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)

In contrast to necrotic cells, the clearance of apoptotic ones usually is an anti-inflammatory process which elicits only a marginal immune response. During apoptosis phosphatidylserine (PS) is exposed on the outer leaflet of the cytoplasmic membrane and serves as target for the PS receptor of phagocytes. The latter is responsible for anti-inflammatory signalling and the induction of TGFbeta. We were interested whether the immunogenicity of apoptotic cells can be increased by masking PS. We observed that treatment of xenogeneic apoptotic cells with annexin V (AxV) significantly increased the humoral immune response against surface epitopes of these cells. Furthermore, AxV-coated irradiated tumour cells were able to elicit a long lasting tumour specific cytotoxic T lymphocyte response. AxV efficiently blocked the uptake of irradiated cells by macrophages but not by dendritic cells. Furthermore, AxV skewed the phagocytosis of irradiated cells towards inflammation. Investigation of patients with autoimmune diseases further supported the role of anionic surface phospholipids for anti-inflammatory clearance of apoptotic cells. Impaired clearance and opsonisation with anti-phospholipid-antibodies are discussed to be responsible for the development of systemic lupus erythematosus and anti-phospholipid-syndrome, respectively. Presentation of cryptic epitopes from late apoptotic cells in a proinflammatory context may challenge T cell tolerance. In addition, accumulation of uncleared apoptotic debris in the germinal centres of lymph nodes may result in the survival of autoreactive B cells.
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PMID:Exposure of anionic phospholipids serves as anti-inflammatory and immunosuppressive signal--implications for antiphospholipid syndrome and systemic lupus erythematosus. 1263 7

A number of previous studies have shown that anti-phospholipid(aPL) antibodies(Abs) do not bind primarily to the negatively-charged phospholipid itself but rather to complexes of the phospholipid and plasma proteins, and that the most common antigenic targets are beta 2-glycoprotein I recognized by anticardiolipin Abs and prothrombin recognized by most lupus anticoagulants. However, resent studies suggest that other phospholipid-binding proteins, particularly protein C, protein S, and annexin V, may be important targets as well. To clarify the association between the various types of aPL Abs and thrombotic complications in patients with systemic lupus erythematosus(SLE), we examined the prevalence of aPL Abs to various phospholipid-binding proteins(beta 2-glycoprotein I, prothrombin, protein C, protein S, and annexin V). We found that anti-beta 2-glycoprotein I Abs may be associated primarily with cerebral infarction and femoral artery thrombosis, and that anti-protein S Abs may be associated primarily with venous thromboembolism and renal thrombotic microangiopathy. Furthermore, anti-annexin V Abs might be closely related to fetal loss. These findings suggest that thrombotic complications in SLE depend on the antigenic specificities of aPL Abs, alone or in combination.
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PMID:[Association between anti-phospholipid antibodies and thrombotic complications in systemic lupus erythematosus]. 1270 97

Maternal hypercoagulability is a possible cause of miscarriage during the eighth and ninth weeks of pregnancy, when the placenta replaces the yolk sac. We thus examined associations between putative markers of an acquired hypercoagulable state and the risk of first miscarriage. We conducted a case-control study comparing 743 women who miscarried in weeks 8 and 9 with 743 women who underwent a first provoked abortion, matched for age, number of pregnancies, and time elapsed since abortion. Levels of plasma homocysteine and of various antiphospholipid/antiprotein and hemostasis-related autoantibodies were categorized in 4 strata (percentiles 1-80, 81-95, 96-99, 100 among control patients) and analyzed in conditional logistic regression models. Pregnancy loss was independently associated with positive lupus anticoagulant (matched odds ratio [OR], 2.6; 95% confidence interval [CI], 1.1-6.0), high levels of immunoglobulin M (IgM) antibodies against cardiolipin (OR for percentile 100 versus 0-80, 3.5; CI, 1.2-10.1) and against phosphatidylethanolamine (OR, 4.7; CI, 1.9-12.1), high levels of IgG antibodies against annexin V (OR, 3.2; CI, 1.1-9.1) and against tissue-type plasminogen activator (OR, 19.5; CI, 7.9-48.0), and high homocystinemia (OR, 4.1; CI, 1.3-12.5). A first early pregnancy loss is associated with increased levels of several autoantibodies and of homocysteine.
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PMID:Antiphospholipid/antiprotein antibodies, hemostasis-related autoantibodies, and plasma homocysteine as risk factors for a first early pregnancy loss: a matched case-control study. 1286 11

Annexin A5 has been proposed to be important for shielding of negatively charged phospholipids from blood, thereby preventing the binding of clotting factors. It has been suggested that antiphospholipid antibodies can disrupt the binding of annexin A5 from negatively phospholipid-containing surfaces, resulting in uncontrolled coagulation. If this hypothesis is correct, than the plasma levels of annexin A5 will be increased in patients with antiphospholipid antibodies. Therefore, we have measured plasma levels of annexin A5 of 175 patients with systemic lupus erythematosus (SLE), of which 104 had antiphospholipid antibodies and 23 patients had primary antiphospholipid syndrome. The annexin A5 levels were compared with the annexin A5 plasma levels measured in 23 patients with diabetes mellitus type 2 and 35 healthy volunteers. We found a significant increase of annexin A5 plasma levels in patients with SLE (median 6.7 ng mL(-1)) and primary antiphospholipid syndrome (median 7.1 ng mL(-1)) as compared to patients with diabetes mellitus type 2 (median 3.3 ng mL(-1)) and healthy volunteers (median 3.9 ng mL(-1)). However, no correlation was found with the presence of antiphospholipid antibodies or with a history of thromboembolic complications. Based on these observations, we conclude that displacement of annexin A5 from cellular surfaces by antiphospholipid antibodies is not a common mechanism in patients with antiphospholipid antibodies.
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PMID:The presence of antiphospholipid antibodies is not related to increased levels of annexin A5 in plasma. 1287 62

In recent years, it has become evident that Systemic Lupus Erythematosus (SLE) is a disease characterized by an array of autoantibodies directed against the native nucleosome, its DNA component and/or its histone component. Nuclear antigens are generated and released in vivo during apoptosis. A hallmark of apoptosis is the cleavage of chromatin by caspase-activated DNase. This fragmentation occurs at the internucleosomal level and leads to DNA ladder formation classically associated with apoptosis. Thus, dysregulation of DNA fragmentation might be directly linked to the induction of autoimmunity in SLE. In our studies, activated human lymphoblasts contain high amounts of core histones in their cell lysates after apoptosis induction. This accumulation correlated highly with markers of early apoptosis (Annexin V positive, propidium iodide negative), but not with markers of late apoptosis or necrosis. Interestingly, accumulation of core histones or nucleosomes in cell lysates was detected as early as 30 or 60 min after UV irradiation, whereas phosphatidylserine externalization occurred 2 hr after apoptosis induction. Our results suggest that extranuclear accumulation of core histones is a very early event in apoptosis, preceding the externalization of phagocytosis signals on the outer membrane surface of apoptotically dying lymphoblasts. The following review will discuss these results in a broader perspective which includes our hypothesis of how apoptosis dysregulation during early phases may contribute to the induction of autoimmunity against nuclear autoantigens as seen in SLE.
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PMID:The putative role of apoptosis-modified histones for the induction of autoimmunity in Systemic Lupus Erythematosus. 1455 19

An improved activated factor X-based clotting method was used to investigate activity of procoagulant phospholipid (PPL) in blood samples collected into various anticoagulants and in plasmas with a range of abnormalities. The dilute activated factor X-activated clotting time (XACT) was carried out on a mixture of specimen with phospholipid-free porcine plasma. PPL from the test sample is then rate-limiting, controlling the clotting time so that the XACT is shortened from a maximum of approximately 120 s with citrated platelet-free plasma to approximately 30 s with freeze-thawed platelet-rich plasma. XACT results were only shortened slightly by fresh normal platelet-rich plasma, but were shortened significantly by platelets that had been activated by freeze-thawing. This improved method for PPL was not prolonged by deficiencies of known clotting factors and therapeutic levels of heparin, and it was surprisingly resistant to most lupus anticoagulants. However, it was extremely sensitive to PPL, detecting down to 50 ng/ml synthetic phospholipid added to phospholipid-free plasma. Excellent correlation was achieved between XACT shortening and microparticle count assessed by annexin V-binding and flow cytometry in normal plasma spiked with platelet microparticles. In citrated blood specimens, XACT shortened with time in a temperature-dependent manner. XACT results on blood samples anticoagulated with ethylenediamine tetra-acetate were more stable, and these would be preferable for assessing PPL expression ex vivo. XACT was significantly shorter in whole blood samples than in normal platelet-rich or platelet-poor plasmas, suggesting that PPL was normally expressed more by cells or aggregates larger than platelets or microparticles.
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PMID:A new activated factor X-based clotting method with improved specificity for procoagulant phospholipid. 1461 60

Women with systemic lupus erythematosus (SLE) are at risk for premature atherothrombosis independent of Framingham risk factors. We investigated whether endothelial cell (EC) apoptosis predicts abnormal vasomotor tone and contributes to circulating tissue factor (TF) levels in this disease. Brachial artery flow-mediated dilation (FMD) and nitroglycerin-mediated dilation were determined in women with SLE, healthy control subjects, and subjects with coronary artery disease (CAD) (n = 43/group). Quantification of circulating apoptotic ECs was performed by flow cytometry (CD146(+) cells that stained for Annexin V [CD146(AnnV+)]) and immunofluorescent microscopy. Plasma TF was measured by enzyme-linked immunosorbent assay (ELISA). Compared with healthy control and CAD subjects, patients with SLE had higher numbers of circulating CD146(AnnV+) cells (10 +/- 3, 18 +/- 5, and 89 +/- 32 cells/mL, respectively, mean +/- SEM; P <.01). Increased CD146(AnnV+) cells correlated strongly with abnormal vascular function (P =.037). After adjusting for known predictors of endothelial function, CD146(AnnV+) was the only variable that predicted FMD (beta = -4.5, P <.001). Increased CD146(AnnV+) was strongly associated with elevated levels of circulating TF (r =.46, P =.002). Circulating apoptotic ECs are elevated in young women with SLE and strongly correlate with markedly abnormal vascular function and elevated TF levels. Heightened endothelial apoptosis may represent an important mechanism for development of atherothrombosis in SLE.
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PMID:Endothelial cell apoptosis in systemic lupus erythematosus: a common pathway for abnormal vascular function and thrombosis propensity. 1472 73

The most likely source of autoantigens in systemic lupus erythematosus (SLE) is apoptotic material. Because increased levels of circulating apoptotic cells are found in SLE we wanted to investigate the capacity of serum from patients with SLE or other autoimmune or infectious diseases and normal healthy donors (NHD) to induce apoptosis in normal monocytes, lymphocytes and corresponding cell lines, in relation to clinical and immunological data. Monocytes and lymphocytes from healthy donors were incubated with sera from 37 SLE patients, 37 sex- and age-matched NHD and sera from patients with rheumatoid arthritis, vasculitis, sepsis and mononucleosis. Sera from SLE patients were sampled at both active and inactive disease. The apoptosis-inducing effect (AIE) of these sera was monitored with flow cytometry using annexin V and propidium iodide (PI) binding. The AIE in monocytes and lymphocytes was significantly higher in sera from SLE patients than in other patient groups and NHD (P < 0.001) and was also higher when cell lines were used. Level of C5a in cell culture supernatant correlated with AIE in monocytes (r = 0.451, P = 0.005), suggesting involvement of complement. Heat-inactivation of sera did not affect the AIE, nor did depletion of IgG by protein G absorption of serum. Kinetic analyses showed a peak in apoptosis induction at 12-16 h, with a delayed PI positivity. AIE was equally high using sera from active and inactive SLE cases, and did not correlate with the SLE Disease Activity Index (SLEDAI). Thus, SLE serum has a strong and apparently disease-specific apoptosis-inducing capacity, which could contribute to a high load of potential autoantigen.
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PMID:Induction of apoptosis in monocytes and lymphocytes by serum from patients with systemic lupus erythematosus - an additional mechanism to increased autoantigen load? 1500 90

Autoantibodies to prothrombin are common in patients with systemic lupus erythematosus. Although their presence is a risk factor for thrombosis, neither their origin nor their precise role in inducing the procoagulant state is known. We have developed a phage-display antibody library from patients with systemic lupus erythematosus with antiprothrombin antibodies, and we have selected two single-chain Fv antibody fragments (ScFvs) by panning on a prothrombin-coated surface. In prothrombin activation assays using purified components, these antibodies promoted prothrombin activation. These ScFvs, termed AN78 and AN129, bound to immobilized prothrombin in a concentration-dependent specific manner but not to other anionic phospholipid binding proteins such as beta2-glycoprotein I or annexin V. Phosphatidylserine-bound prothrombin, but not soluble prothrombin, inhibited the binding suggesting that the epitope is available only on immobilized prothrombin. To localize the epitope, prothrombin was treated with thrombin or factor Xa and various prothrombin activation fragments were subsequently isolated and tested in ELISA with the ScFvs. Both AN78 and AN129 bound to prethrombin I (the fragment lacking the Gla domain and the first kringle domain), to fragment 1.2 (containing Gla and the two kringle domains only) and to fragment 2 but not to thrombin, thus localizing the cognate epitope to the kringle 2 domain in prothrombin. Analysis of the cDNA sequences of these antibodies show clustered mutational patterns in the complementarity determining region, suggesting that variable domains are the products of antigen-driven B cell clonal maturation.
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PMID:Lupus-derived antiprothrombin autoantibodies from a V gene phage display library are specific for the kringle 2 domain of prothrombin. 1504 12

The present study was designed to determine the prevalence of lupus anticoagulant (LA) antibody and several antibodies for antiphospholipid syndrome (APS) in patients with deep vein thrombosis (DVT)/pulmonary embolism (PE) (n = 48), cerebral thrombosis (CT, n = 30), systemic lupus erythematosus (SLE, n = 22), and idiopathic thrombocytopenic purpura (ITP, n = 30). The presence of antibodies was examined by using the respective ELISA kits. LA was positive in 38.6% of patients with DVT/PE, suggesting that LA is one of the most important risk factors in DVT/PE. The highest prevalence of anti-beta(2) glycoprotein I (beta(2)GPI) IgG was in CT and SLE, followed by DVT, and none in ITP and healthy volunteers (control, n = 40), suggesting that it is related to thrombosis, particularly arterial thrombosis. The highest prevalence of anti-prothrombin (aPT) IgG antibody was in DVT, followed by CT and SLE, and none in ITP and the control, suggesting that it is related to thrombosis, especially venous thrombosis. The highest prevalence of antiphospholipid (aPL) IgG was in DVT, CT, and SLE, but 0% in ITP and control. On the other hand, aPL IgM, anti-annexin V IgG, and anti-annexin V IgM were positive in patients both with and without thrombosis, suggesting that they are not related to thrombosis. Our results indicated that among the anti-phospholipid antibodies, LA is the most sensitive marker for APS while anti-beta(2)GPI IgG, aPT IgG, and aPL IgG are risk factors for thrombosis. In particular, aPT IgG is a significant marker for DVT/PE.
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PMID:High prevalence of anti-prothrombin antibody in patients with deep vein thrombosis. 1528 65


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