Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P02749 (beta2-glycoprotein I)
 836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A hallmark of systemic lupus erythematosus (SLE) and related autoimmune diseases such as the antiphospholipid syndrome (APL or Hughes syndrome) is an apparent breakdown in tolerance, the process by which the body distinguishes self from nonself in order to maintain a versatile immune defense while protecting itself from self-annihilation. To some extent, loss of tolerance is a desirable feature of host immunity, and is known to occur in healthy individuals. Optimal tolerance then is probably not an all or nothing phenomenon. Autoimmunity should be seen as a breakdown in homeostasis rather than a completely aberrant kind of immunity. This leads to special considerations in the assessment of potentially toleragenic therapies, in which an attempt is made to re-educate the immune system. LJP 1082 is designed as a polyvalent antigenic structure aimed at crosslinking specific surface immunoglobulin and tolerizing B cells to beta2-glycoprotein I. Issues of antigenic selection and multiplex forces influencing tolerance and immunity may have impact on its optimal development and use in patients.
Lupus 2004
PMID:LJP 1082: a toleragen for Hughes syndrome. 1523 Feb 88

One hundred and forty patients with Graves' disease [32 new patients, 54 treated with propylthiouracil (PTU) for a mean of 27.2 months and 54 treated with methimazole (MMI) for a mean of 48.6 months] were tested for anti-thyroid microsomal antibody (AMA), anti-thyroglobulin antibody (ATA), thyroid binding inhibitory immunoglobulin (TBII), and the non organ specific autoantibodies [i.e., anti-nuclear antibody (ANA), anti-double stranded DNA antibody (anti-dsDNA Ab), anti-cardiolipin antibody (aCL Ab) and anti-beta2-glycoprotein I antibody (IgG beta2GPI)]. Treatment with MMI or PTU produced a significant difference in IgG aCL Ab production but not in ANA, dsDNA Ab, IgM aCL or IgG beta2GPI. For those treated with MMI but not those treated with PTU, ANA and anti-dsDNA Ab were positively correlated. IgG and IgM aCL Ab were positively correlated overall and for those on MMI but not PTU treatment. No significant difference was found for any of the four non organ specific antibodies in AMA positive or negative patients but there was a significant difference in IgG aCL positivity rates for ATA positive and negative patients. On the other hand, ANA negative patients were significantly more likely to have higher TBII values. These results suggest that the appearance of the non organ specific autoantibodies is probably largely a coincidental effect of polyclonal activation - except, perhaps, for IgG aCL, which may be related to treatment.
Lupus 2004
PMID:Anti-nuclear antibody, anti-DNA, and aCL in Graves' disease patients treated with propyluracil or methimazole. 1530 72

Antiphospholipid antibodies detected by lupus anticoagulant, anticardiolipin or anti-beta2 glycoprotein I assays were associated with fetal loss. Rather than being diagnostic tools only, antiphospholipid antibodies are thought to be pathogenic. The strongest demonstration of their pathogenic role lies in the ability to induce fetal resorptions--the experimental equivalents of the human fetal losses--when passively infused in pregnant naive animals. However, still debated is how the antibodies might induce the obstetrical manifestations. Thrombotic events at the placental levels might be related to endothelial cell activation, inhibition of protein C/S system and fibrinolysis as well as to Annexin V displacement. However, the thrombophilic state apparently cannot explain all the miscarriages and a direct antibody-mediated damage on the trophoblast has been suggested. During differentiation to syncytium, trophoblasts express cell membrane anionic phospholipids that can bind beta2 glycoprotein I, the main cationic phospholipid binding protein recognized by the antiphospholipid antibodies. Adhered beta2-glycoprotein I might be recognized by the antibodies that, once bound, strongly interfere with in vitro trophoblast cell maturation so resulting in a defective placentation. These mechanisms have been suggested to play a role in early fetal loss, while thrombotic events would be responsible for miscarriages late in the pregnancy.
Lupus 2004
PMID:Antiphospholipid antibodies as cause of pregnancy loss. 1548 95

Antiphospholipid antibodies are a wide and heterogeneous group of immunoglobulins that include, among others, lupus anticoagulants and anticardiolipin antibodies. Their presence in patients with arterial and venous thrombosis, and/or obstetrical complications, defines the antiphospholipid syndrome. Antiphospholipid antibodies do not recognize anionic phospholipids, but recognize plasma proteins bound to suitable anionic surfaces: beta2-glycoprotein I and prothrombin are the most common and most frequently investigated antigens. We systematically reviewed published articles on the antiphospholipid syndrome to investigate the association between thrombosis and some antiphospholipid antibodies. Lupus anticoagulants were a clear risk factor for thrombosis, irrespective of the site and type of thrombosis, the presence of systemic lupus erythematosus, and the methods used to detect them. Anticardiolipin and anti-beta2-glycoprotein I antibodies were possible risk factors of thrombosis, at least in some selected situations. The measurement of antiprothrombin antibodies is not helpful to define the patient's risk of thrombosis. These results are mainly due to the still far from optimal standardization of the methods to detect antiphospholipid antibodies; the lack of standardized reference materials; the heterogeneity in reagents, calibrators, and assay conditions; and the methods used to calculate the results. Many efforts are currently being made to improve assay standardization and harmonization, which should help to clarify the clinical relevance of antiphospholipid antibodies.
 ...
PMID:Antiphospholipid syndrome: clinical and diagnostic utility of laboratory tests. 1570 71

The antiphospholipid syndrome is defined as the occurrence of one or more episodes of vascular thrombosis and/or miscarriage together with antiphospholipid antibodies. Some of these antibodies can be detected via coagulation assays by prolonging phospholipids-dependent assays. These unspecific inhibitors are termed lupus anticoagulant, due to their first description by Conley and Hartmann in patients with disseminated lupus erythematosus. Lupus anticoagulants are now defined as acquired autoantibodies directed against a phospholipid-binding protein such as beta2-glycoprotein I or prothrombin. Because of this binding, lupus anticoagulants form bivalent complexes which slow down coagulation reactions in vitro by forming stable complexes on coagulation active phospholipids. In vivo, these complexes may result in cellular activation and cause thrombosis. Laboratory diagnosis for the lupus anticoagulant should be performed by a combination of tests, including phospholipid-dependent clotting assays, plasma mixing studies, and demonstration of the phospholipid-dependency of the inhibitory activity.
 ...
PMID:[Laboratory diagnosis of the lupus anticoagulants]. 1571 20

The antiphospholipid syndrome (APS) is characterized by the presence of antiphospholipid antibodies (aPL) in patients with thromboembolic complications. In APS, most aPL are autoantibodies to beta2-glycoprotein I and prothrombin, which play a major role in the APS pathogenesis. Nevertheless, antibodies with the same antigen specificity are also found in aPL patients with leprosy, in whom thromboembolic complications are uncommon. The in vivo upregulation of the tissue factor (TF) pathway and the imbalance of cytokines have been proposed as potential mechanisms of thrombosis in the APS. We measured the circulating levels of TF, interleukin 6 (IL-6), IL-6 receptor (sIL-6R), tumor necrosis factor (TNF-alpha) and interferon gamma (IFN-gamma) in 83 patients with autoimmune aPL (42 with and 41 without clinical features of definite primary APS), 48 leprosy patients (33 with aPL) and 48 normal controls. There was a trend (P = 0.06) to higher median sTF in patients with autoimmune aPL (139 pg/mL) compared with leprosy patients (103.5 pg/mL) and controls (123 pg/mL). In addition, the frequency of raised sTF levels (> 187 pg/mL) was significantly higher in the group with autoimmune aPL [22.9% (APS 21.4%, non-APS 24.4%)] but not in leprosy (10.4%) compared with controls (4.2%). Elevated levels of IL-6 and TNF-alpha and a trend to lower IFN-gamma were found in patients with definite APS. Leprosy patients with aPL, however, had increased TNF-alpha and IFN-gamma but normal IL-6 levels. Levels of sIL-6R did not differ between controls and either patients with autoimmune aPL or leprosy. The different cytokine profiles as well as differences in circulating levels of TF might contribute to the high thrombotic risk found in patients with autoimmune aPL but not in leprosy related aPL patients.
Lupus 2005
PMID:Circulating levels of tissue factor and proinflammatory cytokines in patients with primary antiphospholipid syndrome or leprosy related antiphospholipid antibodies. 1575 17

The aim of this study was to analyse pregestational and pregnancy risk factors for adverse fetal and maternal outcome in lupus pregnancy. Twenty women with systemic lupus erythematosus (SLE) (29 pregnancies) were prospectively evaluated. Mean patient age was 29.5+/-4.7 years, and mean disease duration, 6.3+/-6.5 years. Twenty-two pregnancies (75.9%) ended in live births; preterm delivery occurred in 17.4%, intrauterine growth restriction in 50%, preeclampsia in 3.7%, and gestational hypertension in 8%. Six pregnancies (20.7%) ended in spontaneous abortions. Adverse live-birth outcome was significantly associated with low pregestational serum albumin level, elevated gestational anti-dsDNA antibody, and diabetes mellitus. Spontaneous abortion was directly associated with low levels of pregestational serum albumin, positive anticardiolipin IgA, anti-beta2-glycoprotein I IgM, and anti-La antibodies, and inversely associated with number of patients' children. Postgestational lupus flare-up was noted in six pregnancies. Risk factors included high pregestational SLE Disease Activity Index (SLEDAI), lower serum albumin, elevated serum antibody to dsDNA, proteinuria, and use of prednisone and hydroxychloroquine. We conclude that despite high rate of obstetrical complications and postpartum lupus flare-up, pregnancy poses low risk for the majority of women with SLE.
Lupus 2005
PMID:Maternal and fetal outcome of lupus pregnancy: a prospective study of 29 pregnancies. 1575 19

Among the so called 'antiphospholipid antibodies', the presence of Lupus Anticoagulant (LA) is associated with thrombosis-related events and defines the antiphospholipid syndrome. The role of anti-cardiolipin (aCL) antibodies and anti-human beta2-glycoprotein I (abeta2GPI) antibodies is less striking. Since the problem of standardization for these tests is far from resolved, we evaluated whether the combination of results (antiphospholipid laboratory profiles) could help to better classify these patients. Over a 6-year period, 618 consecutive subjects (55% of whom had previous documented thrombosis-related events) were referred to our clinic for Antiphospholipid antibody detection. LA was detected according to internationally accepted recommendations. ACL and abeta2GPI antibodies were detected by Enzyme-Linked-Immunosorbent Assay (ELISA). Patients' records were reviewed for the presence of previous thromboembolic events or obstetric complications according to Sapporo's clinical criteria for the diagnosis of antiphospholipid syndrome (APS) and each patient underwent a physical examination. When individual tests were considered in a multivariate analysis which took into account age, gender, the presence of SLE or other autoimmune diseases and established risk factors for venous and arterial thromboembolism, LA (Odds Ratio 4.4, Confidence Interval 1.5-13.3) and abeta2GPI antibodies (Odds Ratio 2.9, Confidence Interval 1.1-7.5) but not aCL antibodies (Odds Ratio 1.2, Confidence Interval 0.5-2.7) were found to be independent risk factors for thrombosis-related events. When antiphospholipid antibody profiles instead of individual test positivity were analyzed in the above mentioned model, triple positivity resulted a strong independent risk factor (Odds Ratio 33.3, Confidence Interval 7.0-157.6), retaining its significance when the association with venous or arterial thromboembolism was considered. Double positivity with negative LA was close to significance for thrombosis-related events (Odds Ratio 2.2, Confidence Interval 1.0-5.2, p=0.056) and highly significant risk factor for obstetric complications (Odds Ratio 10.8, Confidence Interval 2.9-40.8). Other combinations did not reach statistical significance. The mean level of IgG abeta2GPI antibodies was statistically higher in triple positive profile and might account for positive LA. As compared to a single test, the analysis of a complete antiphospholipid antibody profile can better determine patients at risk.
 ...
PMID:Antibody profiles for the diagnosis of antiphospholipid syndrome. 1596 1

Antibodies against phospholipids (PL) and PL-binding proteins have been causally implicated in antiphospholipid syndrome (APS). Mutations in the fifth domain of the beta2-glycoprotein I (beta2GPI) protein, a putative PL-binding site, may play a critical role in APS pathogenesis. The purpose of this study was to identify associations between beta2GPI mutations and both antiphospholipid antibodies (aPL) and their associated clinical manifestations in a pediatric and adolescent cohort and to search for novel mutations. Genetic analysis of beta2GPI was performed in 58 youths with systemic lupus erythematosus (SLE) and/or aPL, to identify known polymorphisms at amino acids 247 and 306 as well as novel mutations in exon 7 of the beta2GPI gene, and their association with aPL-associated clinical manifestations. Our results demonstrate an association between substitution of Val for Leu at AA247 (L247V) of beta2GPI and both the development of aPL (P = 0.05) and aPL-associated clinical manifestations (P = 0.03) among pediatric patients. The odds ratio associated with risk of aPL-associated clinical manifestations for the homozygous VV polymorphism was 5.5 (CI 1.3-23, P = 0.03) for the overall cohort, and 4.75 (CI 0.66-55.49, P = 0.06) after adjusting for ethnicity. The association was not significant after stratifying for SLE versus non-SLE. Association between the VV genotype at amino acid 247 of beta2GPI and clinical disease supports a genetic cause for APS among children and adolescents. Neither novel exon 7 beta2GPI mutations or the previously described C306G polymorphism was identified in this pediatric cohort.
Lupus 2005
PMID:Association between beta2-glycoprotein I gene polymorphisms and pediatric SLE and antiphospholipid antibodies. 1603 7

Study objectives were to determine, in children with systemic lupus erythematosus (SLE), (1) the association of antiphosholipid antibody (APLA) subtypes with thrombotic events (TEs) and (2) the predictive value of persistent versus transient antibodies for TEs. This is a cohort study of 58 SLE children in whom lupus anticoagulants (LAs), anticardiolipin antibodies (ACLAs), anti-beta2-glycoprotein-I (anti-beta2-GPI), and antiprothrombin (anti-PT) were assessed on at least 2 occasions (more than 3 months apart). Antibodies were classified as persistent (positive on at least 2 occasions) or transient (positive once). Outcomes were symptomatic TEs confirmed by objective radiographic tests identified retrospectively and prospectively. Seven of the 58 patients (12%) had 10 TEs; 5 patients had TEs during prospective follow-up. Persistent LAs showed the strongest association with TEs (P < .001). Persistent ACLAs (P = .003) and anti-beta2-GPI (P = .002) were significantly associated with TEs; anti-PT (P = .063) showed a trend. Persistent or transient LAs and anti-beta2-GPI showed similar strength of association, while ACLAs and anti-PT were no longer associated with TEs. Positivity for multiple APLA subtypes showed stronger associations with TEs than for individual APLA subtypes because of improved specificity. Lupus anticoagulant is the strongest predictor of the risk of TEs; other APLA subtypes provide no additional diagnostic value. Anticardiolipin antibodies and anti-PT require serial testing because only persistent antibodies are associated with TEs.
 ...
PMID:Predictive value of persistent versus transient antiphospholipid antibody subtypes for the risk of thrombotic events in pediatric patients with systemic lupus erythematosus. 1614 97


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