ingested nuclear material may provide survival signals for autoreactive B cells and consecutively antinuclear autoantibodies (ANA) will be produced. We therefore conclude that drugs promoting the phagocytosis are important candidates of specific therapies in the future which expect a more gentle and purposive treatment of patients with SLE.
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PMID:[An impaired detection and clearance of dying cells can lead to the development of chronic autoimmunity]. 1618 43

Systemic lupus erythematosus (SLE) is characterized by a diverse array of autoantibodies, particularly against nuclear antigens, thought to derive from apoptotic and necrotic cells. Impaired clearance functions for dying cells may explain accumulation of apoptotic cells in SLE tissues, and secondary necrosis of these cells may contribute to the chronic inflammation in this disease. The exposure of phosphatidylserine (PS) and altered carbohydrates on dying cells are important recognition signals for macrophages. Furthermore, serum factors such as complement, DNase I, pentraxins (e.g. C-reactive protein) and IgM contribute to efficient opsonization and uptake of apoptotic and necrotic cells. Defects in these factors may impact the development of SLE in humans and mice in a variety of ways. We observed impaired clearance of apoptotic cells in lymph nodes and skin biopsies of humans with lupus, as well as intrinsic defects of macrophages differentiated in vitro from SLE patients' CD34+ stem cells, demonstrating that apoptotic cells are not properly cleared in a subgroup of patients with SLE. This altered mechanism for the clearance of dying cells may represent a central pathogenic process in the development and acceleration of this autoimmune disease.
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PMID:Clearance of apoptotic cells in human SLE. 1639 61

Systemic lupus erythematosus (SLE) is characterised by the production of autoantibodies against ubiquitous antigens, especially nuclear components. Evidence makes it clear that the development of these autoantibodies is an antigen-driven process and that immune complexes involving DNA-containing antigens play a key role in the disease process. In rodents, DNase I is the major endonuclease present in saliva, urine and plasma, where it catalyses the hydrolysis of DNA, and impaired DNase function has been implicated in the pathogenesis of SLE. In this study we have evaluated the effects of transgenic over-expression of murine DNase I endonucleases in vivo in a mouse model of lupus. We generated transgenic mice having T-cells that express either wild-type DNase I (wt.DNase I) or a mutant DNase I (ash.DNase I), engineered for three new properties - resistance to inhibition by G-actin, resistance to inhibition by physiological saline and hyperactivity compared to wild type. By crossing these transgenic mice with a murine strain that develops SLE we found that, compared to control non-transgenic littermates or wt.DNase I transgenic mice, the ash.DNase I mutant provided significant protection from the development of anti-single-stranded DNA and anti-histone antibodies, but not of renal disease. In summary, this is the first study in vivo to directly test the effects of long-term increased expression of DNase I on the development of SLE. Our results are in line with previous reports on the possible clinical benefits of recombinant DNase I treatment in SLE, and extend them further to the use of engineered DNase I variants with increased activity and resistance to physiological inhibitors.
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PMID:The in vivo expression of actin/salt-resistant hyperactive DNase I inhibits the development of anti-ssDNA and anti-histone autoantibodies in a murine model of systemic lupus erythematosus. 1660 42

Dying cells were basically unnoticed by scientists for a long time and only came back into the spotlight roughly 10 years ago. The process of recognition and uptake of apoptotic and necrotic cells is complex and failures in this process can contribute to the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Here, we discuss the recognition and uptake molecules which are involved in an efficient clearance of dying cells in early and late phases of cell death. The exposure of phosphatidylserine (PS) is an early surface change of apoptosing cells recognized by several receptors and adaptor molecules. We demonstrated that dying cells have cell membranes with high lateral mobility of PS, which contribute to their efficient clearance. Changes of the glycoprotein composition of apoptotic cells occur later than the exposure of PS. We further observed that complement binding is an early event in necrosis and a rather late event in apoptosis. Complement, C-reactive protein (CRP), and serum DNase I act as back-up molecules in the clearance process. Finally, we discuss how the accumulation of secondary necrotic cells and cellular debris in the germinal centers of secondary lymph organs can lead to autoimmunity. It is reasonable to argue that clearance defects are major players in the development of autoimmune diseases such as SLE.
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PMID:Inefficient clearance of dying cells and autoreactivity. 1672 5

Anti-double strand DNA antibodies (anti-dsDNA) involve in lupus nephritis. However, their role in tissue damage mechanism remains unclear. In this study, a 45-kDa cognate antigen of anti-dsDNA monoclonal antibodies 9D7 was identified by two-dimensional gel electrophoresis and determined to be human phosphoglycerate kinase 1 (PGK-1) by MALDI-TOF analysis. The binding of 9D7 to PGK-1 was not affected by DNase I but was inhibited by thymus dsDNA. Human SLE sera with high anti-dsDNA titers had a high affinity with PGK. In activated Jurkat T cells, 9D7 decreased the PGK-1 mRNA production and IL-2 promoter activity. Reduction in IL-2 gene expression and protein production were observed in the 9D7-treated cells. Because PGK-1 deficiency may cause mental tardy and hemolytic anemia, interaction between anti-dsDNA and PGK-1 may be important in lupus pathogenesis. Moreover, reduction in IL-2 production by anti-dsDNA suggests their role in increasing infection rate and decreasing proper generation of activation-induced cell death.
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PMID:Monoclonal anti-double-stranded DNA antibodies cross-react with phosphoglycerate kinase 1 and inhibit the expression and production of IL-2 in activated Jurkat T cell line. 1685 29

We report the development of a novel quartz crystal microbalance immunosensor with the simultaneous measurement of resonance frequency and motional resistance for the detection of antibodies to double-stranded DNA (dsDNA). The immobilization of poly(L-lysine) and subsequent complexation with DNA resulted in formation of a sensitive dsDNA-containing nanofilm on the surface of a gold electrode. Atomic force microscopy has been applied for the characterization of a poly(L-lysine)-DNA film. After the blocking with bovine serum albumin, the immunosensor in flow-injection mode was used to detect the antibodies to dsDNA in purified protein solutions of antibodies to dsDNA and to single-stranded DNA, monoclonal human immunoglobulin G, DNase I and in blood serum of patients with bronchial asthma and systemic lupus erythematosus. Experimental results indicate high sensitivity and selectivity of the immunosensor.
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PMID:Quartz crystal microbalance immunosensor for the detection of antibodies to double-stranded DNA. 1739 48


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