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)

CBA/KlJms-lprcg/lprcg mice with a novel mutation producing systemic lymphoproliferation were investigated for their serological and histological characteristics. The mutant mice showed elevated levels of serum immunoglobulin, C1q-binding immune complexes and antibodies to nuclear antigens such as dsDNA and ssDNA and poly(ADP-ribose). In contrast, histopathological lesions, e.g. glomerulonephritis, vasculitis or interstitial pneumonitis, were not revealed by histological and immunofluorescent examinations, except for lymphocytic infiltration in various organs. These results suggest that this mutant mouse strain may provide a new animal model for autoimmunity. However, further investigations are required to clarify whether this strain is unique as compared with other well-known lupus-prone strains of mice with respect to serological and histological abnormalities and become to be a new model of systemic autoimmune disease.
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PMID:Serological and histological characterization of the new mutant strain of lpr mice, CBA/KlJms-lprcg/lprcg. 230 30

Monoclonal anti-poly(ADP-ribose) (MRP-2) was primarily a product of a hybridoma selected by binding to poly(ADP-ribose) from an autoimmune MRL/Mp-lpr/lpr (MRL/1) mouse. Detailed examination revealed that anti-poly(ADP-ribose) monoclonal IgMK antibody bound not only to left-handed Z-DNA and single-stranded (ss) DNA but also to a conformational epitope formed by histone and double-stranded (ds) DNA. A reconstitution study revealed that association of dsDNA with histone H3 plus H4 was essential for their binding to MRP-2 monoclonal antibody. MRP-2 monoclonal antibody acted as a rheumatoid factor (RF). Since some monoclonal or polyclonal human serum antibodies of rheumatoid arthritis (RA) or mixed connective tissue disease (MCTD) have been reported to recognize shared epitopes of denatured IgG and DNA-histone (nucleosomes), this MRP-2 monoclonal antibody with the similar activity derived from a lupus-prone mouse will be useful for the studies on the etiology of autoantibodies associated with RA, MCTD and systemic lupus erythematosus (SLE).
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PMID:A unique monoclonal antibody derived from a lupus-prone mouse with multiple bindings to autoantigens associated with rheumatic disease. 246 46

An MRP-2 monoclonal antibody (MoAb) was primarily a product of hybridoma selected by binding to poly(ADP-ribose) from a lupus prone MRL/Mp-lpr/lpr (MRL/l) mouse, and was shown to cross-react with single-stranded (ss) DNA. Detailed examination revealed that MRP-2 MoAb bound to a conformational epitope formed between double-stranded (ds) DNA and total histone: both H3 and H4 were essential for the formation of this conformational epitope with dsDNA. Because of this characteristic of the MoAb, its ability to induce lupus erythematosus (LE) cells was examined in an indirect LE test with peripheral blood of MRL/Mp-+/+ (MRL/n) mice, which develop a mild form of lupus after the age of one year. MRP-2 MoAb was found to induce hematoxylin bodies, LE rosettes and LE cells, but a direct LE test using MRL/n mouse blood did not induce LE cell phenomena. This is the first demonstration of induction of LE cells by a MoAb that binds to dsDNA-histone complexes.
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PMID:Lupus erythematosus cell formation by a monoclonal antibody derived from an autoimmune MRL/Mp-lpr/lpr mouse. 246 47

In pregnant autoimmune MRL/Mp-lpr/lpr (MRL/l) mice with many fetuses the level of anti-poly(ADP-ribose) antibodies was found to be the same as that of age-matched non-pregnant female mice, whereas in mice with few fetuses the level of anti-poly(ADP-ribose) antibodies was high in the early period of pregnancy and rapidly returned to control level at puerperium. The anti-poly(ADP-ribose) antibody that increased during pregnancy seemed to be mono-specific for its antigen, whereas the antibody that increased with age was polyspecific. The isotype/subclass of the former was mainly IgG2a. The marked increase in anti-poly(ADP-ribose) antibodies in the early period of pregnancy suggests endogenous sensitization to poly(ADP-ribose), which may be synthesized abnormally or stored during pregnancy, and is a predictive sign in pregnant lupus mice of a low litter size. This finding is applicable to pregnant patients with systemic lupus erythematosus (SLE); that is, it is a predictive sign of fetal loss and/or maternal risk. This was confirmed in the human cases examined so far.
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PMID:Antibody to poly(ADP-ribose) as a predictor of obstetric complications in autoimmune MRL/Mp-lpr/lpr mice: basis for its application to pregnant patients with systemic lupus erythematosus. 337 31

The genetic background of systemic lupus erythematosus (SLE) has been reexamined in a study of the serum of 31 lupus patients and 80 asymptomatic first degree relatives by measuring a common, cross reacting anti-DNA antibody idiotype designated 134, antibodies to poly(ADP-ribose), serum C3, circulating immune complexes, and antinuclear antibodies (ANA). Over 30% of the relatives had raised 134 and anti-poly(ADP-ribose) levels, and 9% had ANA titres greater than 1/20. In contrast, only one relative had a low serum C3 level. These results confirm that immunogenetic abnormalities associated with the production of autoantibodies and particular idiotypes must exist amongst lupus relatives as well as the patients. The production of autoantibodies, however, is not necessarily matched to the clinical expression of SLE.
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PMID:A study of anti-poly (ADP-ribose) antibodies and an anti-DNA antibody idiotype and other immunological abnormalities in lupus family members. 348 36

Anti-double stranded (ds) DNA antibodies in the sera of lupus-prone MRL/Mp-lpr/lpr (MRL/l) mice were determined by an enzyme-linked immunosorbent assay in parallel with anti-single stranded (ss) DNA, anti-left-handed Z-DNA and anti-poly(ADP-ribose) antibodies. The serum levels of these antibodies in these mice increased with age, and in particular anti-dsDNA antibodies appeared in mice more than 14 weeks old, along with progressive lymphadenopathy. We therefore established a hybridoma producing monoclonal anti-dsDNA antibody (2C10) from an 8-month-old MRL/l mouse. Monoclonal antibody 2C10 did not react with either poly(dT) or poly(I), which are major cross-reactants with previously reported monoclonal MRL mouse autoantibodies. Antibody 2C10 showed preference for phi X-174 replicative form DNA and calf thymus dsDNA over ssDNA. 2C10 idiotype (Id) was present in the sera of MRL/l mice, but only occasionally at high levels even in the aged mice tested. This result suggested that many Ids with anti-dsDNA antibody activity may contribute to lupus pathogenesis in this strain of mouse.
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PMID:A monoclonal anti-double stranded DNA antibody from an autoimmune MRL/Mp-lpr/lpr mouse: specificity and idiotype in serum immunoglobulins. 349 43

The prescription drugs procainamide (PA) and hydralazine (HYD) are associated with the induction of autoimmunity and a clinical syndrome called drug-induced lupus. Since PA- and HYD-induced autoantibodies are directed primarily against histones and histones are prime acceptors of poly (ADP-ribose) (PADPR), we have investigated the effects of PA and HYD on the activity of poly (ADP-ribose) polymerase (PADPRP). Control substances, with structures similar to PA and HYD but not known to induce lupus, included N-acetylprocainamide (NAPA) and the amino acids phenylalanine, tryptophan and proline, and their amide derivatives. Wil-2 cells were incubated in 0.5-50 microM PA, NAPA and HYD, which included therapeutic concentrations of these drugs. The mean enhancement of incorporation of [3H]-nicotinamide adenine dinucleotide (NAD) into PADPR was 1.84 (P = 0.005) with PA, with HYD 1.48 (P = 0.029), and with NAPA 1.38 (P = 0.036). This increase was suppressed by 3-aminobenzamide, an inhibitor of PADPRP activity. Little or no increase in [3H]-NAD incorporation was observed with equivalent concentrations of phenylalanine, phenylalaninamide or tryptophan. However, a 1.29-fold increase was noted with 0.5 microM tryptophanamide, a 1.26-fold increase with 0.5 microM prolinamide and a 1.4-fold increase with 50 microM proline. PA increased PADPRP activity in B- and T-cell lines but not in promyelocytic leukemia or epithelial cell lines. Since poly (ADP-ribosylation) is important in the cellular response to various agents, the increased ADP-ribosylation of intracellular molecules may be a key event in the induction of autoantibodies.
Lupus 1993 Jun
PMID:Effect of procainamide and hydralazine on poly (ADP-ribosylation) in cell lines. 769 Feb 94

Poly(ADP-ribose) metabolism is altered in patients with SLE. In order to localize the defect, the levels of poly(ADP-ribose) polymerase-specific mRNA were measured from dot blots of total RNA from peripheral blood lymphocytes. In this preliminary study, eleven patients with SLE and two with antiphospholipid syndrome were compared to three controls. It was found that the mean levels of specific mRNA were ten fold lower in the PBL from SLE patients compared to controls and no overlap of values was seen between the two groups. No such decrease was seen in the PBL from the patients with antiphospholipid syndrome. It is concluded that the defect in poly(ADP-ribose) polymerase metabolism that is seen in SLE patients occurs at the level of transcription or mRNA turnover.
Lupus 1994 Apr
PMID:Decreased mRNA levels coding for poly(ADP-ribose) polymerase in lymphocytes of patients with SLE. 792 Jun 10

Antiphospholipid antibodies (aPL) are associated with neurological diseases such as stroke, migraine, epilepsy and dementia and are thus associated with both vascular and non-vascular neurological disease. We have therefore examined the possibility that these antibodies interact directly with neuronal tissue by studying the electrophysiological effects of aPL on a brain synaptosoneurosome preparation. IgG from patients with high levels of aPL and neurological involvement was purified by protein-G affinity chromatography as was control IgG pooled from ten sera with low levels of aPL. Synaptoneurosomes were purified from perfused rat brain stem. IgG from the patient with the highest level of aPL at a concentration equivalent to 1:5 serum dilution caused significant depolarization of the synaptoneurosomes as determined by accumulation of the lipophylic cation [3H]-tetraphenylphosphonium. IgG from this patient as well as IgG from two elderly patients with high levels of aPL were subsequently shown to permeabilize the synaptosomes to labeled nicotinamide adenine dinucleotide (NAD) and pertussis toxin-ADP-ribose transferase (PTX-A protein) as assayed by labeled ADP-ribosylation of G-proteins in the membranes. No such effects were seen with the control IgG. aPL may thus have the potential to disrupt neuronal function by direct action on nerve terminals. These results may explain some of the non-thromboembolic CNS manifestations of the antiphospholipid syndrome.
Lupus 1999
PMID:Antiphospholipid antibodies permeabilize and depolarize brain synaptoneurosomes. 1019 7

Poly(ADP-ribose) and poly(ADP-ribose) polymerase (PARP) were discovered about 40 years ago, but their significance was not well elucidated until recently. In the early stage of the history of PARP, the presence of antibodies in the sera of human patients with lupus erythematosus indicated its natural occurrence. PARP, as well as the degrading enzyme, poly(ADP-ribose) glycohydrolase (PARG), are present in most eukaryotes except for yeasts. Studies that used inhibitors of PARP indicated the involvement of PARP and poly(ADP-ribose) in DNA damage repair, and eventually PARP was purified and the gene was cloned. Molecular analysis then revealed various functional domains, such as the one for binding to strand breaks of DNA. Parp-1-deficient and Parg-deficient cells showed, in general, enhanced sensitivity to the lethal effects of ionizing radiation and alkylating agents. Parp-1 knockout mouse embryonic stem cells developed into teratocarcinoma-like tumors when injected subcutaneously into nude mice, these tumors featuring giant cells similar to syncytiotrophoblastic giant cells with hyperploidy. Parp-1 was also found in centrosomes, suggesting that poly(ADP-ribose) and PARP-1 are functionally involved in the maintenance of chromatin structure and the equal distribution of chromosomes into daughter cells. Intriguing findings on the real biological significance continue to be generated, with new light shed on mechanisms of carcinogenesis and pointing to novel cancer treatments. Highlights during the last four decades of studies by laboratories focusing on poly(ADP-ribose)/PARP, including our own, are condensed and summarized in this review.
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PMID:Poly(ADP-ribose) and carcinogenesis. 1456 54


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