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)

The effects of recombinant mouse DNase on a well established murine model of spontaneous SLE have been evaluated. Daily intraperitoneal injections of DNase were given to female NZB/NZW F1 mice during the period of disease development from 4 to 7 months of age or at the height of disease activity from the age of 7 months for 3 weeks. This treatment was compared with the injections of diluent and with an immunosuppressive dose of dexamethasone. The effects of treatment were evaluated using the immunological parameters of disease activity (antinucleoprotein antibody, immune complexes, serum immunoglobulins, anti-cardiolipin antibodies), protein-uria, serum creatinine and renal histopathology (light microscopy, immunofluorescence and electron microscopy). The dose of dexamethasone used (1 mg/kg per day from the age of 4 months) was sufficient to suppress the development of lupus entirely. Treatment with DNase starting at the age of 4 months postponed the development of the disease by about 1 months and extended the period from the onset of disease to death by about 30%. Mice treated for 3 weeks during the most active phase of the disease at 7 months of age showed more dramatic effects. Proteinuria and serum creatinine were significantly reduced and renal histopathology was strikingly less severe than in the control group. Immune complexes involving DNA-containing antigens are believed to play a crucial role in the pathogenesis of SLE. DNA-nucleoprotein, even in immune complexes, can be destroyed by DNase. This enzyme therefore provides a rational way to interfere with the disease process. The results reported here encourage a trial of recombinant human DNase in human SLE and lupus nephritis.
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PMID:The treatment of systemic lupus erythematosus (SLE) in NZB/W F1 hybrid mice; studies with recombinant murine DNase and with dexamethasone. 891 61

A new radial enzyme diffusion (RED) method for the measurement of DNase activity in serum and urine is described. The sensitivity of the assay is in the range of 15.6-500 ng/ml. The assay is based on the hydrolysis of double-stranded (ds) DNA (or nucleosomes) in agarose. The specificity of the reaction for DNase I was established by showing that either EDTA in the reaction buffer or G-actin abolished DNase activity. Being a functional assay, RED has advantages over radioimmunoassay (RIA) or ELISA, since antigenic assays may also measure complexes of DNase with actin. This method was used to measure DNase activity in the sera and urine of lupus-prone mice (NZB/NZW F1 hybrids, aged 4-6 weeks). Serum DNase activity in these mice was significantly lower (mean 9 ng/ml) than in control, normal mice of the same age and sex (mean 37 ng/ml). Concentration of DNase in the urine of 4-6-week-old female NZB/NZW F1 hybrids (24 ng/ml) was significantly lower then in control mice (521 ng/ml). The RED method was used to measure the concentration of actin as the DNase inhibitor in serum. G-actin in the presence of ATP binds DNase and inhibits its nucleolytic activity. Since ATP is necessary for the actin inhibition of DNase I, this shows that there is actin as well as DNase I in the serum. Actin is not only ATP-dependent, but also heat-labile. Heating the sera for 10 min at 50 degrees C increases DNase activity. This is an alternative method for measuring the concentration of actin in the serum. An almost identical estimate of actin concentration in sera of normal mice was found from the difference of DNase activity in the presence or absence of ATP (mean actin concentration = 21 ng/ml) or from the difference of DNase activity in heated and non-heated serum (mean actin concentration 18 ng/ml). We were not able to demonstrate DNase inhibitors in the urine of either control or NZB/W F1 hybrid mice.
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PMID:Measurement of deoxyribonuclease I (DNase) in the serum and urine of systemic lupus erythematosus (SLE)-prone NZB/NZW mice by a new radial enzyme diffusion assay. 915 89

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

In systemic lupus erythematosus hyperactive helper T-cells drive polyclonal B-cell activation and secretion of pathogenic auto-antibodies. The auto-antibodies form immune complexes with their respective auto-antigens, which in turn deposit in sites such as the kidney and initiate a destructive inflammatory reaction. Lupus nephritis can be managed successfully in the majority of cases; however, the most widely used immunosuppressive therapies, notably corticosteroids and cyclophosphamide are non-specific and are associated with substantial toxicities. Novel treatments for lupus nephritis have to be at least as effective and less toxic than existing therapies. The ultimate aim is to develop treatments that target specific steps in the disease process. Novel therapeutic strategies in the short-term more likely will focus on refining regimens of drugs that are already in use (mycophenolate mofetil, adenosine analogues) and combinations of existing chemotherapeutic agents, as well as attempts to achieve immunological reconstitution using immunoablative chemotherapy with or without haematopoietic stem cell rescue. Several new agents targeting specific steps in the pathogenesis of lupus are in various phases of clinical development. Interrupting the interactions between T-lymphocytes and other cells by blocking co-stimulatory molecules, such as CD40 ligand or CTLA4-Ig, may interfere with the early steps of pathogenesis. Blocking IL-10 may decrease auto-antibody production and help normalise T-cell function. Treating patients with DNase or interfering with the complement cascade by blocking C5, or neutralising pathogenic antibodies by administering specific binding peptides or inducing specific anti-idiotype antibodies may prevent immune complex formation and/or deposition.
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PMID:Novel approaches in the treatment of lupus nephritis. 1177 39

Anti-DNA Abs commonly found in patients with systemic lupus erythematosus are thought to play an important pathogenic role in lupus nephritis. Anti-DNA Abs may contribute to renal disease by cross-reactivity with renal Ags, the identity of which remain elusive. To identify a target Ag for pathogenic anti-DNA Abs, we performed Western blotting and immunoprecipitations of mesangial cell lysates from the lupus-prone MRL-lpr/lpr mouse and a nonautoimmune BALB/c mouse with the pathogenic anti-DNA Ab R4A. We found that R4A (but not a nonpathogenic Ab mutant of R4A) binds to and immunoprecipitates a 100-kDa protein expressed on the cell surface and in lysates of MRL-lpr/lpr mesangial cells. DNase treatment of the lysate and of the R4A Ab did not effect binding, indicating that the binding of R4A to the 100-kDa protein was direct and not mediated by an antigenic bridge containing DNA. Binding was greatly diminished in BALB/c lysates, suggesting that Ag expression or availability at the level of the target organ may be a factor in determining susceptibility to lupus nephritis. Following identification of this 100-kDa protein as nonmuscle alpha-actinin, binding of R4A to alpha-actinin was confirmed by Western blot, ELISA, inhibition studies, and immunofluorescence. High titers of anti-alpha-actinin Abs were present in sera and kidney eluates of lupus mice with active nephritis. These results indicate that the nephritogenicity of some anti-DNA Abs may be mediated via cross-reactivity with alpha-actinin. Furthermore, variations in target Ag display between individuals may underlie differential susceptibility to anti-DNA Ab-induced renal disease.
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PMID:Alpha-actinin is a cross-reactive renal target for pathogenic anti-DNA antibodies. 1188 81

The mechanisms by which anti-DNA antibodies contribute to the pathogenesis of lupus nephritis (LN) remain to be elucidated. This study investigates the binding of polyclonal anti-DNA immunoglobulins from patients with systemic lupus erythematosus (SLE) to human mesangial cells (HMC) in vitro. Testing of cross-sectional serum samples from 280 LN patients (108 during active disease; 172 during remission), 35 SLE patients without renal involvement, 72 patients with non-lupus primary glomerular diseases, and 37 healthy subjects with a cellular enzyme-linked immunosorbent assay showed significant IgG mesangial cell-binding activity in patients with SLE, particularly those with active LN (P < 0.0001). Significant HMC-binding activity was demonstrated in 83.9%, 42.8%, and 47.1% of patients with active LN, inactive LN, and non-renal SLE, respectively. This was predominantly attributed to binding by anti-DNA antibodies, and immune complex binding accounted for 4.6%, 3.5%, and 2.8% of seropositive samples in the respective groups. Longitudinal studies in 27 LN patients demonstrated correlation between serial levels of anti-DNA antibodies, serum HMC-binding activity, and disease activity in 18 patients (66.7%). Affinity-purified polyclonal IgG anti-DNA antibodies from sera with HMC-binding activity showed significant binding to cultured HMC, and to a lesser extent glomerular and proximal tubular epithelial cells and human umbilical vein endothelial cells, but not tumor cell lines, peritoneal mesothelial cells, bronchial epithelial cells, or fibroblasts. The binding of anti-DNA antibodies to HMC was increased 1.47-fold (P = 0.0059) after the removal of Ig-associated DNA by DNase treatment, but it was unaffected by DNase treatment of HMC membrane. Controlled trypsinization of membrane proteins in HMC resulted in a 1.26-fold (P = 0.0025) increase in their binding by anti-DNA antibodies. In conclusion, subsets of anti-DNA antibodies from patients with SLE are capable of binding to HMC. The association of such binding with renal involvement and disease activity and its modulation by DNA concentration suggest that Ig binding to HMC can be a potential marker for disease activity in selected patients and that the binding of anti-DNA antibodies to HMC may be a pathogenetic mechanism in LN.
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PMID:Mesangial cell-binding anti-DNA antibodies in patients with systemic lupus erythematosus. 1196 Oct 9

The dominant autoantigen in SLE is the nucleosome and immune complexes involving nucleosomes are the major cause of tissue damage. Nucleosomes can be broken down in vivo with Desoxyribonuclease 1. DNase 1 from humans and mice is inhibited by actin and it is proposed that the release of platelet actin at inflammatory sites is one mechanism which causes nucleosomes to become antigenic. Rats whose DNase 1 is not inhibited by actin do not get lupus. Treatment of NZB/W mice with recombinant DNase slows the onset of their disease if given early and improves the renal disease if given later. This disease can also be entirely prevented by treatment with dexamethasone. Mice whose DNase 1 gene is knocked out are known to develop lupus and to be otherwise normal. DNase 1 especially in its mutant actin and salt resistant forms remains an attractive candidate for the treatment of SLE.
Lupus 2003
PMID:Lupus and desoxyribonuclease. 1270 82

Deoxyribonucleases (DNases) are key enzymes for digesting DNA. Abnormalities in the function of these enzymes may contribute to the development of anti-DNA antibodies in systemic lupus erythematosus (SLE). In this study, we used bovine DNase 1-coated ELISA plates to screen anti-DNase antibodies in SLE patients. About 62% of the sera of SLE patients (63/101) were positive for anti-DNase antibodies compared to only 8% of normal controls (8/98). A positive correlation was also found between the concentrations of anti-DNase and anti-DNA antibodies in sera of SLE patients. Affinity-purified anti-DNase immunoglobulin G (IgG) from pooled sera of SLE patients bound to bovine DNase as well as DNA. A synthetic peptide, corresponding to the catalytic site of DNase, was able to completely inhibit the binding of anti-DNase IgG to DNase. In addition to bovine DNase, the anti-DNase IgG also bound to and inhibited the enzymatic activities of DNase present in streptococcal supernatants and human urine. Immunization of lupus-prone NZB/NZW mice with bovine DNase enhanced the production of anti-DNase and DNA antibodies, and accelerated the occurrence of proteinuria. Taken together, these results suggest that DNase-inhibitory antibodies which recognize a conserved epitope near the catalytic site of DNase may act in the pathogenesis of SLE.
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PMID:Deoxyribonuclease-inhibitory antibodies in systemic lupus erythematosus. 1292 95

Two outstanding questions concerning antinuclear antibodies (ANAs) in lupus involve their pathogenic potential and their molecular signatures. To address these questions, a panel of 56 antinuclear and 47 nonnuclear binding monoclonal antibodies was rescued from four seropositive NZM2410 lupus mice. The monoclonals varied in their reactivity to nucleosomes, ssDNA, dsDNA, and glomerular substrate. A large fraction of the antibodies demonstrated apparent polyreactivity (to DNA, histones, and glomerular antigens) due to bound, DNase-1 sensitive nuclear antigenic bridges. Although nephrophilic immunoglobulin (Ig) M and IgG antibodies were the most pathogenic, the dsDNA-binding antibodies were modestly so; in contrast, antinucleosome antibodies were clearly not pathogenic. Compared with the nonnuclear antigen-binding monoclonal antibodies rescued from the same mice, ANAs exhibited increased utilization of VH5/7183 genes and highly cationic heavy chain (HC) CDR3 regions. Most intriguingly, the CDR3 regions of the ANAs exhibited alternating arginine/lysine peaks at H96, H98, and H100, with neutral troughs at H95, H97, and H99. To summarize, glomerular-binding anti-dsDNA antibodies appear to be the most pathogenic variety of lupus autoantibodies. The presence of an alternating charge pattern in their HC CDR3 regions appears to be a prominent hallmark of ANAs.
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PMID:Pathogenic profiles and molecular signatures of antinuclear autoantibodies rescued from NZM2410 lupus mice. 1475 44

DNA/anti-DNA Ab immune complexes seem to play the critical roles in the development of systemic lupus erythematosus (SLE). However, little is known about the removal of DNA by MPhi and DC. We found that elicited peritoneal MPhis and BM-derived DCs from a lupus-prone strain of New Zealand Black/White F(1) (NZB/W) mice showed impaired DNA uptake and degradation compared with those from control ICR mice. The impairment was mainly observed as the reduced degradation of DNA probably in endosomal compartment and this impaired DNA degradation might, at least in part, result from the reduced DNA uptake in these phagocytic cells. In addition, these impairments was not related to the disease progression since the cells from diseased, 6-month-old NZB/W mice as well as the cells from prediseased, 5-week-old NZB/W mice also exhibited the similar impairment. We also found that the MPhis and DCs of diseased NZB/W mice showed reduced DNA binding at 4 degrees C. However, this reduced DNA binding could be restored to the control level by pretreatment with DNase. Interestingly, this pretreatment had little effect on the DNA uptake in MPhis and DCs of diseased NZB/W mice at 37 degrees C. Hence, the present results imply an impaired function of lupus MPhis and DCs of NZB/W mice to cause retained DNA clearance.
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PMID:The uptake and degradation of DNA is impaired in macrophages and dendritic cells from NZB/W F(1) mice. 1597 58


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