Journal articles on the topic 'Beta2 glycoprotein 1 antibody'
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1
Maggiorini, M., A. Knoblauch, J. Schneider, and EW Russi. "Diffuse microvascular pulmonary thrombosis associated with primary antiphospholipid antibody syndrome." European Respiratory Journal 10, no. 3 (March 1, 1997): 727–30. http://dx.doi.org/10.1183/09031936.97.10030727.
Abstract:
Thromboembolism is a well-known complication of the hypercoagulable state associated with antiphospholipid (aPL) antibodies. Acute respiratory failure (ARF) with diffuse pulmonary infiltrates has been reported in only a few patients with aPL antibodies. We describe a 49 year old patient with spiking fever, livedo reticularis, mild haemoptysis and ARF. Chest radiography revealed diffuse bilateral pulmonary infiltrates, and high resolution computed tomography (CT) revealed patchy distribution of areas of ground-glass attenuations. Pulmonary emboli were excluded with angiography. Lung biopsy revealed diffuse microvascular thrombosis, without capillaritis. High serum levels of anticardiolipin (aCL) antibodies were found. The patient's condition improved dramatically after intravenous infection of 1 g methylprednisolone on three consecutive days, followed by 50 mg prednisone orally. The rapid improvement following the administration of glucocorticosteroids suggests that anticardiolipin associated microvascular thrombosis, without inflammatory lesions, may depend on an interference with beta2-glycoprotein I (beta2=GPI) by anticardiolipin.
2
de Laat, Bas, Sander B. Meijer, Carel M. Eckmann, M. van Schagen, Koen Mertens, and Jan A. van Mourik. "Antiphospholipid Antibodies with LAC Activity That Bind beta2-Glycoprotein I Cause Increased Resistance Against Activated Protein C." Blood 110, no. 11 (November 16, 2007): 3622. http://dx.doi.org/10.1182/blood.v110.11.3622.3622.
Abstract:
Abstract Background: The antiphospholipid syndrome is characterized by the occurrence of vascular thrombosis combined with the presence of antiphospholipid antibodies (aPL) in plasma of patients. Recently it was published that aPL with lupus anticoagulant activity (LAC), caused by anti-beta2-glycoprotein I (beta2GPI) antibodies, highly correlate with a history of thrombosis. aPL-related resistance against activated protein C (APC) is one of the proposed mechanism responsible for thrombosis. We investigated a possible correlation between a beta2GPI-dependent LAC and increased APC-resistance in a population of 22 plasma samples with LAC activity. Methods: Twenty-two LAC-positive plasma samples were tested for beta2GPI-dependence (titration of cardiolipin into an APTT-based assay), increased APC-resistance, anti-beta2GPI IgG/IgM antibodies, anti-prothrombin IgG/IgM antibodies and anti-protein C IgG/IgM antibodies. In addition, a monoclonal anti-beta2GPI antibody and patient-purified IgG (both with LAC activity) were diluted in plasma with/without protein C and tested for occurrence of a beta2GPI-dependent LAC (normalization of clotting time by the addition of cardiolipin). To study aPL-induced APC-resistance in more detail, surface plasmon resonance analysis was used to investigate binding between APC and beta2GPI in the presence/absence of a mouse-derived monoclonal anti-beta2GPI antibody. Results: Eleven plasma samples that displayed a beta2GPI-dependent LAC also showed increased APC resistance. In contrast, only 1 of the 11 plasma samples with a beta2GPI-independent LAC displayed increased APC-resistance. None of the other serological parameters (antibodies against beta2-glycoprotein I, prothrombin or protein C) displayed the same association with increased APC resistance as a beta2-glycoprotein I dependent LAC. Furthermore, we found a linear correlation between the potency of a beta2GPI-dependent LAC and the level of APC-resistance. When a monoclonal anti-beta2GPI antibody and a patient-purified IgG were tested for a beta2GPI-dependent LAC, both antibodies did not display a beta2GPI-dependent LAC when diluted in protein C deficient plasma. In literature it has been proposed that direct binding of beta2GPI to APC results in a decreased activity of APC. By using surface plasmon resonance analysis, we found that beta2GPI displayed a higher affinity for coated APC in the presence of the monoclonal anti-beta2GPI antibody (4 nM) compared to beta2GPI alone (400 nM). Conclusion: The results of this study indicate that by adding cardiolipin into an APTT-based clotting assay, one can detect beta2GPI-dependent LAC based on increased resistance against APC. Increased resistance against activated protein C might result from direct binding of beta2GPI to activated protein C. In conclusion, our observations indicate a direct correlation between a major clinical symptom of APS (thrombosis), a diagnostic assay (beta2GPI-dependent LAC) and a potential mechanism responsible for thrombosis in the antiphospholipid syndrome (increased APC-resistance).
3
Ram S, Bharath, Monisha Harimadhavan, Shilpa Prabhu, Karthick R G, Devi Prasad Shetty, and Sharat Damodar. "Acquired and Inherited Thrombophilia Testing in Patients with Chronic Thromboembolic Pulmonary Hypertension: Value of Testing in an Academic Health Center." Blood 138, Supplement 1 (November 5, 2021): 4256. http://dx.doi.org/10.1182/blood-2021-148655.
Abstract:
Abstract Introduction Chronic thromboembolic pulmonary hypertension (CTEPH) is classed as group 4 in the present classification of pulmonary hypertension. The pathophysiology of CTEPH is complex, mainly is a consequence of prior acute pulmonary embolism with failure of thrombi to resolve and the recent recognition of added small vessel changes which impacts long-term outcomes even after surgical management. The role of thrombophilia testing in this condition has been debated. Hence, we here analyzed the utility of thrombophilia testing in CTEPH from a center in a developing country. Methods This is a single institution (Narayana Health City, Bangalore); retrospective study including patients ≥ 18 years of age who underwent thrombophilia workup in a diagnosis of CTEPH from January 2019 till July 2021. Tests done to evaluate thrombophilia included factor V Leiden; prothrombin F20210A mutation; MTHFR gene mutation; Protein C, S, and antithrombin deficiency; lupus anticoagulant, anti-beta2 glycoprotein I (IgM and IgG) and anticardiolipin antibody (IgM and IgG); hyperhomocysteinemia and anti-nuclear antibody testing (ANA-IF). The study was approved by the ethics committee of the institute and was carried out in accordance with the principles of the declaration of Helsinki. Results and discussion The study included 56 patients with a median age of 37 years (range 23-50), and 36 (64%) were males. Patients with recurrent venous thrombosis included 37 (66%), with the majority having thrombosis at 2 sites (53%; 22 patients with associated deep vein thrombosis). A family history of thrombosis was present in 4 patients. The majority of patients received vitamin K antagonists (76%), with the rest receiving direct oral anticoagulants (DOAC). Among the tests sent for acquired thrombophilia, ANA-IF and antiphospholipid antibody (APLA) were most frequently evaluated (94%). ANA-IF and APLA tests were positive in 5.6% and 30.1%, respectively. Among the APLA tests, Anti-beta2 glycoprotein I (IgM or IgG) was the most commonly detected antibody (13/46), followed by anticardiolipin antibody (IgG or IgM) (9/43) and lupus anticoagulant (7/40). Double and triple positive APLA were present in 3 and 4 patients, respectively. Homocysteine levels were high in 93.7% though only 16 patients were tested in this cohort. Among the tests for inherited thrombophilia, genetic tests (factor V Leiden, prothrombin F20210A mutation, and MTHFR gene mutation) were tested in only ~50%. Twenty-three percent were positive for heterozygous MTHFR followed by MTHFR compound heterozygous (10%) and heterozygous factor V Leiden heterozygous (10%). Antithrombin III, protein C, and S were tested in ~30% of patients. Antithrombin III was low in only 1 patient, with protein C and S assays being normal in all the patients. The cost analysis was calculated, showed a median of $364 (₹ 27,055) was spent per person on thrombophilia workup. The median cost incurred per patient for inherited thrombophilia workup was $232 (₹ 17,300) and for acquired thrombophilia was $132 (₹ 9814), respectively. Conclusion This single-institution study on thrombophilia workup in CTEPH patients reveals that APLA was the most commonly performed test with high positivity rates of 30.1%. Among the inherited thrombophilia, the positivity rate of MTHFR mutation was highest (33.3%), with other tests having a low positivity rate (0-10%). Hence, we would recommend APLA testing in all patients with CTEPH considering its high positivity and clinical utility. Testing for other thrombophilias should be pursued judiciously especially in economically restrictive settings. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
4
Kolyada, Alexey, Alfredo De Biasio, and Natalia Beglova. "Probing Anticoagulant Fondaparinux for Interference with Prothrombotic B2GPI/Anti-B2GPI Antibody Complexes." Blood 118, no. 21 (November 18, 2011): 1209. http://dx.doi.org/10.1182/blood.v118.21.1209.1209.
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Abstract Abstract 1209 Background: The presence of autoimmune antibodies directed to beta2-glycoprotein-I (B2GPI) often leads to thrombosis in antiphospholipid syndrome (APS). Heparin, low molecular weight heparin (LMWH) and fondaparinux are commonly used for prophylaxis and treatment of thromboses in APS. These drugs bind and activate antithrombin III to inactivate blood clotting proteases. Fondaparinux is a synthetic pentasaccharide matching a specific sequence within heparin interacting with antithrombin. Aim: We investigated if fondaparinux can bind B2GPI and ameliorate prothrombotic properties of B2GPI/anti-B2GPI antibody complexes. Results: We found that fondaparinux interacts with B2GPI and that the binding is dominated by electrostatic interactions. We measured the binding affinity by monitoring changes in the intrinsic fluorescence of domain V of B2GPI (B2GPI-DV) upon titration with fondaparinux. In the presence of 100 mM NaCl, the binding affinity was about 1.5 uM and stoichiometry of the binding is 1:1. Using solution NMR spectroscopy, we determined that the binding interface of the complex is centered on Lys251 of B2GPI-DV. This observation was confirmed by site-directed mutagenesis. The Lys251/Asp mutant fails to bind B2GPI-DV. Interestingly, the binding site for fondaparinux on B2GPI does not overlap with the major binding site for heparin. Cellular activation by the binding of B2GPI/anti-B2GPI antibody complexes with cell-surface receptors (among them ApoER2, a lipoprotein receptor from the LDLR family) and interference with the protective function of annexin V on anionic phospholipids expressed on the surfaces of activated cells are two potential prothrombotic mechanisms of B2GPI/antibody complexes. We found that fondaparinux does not prevent the association of the ligand-binding modules from ApoER2 with B2GPI-DV. Therefore, fondaparinux does not interfere with the binding of B2GPI/anti-B2GPI antibody complexes with lipoprotein receptors. Neither fondaparinux, nor heparin and LMWH were effective in inhibiting the binding of B2GPI/anti-B2GPI antibody complexes to cardiolipin-coated plates suggesting that these drugs do not prevent the destructive effect of B2GPI/antibody complexes on antithrombotic function of annexin V. Conclusions: At therapeutic concentrations, fondaparinux forms only small number of complexes with B2GPI, given that the binding affinity of the complex is in a micromolar range. When bound to B2GPI, fondaparinux does not interfere with the binding of B2GPI/anti-B2GPI antibody complexes to lipoprotein receptors and anionic phospholipids. Disclosures: No relevant conflicts of interest to declare.
5
Beglova, Natalia, and Chang-Jin Lee. "Mapping Interactions Between B2GPI and the Lipoprotein Receptors by Solution NMR Spectroscopy." Blood 112, no. 11 (November 16, 2008): 2018. http://dx.doi.org/10.1182/blood.v112.11.2018.2018.
Abstract:
Abstract Antiphospholipid syndrome (APS) is an autoimmune disease characterized by venous or arterial thrombosis and recurrent pregnancy loss. Beta2 glycoprotein I (B2GPI) is the major target for these antibodies. Current evidence suggests that B2GPI acquires pathological properties leading to APS after association with antibodies. It was demonstrated that APS related antibodies induce activation of endothelial cells, monocytes and platelets, although the identity of a cell-surface receptors that transmit the antibody-induced signaling inside cells remain unclear. Biochemical studies have shown that the receptors of the low-density lipoprotein receptor (LDLR) family are all capable to bind B2GPI/antibody complexes. These receptors are abundantly expressed by many cell types. The ligand-binding activity of the lipoprotein receptors is confined primarily to structurally homologous LA modules, which are arranged in sequence to form a ligand-binding domain. We investigated at the atomic level the features of the ligand-binding LA modules required for interaction with B2GPI. We sought to determine whether the same residues that form the ligand-binding pocket on the LA modules in the crystal structure of a RAP/LA3-4 complex also recognize B2GPI. We demonstrated that the same residues that form the ligand-binding pocket on LA4 in the crystal structure of the RAP/LA3-4 complex comprise the contact site for B2GPI. The domain 5 from B2GPI (B2GPI-D5) was expressed and labeled for NMR studies. The residues of B2GPI-D5 that are perturbed when B2GPI-D5 was titrated with LA4 are located at the C-terminus of domain 5. Using NMR relaxation measurements, we determined that B2GPI-D5 binds LA4 with 1:1 stoichiometry. The estimated Kd of the B2GPI-D5/LA4 complex is about 30 uM. NMR experimental data was used to build a docking model of the complex.
6
Xu, Jinfeng, Daijuan Chen, Yuan Tian, Xiaodong Wang, and Bing Peng. "Antiphospholipid Antibodies Increase the Risk of Fetal Growth Restriction: A Systematic Meta-Analysis." International Journal of Clinical Practice 2022 (January 31, 2022): 1–10. http://dx.doi.org/10.1155/2022/4308470.
Abstract:
Objective. Antiphospholipid syndrome (APS) is a chronic autoimmune disease with a high prevalence in females. Published data have identified pregnant women with APS may suffer from recurrent miscarriage, fetal death. However, the association between antiphospholipid antibody (aPL) and fetal growth restriction (FGR) remains controversial. This study aims to systematically review the literature on population-based studies investigating an association between aPL and FGR. Methods. The literature was searched on 1 November, 2021, using Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL), following the MOOSE checklist. Study inclusion criteria focused on peer-reviewed published articles that reported an association between aPL and FGR. Quality assessment was performed based on the Newcastle-Ottawa scale. The between-study heterogeneity was assessed by the Q test. Publication bias was assessed by funnel plots. Results. Twenty-two studies (with 11745 pregnant women) were included in the final analysis. Pooled odds ratio for association of aPL, anticardiolipin antibodies (ACA), anti-beta2 glycoprotein 1 antibodies (β2GP1), and FGR was 1.26 (95%CI 1.12, 1.40), 2.25 (95%CI 1.55, 2.94), and 1.31 (95% CI 1.12, 1.49), respectively. Lupus anticoagulant (LA) did not increase the chance of FGR (OR 0.82, 95%CI 0.54, 1.10). Conclusions. Our meta-analysis showed that aPL increased the risk of FGR. The risk of FGR varies with the aPL types. ACA and β2GP1 are strongly associated with FGR. There are currently insufficient data to support a significant relationship between LA and FGR.
7
Krueger, Irena, Lothar Gremer, Lena Mangels, Meike Klier, Kerstin Jurk, Dieter Willbold, Hans H. Bock, and Margitta Elvers. "Reelin Amplifies Glycoprotein VI Activation and AlphaIIb Beta3 Integrin Outside-In Signaling via PLC Gamma 2 and Rho GTPases." Arteriosclerosis, Thrombosis, and Vascular Biology 40, no. 10 (October 2020): 2391–403. http://dx.doi.org/10.1161/atvbaha.120.314902.
Abstract:
Objective: Reelin, a secreted glycoprotein, was originally identified in the central nervous system, where it plays an important role in brain development and maintenance. In the cardiovascular system, reelin plays a role in atherosclerosis by enhancing vascular inflammation and in arterial thrombosis by promoting platelet adhesion, activation, and thrombus formation via APP (amyloid precursor protein) and GP (glycoprotein) Ib. However, the role of reelin in hemostasis and arterial thrombosis is not fully understood to date. Approach and Results: In the present study, we analyzed the importance of reelin for cytoskeletal reorganization of platelets and thrombus formation in more detail. Platelets release reelin to amplify alphaIIb beta3 integrin outside-in signaling by promoting platelet adhesion, cytoskeletal reorganization, and clot retraction via activation of Rho GTPases RAC1 (Ras-related C3 botulinum toxin substrate) and RhoA (Ras homolog family member A). Reelin interacts with the collagen receptor GP (glycoprotein) VI with subnanomolar affinity, induces tyrosine phosphorylation in a GPVI-dependent manner, and supports platelet binding to collagen and GPVI-dependent RAC1 activation, PLC gamma 2 (1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase gamma-2) phosphorylation, platelet activation, and aggregation. When GPVI was deleted from the platelet surface by antibody treatment in reelin-deficient mice, thrombus formation was completely abolished after injury of the carotid artery while being only reduced in either GPVI-depleted or reelin-deficient mice. Conclusions: Our study identified a novel signaling pathway that involves reelin-induced GPVI activation and alphaIIb beta3 integrin outside-in signaling in platelets. Loss of both, GPVI and reelin, completely prevents stable arterial thrombus formation in vivo suggesting that inhibiting reelin-platelet-interaction might represent a novel strategy to avoid arterial thrombosis in cardiovascular disease.
8
Demir, S., J. Li, L. Magder, and M. A. Petri. "SAT0203 SINGLE LAC POSITIVITY VERSUS DOUBLE AND TRIPLE POSITIVITY FOR THROMBOSIS IN SLE." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1044.1–1044. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2762.
Abstract:
Background:The antiphospholipid syndrome (APS) is defined by the development of venous and/or arterial thromboses, and pregnancy morbidity, in the presence of antiphospholipid antibodies (aPL); lupus anticoagulant, moderate-to-high titer anticardiolipin (aCL) and anti-β2-glycoprotein (aB2GPI). It has been suggested that the incidence of thromboembolic events were significantly higher in the triple positive subjects, and the rate of pregnancy loss was also significantly much higher in double positive subjects (1). On the other hand several studies showed that LAC is more highly associated with thrombosis risk (2).Objectives:We aimed to investigate the risk of thrombosis in Systemic Lupus Erythematosus (SLE) patients with single LAC positivity versus double and triple positivity in Hopkins Lupus Cohort.Methods:The Hopkins Lupus Cohort is a prospective longitudinal cohort of SLE patients ongoing since 1987. This analysis was based on cohort experience from 2003 through October 2019. Anticardiolipin and anti-Beta2 glycoprotein were defined as positive when the antibody titer exceeded 20 units. The lupus anticoagulant was determined by dilute Russell’s viper venom time (dRVVT) and confirmatory mixing studies, if prolonged. It is defined as positive if a patient had a dRVVT of 45 or more second and a positive confirm ratio of more than 1.4. For each aPL, we defined the patient as positive at a given month of follow up if they ever had a positivity in previous measures. The relationships between thrombosis and aPL were adjusted for number of prior aPL assessment.Results:There were 805 patients with a complete profile of 7 antiphospholipid antibodies, with a total of 73417 person months (6118 person years) of follow up. For any thrombosis when compared to patients with LAC positivity only, double positivity with any isotypes [1.15(0.50, 2.66) p=0.7484] and triple positivity with any isotypes [1.68(0.74, 3.80), p=0.2145] showed a higher point estimates but statistically not significant (Table 1).Table 1.Single, double and triple positive patterns and the risk of any thrombosis.PatternNumber of eventsPerson-yearsRate per 1000 person-yearsadjusted RR (95% CI)p-valueLAC positivity only1063315.81.00 (Ref)Never any aPL33258112,80.73(0.36, 1.47)0.3819any aCL positivity only67937,60.43(0.16, 1.18)0.1028any aB2GPI positivity only751713,50.78(0.30,2.05)0.6195any aCL and aB2GPI positivity only540412,40.71(0.24,2.04)0.5211LAC and ACL positivity740617,31.15(0.50,2.66)0.7484LAC and aB2GPI positivity1249024,5Triple positivity01470,01.68(0.74,3.80)0.2145Conclusion:We found that triple or double positive aPL profiles are not superior to single LAC positivity in their association with any thrombosis in SLE patients.References:[1]Pengo V, Ruffatti A, Del Ross T, Tonello M, Cuffaro S, Hoxha A, Banzato A,Bison E, Denas G, Bracco A, Padayattil Jose S. Confirmation of initial antiphospholipid antibody positivity depends on the antiphospholipid antibody profile. J Thromb Haemost. 2013 Aug;11(8):1527-31.[2]Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood. 2003; 101(5):1827-32.Disclosure of Interests:Selcan Demir: None declared, Jessica Li: None declared, Laurence Magder: None declared, Michelle A Petri Grant/research support from: GSK, Eli Lilly and Company, Consultant of: Eli Lilly and Company
9
Porter, Andrew, and Natalia Beglova. "Pharmacokinetics, Serum Stability and Immunogenicity of A Polypeptide Inhibitor of B2GPI/Antibody Complexes Tested in Mice." Blood 120, no. 21 (November 16, 2012): 2205. http://dx.doi.org/10.1182/blood.v120.21.2205.2205.
Abstract:
Abstract Abstract 2205 Background: Antiphospholipid syndrome (APS) is an autoimmune disease with clinical features of thrombosis and pregnancy loss. Beta2-glycoprotein I (B2GPI) is the major antigen for APS-related antibodies. We engineered a polypeptide consisting of two ligand-binding A1 modules from the ApoE receptor 2. Previously, we demonstrated that this polypeptide, A1-A1, preferentially binds B2GPI/antibody complexes compared to B2GPI alone and efficiently inhibits the binding of B2GPI/antibody complexes to negatively charged phospholipids. Therefore, A1-A1 effectively interferes with two pathological mechanisms of B2GPI/antibody complexes: the binding to anionic phospholipids and ApoER2. In order to use A1-A1 to study pathological mechanisms of B2GPI/antibody complexes in vivo, we tested its pharmacokinetic, serum stability and immunogenicity in mice. To visualize A1-A1, we labeled it with a fluorescent probe Atto-488 attached to the N-terminus. Results: We monitored clearance of A1-A1 from the circulation after intraperitoneal and intravenous administration. After intraperitoneal administration, the concentration of A1-A1 in the blood reached its maximum at 30 min after injection and cleared from the blood in 6–8 hours. When A1-A1 was injected intravenously, 14% of A1-A1 remained in the blood 1 hour after administration and decreased to 4% in 3 hours. We assessed the binding of A1-A1 to serum proteins in both mouse and human serum by gel-filtration chromatography. Chromatograms of A1-A1 in both mouse and human serum collected just after mixing of A1-A1 with serum were almost identical to those collected after 2 hours of incubation at 37° C. About 90% of A1-A1 stays free from serum proteins. Previously, we demonstrated that A1-A1 has a favorable stability in human serum. More than 35% of A1-A1 remained in human serum after 15 days of incubation at 37° C. Here, we determined whether A1-A1 is cleaved by proteases in mouse serum. Degradation of A1-A1 was monitored by the reversed-phase HPLC by comparing the peak corresponding to intact A1-A1 and A1-A1 incubated with serum for 2 hours at 37° C. After incubation with mouse serum, A1-A1 eluted at the same time as intact A1-A1 and the intensity of the elution peak did not decrease, indicating that A1-A1 remains intact in mouse serum. To evaluate immunogenecity of A1-A1, we immunized mice with A1-A1, A1-A1 in the presence of adjuvant and A1-A1 conjugated to a carrier protein. A1-A1 did not induce detectable anti-A1-A1 IgG production even in the presence of adjuvant or carrier protein. Conclusions: A1-A1 has favorable properties for use in vivo. It stays in the circulation for more than one hour following intravenous injection. After intraperitoneal administration, A1-A1 is rapidly absorbed into blood and cleared in about 6 hours. A1-A1 is resistant to both human and mouse proteases, has low immunogenicity and its amount in the blood is not depleted by binding to serum proteins. Disclosures: No relevant conflicts of interest to declare.
10
Lenting, Peter J., Janine J. Hulstein, Bas de Laat, Ronald H. Derksen, Rob Fijnheer, and Philip G. de Groot. "Beta2-Glycoprotein I Interferes with von Willebrand Factor-Dependent Platelet Adhesion." Blood 108, no. 11 (November 16, 2006): 415. http://dx.doi.org/10.1182/blood.v108.11.415.415.
Abstract:
Abstract Patients with the antiphospholipid syndrome are characterized by the association of thrombosis or pregnancy morbidity with the presence of antibodies against phospholipid-binding proteins, such as beta2-Glycoprotein (beta2-GPI) or prothrombin. In particular, antibodies against beta2-GPI strongly correlate with thrombotic complications. One model that explains this correlation involves an antibody-induced gain-of-function of beta2-GPI, which results in prothrombotic properties of this plasma protein. In an alternative model, beta2-GPI may display anti-thrombotic properties that disappear in an antibody-dependent manner. Of course, both possibilities may occur simultaneously. It should be noted, however, that little is known about the physiological function of beta2-GPI. Several in vitro-based studies have pointed to beta2-GPI as a potential inhibitor of fibrinolysis and/or the intrinsic pathway of coagulation. In the present study, we investigated the hypothesis that beta2-GPI affects platelet function. Addition or immune-depletion of beta2-GPI from platelet-rich plasma had little effect on ADP- or collagen-induced platelet aggregation, whereas it did modulate ristocetin-induced platelet aggregation. In a system employing washed platelets, beta2-GPI completely inhibited platelet aggregation induced by VWF/ristocetin or by a recombinant VWF type 2B mutant (VWF/R1306Q). This suggests that beta2-GPI is directed to the von Willebrand (VWF)-glycoprotein Ib axis. Indeed, beta2-GPI interfered with platelet adhesion to VWF-coated coverslips under conditions of flow as well, resulting in a 2-fold reduction of platelet coverage. In direct binding studies, wt-VWF displayed weak binding to immobilized beta2-GPI. However, conversion of latent VWF into a platelet-binding conformation (either via ristocetin or via a type 2B mutation) induced efficient, dose-dependent and saturable binding of VWF to beta2-GPI. By using a number of recombinant deletion-mutants and individual domains, we found that binding was mediated by the VWF A1 domain. Interestingly, anti-beta2-GPI antibodies isolated from patients with the antiphospholipid syndrome not only interfered with the interaction between beta2-GPI and VWF, but also neutralized the inhibitory effect of beta2-GPI towards VWF-dependent platelet aggregation. Finally, we analysed plasma of antiphospholid-syndrome patients for the presence of VWF that is in its platelet-binding conformation by using a specific nanobody (Hulstein et al (2005) Blood106:3035). Levels of active VWF were increased 1.7-fold in patients compared to healthy individuals or patients that lack beta2-GPI-directed antibodies (p<0.0001). This increase in active VWF is similar to that observed in patients with acquired TTP. In conclusion, we demonstrate that beta2-GPI interacts preferentially with the platelet-binding conformation of VWF, thereby inhibiting VWF-dependent platelet adhesion and aggregation. Anti-beta2-GPI antibodies obtained from antiphospholipid-syndrome patients reverse this anti-thrombotic effect of beta2-GPI. We propose that beta2-GPI functions as a natural first-line barrier that prevents small amounts of active VWF to interact with platelets.
11
De Laat, Bas, Philip G. de Groot, Ronald H. W. M. Derksen, Rolf T. Urbanus, Koen Mertens, Frits Rosendaal, and Carine J. M. Doggen. "Decreased beta2-Glycoprotein I Plasma Levels as a Risk Factor for Myocardial Infarction in Men." Blood 112, no. 11 (November 16, 2008): 1813. http://dx.doi.org/10.1182/blood.v112.11.1813.1813.
Abstract:
Abstract Background: Several factors influence the occurrence of acute myocardial infarction. One of these factors is thought to be Von Willebrand Factor which serves as adhesive surface for platelets to adhere to the vessel wall. We have recently found that beta2- glycoprotein I is able to inhibit platelet binding to von Willebrand Factor by binding to the A1 domain of Von Willebrand Factor 1. This could indicate that beta2-glycoprotein I possesses antithrombotic properties with respect to arterial thrombosis. In the present study we investigated whether differences in beta2-glycoprotein I plasma levels influence the risk of myocardial infarction. Methods and Results: We have measured beta2-glycoprotein I and Von Willebrand Factor antigen levels in 539 men with a first myocardial infarction and in 611 control subjects who participated in the case-control Study of Myocardial Infarction Leiden (SMILE). Although we did not find a profound effect of beta2-glycoprotein I plasma levels on myocardial infarction in the overall population (odds ratio 0.93, 95% confidence interval 0.65–1.33), there appeared to be a dose-dependent protective effect of increasing beta2-glycoprotein I plasma levels on myocardial infarction in men of 60 years and older. In this age group we found an odds Ratio of 0.44 (95% confidence interval 0.25–0.77) for high beta2-glycoprotein I levels compared to low levels. Furthermore, high plasma levels of beta2-glycoprotein I remained protective for myocardial infarction despite high levels of Von Willebrand Factor. In addition, we studied a possible association between age and Von Willebrand Factor and beta2-glycoprotein I plasma levels. It appeared that both Von Willebrand Factor and beta2-glycoprotein I plasma levels increased with age, but a larger increase in Von Willebrand Factor plasma levels was observed than in beta2-glycoprotein I plasma levels (13.7 % every 10 years versus 5.7% every 10 years). Conclusions: In this study high circulating levels of beta2-glycoprotein I appeared to be associated with a lower risk of myocardial infarction in men over 60 years. In addition we observed a larger increase in Von Willebrand Factor levels with age than beta2- glycoprotein I levels. As beta2-glycoprotein I possesses antithrombotic properties by inhibiting the activity of Von Willebrand Factor in-vitro, this might indicate that during aging the haemostatic balance slowly shifts to a more prothrombotic state 1. Future in-vivo experiments are needed to investigate the exact contribution of beta2-glycoprotein I on the pathophysiology of myocardial infarction and arterial thrombosis in general.
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Chen, Wei Hsi. "Anti-beta2-Glycoprotein I Antibody and Hypertension in Cerebral Ischemia." Clinical and Applied Thrombosis/Hemostasis 10, no. 1 (January 2004): 55–60. http://dx.doi.org/10.1177/107602960401000109.
13
Beglova, Natalia, Chang-Jin Lee, and Alfredo De Biasio. "Recognition of B2GPI by the Lipoprotein Receptors." Blood 114, no. 22 (November 20, 2009): 851. http://dx.doi.org/10.1182/blood.v114.22.851.851.
Abstract:
Abstract Abstract 851 Lipoprotein receptors of the LDLR family serve as clearance receptors for beta2-glycoprotein-I (B2GPI) and as signaling receptors for the B2GPI/antibody complexes in patients with antiphospholipid syndrome (APS). B2GPI binds lipoprotein receptors through its domain V (B2GPI-DV) and the lipoprotein receptors use the LA modules to interact with B2GPI. The LA modules, which are about 40 residues each, are arranged in sequence to form the ligand-binding domains of the receptors. The LA modules have little sequence homology both within a single receptor and between different receptors, but adopt a very similar three dimensional structure. We have investigated the structural features of the contact interface in the B2GPI-DV/LA complexes and the characteristic features of the LA modules required for efficient binding to B2GPI. Using solution NMR spectroscopy, we have demonstrated that three different LA modules bind to the same site on B2GPI-DV and that the binding site for B2GPI-DV on these LA modules is centered on the residues involved in coordination of the calcium ion. The dissociation constants measured for different LA complexes are in the range from 1 mM to approximately 100 mM. The difference in binding affinity is attributed to the auxiliary contacts that augment the interactions of the residues at the core of the binding interface. We have solved the structure of the B2GPI-DV/LA4 complex by molecular docking guided by NMR-derived restraints and have validated the structure by four independent experimental observations based on mutagenesis, solution NMR spectroscopy, fluorescence polarization and intrinsic tryptophan fluorescence measurements. The structure identified three lysine residues of B2GPI-DV, Lys308, Lys317 and Lys282, as critical for binding the LA modules. Our data shows that not all the LA modules can bind B2GPI-DV and that those LA modules capable of binding B2GPI-DV will interact with it in a similar fashion as observed in the B2GPI-DV/LA4 complex. Whether an LA module is capable of binding B2GPI could be distinguished based on the primary sequence in the vicinity of the calcium-coordinating residues. According to the current hypothetical model, the binding of B2GPI to anionic phospholipids in the presence of APS-related antibodies is the first event leading to the pathology of APS. However, we have shown that the LA modules interfere with binding of B2GPI-DV to cardiolipin indicating that B2GPI-DV cannot simultaneously bind to anionic phospholipids and lipoprotein receptors. Disclosures: No relevant conflicts of interest to declare.
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Maejima, M., T. Fujii, T. Okai, S. Kozuma, Y. Shibata, and Y. Taketani. "Beta2-glycoprotein I-dependent anticardiolipin antibody in early recurrent spontaneous abortion." Human Reproduction 12, no. 10 (October 1, 1997): 2140–42. http://dx.doi.org/10.1093/humrep/12.10.2140.
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Chen, W.-H., H.-L. Yin, and C.-J. Chen. "Anti-beta2-glycoprotein I antibody and cerebellar ataxia in breast cancer." Lupus 21, no. 4 (March 16, 2012): 460–62. http://dx.doi.org/10.1177/0961203312437436.
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Itelman, E., M. Perelman, D. Kent, N. Bibar, G. Segal, L. Negru, and A. Dagan. "POS0784 LOW COMPLEMENT LEVELS ARE ASSOCIATED WITH HIGHER MORTALITY IN HOSPITALIZED PATIENTS WITH POSITIVE ANTIPHOSPHOLIPID ANTIBODIES." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 679.1–679. http://dx.doi.org/10.1136/annrheumdis-2022-eular.4815.
Abstract:
BackgroundAntiphospholipid Syndrome is an autoimmune disease characterized by increased risk for vascular thrombosis (arterial and/or venous) thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies. The mechanisms by which aPLs induce thrombosis are unclear; several have been suggested, among them complement activation.(1-2) The complement system is a system of enzymes and regulatory proteins of the innate immune system that play a crucial role in the inflammatory response to various pathogenic stimuli. The complement and coagulation pathways are interconnected, and expanding evidence indicates that complement may be activated in patients with antiphospholipid syndrome (3-5).ObjectivesOur study was intended to better characterize the complicated relations between antiphospholipid antibodies and complement activation among hospitalized patients with antiphospholipid syndrome and its impact on short- and long-term prognosisMethodsA retrospective cohort studies. Clinical and prognostic data of hospitalized patients with antiphospholipid syndrome and a measurement of complement levels (C3 or C4) were obtained. Rates of long-term mortality, one-year mortality, deep vein thrombosis (DVT), and pulmonary emboli (PE) were compared between patients with low complement levels and patients with normal complement levels. Low complement was defined as C3 < 90 mg/dl or C4 < 10 mg/dl. A multivariate analysis was performed to control for Anticardiolipin levels, β₂ macroglobulin levels and RVVT ratio.ResultsComplete data was available for 6,599 patients, of which 712 (11%) had low complement levels. The median age of the cohort was 47.7, and most of the patients were females (56%). Patients with low complement levels had significantly higher mortality rates 30% vs. 18%, p < 0.001 for long-term mortality (Figure 1) and 15% vs. 5%, p < 0.001 for 1 year mortality when compared to patients with normal complement levels. DVT and PE rates were similar (4% vs 3.8%, P = 0.78 and 4% vs 2.4%, P = 0.13 respectively). Results of the multivariate analysis (Table 1) were consistent and showed that patients with low complement levels had 111% higher mortality rates (CI 1.52-2.90, P < 0.001).Table 1.Multivariate Analysis for long term mortalityMultivariate AnalysisOR (CI)pLow Complement2.11 [1.52, 2.90]<0.001Anticardiolipin IGG1.00 [1.00, 1.01]0.243Anticardiolipin IGM0.99 [0.98, 1.00]0.084β₂ IGM1.01 [1.00, 1.01]0.017β₂ IGG1.00 [0.99, 1.00]0.663RVVT Ratio0.99 [0.63, 1.52]0.954Figure 1.Cumulative 10-Year survivalConclusionIn hospitalized patients with high aPLs, low complement levels are associated with significantly higher mortality rates. This finding is in correlation with recent literature, suggesting an important role for complement activation in APS.References[1]Chaturvedi S, Brodsky RA, McCrae KR. Complement in the pathophysiology of the antiphospholipid syndrome. Front Immunol. 2019 Mar 14;10:449.[2]Bu C, Gao L, Xie W, Zhang J, He Y, Cai G, et al. beta2-glycoprotein i is a cofactor for tissue plasminogen activator-mediated plasminogen activation. Arthritis Rheum. 2009 Feb;60(2):559–568.[3]Tedesco F, Borghi MO, Gerosa M, Chighizola CB, Macor P, Lonati PA, et al. Pathogenic role of complement in antiphospholipid syndrome and therapeutic implications. Front Immunol. 2018 Jun 19;9:1388.[4]Oku K, Nakamura H, Kono M, Ohmura K, Kato M, Bohgaki T, et al. Complement and thrombosis in the antiphospholipid syndrome. Autoimmun Rev. 2016 Oct;15(10):1001–1004.[5]Salmon JE, Girardi G, Holers VM. Complement activation as a mediator of antiphospholipid antibody induced pregnancy loss and thrombosis. Ann Rheum Dis. 2002 Nov;61 Suppl 2:ii46–50.Disclosure of InterestsNone declared
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Favaloro, Emmanuel J., Richard C. W. Wong, Roger Silvestrini, Robert McEvoy, Susan Jovanovich, and Peter Roberts-Thomson. "A Multilaboratory Peer Assessment Quality Assurance Program-Based Evaluation of Anticardiolipin Antibody, and beta2-Glycoprotein I Antibody Testing." Seminars in Thrombosis and Hemostasis 31, no. 01 (February 2005): 73–84. http://dx.doi.org/10.1055/s-2005-863808.
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Soon Song, Young Ah Kim, Hyon Suk K, Kyung. "Prevalence of anti-beta2 glycoprotein-I antibody in patients with primary or secondary immune thrombocytopenia." Platelets 10, no. 4 (January 1999): 219–22. http://dx.doi.org/10.1080/09537109976059.
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Abou-Nassar, Karim, Mark Walker, Shi-Wu Wen, Marisa Freedman, Steve Doucette, Julie Lafleche, and Marc Rodger. "The Association Between Anti-beta2 Glycoprotein 1 Antibodies and Adverse Pregnancy Outcomes." Blood 114, no. 22 (November 20, 2009): 4003. http://dx.doi.org/10.1182/blood.v114.22.4003.4003.
Abstract:
Abstract Abstract 4003 Poster Board III-939 BACKGROUND The Sapporo criteria include anti-β2 glycoprotein1 (anti-B2GP1) antibodies among antiphospholipid antibodies used to diagnose the antiphospholipid syndrome (APS). Although pre-eclampsia, intra-uterine growth restriction (IUGR), late fetal loss and placental abruption, collectively termed “placenta mediated complications”, are recognized as clinical criteria for the APS, strong evidence to support their association with anti-B2GP1 antibodies is lacking. OBJECTIVE This study aims to assess the association between anti-B2GP1 antibodies and placenta mediated complications. METHODS We performed a nested case-control study from a prospective cohort of 7000 mother baby pairs whereby women and their fetuses were recruited between 12-20 weeks gestation. Five hundred cases were randomly selected amongst women who experienced one of the following adjudicated adverse pregnancy outcomes: pre-eclampsia (BP ≥140/90 with proteinuria), placental abruption (antepartum bleeding with objective evidence of placental thrombus), late pregnancy loss (≥ 12 weeks gestation) and IUGR (birth weight less than the 10th percentile of normal population). Random selection of 500 controls was performed amongst women who did not experience the above mentioned adverse pregnancy outcomes. Stored blood samples were analyzed for the presence of anti-B2GP1 IgG and IgM antibodies by enzyme-linked immunosorbent assay. Titers ≥ than 20 G or M units were considered positive. This study has an 80% power to detect an odds ratio of 2.25 at the 5% level of significance based on an estimated 4 % prevalence of anti-B2GP1 IgG and/or IgM antibodies in titers ≥ 20 G/M units in our cohort of pregnant women. RESULTS Anti-B2GP1 IgG and/or IgM antibodies in titers ≥ 20 G/M units were present in 24/497 (4.8%) controls and 33/503 (6.6%) cases. The presence of anti-B2GP1 IgG and/or IgM in titers ' 20 G/M units was not significantly associated with a composite outcome of pre-eclampsia, IUGR, late fetal loss and placental abruption (OR 1.38; 95%CI 0.8-2.37 p=0.18). This combination of antibodies and titers only demonstrated a weak association with IUGR (OR 1.86; 95%CI 1.09-3.18 p=0.02). The presence of anti-B2GP1 IgG and/or IgM antibodies in titers ≥ 40 G/M units also failed to show an association with a composite outcome of pre-eclampsia, IUGR, late fetal loss and placental abruption (OR 2.65; 95%CI 0.7-10.04 p=0.15). However, stronger associations were observed with placental abruption (OR 4.87; 95%CI 1.02-23.25 p=0.047) and IUGR (OR 3.53; 95%CI 1.03-12.15 p=0.045). CONCLUSION The presence of anti-B2GP1 IgG and/or IgM antibodies in titers 20 ≥ G/M units during pregnancy is only associated with an increased risk of IUGR. Anti-B2GP1 antibodies in titers ' 40 G/M units, as suggested in the Sapporo diagnostic criteria for the APS, are associated with IUGR and placental abruption and possibly other placenta mediated complications. Larger adequately powered studies will be required to provide definitive answers. Disclosures: No relevant conflicts of interest to declare.
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Endresen, Gerhard K. M., and Øystein Førre. "Studies on the Binding of Proteins to the Human Platelet Surface: Relation to Platelet Activation." Thrombosis and Haemostasis 53, no. 03 (1985): 360–65. http://dx.doi.org/10.1055/s-0038-1661315.
Abstract:
SummarySeveral antibody fractions and sera from patients with rheumatoid arthritis, systemic lupus erythematosus and chronic idiopathic thrombocytopenic purpura were examined for their ability to bind to normal platelets using immunofluorescent staining techniques. Platelet aggregometry was used to study the activating capacity of the samples.Both C1q, C1s, C1 inactivator, fibrinogen, factor VIII-related antigen, alpha1-acid glycoprotein, alpha1-antitrypsin, beta2-micro- globulin and isoantigens A and B, as well as fibronectin and plasminogen were found on the platelet surface. Only antibodies to C1q, C1s and beta2-microglobulin were able to induce platelet aggregation. Sera containing immune complexes or platelet autoantibodies revealed positive surface staining for IgG, or for IgG and IgM. These sera also induced aggregation of platelets. Sera not containing immune complexes or autoantibodies gave negative staining and aggregation results. Thus, only some of the ligand receptor interactions were able to induce platelet aggregation.
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WANG, Hsueh-Hsiao, and An-Na CHIANG. "Cloning and characterization of the human beta2-glycoprotein I (beta2-GPI) gene promoter: roles of the atypical TATA box and hepatic nuclear factor-1alpha in regulating beta2-GPI promoter activity." Biochemical Journal 380, no. 2 (June 1, 2004): 455–63. http://dx.doi.org/10.1042/bj20031610.
Abstract:
β2-Glycoprotein I (β2-GPI) is a plasma glycoprotein primarily synthesized in the liver. The interindividual variability of β2-GPI expression in subjects with various metabolic syndromes and disease states suggests that it may have clinical importance. However, the regulation of β2-GPI gene expression has not been clarified. To gain more insight into the control of β2-GPI gene expression, we cloned the 4.1-kb 5´-flanking region and characterized the proximal promoter of the β2-GPI gene in this study. Cis-acting elements required for β2-GPI promoter activity were identified with transient transfection assays in the hepatoma cell lines HepG2 and Huh7 and in non-hepatic HeLa cells. Serial deletion analyses of the β2-GPI 5´-flanking sequence revealed that the region from −197 to +7 had strong promoter activity in hepatoma cells but not in HeLa cells. Truncation and site-directed mutagenesis of putative cis-elements within this region showing an atypical TATA box and a HNF-1 (hepatic nuclear factor-1) element were both essential for the β2-GPI promoter activity. Subsequent gel mobility shift assays confirmed the interaction of HNF-1α with the HNF-1 site residing downstream of the TATA box. Co-transfection of β2-GPI promoter-luciferase vector with HNF-1α expression vector in Huh7 and HNF-1-deficient HeLa cells demonstrated the transactivation effect of HNF-1α on β2-GPI promoter activity. In addition, overexpression of HNF-1α enhanced the endogenous β2-GPI expression. These results suggest that the atypical TATA box and HNF-1 cis-element are critical for β2-GPI transcription and HNF-1α may play an important role in cell-specific regulation of β2-GPI gene expression.
22
Chen, Wei H., Yi F. Kao, and Jia S. Liu. "An increase of blood anti-beta2-glycoprotein I antibody in Japanese encephalitis associated with cerebral ischemia." Blood Coagulation & Fibrinolysis 16, no. 1 (January 2005): 55–59. http://dx.doi.org/10.1097/00001721-200501000-00009.
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Carmo-Pereira, S. "Value of IgA anticardiolipin and anti-beta2-glycoprotein I antibody testing in patients with pregnancy morbidity." Annals of the Rheumatic Diseases 62, no. 6 (June 1, 2003): 540–43. http://dx.doi.org/10.1136/ard.62.6.540.
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Audrain, M. A. P. "Value of autoantibodies to beta2-glycoprotein 1 in the diagnosis of antiphospholipid syndrome." Rheumatology 41, no. 5 (May 1, 2002): 550–53. http://dx.doi.org/10.1093/rheumatology/41.5.550.
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DIENAVA-VERDOOLD, I., M. G. BOON-SPIJKER, P. G. DE GROOT, H. J. M. BRINKMAN, J. VOORBERG, K. MERTENS, R. H. W. M. DERKSEN, and B. DE LAAT. "Patient-derived monoclonal antibodies directed towards beta2 glycoprotein-1 display lupus anticoagulant activity." Journal of Thrombosis and Haemostasis 9, no. 4 (April 2011): 738–47. http://dx.doi.org/10.1111/j.1538-7836.2011.04212.x.
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Panunto-Castelo, A., I. C. Almeida, J. C. Rosa, L. J. Greene, and M. C. Roque-Barreira. "The Rubino test for leprosy is a beta2-glycoprotein 1-dependent antiphospholipid reaction." Immunology 101, no. 1 (September 2000): 147–53. http://dx.doi.org/10.1046/j.1365-2567.2000.00081.x.
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LYNCH, ANNE, TIM BYERS, WOODRUFF EMLEN, DAWN RYNES, SUSAN M. SHETTERLY, and RICHARD F. HAMMAN. "Association of Antibodies to Beta2-Glycoprotein 1 With Pregnancy Loss and Pregnancy-Induced Hypertension." Obstetrics & Gynecology 93, no. 2 (February 1999): 193–98. http://dx.doi.org/10.1097/00006250-199902000-00007.
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IWATA, Hiroyuki, Kohtaro MURASE, and Takeshi INOUE. "Monoclona Antibody against Bovine .ALPHA.1-Acid Glycoprotein." Journal of Veterinary Medical Science 62, no. 10 (2000): 1099–100. http://dx.doi.org/10.1292/jvms.62.1099.
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Guo, Han, Yuncong Zhang, Aiwei Li, Chanjuan Wang, Shuo Yang, Yinmei Zhang, Jie Zhang, and Rui Qiao. "Anti-domain 1 of beta2-glycoprotein I aids risk stratification in lupus anticoagulant-positive patients." Clinical and Experimental Medicine 19, no. 3 (May 15, 2019): 339–45. http://dx.doi.org/10.1007/s10238-019-00555-w.
30
Born, W. K., M. Vollmer, C. Reardon, E. Matsuura, D. R. Voelker, P. C. Giclas, and R. L. O'Brien. "Hybridomas Expressing gammadelta T-Cell Receptors Respond to Cardiolipin and beta2-Glycoprotein 1 (Apolipoprotein H)." Scandinavian Journal of Immunology 58, no. 3 (September 2003): 374–81. http://dx.doi.org/10.1046/j.1365-3083.2003.01315.x.
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Jones, R. A., C. S. Scott, and J. A. Child. "Quantitation of cell-surface beta2-microglobulin (β2m) using a comparative antibody inhibition assay." Journal of Immunological Methods 96, no. 1 (January 1987): 87–96. http://dx.doi.org/10.1016/0022-1759(87)90371-1.
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Karata, Suat, Yavuz Aydin, Fahri Ocer, Aysenur Buyru, and Huriye Balci. "Hereditary Thrombophilia, Anti-Beta2 Glycoprotein 1 IgM, and Anti-Annexin V Antibodies in Recurrent Pregnancy Loss." American Journal of Reproductive Immunology 67, no. 3 (November 22, 2011): 251–55. http://dx.doi.org/10.1111/j.1600-0897.2011.01092.x.
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Smalley, Haley, Jennifer M. Rowe, Fernando Nieto, Jazmin Zeledon, Kellyn Pollard, John M. Tomich, and Sherry D. Fleming. "Beta2 glycoprotein I-derived therapeutic peptides induce sFlt-1 secretion to reduce melanoma vascularity and growth." Cancer Letters 495 (December 2020): 66–75. http://dx.doi.org/10.1016/j.canlet.2020.08.039.
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Szabó, G., T. Tarr, P. Soltész, and J. Kappelmayer. "PF796 THE EFFECT OF ANTI-BETA2-GLYCOPROTEIN I ANTIBODY UPON THROMBIN GENERATION IN NORMAL, LEIDEN HETEROZYGOUS AND FACTOR DEFICIENT PLASMAS." HemaSphere 3, S1 (June 2019): 351–52. http://dx.doi.org/10.1097/01.hs9.0000561468.98984.5a.
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Meroni, PL, F. Tedesco, M. Locati, A. Vecchi, N. Di Simone, B. Acaia, SS Pierangeli, and MO Borghi. "Anti-phospholipid antibody mediated fetal loss: still an open question from a pathogenic point of view." Lupus 19, no. 4 (March 30, 2010): 453–56. http://dx.doi.org/10.1177/0961203309361351.
Abstract:
Antiphospholipid antibodies (aPL) are associated with recurrent miscarriages and pregnancy complications, however their pathogenic mechanisms are still matter of research. Thrombotic events at the placental level cannot explain all of the clinical manifestations. It has been suggested that aPL may be responsible for a local acute inflammatory response mediated by complement activation and neutrophil infiltration eventually leading to fetal loss. However histological and immunohistological studies on human placental samples do support such a mechanism only in part and with no any clear relationship with the pregnancy outcome. A direct effect of aPL on both maternal and fetal placental tissues has been reported through the reactivity of the antibodies with beta2 glycoprotein I (β2GPI) expressed on the cell membranes. These events do not require an inflammatory response and can be in part related to the inhibition of growth factors favouring a physiological placentation. Understanding the different pathogenic mechanisms of aPL-associated miscarriages may help in improving our therapeutic approach particularly in recurrent cases not responsive to the usual treatment. Lupus (2010) 19, 453—456.
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Dry, Inga, Helen Todd, David Deane, Ann Percival, Kevin Mclean, Neil F. Inglis, Erin D. T. Manson, et al. "Alcelaphine herpesvirus 1 glycoprotein B: recombinant expression and antibody recognition." Archives of Virology 161, no. 3 (December 9, 2015): 613–19. http://dx.doi.org/10.1007/s00705-015-2701-y.
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Posch, Florian, Johanna Gebhart, Jacob H. Rand, Bas de Laat, Silvia Koder, Peter Quehenberger, Cihan Ay, and Ingrid Pabinger. "Thrombotic Events in Lupus Anticoagulant Positive Patients Prospectively Correlate with Clinical Risk Factors - the Vienna Lupus Anticoagulant and Thrombosis Study (LATS)." Blood 126, no. 23 (December 3, 2015): 652. http://dx.doi.org/10.1182/blood.v126.23.652.652.
Abstract:
Abstract INTRODUCTION: Patients with the lupus anticoagulant (LA) are at an increased risk of thrombotic events (TE), which in turn increase the risk of death (Gebhart J et al. Blood. 2015. 125:3477). Understanding the determinants of thrombotic risk in LA patients may pave the way towards targeted thromboprophylaxis. To date, several retrospective studies have investigated the association between anamnestic thrombosis and certain factors, such as antibodies against cardiolipin and beta2-glycoprotein I. However, robust prospective evidence is still limited. We aimed to investigate clinical and laboratory risk factors for development of TE in patients with a persistently positive LA. PATIENTS & METHODS: In this prospective, observational cohort study with a baseline biobank we followed 150 patients (median age: 41.3 years, interquartile range (IQR): 32.3-60.2, female gender: n=122 (81.3%)), who tested repeatedly positive for the LA until the development of TE, death, or censoring. The primary endpoint was the time-to-TE during the observation period, defined as a composite of arterial or venous, independently-adjudicated thrombotic complications. Ninety-eight (65.3%) of the 150 patients had a history of at least one TE event (arterial TE: n=21, venous TE: n=84, both: n=7), and 70 (46.7%) were on oral anticoagulation at baseline. Sixty-five (43.3%) patients also had IgM and/or IgG isotype antibodies against cardiolipin and beta2-glycoprotein I ("Triple positivity"). For investigation of the LA, lupus-sensitive aPTT reagents were used (aPTT-LA, Diagnostica Stago, Asnieres, France). Prospective associations were analyzed using competing risk analysis treating death-from-any-cause as the competing event. Evaluated risk factors included (1) the lupus-sensitive activated partial thromboplastin time (aPTT-LA), (2) antibodies against cardiolipin, beta2-glycoprotein I, domain 1 of beta2-glycoprotein I, prothrombin, and "triple positivity", (3) general cardiovascular risk factors (diabetes, hypertension, smoking, and hypertriglyceridemia, body mass index), and (4) AnnexinA5 resistance (A5R). RESULTS: During a median follow-up period of 8.7 years (range: 12 days - 12.4 years), 30 TE events occurred (arterial TE: n=14, venous TE: n=16), and 20 patients died. The cumulative incidence of TE at 1, 5, and 10 years of follow-up were 4.0% (95% Confidence Interval (CI): 1.7-8.1), 12.8% (95% CI: 7.9-18.9), and 24.4% (95% CI: 16.8-32.8), respectively. In univariable analysis, a prolonged aPTT-LA (Subhazard ratio (SHR) for aPTT≥118 seconds (i.e. 75th percentile of the aPTT-LA distribution)=2.59, 95%CI: 1.27-5.31, p=0.009), diabetes (SHR=4.36, 95%CI: 1.44-13.19, p=0.009), active smoking (SHR=2.35, 95%CI: 1.16-4.77, p=0.018), and elevated triglycerides (SHR per 50mg/dL increase=1.14, 95%CI: 1.09-1.18, p<0.001) were associated with a higher risk of TE events. In multivariable analysis, the only independent predictors of a higher thrombotic risk were a prolonged aPTT-LA (adjusted SHR=2.33, 95%CI: 1.06-5.13, p=0.035), diabetes (adjusted SHR=3.79, 95%CI: 1.12-12.89, p=0.033), and active smoking (adjusted SHR=2.62, 95%CI: 1.24-5.52, p=0.012). These results prevailed after adjusting for anticoagulation at baseline. Using these three parameters allowed identification of clinical subgroups with a very high and a low risk of TE events (cumulative risk of TE after 5 years 43.3% in the high risk group and 5.6% in the low risk group, respectively, Figure 1). The other risk factors did neither in univariable nor in multivariable analysis emerge as predictors of thrombotic risk in this large cohort. CONCLUSION: Diabetes and smoking, which are established risk factors for vascular events in the general population, turned out to be relevant also in patients with the LA. Moreover, a very long lupus sensitive aPTT was as well predictive for occurrence of TE in these patients. This effect was independent of anticoagulation. Interestingly, disease defining antibodies, such as those against cardiolipin or beta2-glycoprotein I (including those against domain I) were not associated with future occurrence of TE in this LA positive patient population. These data suggest that above standard anticoagulation, interventions to control and improve metabolic status and smoking habits might influence the rates of future TE in patients with known persistent LA. Disclosures No relevant conflicts of interest to declare.
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Montalvao, Silmara Aparecida De Lima, Priscila Elidio Soares, Sabrina Saraiva, Bruna Moraes Mazetto, Marina Pereira Colella, Erich Vinicius De Paula, Simone Appenzeller, Joyce Maria Annichino-Bizzacchi, and Fernanda Andrade Orsi. "Antibodies Directed Against the Domain 1 of Beta2-Glicoprotein 1 May be Associated with Secondary Antiphospholipid Syndrome." Blood 126, no. 23 (December 3, 2015): 768. http://dx.doi.org/10.1182/blood.v126.23.768.768.
Abstract:
Abstract Background: The diagnosis of antiphospholipid syndrome (APS) is based on the persistent positivity of lupus anticoagulant (LA), IgM or IgG anticardiolipin (aCL) or IgG anti-β2 glicoprotein 1 (aβ2GP1) antibodies in patients plasma. Particularly, the role of antibodies directed against the domain 1 of β2GP1 (aβ2GP1-D1) has been described as relevant for the mechanism of immunopathogenesis in APS. However, the role of the aβ2GP1-D1 antibodies in clinical diagnosis and management of APS has not been established. Aim: The aim of this study was to evaluated the association of the presence of aβ2GP1-D1 antibodies with the clinical course of patients with thrombotic APS. Patients and methods: Patientspreviously diagnosed with thrombotic APS were consecutively selected for the study, from December 2013 to July 2014, in the Hemostasis Clinic of the Hematology and Hemotherapy Center of the University of Campinas. Demographic features and clinical conditions were recorded at the inclusion and during the follow-up. The clinical parameters analyzed were APS etiology (primary versus secondary to systemic autoimmune diseases), vascular bed of the thrombosis, history of multiple thrombosis, concomitant obstetrical morbidity, the presence of antinuclear antibodies (ANA) and the profile of the antiphospholipid antibodies. Anti-β2GP1-D1 antibodies were determined in patients plasma by chemiluminescence (BioFlash/AcuStar®, Barcelona, ES). Exact Fisher test and logistic regression were performed for statistical analysis. P < 0.05 were considered statistical significant. Results: Eight-five patients were included in the study, all patients presented venous or arterial thrombosis. The antibodies distribution among patients was: 80% LA positive, 50% aCL positive, 54% aβ2GP1 positive and 26% triple positive. Twenty-one patients (25%) tested positive for aβ2GP1-D1, 94% of them had positive aβ2GP1 antibody, previously detected at diagnosis. The presence of aβ2GP1-D1 was not associated with age or gender. Detected clinical conditions related to APS severity, such as thrombosis recurrence, concomitant obstetrical and vascular morbidity and triple positive antiphospholipid antibodies were evaluated. The positivity for aβ2GPI-DI antibodies was not associated with thrombosis recurrence (OR=1.0, 95%CI=0.37-2.71,P=1.0), concomitant obstetrical and vascular morbidity (OR=1.5, 95%CI=0.33-7.34, P=0.58), or triple positive antibodies (OR=2.79 , 95%CI=0.76 - 8.84, P=0.13). Anti-β2GP1-D1 antibodies were associated with the diagnosis of systemic autoimmune disease, in particular with lupus, (OR= 3.49 , 95%CI=1.25-9.76, P=0.01) and with positive ANA test (OR= 3.3, 95%CI=1.08-10.1, P=0.03). Conclusion: In this study, aβ2GPI-DI antibody was detected mainly in patients who had already tested positive for aβ2GP1 antibody, so it is possible that aβ2GP1-D1 assay may not provide additional sensibility to the diagnosis of APS. However, our results also suggested that the presence of aβ2GP1-D1 antibody might be associated to the diagnosis of secondary APS. The diagnosis of primary APS is based on the exclusion of systemic autoimmune diseases and there are no current laboratory parameters that discriminate between primary and secondary APS. Besides the laboratory criteria for lupus diagnosis, there may be overlapping of the antibodies and hematological features between APS and lupus. Furthermore, after the diagnosis of primary APS, it may take long time of follow-up to detect the underlying autoimmune disease. Therefore, if our findings are confirmed, aβ2GP1-D1 assays may play a role as a laboratory tool for the differential diagnosis between primary and secondary APS. Disclosures No relevant conflicts of interest to declare.
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Sangle, Nikhil A., and Kristi J. Smock. "Antiphospholipid Antibody Syndrome." Archives of Pathology & Laboratory Medicine 135, no. 9 (September 1, 2011): 1092–96. http://dx.doi.org/10.5858/2010-0325-rsr.1.
Abstract:
Antiphospholipid antibodies are directed against phospholipid-protein complexes and include lupus anticoagulant, anticardiolipin antibodies, and anti–beta-2 glycoprotein I antibodies. Antiphospholipid antibody syndrome is a common cause of acquired thrombophilia and is characterized by venous or arterial thromboembolism or pregnancy morbidity and the presence of antiphospholipid antibodies. Antibodies should be demonstrable on at least 2 occasions separated by 12 weeks. Heterogeneity of the autoantibodies and absence of gold standard assays makes interpretation of laboratory results a challenge for both laboratorians and clinicians. This review discusses the key laboratory and clinical aspects of antiphospholipid antibody syndrome. Particular focus is given to lupus anticoagulant detection, in view of recently updated laboratory guidelines.
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Yang, Xinzhen, Svetla Kurteva, Sandra Lee, and Joseph Sodroski. "Stoichiometry of Antibody Neutralization of Human Immunodeficiency Virus Type 1." Journal of Virology 79, no. 6 (March 15, 2005): 3500–3508. http://dx.doi.org/10.1128/jvi.79.6.3500-3508.2005.
Abstract:
ABSTRACT The human immunodeficiency virus envelope glycoproteins function as trimers on the viral surface, where they are targeted by neutralizing antibodies. Different monoclonal antibodies neutralize human immunodeficiency virus type 1 (HIV-1) infectivity by binding to structurally and functionally distinct moieties on the envelope glycoprotein trimer. By measuring antibody neutralization of viruses with mixtures of neutralization-sensitive and neutralization-resistant envelope glycoproteins, we demonstrate that the HIV-1 envelope glycoprotein trimer is inactivated by the binding of a single antibody molecule. Virus neutralization requires essentially all of the functional trimers to be occupied by at least one antibody. This model applies to antibodies differing in neutralizing potency and to virus isolates with various neutralization sensitivities. Understanding these requirements for HIV-1 neutralization by antibodies will assist in establishing goals for an effective AIDS vaccine.
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Yang, Xinzhen, Vesko Tomov, Svetla Kurteva, Liping Wang, Xinping Ren, Miroslaw K. Gorny, Susan Zolla-Pazner, and Joseph Sodroski. "Characterization of the Outer Domain of the gp120 Glycoprotein from Human Immunodeficiency Virus Type 1." Journal of Virology 78, no. 23 (December 1, 2004): 12975–86. http://dx.doi.org/10.1128/jvi.78.23.12975-12986.2004.
Abstract:
ABSTRACT The core of the gp120 glycoprotein from human immunodeficiency virus type 1 (HIV-1) is comprised of three major structural domains: the outer domain, the inner domain, and the bridging sheet. The outer domain is exposed on the HIV-1 envelope glycoprotein trimer and contains binding surfaces for neutralizing antibodies such as 2G12, immunoglobulin G1b12, and anti-V3 antibodies. We expressed the outer domain of HIV-1YU2 gp120 as an independent protein, termed OD1. OD1 efficiently bound 2G12 and a large number of anti-V3 antibodies, indicating its structural integrity. Immunochemical studies with OD1 indicated that antibody responses against the outer domain of the HIV-1 gp120 envelope glycoprotein are rare in HIV-1-infected human sera that potently neutralize the virus. Surprisingly, such outer-domain-directed antibody responses are commonly elicited by immunization with recombinant monomeric gp120. Immunization with soluble, stabilized HIV-1 envelope glycoprotein trimers elicited antibody responses that more closely resembled those in the sera of HIV-1-infected individuals. These results underscore the qualitatively different humoral immune responses elicited during natural infection and after gp120 vaccination and help to explain the failure of gp120 as an effective vaccine.
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Yu, Xiuqun, Danqing Kong, Zhaoyue Wang, Jie Yin, and Ziqiang Yu. "The coexistence of antiβ2 glycoprotein 1 antibody antibody has no effect on hemophilia A patient." Blood Coagulation & Fibrinolysis 33, no. 6 (September 2022): 348–50. http://dx.doi.org/10.1097/mbc.0000000000001137.
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Arad, Ariela, Richard A. Furie, Barbara C. Furie, and Bruce Furie. "Affinity-Purified Anti-Beta-2 Glycoprotein-1 Antibodies from a Patient with Lupus Anticoagulant-Associated Thrombosis Amplify Thrombus Formation in the Living Mouse." Blood 114, no. 22 (November 20, 2009): 146. http://dx.doi.org/10.1182/blood.v114.22.146.146.
Abstract:
Abstract Abstract 146 Antiphospholipid syndrome (APS) is characterized by thrombosis, recurrent fetal loss and the presence of the lupus anticoagulant, anticardiolipin antibodies or anti-beta-2 glycoprotein 1 antibodies. Sera from patients with APS contain polyclonal antibodies that bind to various plasma proteins including beta-2 glycoprotein 1. Although beta-2 glycoprotein 1 antibodies have been well-documented as a biomarker for the diagnosis of APS, their direct role in the pathogenesis of thrombosis is unknown. Here, we have demonstrated using intravital microscopy that purified anti-beta-2 glycoprotein 1 antibodies isolated from the serum of a patient with APS greatly amplify thrombus size following laser-induced vessel wall injury in live mice. A patient with systemic lupus and APS complicated by pulmonary embolism was studied. IgG was isolated from serum by affinity chromatography using a Protein A/G column. Anti-beta-2 glycoprotein 1 antibodies in the IgG fraction were affinity-purified using homogeneous beta-2 glycoprotein 1 covalently bound to CNBr-activated agarose beads. Purified anti-beta-2 glycoprotein 1 antibodies were eluted at low pH. Patient IgG depleted of anti-beta-2 glycoprotein 1 antibodies was obtained by repeated chromatography over the beta-2 glycoprotein 1 column. The effects of (a) purified anti-beta-2 glycoprotein 1 antibodies, (b) anti-beta-2 glycoprotein 1 antibody-depleted patient IgG, and (c) IgG from normal human sera on thrombus formation were studied quantitatively in the live mouse. Intravital microscopy was performed using the cremaster muscle as a vascular window, and thrombus formation was initiated by laser injury to the arteriolar wall. Five minutes prior to vessel wall injury, purified anti-beta-2 glycoprotein 1 antibodies, anti-beta-2 glycoprotein 1 antibody-depleted patient IgG, or normal human IgG were infused via a jugular catheter. Platelet thrombus size was determined by widefield microscopy and Alexa 647-conjugated Fab fragments of an anti-CD 41 monoclonal antibody. Up to 10 thrombi were generated per mouse, and the median integrated fluorescence for 25-30 thrombi determined. Infusion of anti-beta-2 glycoprotein 1 antibodies increased thrombus size in a dose-dependent manner. Infusion of purified anti-beta-2 glycoprotein 1 antibodies at 0.12 μg/g mouse and 0.40 μg/g mouse increased thrombus size by about 18-fold and 122-fold respectively over thrombi formed in untreated mice. However, anti-beta-2 glycoprotein 1 antibody-depleted patient IgG and normal human IgG did not affect platelet thrombus size. These results indicate that the anti-beta-2 glycoprotein 1 antibodies isolated from APS patient serum are responsible for markedly increased thrombus size in this thrombosis model. The target cellular antigen of the anti-beta-2 glycoprotein 1 antibodies and the mechanism of enhanced thrombus formation remain unknown. However, these results provide evidence that anti-beta-2 glycoprotein 1 antibodies are not only a marker but are directly involved in the pathogenesis of thrombosis. This in vivo animal model offers an approach to identifying inhibitors of anti-beta-2 glycoprotein 1-mediated thrombosis. Disclosures: No relevant conflicts of interest to declare.
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Tincani, A., L. Spatola, E. Prati, F. Allegri, P. Ferremi, R. Cattaneo, P. Meroni, and G. Balestrieri. "The anti-beta2-glycoprotein I activity in human anti-phospholipid syndrome sera is due to monoreactive low-affinity autoantibodies directed to epitopes located on native beta2-glycoprotein I and preserved during species' evolution." Journal of Immunology 157, no. 12 (December 15, 1996): 5732–38. http://dx.doi.org/10.4049/jimmunol.157.12.5732.
Abstract:
Abstract To characterize the reactivity pattern of Abs directed to beta2-glycoprotein I (anti-beta2GPI) in patients with anti-phospholipid syndrome, we have purified anti-beta2GPI Abs by affinity chromatography using the IgG fractions from sera of five different anti-phospholipid syndrome patients. Affinity-purified anti-beta2GPI were shown to be representative of Abs found in human sera because their activity could be virtually abolished from the IgG preparations after repeated absorptions on immobilized human beta2GPI column. Our results show that affinity-purified anti-beta2GPI: 1) do react with beta2GPI in the absence of any phospholipid, as demonstrated by the lack of phosphorus contaminant in the employed reagents, as well as by their comparable binding activity before and after extensive delipidation procedure; 2) can recognize beta2GPI regardless of its origin from different animal species; 3) are able to bind soluble beta2GPI with a mean Kd value of 4.65 x 10(-6) M (range 3, 4-7, 2 x 10(-6) M); 4) significantly enhance their binding avidity when beta2GPI is linked to a solid support; and 5) appear to be mainly monoreactive autoantibodies. In conclusion, we have shown that human polyclonal anti-beta2GPI are low affinity, mainly monoreactive autoantibodies directed to an epitope located on native beta2GPI, preserved along the species evolution.
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Motta, Mario, Gaetano Chirico, Chiara Rebaioli, David Faden, Andrea Lojacono, Flavio Allegri, Claudio Migliori, and Angela Tincani. "Anticardiolipin and Anti-Beta2 Glycoprotein I Antibodies in Infants Born to Mothers with Antiphospholipid Antibody-Positive Autoimmune Disease: A Follow-Up Study." American Journal of Perinatology 23, no. 4 (April 2006): 247–52. http://dx.doi.org/10.1055/s-2006-939533.
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Sato, Ryosuke, Kazuo Okanari, Tomoki Maeda, Kimihiko Kaneko, Toshiyuki Takahashi, and Ihara Kenji. "Postinfectious Acute Disseminated Encephalomyelitis Associated With Antimyelin Oligodendrocyte Glycoprotein Antibody." Child Neurology Open 7 (January 1, 2020): 2329048X2094244. http://dx.doi.org/10.1177/2329048x20942442.
Abstract:
Myelin oligodendrocyte glycoprotein is a major target of the humoral immune response in children affected by inflammatory demyelinating diseases of the central nervous system. Although myelin oligodendrocyte glycoprotein causes autoimmune encephalitis in different animal models, the relevance of this mechanism in human autoimmune diseases of the central nervous system is unclear. We herein report a child with acute disseminated encephalomyelitis possibly triggered by central nervous system infection of primary herpes simplex virus in the presence of antimyelin oligodendrocyte glycoprotein antibody. A healthy 5-year-old Japanese boy suffered from acute disseminated encephalomyelitis. He was positive for antimyelin oligodendrocyte glycoprotein antibody in both the serum and the cerebrospinal fluid, and herpes simplex virus-1 DNA on polymerase chain reaction of the cerebrospinal fluid. We speculated that the central nervous system infection of primary herpes simplex virus disrupted the blood–brain barrier, and antimyelin oligodendrocyte glycoprotein antibody already present in serum was transferred to the cerebrospinal fluid, resulting in the onset of acute disseminated encephalomyelitis. This might be the mechanism underlying postinfectious acute disseminated encephalomyelitis associated with myelin oligodendrocyte glycoprotein antibody.
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Ren, Xinping, Joseph Sodroski, and Xinzhen Yang. "An Unrelated Monoclonal Antibody Neutralizes Human Immunodeficiency Virus Type 1 by Binding to an Artificial Epitope Engineered in a Functionally Neutral Region of the Viral Envelope Glycoproteins." Journal of Virology 79, no. 9 (May 1, 2005): 5616–24. http://dx.doi.org/10.1128/jvi.79.9.5616-5624.2005.
Abstract:
ABSTRACT Neutralizing antibodies often recognize regions of viral envelope glycoproteins that play a role in receptor binding or other aspects of virus entry. To address whether this is a necessary feature of a neutralizing antibody, we identified the V4 region of the gp120 envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) as a sequence that is tolerant of drastic change and thus appears to play a negligible role in envelope glycoprotein function. An artificial epitope tag was inserted into the V4 region without a significant effect on virus entry or neutralization by antibodies that recognize HIV-1 envelope glycoprotein sequences. An antibody directed against the artificial epitope tag was able to neutralize the modified, but not the wild-type, HIV-1. Thus, the specific target of a neutralizing antibody need not contribute functionally to the process of virus entry.
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Hou, F. F., J. Boyce, G. M. Chertow, J. Kay, and W. F. Owen. "Aminoguanidine inhibits advanced glycation end products formation on beta2-microglobulin." Journal of the American Society of Nephrology 9, no. 2 (February 1998): 277–83. http://dx.doi.org/10.1681/asn.v92277.
Abstract:
Because advanced glycation end products (AGE)-modified beta2-microglobulin (AGE-beta2M) is a dominant constituent of amyloid in dialysis-related amyloidosis (DRA), AGE-beta2M may be directly involved in the pathobiology of DRA. In experimental diabetes mellitus, blocking the formation of AGE prevents AGE-mediated tissue damage. In this study, it is postulated that similar pharmacologic intervention may be beneficial in DRA. Aminoguanidine, a nucleophilic hydrazine compound that prevents AGE formation on collagen, may have a similar effect on the advanced glycation of beta2M. To test this hypothesis, beta2M was incubated in vitro with 50 or 100 mM D-glucose for 3 wk in the presence and absence of incremental concentrations of aminoguanidine. On the basis of enzyme-linked immunosorbent assay and immunoblots using anti-AGE-keyhole limpet hemocyanin antibody, aminoguanidine inhibited glucose-induced N(epsilon)-(carboxymethyl)lysine formation on beta2M. At aminoguanidine-glucose molar ratios of 1:8 to 1:1, 26 to 53% inhibition occurred. Fluorospectrometry examination showed that aminoguanidine also inhibited the formation of fluorescent AGE on beta2M in a dose-dependent manner. At aminoguanidine-glucose molar ratios of 1:8 to 1:1, fluorescent product generation was inhibited by 30 to 70%. Furthermore, aminoguanidine suppressed the AGE formation on beta2M bound to AGE-modified collagen. If aminoguanidine is similarly active in vivo, this compound may be of clinical utility for treating DRA in patients on maintenance dialysis.
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Steve, Runal John, Diviya Alex, Binesh Lal Yesudhason, John Antony Jude Prakash, Nitty Skariah Mathews, Dolly Daniel, Veena Vadhini Ramalingam, et al. "Autoantibodies Among HIV-1 Infected Individuals and the Effect of Anti-Retroviral Therapy (ART) on It." Current HIV Research 19, no. 3 (May 6, 2021): 277–85. http://dx.doi.org/10.2174/1570162x19666210217120337.
Abstract:
Background:: Antiretroviral therapy (ART) has led to a decline in autoimmune diseases but lacks studies on its effect on autoantibodies. Methods: It is a cross-sectional study with archived samples from 100 paired HIV-1 infected ART naïve and experienced individuals and 100 prospectively collected matched blood-donor controls. Antinuclear antibody, IgG anticardiolipin antibody, IgM and IgG β2 glycoprotein-1 antibodies, and total IgG levels were detected. Results are expressed as mean with standard deviation (SD), median, percentage positivity, and a p<0.05 is considered significant. The study was approved by the Institutional Review Board. Results: The median viral load of the treatment naïve samples was 4.34 Log copies/mL, while all were virally suppressed post ART with a median duration of treatment for 12 months (range: 3-36 months). The percentage of antinuclear antibody positivity was 5% among ART naïve and controls, with a decrease of 2% post ART (p= 0.441). The positivity for anti-cardiolipin antibody was 15% among ART naïve while none of the ART experienced or controls were positive (p<0.05). IgM β2 glycoprotein-1 were 4%, 1% and 3% among ART naïve, treated and controls, respectively (p<0.05). IgG β2 glycoprotein-1 was 2% among ART naïve while none of the treated and controls were positive (p<0.05). The mean total IgG level among ART naïve, experienced, and controls were 21.82 (SD 6.67), 16.91 (SD 3.38), 13.70 (SD 2.24) grams/Litre, respectively (p<0.05). Conclusion: ART has a significant effect on IgG anti-cardiolipin antibody and total IgG but only a marginal effect on ANA, IgM, and IgG β2 glycoprotein-1 antibodies.
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Weckbach, Ludwig T., Andreas Uhl, Felicitas Boehm, Valentina Seitelberger, Bruno C. Huber, Gabriela Kania, Stefan Brunner, and Ulrich Grabmaier. "Blocking LFA-1 Aggravates Cardiac Inflammation in Experimental Autoimmune Myocarditis." Cells 8, no. 10 (October 17, 2019): 1267. http://dx.doi.org/10.3390/cells8101267.
Abstract:
The lymphocyte function-associated antigen 1 (LFA-1) is a member of the beta2-integrin family and plays a pivotal role for T cell activation and leukocyte trafficking under inflammatory conditions. Blocking LFA-1 has reduced or aggravated inflammation depending on the inflammation model. To investigate the effect of LFA-1 in myocarditis, mice with experimental autoimmune myocarditis (EAM) were treated with a function blocking anti-LFA-1 antibody from day 1 of disease until day 21, the peak of inflammation. Cardiac inflammation was evaluated by measuring infiltration of leukocytes into the inflamed cardiac tissue using histology and flow cytometry and was assessed by analysis of the heart weight/body weight ratio. LFA-1 antibody treatment severely enhanced leukocyte infiltration, in particular infiltration of CD11b+ monocytes, F4/80+ macrophages, CD4+ T cells, Ly6G+ neutrophils, and CD133+ progenitor cells at peak of inflammation which was accompanied by an increased heart weight/body weight ratio. Thus, blocking LFA-1 starting at the time of immunization severely aggravated acute cardiac inflammation in the EAM model.