A chemically defined, toleragen-based approach for targeting anti-β2-glycoprotein I antibodies

Lupus ◽  
1998 ◽  
Vol 7 (2_suppl) ◽  
pp. 166-229 ◽  
Author(s):  
GM Iverson ◽  
DS Jones ◽  
D Marquis ◽  
MD Linnik ◽  
EJ Victoria
Keyword(s):  
Antiphospholipid Syndrome ◽  
Antiphospholipid Antibodies ◽  
Keyhole Limpet Hemocyanin ◽  
Cell Tolerance ◽  
Prothrombotic State ◽  
B Cell Tolerance ◽  
Glycoprotein I ◽  
Antibody Levels ◽  
Dose Dependent

Antiphospholipid syndrome is characterized by a prothrombotic state and the presence of β2-glycoprotein I (β2-GPI)-dependent antiphospholipid antibodies. The feasibility of a B cell tolerance-based approach for specific reduction of anti-β2-GPI antibodies was investigated. Anti-β2GPI antibodies isolated from a patient with antiphospholipid syndrome were used to screen peptide libraries expressed in phage, resulting in the identification of a phage that specifically bound anti-β2-GPl antibodies. The phage-displayed peptide was identified and chemically optimized to generate a synthetic 14-mer peptide with an internal thioether linkage (LJP 685) that retained the binding profile of the original phage. LJP 685 was conjugated to a defined, non-immunogenic organic platform to generate a tetravalent presentation of LJP 685 for use as a toleragen. Tetravalent LJP 685 induced a dose-dependent reduction in antibody levels in mice previously immunized and boosted with LJP 685 coupled to the carrier keyhole limpet hemocyanin. These experiments support the technical feasibility of a tolerance-based approach for reducing anti-β2GPI antibodies in vivo.

Ongoing Prothrombotic State in Patients With Antiphospholipid Antibodies: A Role for Increased Lipid Peroxidation

Blood ◽  
1999 ◽  
Vol 93 (10) ◽  
pp. 3401-3407 ◽  
Author(s):  
Domenico Praticò ◽  
Domenico Ferro ◽  
Luigi Iuliano ◽  
Joshua Rokach ◽  
Fabrizio Conti ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Lupus Erythematosus ◽  
Antiphospholipid Antibodies ◽  
Antioxidant Vitamins ◽  
Prothrombotic State ◽  
Antioxidant Treatment ◽  
Clotting System ◽  
Prothrombin Fragment ◽  
Circulating Levels

We measured the urinary excretion of Isoprostane F2-III and Isoprostane-F2-VI, two markers of in vivo lipid peroxidation, and the circulating levels of the prothrombin fragment F1+2, a marker of thrombin generation, in 18 antiphospholipid antibodies-positive patients, in 18 antiphospholipid antibodies-negative patients with systemic lupus erythematosus, and in 20 healthy subjects. Furthermore, 12 patients positive for antiphospholipid antibodies were treated with (n = 7) or without (n = 5) antioxidant vitamins (vitamin E at 900 IU/d and vitamin C at 2,000 mg/d) for 4 weeks. Compared with antiphospholipid antibodies-negative patients, antiphospholipid antibodies-positive patients had higher urinary values of Isoprostane-F2-III (P = .0001), Isoprostane-F2-VI (P = .006), and plasma levels of the prothrombin fragment F1+2 (P= .0001). In antiphospholipid-positive patients, F1+2 significantly correlated with Isoprostane-F2-III (Rho = .56,P = .017) and Isoprostane-F2-VI (Rho = .61, P = .008). After 4 weeks of supplementation with antioxidant vitamins, we found a significant decrease in F1+2 levels (P < .005) concomitantly with a significant reduction of both Isoprostane-F2-III (P = .007) and Isoprostane-F2-VI (P < .005). No change of these variables was observed in patients not receiving antioxidant treatment. This study suggests that lipid peroxidation might contribute to the activation of clotting system in patients positive for antiphospholipid antibodies.

β2-Glycoprotein I: Target antigen for ‘antiphospholipid’ antibodies. Immunological and molecular aspects

Lupus ◽  
1998 ◽  
Vol 7 (2_suppl) ◽  
pp. 5-9 ◽  
Author(s):  
Y Sheng ◽  
DA Kandiah ◽  
SA Krilis
Keyword(s):  
Antiphospholipid Syndrome ◽  
Antiphospholipid Antibodies ◽  
Fluid Phase ◽  
Target Antigen ◽  
Phospholipid Membranes ◽  
Anionic Phospholipid ◽  
Glycoprotein I ◽  
High Concentrations ◽  
Molecular Aspects ◽  
Anionic Phospholipid Membranes

It has become clear that β2-glycoprotein I (β2GPI) is the most common and best-characterised antigenic target for ‘antiphospholipid’ (aPL) autoantibodies. These antibodies preferentially bind β2GPI that has been immobilised on anionic phospholipid membranes or certain synthetic surfaces. These surfaces appear to act by increasing antigen density to allow binding of intrinsically low-affinity anti-β2GPI autoantibodies. Binding of β2GPI in fluid phase is weak and requires high concentrations of β2GPI. Our understanding of the pathophysiology of the ‘Antiphospholipid’ Syndrome (APS) has increased exponentially with the number of studies into the interactions of aPL antibodies and β2GPI.

scholarly journals Decoration of T-independent antigen with ligands for CD22 and Siglec-G can suppress immunity and induce B cell tolerance in vivo

2010 ◽  
Vol 207 (2) ◽  
pp. 445-445 ◽  
Author(s):  
Bao Hoa Duong ◽  
Hua Tian ◽  
Takayuki Ota ◽  
Gladys Completo ◽  
Shoufa Han ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Tolerance ◽  
B Cell Tolerance

Association between beta2-glycoprotein I plasma levels and the risk of myocardial infarction in older men

Blood ◽  
2009 ◽  
Vol 114 (17) ◽  
pp. 3656-3661 ◽  
Author(s):  
Bas de Laat ◽  
Philip G. de Groot ◽  
Ronald H. W. M. Derksen ◽  
Rolf T. Urbanus ◽  
Koen Mertens ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Plasma Levels ◽  
High Plasma ◽  
In Vivo Experiments ◽  
Glycoprotein I ◽  
Adhesive Surface ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Dose Dependent

Abstract von Willebrand factor (VWF) 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 VWF, indicating a role in the pathophysiology of arterial thrombosis. In the present study, we investigated whether differences in beta2-glycoprotein I plasma levels influence the risk of myocardial infarction. We have measured beta2-glycoprotein I and VWF antigen levels in 539 men with a first myocardial infarction and in 611 control subjects. Although we did not find a profound effect of beta2-glycoprotein I plasma levels on myocardial infarction in the overall population, we found a dose-dependent protective effect of increasing beta2-glycoprotein I plasma levels on myocardial infarction in men 60 years and older. In this age group, we found an odds ratio of 0.41 (95% confidence interval, 0.22-0.74) for high beta2-glycoprotein I levels compared with low levels. High plasma levels of beta2-glycoprotein I remained protective for myocardial infarction despite high levels of VWF. To conclude, high circulating levels of beta2-glycoprotein I appeared to be associated with a reduced risk of myocardial infarction in elderly men. In vivo experiments are needed to investigate the exact contribution of beta2-glycoprotein I on the pathophysiology of myocardial infarction.

Atherosclerosis and the antiphospholipid syndrome: A link unravelled?

Lupus ◽  
1998 ◽  
Vol 7 (2_suppl) ◽  
pp. 140-143 ◽  
Author(s):  
Y Shoenfeld ◽  
D Harats ◽  
J George
Keyword(s):  
Antiphospholipid Syndrome ◽  
Antiphospholipid Antibodies ◽  
Dominant Role ◽  
Clinical Manifestations ◽  
Humoral Response ◽  
Arterial System ◽  
Glycoprotein I ◽  
Shock Proteins ◽  
Modified Forms ◽  
Progression Of Atherosclerosis

Atherosclerosis is a multifactorial disease that involves the arterial system. Recent data suggest that immune and autoimmune factors play a dominant role in mediating the progression of atherosclerosis. Among these factors, humoral response to modified forms of LDL and heat-shock proteins has been shown to be influential. The antiphospholipid syndrome (APS) entails clinical manifestations that result from a hypercoagulable state. Antibodies to phospholipids and to β2-glycoprotein I have been suggested to confer the tendency to thrombosis. In a set of recent studies, we have been able to show that generation of antiphospholipid antibodies in mice is associated with enhanced atherosclerosis. These findings imply that APS and atherosclerosis may share a common etiologic background, which may have direct implications for the management of both conditions.

Role Of B Cell Tolerance In PF4/Heparin Antibody Production

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2396-2396
Author(s):  
Yongwei Zheng ◽  
Alexander W Wang ◽  
Mei Yu ◽  
Anand Padmanabhan ◽  
Benjamin E Tourdot ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Board Of Directors ◽  
Cell Tolerance ◽  
Inflammatory Stimulus ◽  
Wild Type ◽  
B Cell Tolerance ◽  
Advisory Committees

Abstract Heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder that can cause fatal arterial or venous thrombosis/thromboembolism. Immune complexes consisting of heparin, platelet factor 4 (PF4) and PF4/heparin-reactive antibodies are central to the pathogenesis of HIT. However, heparin, a glycosoaminoglycan, and PF4 are normal body constituents and it is as yet unclear what triggers the initial induction of pathogenic antibodies. Here we described detection of B cells among peripheral blood mononuclear cells (PBMCs) from each of 9 healthy adults that produced PF4/heparin-specific IgM antibodies following in vitro stimulation with ubiquitous pro-inflammatory molecules containing unmethylated CpG dinucleotides derived from bacterial and viral DNA. PF4/heparin-specific IgM-generating B cells were present at a frequency of at least 0.03 to 1 per thousand B cells present in the PBMC population. Similarly, splenic B cells isolated from unmanipulated wild-type mice consistently produced PF4/heparin-reactive antibodies following in vitro stimulation with CpG. In addition, wild-type mice produced PF4/heparin-reactive antibodies upon in vivo challenge with CpG whereas unchallenged wild-type mice did not. These findings demonstrate that both humans and mice possess pre-existing, inactive and tolerant PF4/heparin-specific B cells. We suggest that tolerance can be broken by a strong inflammatory stimulus, leading to activation of these B cells and production of antibodies that recognize PF4/heparin in vitro and in vivo. Consistent with this concept, mice lacking protein kinase Cd (PKCd), a signaling molecule of the B-cell survival factor BAFF (B-cell activation factor), that are known to have breakdown of B-cell tolerance to self-antigens, spontaneously produced anti-PF4/heparin antibodies in the absence of an inflammatory stimulus. Taken together, these findings demonstrate that breakdown of tolerance can lead to PF4/heparin-specific antibody production and that B-cell tolerance plays an important role in HIT pathogenesis. Disclosures: White II: Bayer: Membership on an entity’s Board of Directors or advisory committees; CSL-Behring: Membership on an entity’s Board of Directors or advisory committees; NIH: Membership on an entity’s Board of Directors or advisory committees; Asklepios: Membership on an entity’s Board of Directors or advisory committees; Wyeth: Membership on an entity’s Board of Directors or advisory committees; Entegrion: Membership on an entity’s Board of Directors or advisory committees; Biogen: Membership on an entity’s Board of Directors or advisory committees; Baxter: Membership on an entity’s Board of Directors or advisory committees.

scholarly journals The in vitro induction of immunological tolerance in the B lymphocyte by oligovalent thymus-dependent antigens.

1975 ◽  
Vol 141 (5) ◽  
pp. 962-973 ◽  
Author(s):  
J W Schrader
Keyword(s):  
T Cells ◽  
B Cell ◽  
Gamma Globulin ◽  
Tolerance Induction ◽  
Marginal Effect ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
In Vitro System

B-cell tolerance has been induced by oligovalent thymus-dependent antigens in an entirely in vitro system. Dissociated spleen cells from congenitally athymic (nu/nu) mice were preincubated for 24 h with 0.1 -- 1 mg/ml of either fowl gamma globulin (FGG) of DNP-human gamma globulin (DNP-HGG). After washing, the cells were tested for the ability to mount in vitro, thymus-independent responses against FGG and DNP. A state of specific responsiveness to either FGG or DNP was thus demonstrated. Features of this wholly in vitro system that paralleled previous findings on the in vivo induction of B-cell tolerance in nu/nu mice were the kinetics, 24 h being required for tolerance induction in either case, the abrogation of tolerance induction by the presence of POL both in vivo and in vitro, and finally the observation that in neither case was there a requirement for the antigens to be deaggregated. It was shown that DNP-(Fab) 2 fragments prepared from HGG induced DNP-specific tolerance indicating that the Fc piece was not required for tolerance induction in this in vitro system. DNP-bovine serum albumin was less effective than DNP-HGG or DNP-(Fab)2. Preincubation with subtoxic concentrations of DNP-lysine of DNP-epsilon-capric acid had only a marginal effect on DNP responsiveness. Since nu/nu mice, lacking in detectable T-cell function, were used as spleen cell donors, this work provides further evidence that B-cell tolerance to thymus-dependent antigens can be induced without the participation of T cells. It is suggested that B-cell tolerance to thymus-dependent antigens occurs when the antigen in a sufficient concentration and over a sufficient period of time has direct access to the B cell. This contact with antigen must be in the absence of an additional influence provided either by adjuvants like endotoxin or POL, or by activated macrophages, which may be stimulated by activated T cells; otherwise not tolerance but B-cell activation will occur.

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