Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular injury and microvascular thrombosis are prominent features of systemic lupus erythematosus, as are circulating DNA-binding antibodies (DNAb). Experimental glomerulonephritis can be induced by anti-endothelial cell antibodies, and polyreactive DNAb might be pathogenetic by binding to endothelial cells, perhaps influencing their non-thrombogenic nature. To test this hypothesis, eight monoclonal antibodies (mAb) that bind to DNA derived from (NZB x NZW)F1 or MRL/Mp-lpr/lpr mice, were tested for their ability to bind to human umbilical vein endothelial cells (HUVEC). Binding was assessed using flow cytometry, fluorescence microscopy and cellular ELISA. Three of the eight mAb, at concentrations employed in this study, bound to HUVEC and dermal fibroblasts. Of these three mAb, one bound also to platelets. Two of the three demonstrated strong binding to (1) freshly isolated, collagenase-digested HUVEC, (2) 2nd passage HUVEC in suspension after trypsinization and, (3) 2nd passage HUVEC growing on plastic plates. To determine whether DNA itself acted as a ligand in this binding, prior treatment with DNAase was studied. Treatment of the endothelial cells with DNAase had no effect on the binding of one mAb, but DNAase treatment of this monoclonal itself resulted in a 60% reduction in binding to HUVEC, suggesting that the binding might be mediated through DNA in the form of a DNA/anti-DNA immune complex. In contrast, DNAase digestion of the endothelial cells caused a 40% reduction in the binding of the other two monoclonal antibodies. Furthermore, one of the two mAb bound 30% more to HUVEC after themselves being subjected to DNAase treatment. These two monoclonals may therefore be binding directly to HUVEC, possibly to DNA associated with the membrane. Prior DNAase digestion of dermal fibroblasts had a more profound effect on the binding of all three autoantibodies compared to HUVEC after similar treatment. Therefore, DNA can bind independently to either antibody or cell, thus supporting build up of complexes and capture of preformed complexes. Functionally, the binding of mAb to HUVEC did not influence thrombin-induced prostacyclin synthesis, in contrast to a control monoclonal anti-endothelial cell antibody EN4, which did.
 ...
PMID:A role for DNA in anti-DNA antibodies binding to endothelial cells. 191 Apr 25

Six monoclonal antibodies for human thrombomodulin (TM) were prepared. All of them recognized an elastase-digested fragment of TM which contains 6 epidermal growth factor (EGF)-like structural domains. We developed a one-step sandwich enzyme immunoassay for soluble TM by using 2 antibodies; one of them, which inhibited thrombin-binding to TM, was fixed to polystyrene balls, and the other, which did not inhibit the thrombin-binding, but inhibited the protein C-activating cofactor activity of TM, was used as peroxidase-labeled conjugate. The sensitivity of this assay was 1 microgram/l for soluble TM. The level of soluble TM was found to be significantly increased in sera of patients with systemic lupus erythematosus in comparison to the level in sera of healthy subjects.
 ...
PMID:One-step sandwich enzyme immunoassay for soluble human thrombomodulin using monoclonal antibodies. 196 42

The lupus anticoagulant is an antiphospholipid antibody found in association with systemic lupus erythematosus and in a variety of other diseases, as well as in healthy individuals. In the laboratory, the antibody interferes with the conversion of prothrombin to thrombin and prolongs the partial thromboplastin time. In vivo, it exerts a procoagulant effect resulting in thrombosis, mainly of the larger veins and arteries. The case of a young woman who developed superficial migratory thrombophlebitis in association with a high titer lupus anticoagulant is presented. Her diagnosis was initially missed because the partial thromboplastin time was not elevated. This appears to have resulted from the use of a specific thromboplastin relatively insensitive to the presence of the antibody. Retesting with a more sensitive reagent showed a markedly prolonged partial thromboplastin time.
 ...
PMID:Superficial migratory thrombophlebitis and the lupus anticoagulant. 211 May 53

To clarify the pathogenesis of antiphospholipid antibody (aPL) syndrome, the reactivities of anticardiolipin antibodies (aCL) in sera of patients with systemic lupus erythematosus (SLE) or other diseases to fresh, activated or destroyed blood cells were examined by the inhibition assay using an enzyme-linked immunosorbent assay. In addition, the effects of lupus anticoagulants (LA) in the patients' plasma and of immune complexes formed between LA and PL antigens on platelet aggregations were also determined. The IgG-aCL activity of patients' sera was markedly inhibited by pre-incubation with freeze-thawed blood cells, including erythrocytes (RBC), mononuclear cells (MNC) and platelets, but not fresh platelets or RBC. The aCL activity was slightly inhibited by fresh MNC, and was definitely inhibited by thrombin-activated platelets and polymorphonuclear cells (PMN) stimulated with phorbol 12-myristate 13-acetate (PMA). However, the activity was not inhibited by platelets stimulated with adenosine 5'-diphosphate (ADP; 10 microM). Twenty-two LA positive plasma and 17 LA negative plasma from patients similarly enhanced the aggregation of platelets which were obtained from healthy adults and stimulated with low concentrations of ADP (1 or 2 microM). However, such enhancement of platelet aggregation was not observed when high concentrations of ADP (5 microM) or collagen (2 micrograms/ml) were used as stimulators. In four of the 16 LA positive plasma examined, the mixture of plasma and phospholipid reagent for activated partial thromboplastin time induced platelet aggregations without the other stimulations, but the plasmas themselves did not induce such a reaction. The above results indicate that the aPL from patients do not react with intact blood cells in vitro, but they can react with activated or destroyed blood cells.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Reactivities of antiphospholipid antibodies to blood cells and their effects on platelet aggregations in vitro. 212 28

Platelets play a central role in haemostasis. Not only are they involved in aggregatory and agglutination responses but they are also implicated in the clotting system. The conversion of prothrombin to thrombin, in the presence of coagulation factors Va, Xa and calcium ions, is termed prothrombinase activity. For optimal expression of this process a negatively charged phospholipid surface is required. Platelets can provide such an environment, by exposing negatively charged phospholipids at their external plasma membrane, by a 'flip-flop' process whereby negatively charged phospholipids, predominantly phosphatidylserine, move from the inner plasma membrane leaflet to the outer leaflet upon the activation of platelets by certain agonists. Such agonists include collagen and thrombin and the amount of prothrombinase activity expressed is well correlated with the propensity of the agonist to activate platelet calcium-dependent protease, calpain. This enzyme is then thought to act upon platelet cytoskeletal components, thus breaking the restraining action of the cytoskeleton upon the platelet plasma membrane and facilitating 'flip-flop'. The platelet plasma membrane is therefore a dynamic surface capable of catalytic functions in coagulation systems. Recent research has high-lighted abnormalities in platelet prothrombinase expression in certain disease states. These include Bernard-Soulier syndrome, essential thrombocythaemia and conditions where the lupus anticoagulant may be present.
 ...
PMID:Platelet prothrombinase in health and disease. 213 Sep 28

In order to define the behavior of the lupus anticoagulant and/or antiphospholipid antibodies, we investigated the possible association with protein C, protein S and thrombomodulin. In 19 patients with established diagnosis of an autoimmune disease and coexisting lupus anticoagulant protein C (antigen and activity), protein S (total and free), anticardiolipin and antiphosphatidylserine antibodies were estimated. In one case the IgG globulin fraction containing the inhibitor was separated. The activation rate of pure protein C to its activated form using thrombin/thrombomodulin as activator was then measured in the presence or absence of lupus anticoagulant. No overall decrease of protein C or protein S was detected in patients' plasma. Nevertheless, the lupus anticoagulant had a specific effect on the protein C system, inhibiting the catalytic activity of thrombomodulin without causing a functional protein C deficiency. This specific effect upon thrombomodulin can be a main cause, but not necessarily the only one, for the thrombophilic tendency of patients with the lupus anticoagulant.
 ...
PMID:Lupus anticoagulant--antiphospholipid antibodies and thrombophilia. Relation to protein C--protein S--thrombomodulin. 216 70

In this review paper, the salient features of the anticoagulant/fibrinolytic mechanism depending on coagulation protein C, protein S and thrombomodulin are reviewed. Coagulation protein C, activated at the endothelial cell surface in the presence of the complex thrombin/thrombomodulin exerts two anti-thrombotic effects: one anticoagulant dependent on the free protein S and the other pro-fibrinolytic, independent of protein S. Both inherited and acquired deficiencies of protein C and/or protein S lead to a thrombosis-prone state that has to be identified promptly to avoid vaso-occlusive episodes. The experience in Mexico with both the identification and treatment of these deficiencies is reviewed; it is interesting that we have found that patients with autoimmune disorders, mainly systemic lupus erythematosus and primary anti-phospholipid syndrome, have acquired deficiencies of this anticoagulant mechanism that may be related to the thrombogenesis observed in these patients.
 ...
PMID:[Protein C, protein S and thrombomodulin: one of the natural antithrombotic mechanisms]. 217 90

The investigation of in vitro platelet functions from patients with SLE and rheumatoid arthritis (RA) revealed a distinctly reduced aggregation mass after both collagen und ADP induction. The platelet serotonin contents were significantly decreased in both groups. An "aspirin-like" platelet defect could be excluded by finding a normal malonyldialdehyde release of patients' platelets upon thrombin stimulation. Significantly increased platelet associated IgG was also detected, whereas platelet associated IgM remained within normal limits. These results are interpreted as indicating an ongoing platelet release reaction induced by IgG platelet antibodies, which induce the observed impairment of platelet functions and may also lead to the release of proinflammatory platelet mediators.
 ...
PMID:[Thrombocyte function and thrombocyte-associated immunoglobulins in patients with systemic lupus erythematosus and chronic polyarthritis]. 235 25

A 37-year-old intravenous drug abuser with acquired immune deficiency syndrome showed elevated activated partial thromboplastin time (APTT) and prothrombin time, normal thrombin time and fibrinogen, and borderline low platelet counts. The patient subsequently had a fracture of the left zygomatic arch, which did not produce uncontrollable bleeding. The coagulogram repeated at this admission showed persistent elevation of APTT. Further coagulation workup showed the presence of a lupus anticoagulant with mild specific inhibition of Factor VII. Platelet aggregation and Factor II levels were normal.
 ...
PMID:Lupus anticoagulant associated with specific inhibition of factor VII in a patient with AIDS. 249 80

A patient with microvascular thrombosis and thrombocytopenia was found to have a high-titre lupus anticoagulant. The biological effects of the patient's lupus anticoagulant were studied using whole patient serum and plasma. Staph Protein A eluate, and affinity-purified lupus anticoagulant. The latter was isolated by immunoadsorption of serum onto cardiolipin/phosphatidylserine/cholesterol liposomes. Each source of lupus anticoagulant demonstrated 'anticoagulant' activity, defined as prolongation of a modified kaolin clotting time, and contained antibody which bound to endothelial monolayers. Each interfered with thrombin-mediated prostacyclin release from endothelial cells, but had no effect on arachidonate-induced prostacyclin release. In addition, the lupus anticoagulant selectively blocked platelet aggregation in response to thrombin, but not in response to arachidonate, ADP or epinephrine. Lupus anticoagulant also reduced thrombin-stimulated shifts in cytosolic calcium. Thrombin-mediated membrane inositol metabolism and total thrombin binding to endothelium were unaffected by lupus anticoagulant, and another endothelial anticoagulant function related thrombin binding. Protein C activation by thrombomodulin, was not altered. We conclude that the binding of lupus anticoagulant to endothelial cells and platelets does not prevent all thrombin signalling events, but does interrupt prostacyclin production.
 ...
PMID:Lupus anticoagulant induces a selective defect in thrombin-mediated endothelial prostacyclin release and platelet aggregation. 249 19


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>