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Biomedical subjects

Y Levy

Publications and source records attributed to Y Levy.

At least 127 records · Page 7Linked to original sources
PubMed1999

Beta2 glycoprotein I containing immune-complexes in lupus patients: association with thrombocytopenia and lipoprotein (a) levels.

In this study we determined the prevalence and clinical associations of immune-complexes-containing beta-2-glycoprotein I (beta2GPI) in randomly selected SLE patients. We studied 38 consecutive SLE patients attending the Rheumatology Unit. Previous arterial or venous-thrombosis were documented by the appropriate diagnostic test. Lipid profile including total cholesterol, LDL, VLDL, HDL and Lp(a) levels were determined from the sera of the fasting patients. Antibodies to cardiolipin, oxidized LDL and beta2GPI were detected employing ELISA. Beta2GPI containing IgG immune-complexes were assayed by using a dot-blot assay. Fourteen SLE patients (36.8%) were found to be positive for the presence of IgG anti-beta2GPI antibodies. Ten of the SLE patients (26.3%) were found to have high levels of beta2GPI containing immune-complexes. There was a positive correlation between beta2GPI-IC levels and the occurrence of thrombocytopenia in the patients (P < 0.05). Furthermore, patients with SLE and venous thrombosis had higher levels of beta2GPI-IC when compared with thrombosis-free patients or with healthy controls (P < 0.05). Patients with higher Lp(a) levels (> 50 mg/dl) possessed higher levels of beta2GPI-IC as compared with patients with lower Lp(a) concentration (< 20 mg/dl) (P < 0.05). These results suggest that IC-containing beta2GPI can help in defining a subpopulation of SLE patients with increased risk of thrombocytopenia and further aid in resolving mechanisms of immune-mediated tissue damage.

Adult↗
PubMed1999

Atherosclerosis-related markers in systemic lupus erythematosus patients: the role of humoral immunity in enhanced atherogenesis.

Systemic Lupus Erythematosus (SLE) patients experience premature atherosclerosis. A deranged lipid metabolism and use of immunosuppressive medications accounts partially for the accelerated process. The role of autoimmunity in atherosclerosis has recently been highlighted. Autoantigenic determinants thought to play a role in the development of atherosclerosis include: modified lipoproteins, heat shock proteins and beta2-glycoprotein I (a target of 'autoimmune' anticardiolipin antibodies). In this present work we determined autoimmune markers which may be associated with premature atherosclerotic process found in SLE patients. We have found that antibodies to oxLDL were raised in the sera of lupus patients and cross-reacted with cardiolipin and with beta2GPI. OxLDL containing immune-complexes of the IgG and IgM isotypes were both elevated in the SLE patients as compared with healthy controls. Patients with high Lipoprotein (a) concentrations (>30 mg/dl) had higher levels of IgM oxLDL-containing immune-complexes. IgM but not IgG anti-HSP-65 antibodies were elevated in the lupus patients and levels of oxLDL containing immune-complexes correlated positively with the presence of anti-HSP 65 antibodies. Lysophosphatidylcholine (LPC) is a peroxide-derivative formed during LDL oxidation, was shown to evoke a humoral response in healthy subjects. Antibodies to lysophosphatidylcholine of the IgG but not the IgM isotype were reduced in SLE patients compared with controls, suggesting it may be 'consumed' into oxLDL containing immune complexes. Therefore, SLE patients exhibit a humoral autoimmune response towards the antigenic candidates incriminated in the progression of atherosclerosis. These findings may help identify factors that are involved in accelerating atherogenesis in SLE patients.

Adult↗
PubMed1999

Treatment of chronic bilateral pleural effusions with intravenous immunoglobulin and cyclosporin.

A 48 y old woman with unremarkable medical history was admitted with bilateral pleural effusions; even though the fluid was drained, it re-accumulated and necessitated many repeated drainages in the following 2.5 y (56 hospitalisations). The patient underwent an extensive diagnostic work-up that disclosed elevated serum antinuclear antibodies, serum anti-dsDNA antibodies, pleural fluid anti-dsDNA and decreased pleural fluid C3 and C4. During that period she has been treated with a variety of immunomodulating agents, several pleural talcage and pleurectomy, without any apparent response. Thereafter, she received six courses of IVIg (2 g/kg body weight) in monthly intervals, followed by four months treatment with cyclosporin. This treatment resulted in gradual and eventually complete disappearance of the pleural effusion, and now after more than 2 y the patient is free of symptoms and receives no further medications.

Antibodies, Antinuclear↗
PubMed1999

Immunomodulation of various autoimmune diseases by intravenous immunoglobulin.

Intravenous immunoglobulin (IVIg) is currently an accepted treatment for some autoimmune diseases and it has recently been used empirically in various other autoimmune conditions. This review discusses the role of IVIg in autoimmunity, mainly in systemic lupus erythematosus and systemic vasculitis. Clinical experience with IVIg, as well as its mechanisms of action with special emphasis on modulation of the idiotypic network, are also presented.

Journal Article↗
PubMed1999

Antibodies to the cytoplasm, cell membrane and nuclear membrane of malignant neoplasms in pooled normal human polyspecific immunoglobulin G.

IVIg is a preparation of normal polyspecific IgG obtained from pooled plasma of a large number of healthy donors. IVIg treatment of patients with chronic lymphocytic leukemia induced a reduction in the total number of lymphocytes in the peripheral blood. Regression of Kaposi's sarcoma was also noted in an HIV patient treated with IVIg. The aim of this study was to determine whether F(ab')2 prepared from IVIg binds to cellular structures of different tumor tissues. Biotinylated F(ab')2 was prepared from 3 different preparations of IVIg and from affinity purified IgG from a patient with multiple myeloma. Direct immunohistochemistry using a streptavidin peroxidase staining method was performed on biopsy samples of 18 different tumor tissues. Positive staining of the cytoplasm, cell membrane and nuclear membrane of several types of malignant tumors by F(ab')2 from IVIg was immunohistochemically demonstrated. Nuclear staining of tumor cells by IVIg was rare. IVIg bound to different tumors of epithelial origin, especially colon carcinoma, breast carcinoma and squamous cell carcinoma of the lung. Malignant tumors of mesenchymal origin such as leiomyosarcoma have also demonstrated positive staining by IVIg. IVIg contains antibodies to the cytoplasm, nuclear membrane and cell membrane of different malignant tumors especially of epithelial origin. This binding might provide a basis for the assumption that IVIg treatment of cancer patients may induce antibody dependent cell mediated cytotoxicity response against tumors, and implies that it can be potentially beneficial as adjuvant treatment of malignant diseases.

Antibody Affinity↗
PubMed1999

Anti-cardiolipin, anti-endothelial-cell and anti-malondialdehyde-LDL antibodies in uremic patients undergoing hemodialysis: relationship with vascular access thrombosis and thromboembolic events.

Patients with chronic renal failure requiring regular hemodialysis are known to be prone to thromboembolic events due to a hypercoagulable state. Vascular access thrombosis (VAT; including thrombosis of the vascular shunt or graft) represents a serious complication and jeopardizes life in these patients. In the current study, conducted on 81 consecutive patients from the Hemodialysis Unit, we have employed ELISA for the estimation of various autoantibody levels (anti-endothelial cell antibodies, anti-cardiolipin, anti-beta 2GPI and anti-modified LDL antibodies) and correlated them with the occurrence of thromboembolic events in general, and VAT in particular. We have found that the levels of antibodies reactive with human umbilical vein endothelial cells (HUVEC) but not with other EC lines (microvascular or EaHy 929) were significantly higher in hemodialysed patients with VAT in comparison with patients with no VAT (p = 0.001). A weaker but yet positive correlation was observed between the levels of anti-HUVEC and anti-cardiolipin antibodies and the occurrence of thromboembolic events including deep vein thrombosis, pulmonary infarction, cerbrovascular events and VAT (both p-values equal 0.02). Anticardiolipin antibodies (aCL) were not cross reactive with beta 2GPI or with HUVEC. Antibodies to modified LDL, although higher in hemodialyzed patients, did not correlate with thromboembolic events. The results of this study suggest that antibodies to HUVEC may prove as a fairly good marker of VAT in hemodialysis. High levels of aCL are weakly associated with thromboembolic events and antibodies to modified LDL do not correlate with a prothrombotic state.

Adult↗
PubMed1999

Elevated homocysteine levels in patients with Raynaud's syndrome.

OBJECTIVE: Patients with Raynaud's phenomenon (RP) have vasomotor dysregulation, the etiology of which has not yet been elucidated. We investigated plasma levels of homocysteine and folate in patients with primary or secondary RP in comparison with healthy subjects. METHODS: Plasma from patients with RP, either primary (n = 10) or secondary to scleroderma (n = 10), and from healthy subjects (n = 20) was obtained for homocysteine determination using high performance liquid chromatography. RESULTS: Patients with primary and secondary RP had significantly higher homocysteine concentrations (mean 15.5 +/- 4.1 and 11.6 +/- 6.2 micromol/l, respectively; p < 0.05) compared to healthy individuals (mean 5.9 +/- 2.0 micromol/l). Patients with primary RP had significantly lower plasma levels of folate in comparison with patients with secondary RP or healthy individuals. CONCLUSION: This is the first study to show higher plasma levels of homocysteine in patients with RP. Given the obscure etiology of this disorder, these findings may provide new clues in the understanding of vasomotor dysfunction in RP.

Adult↗
PubMed1999

Increased plasma oxidizability and decreased erythrocyte and plasma antioxidative capacity in patients with NIDDM.

BACKGROUND: Atherosclerosis and microvascular complications in patients with non-insulin-dependent diabetes have been linked to increased oxidative stress. The glutathione redox cycle is a major determinant of the antioxidative capacity of plasma and its constituents. METHODS: We attempted to investigate plasma oxidation and plasma and erythrocyte glutathione and glutathione enzymes in 20 patients with NIDDM, compared with euglycemic matched controls. Plasma oxidation was analyzed both basally (without) and as induced by 2,2'-azobis,2-amidopropane hydrochloride measured by the generation of thiobarbituric acid reactive substances and lipid peroxides. RESULTS: There was a significant increase in oxidation both basally (without) and as induced by AAPH. Plasma glutathione was lowered by 50% (P < 0.01) and erythrocyte glutathione peroxidase, glutathione s-transferase and glutathione reductase activities were lower by 30%, 27% and 46%, respectively (P < 0.01) in the patients with NIDDM. CONCLUSIONS: Confronted by increased oxidation, patients with NIDDM show an abnormal plasma and erythrocyte antioxidative capacity, which may result in an accelerated rate of complications.

Adult↗
PubMed1998

[Development of pulmonary hypertension and multi-valvular damage caused by appetite depressants].

Marked obesity is an independent risk factor for multi-system morbidity. The use of anorectic drugs is an aggressive strategy for weight reduction. It appears to be an easy way of dealing with the problem, because the patient needn't change his behavior. However, such treatment is not harmless. At the end of the 60's an outbreak of pulmonary hypertension was associated with the drug aminorex, and it was soon withdrawn from the market. 30 years later it became clear that new-generation anorectic drugs (fenfluramine, dexfenfluramine, phentermine), which were being used world-wide, lead to both pulmonary hypertension and valvular damage. We describe a woman of 70 with both these complications which developed after prolonged anorectic therapy with a fenfluramine-phentermine combination.

Aged↗
PubMed1998

Defect in IgV gene somatic hypermutation in common variable immuno-deficiency syndrome.

Common Variable Immuno-Deficiency (CVID) is the most common symptomatic primary antibody-deficiency syndrome, but the basic immunologic defects underlying this syndrome are not well defined. We report here that among eight patients studied (six CVID and two hypogammaglobulinemic patients with recurrent infections), there is in two CVID patients a dramatic reduction in Ig V gene somatic hypermutation with 40-75% of IgG transcripts totally devoid of mutations in the circulating memory B cell compartment. Functional assays of the T cell compartment point to an intrinsic B cell defect in the process of antibody affinity maturation in these two cases.

Adult↗
PubMed1998

Induction of early atherosclerosis in LDL-receptor-deficient mice immunized with beta2-glycoprotein I.

BACKGROUND: Immunization with beta2-glycoprotein I (beta2GPI), the probable target of autoimmune anticardiolipin antibodies, results in experimental antiphospholipid syndrome in different mouse strains. The present study was undertaken to evaluate the effect of beta2GPI immunization on the progression of atherosclerosis. METHODS AND RESULTS: In the first experiment, 3 groups of LDL receptor-deficient (LDL-RD) mice (n=15 per group) were immunized with either beta2GPI or ovalbumin or were not immunized and were fed a chow diet for 12 weeks. In a second experiment, 3 groups of LDL-RD mice (n=10 per group) were immunized similarly and fed an atherogenic diet for 6 weeks. All beta2GPI-immunized mice developed high titers of anti-beta2GPI antibodies as well as a specific lymph node proliferation to beta2GPI. The average cholesterol levels did not differ between the mice fed similar diets, regardless of the immunization protocol. Atherosclerosis was enhanced in the beta2GPI-immunized mice (mean aortic lesion, 26 000+/-5700 microm2) in comparison with their ovalbumin-immunized (mean, 3000+/-1099 microm2; P<0.01) and nonimmunized (mean, 2250+/-700 microm2; P<0.01) littermates. The average lesion size in the beta2GPI-immunized mice fed an atherogenic diet (mean, 98 000+/-8305 microm2) was larger than the ovalbumin-immunized mice (mean, 81 250+/-12 933 microm2; P=NS) or the nonimmunized controls (mean, 75 625+/-7281 microm2; P=NS). The atherosclerotic plaques in the beta2GPI-immunized mice appeared to be more mature, and denser infiltration of CD4 lymphocytes was present in the subendothelium of the aortic sinuses from this group of mice. CONCLUSIONS: The results of the present study provide the first direct evidence for the proatherogenic effect of ss2GPI immunization and establish a new model for immune-mediated atherosclerosis.

Animals↗
PubMed1998

Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1alpha/ARNT.

Hypoxic stress induces the expression of genes associated with increased energy flux, including the glucose transporters Glut1 and Glut3, several glycolytic enzymes, nitric oxide synthase, tyrosine hydroxylase, erythropoietin and vascular endothelial growth factor (VEGF). Induction of these genes is mediated by a common basic helix-loop-helix-PAS transcription complex, the hypoxia-inducible factor-1alpha (HIF-1alpha)/aryl hydrocarbon nuclear translocator (ARNT). Insulin also induces some of these genes; however, the underlying mechanism is unestablished. We report here that insulin shares with hypoxia the ability to induce the HIF-1alpha/ARNT transcription complex in various cell types. This induction was demonstrated by electrophoretic mobility shift of the hypoxia response element (HRE), and abolished by specific antisera to HIF-1alpha and ARNT, and by transcription activation of HRE reporter vectors. Furthermore, basal and insulin-induced expression of Glut1, Glut3, aldolase A, phosphoglycerate kinase and VEGF was reduced in cells having a defective ARNT. Similarly, the insulin-induced activation of HRE reporter vectors and VEGF was impaired in these cells and was rescued by re-introduction of ARNT. Finally, insulin-like growth factor-I (IGF-I) also induced the HIF-1alpha/ARNT transcription complex. These observations establish a novel signal transduction pathway of insulin and IGF-I and broaden considerably the scope of activity of HIF-1alpha/ARNT.

Animals↗
PubMed1998

The binding of some human antiendothelial cell antibodies induces endothelial cell apoptosis.

The pathogenic role of antiendothelial cell antibodies (AECA) remains unclear. They are frequently associated with antibodies to anionic phospholipids (PL), such as phosphatidylserine (PS), which is difficult to reconcile with the distribution of PL molecular species within the plasma membrane. Since it is already known that PS is transferred to the outer face of the membrane as a preclude to apoptosis, the possibility exists that apoptosis is initiated by AECA. AECA-positive/anti-PL antibody-negative sera from eight patients with systemic sclerosis (SS) and 21 control patients were evaluated. Endothelial cells (EC) were incubated with AECA and the exposure of PS was established through the binding of annexin V. Hypoploid cell enumeration, DNA fragmentation, and optical and ultrastructural analyses of EC were used to confirm apoptosis. Incubation of EC with AECA derived from six of eight patients with SS led to the expression of PS on the surface of the cells. This phenomenon was significantly more frequent in SS (P < 0.04) than in control diseases. The redistribution of plasma membrane PS preceded other events associated with apoptosis: hypoploidy, DNA fragmentation, and morphology characteristic for apoptosis. Apoptosis-inducing AECA did not recognize the Fas receptor. We conclude that AECA may be pathogenic by inducing apoptosis.

Annexin A5↗
PubMed1998

Target recognition of beta2-glycoprotein I (beta2GPI)-dependent anticardiolipin antibodies: evidence for involvement of the fourth domain of beta2GPI in antibody binding.

Beta2-glycoprotein I (beta2GPI) is an absolute requirement for the binding of autoimmune anticardiolipin Abs (aCL) to cardiolipin (CL). We evaluated the target recognition of human beta2GPI by IgG derived from two patients with primary and two with secondary antiphospholipid syndrome. The total IgG serum fractions and beta2GPI affinity-purified IgGs were assessed by using various domain-deleted mutants (DM) of human beta2GPI (DMs: I-III, I-IV, II-V, III-V, IV-V, and V) and mouse mAbs against individual beta2GPI domains. The four IgGs bound slightly to CL in the absence of beta2GPI and showed increased binding in the beta2GPI presence. Following affinity purification of the IgGs on a beta2GPI column, reactivity toward CL was absent. DMs containing domain V inhibited the binding of biotinylated beta2GPI to CL. The addition to CL-coated plates of DM V, but not the other DMs, reduced the binding of all four IgGs. The anti-beta2GPI IgGs bound only to complete beta2GPI and DM I-IV coated on the plates. The binding to plate-adsorbed beta2GPI could be inhibited by complete beta2GPI and DM I-IV, the latter being a more efficient inhibitor. Further, the human anti-beta2GPI IgGs could compete with the binding to beta2GPI of Cof-21 mouse mAb (directed at domain IV), but not with the two other mouse mAbs. The results suggest that some "autoimmune:" beta2GPI-dependent anticardiolipin Abs recognize a beta2GPI target that is distinct from the CL-binding site in domain V. The target site for some antiphospholipid syndrome IgGs appear to reside in domain IV of beta2GPI.

Animals↗
PubMed1998

[Effect of an extract containing esterol on plasma cholesterol and oxidants].

16 patients with hypercholesterolemia were treated with an extract of alpha-alpha leaves (esterol) while on a low-fat, low-cholesterol diet. Esterol is believed to inhibit the absorption of cholesterol and bile acids and may interfere with the absorption of essential nutrients. As oxidative modification of lipoproteins is required for the process of atherosclerosis, plasma antioxidant vitamins were followed. After 4 months of treatment, plasma cholesterol decreased by 10% from 282 to 250 mg/dl (p < 0.001) and LDL cholesterol by 13%, from 203 to 177 mg/dl (p < 0.001). Plasma antioxidant vitamins E, A and beta-carotene were unchanged. Thus, esterol has a cholesterol-lowering effect but apparently does not lower fat-soluble, plasma antioxidant vitamins. Both cholesterol-lowering and plasma antioxidant vitamins are important for the primary prevention of coronary artery disease in hypercholesterolemia.

Adult↗
PubMed1998

Differential effects of anti-beta2-glycoprotein I antibodies on endothelial cells and on the manifestations of experimental antiphospholipid syndrome.

BACKGROUND: The antiphospholipid syndrome (APS) entails a prothrombotic state associated with the presence of anticardiolipin antibodies (aCL). aCL were shown to promote endothelial cell and platelet activation and to induce an APS-like syndrome in mice when administered intravenously. Recent data suggest that aCL target the plasma cofactor beta2-glycoprotein I (beta2GPI) rather than negatively charged phospholipids. However, it has not been determined whether different epitope-specific anti-beta2GPI antibodies obtained from one patient possess pathogenic properties. METHODS AND RESULTS: Three beta2GPI-binding IgM monoclonal antibodies (mAbs) (ILA-1, ILA-3, and ILA-4) were cloned from a patient with APS. The three antibodies were shown to bind beta2GPI immobilized on irradiated plates, yet only ILA-1 bound beta2GPI coated onto nonirradiated plates. Furthermore, when using the anti-beta2GPI enzyme-linked immunosorbent assay, ILA-1 was the only mAb inhibited by fluid phase beta2GPI. ILA-1 and ILA-3, but not ILA-4, induced adherence of U937 cells to endothelial cells in vitro (reflecting activation of endothelial cells). mAbs ILA-1 and ILA-3 as opposed to ILA-4 induced significant expression of adhesion molecules when preincubated with human umbilical vein endothelial cells. Passive administration of ILA-1 and ILA-3 to pregnant BALB/c mice induced clinical findings consistent with APS (increased fetal resorptions, reduced platelet counts, and prolonged activated partial thromboplastin time), whereas both ILA-4 and the control human IgM did not produce similar effects. CONCLUSIONS: The results of the study demonstrate the differential effects of various populations of anti-beta2GPI antibodies on endothelial cell activation and on experimental APS.

Adult↗