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Anti-β2-glycoprotein I (anti-β2GPI) antibodies are the main antiphospholipid antibodies, along with anticardiolipin and lupus anticoagulant, that characterize the autoimmune disease antiphospholipid syndrome (APS). While the exact physiological functions of β2GPI are unknown, there is overwhelming evidence that anti-β2GPI antibodies are pathogenic, contributing to thrombosis, pregnancy morbidity, and accelerated atherosclerosis in APS and systemic lupus erythematosus patients. The revelation that these antibodies play a central role in the pathogenesis and pathophysiology of APS has driven research to characterize the physiology and structure of β2GPI as well as the pathogenic effects of anti-β2GPI antibodies. It has also resulted in the development of improved testing methodologies for detecting these antibodies. In this review we discuss the characteristics of β2GPI; the generation, pathogenic effects, and standardized testing of anti-β2GPI antibodies; and the potential use of therapies that target the β2GPI/ anti-β2GPI interaction in the treatment of APS. [ABSTRACT FROM AUTHOR]

The article summarizes reports on the concurrence of Klinefelter's syndrome (KS) with inflammatory rheumatic diseases, rheumatoid arthritis (RA), juvenile idiopathic arthritis, psoriatic arthritis, polymyositis/dermatomyositis, systemic lupus erythematosus, systemic sclerosis, mixed connective tissue disease, the antiphospholipid syndrome, and ankylosing spondylitis. These include two case reports of patients with KS concurrently associated with RA or antisynthetase syndrome, respectively, previously reported by the author and his coworkers. Attention is paid to the pathogenesis and the course of the disease in patients with KS. The importance of early diagnosis of the syndrome, when occurring simultaneously with other diseases of connective tissue, is emphasized. [ABSTRACT FROM AUTHOR]

β2-glycoprotein-I (β2-GPI, also known as apolipoprotein H) is a major autoantigen in the antiphospholipid syndrome (APS), a disease commonly affecting the central nervous system. We examined whether β2-GPI and similar proteins exist in rat and human brains. No expression was found on Northern blot analysis of human brain. Utilizing a standard procedure for the isolation of serum β2-GPI we purified a 100 kD human brain protein, which was found by peptide sequencing to have full homology with the serum protein, histidine-rich glycoprotein (HRGP). Expression of HRGP in rat and human brain was established by RT-PCR studies and a partial sequence of rat brain HRGP was obtained showing 68% homology with the human protein. IgG from most APS patients bound to HRGP, which shares distinct biochemical properties with β2-GPI, is present in the brain and may be an important autoantigen. [ABSTRACT FROM AUTHOR]

Although less than 1% of patients with the antiphospholipid syndrome (APS) develop the catastrophic variant, its potentially lethal outcome emphasizes its importance in clinical medicine today. However, the rarity of this variant makes it extraordinarily difficult to study in any systematic way. In order to put together all the published case reports as well as the new diagnosed cases from all over the world, an international registry of patients with catastrophic APS (“CAPS Registry”) was created in 2000 by the European Forum on Antiphospholipid Antibodies. Currently, it documents the entire clinical, laboratory, and therapeutic data of more than 300 patients whose data have been fully registered. This registry can be freely consulted at the Internet ( ) and it is expected that the periodical analysis of these data will allow us to increase our knowledge of this condition. [ABSTRACT FROM AUTHOR]

Macrophage uptake of oxidized LDL (oxLDL) plays a critical role in early stages of atherosclerosis. We previously reported that oxLDL forms stable complexes with β2-glycoprotein I (β2GPI), and that these complexes were frequently present in the sera of patients with systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS). oxLDL/β2GPI complexes were shown to be antigenic targets for autoantibodies present in APS. To understand the role of autoantibodies in accelerated atherosclerosis of SLE and APS, we investigated the binding characteristics of β2GPI and oxLDL to mouse macrophages, and the effect of anti-β2GPI and anti-oxLDL autoantibodies on this macrophage binding. IgM anti-oxLDL antibody (derived from Apoe−/– mouse) showed inhibitory effect on oxLDL binding to macrophages. Although β2GPI partly inhibited oxLDL binding to macrophages, IgG anti-β2GPI autoantibody (derived from APS model mouse) showed pro-atherogenic property by promoting the binding of oxLDL/β2GPI to macrophages. [ABSTRACT FROM AUTHOR]

Twenty-one cases from several medical centers (Brazil, Italy, Serbia, South Africa, Israel, and the United Kingdom) with severe peripheral vascular disease progressing to amputations of limbs/digits, all of whom tested positive for antiphospholipid antibodies, are documented. The patients were suffering from either systemic lupus erythematosus, discoid LE, “primary” antiphospholipid syndrome (PAPS), “lupus-like” disease, undifferentiated connective tissue disease. A high frequency of livedo reticularis preceding the arterial occlusions in our series of patients who subsequently progressed to ischemic necrosis and amputation of limbs/digits was noted. Five of the 10 patients, in whom histopathological studies had been performed, demonstrated the typical vasculopathy seen with the antiphospholipid syndrome (“APS vasculopathy”). Complicating vasculitis was present in seven of the patients. Five of the patients developed severe peripheral vascular disease during the course of the catastrophic antiphospholipid (Asherson's) syndrome. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a chronic inflammatory process of the arterial wall associated with systemic and local immune responses to various antigens, oxidized low-density lipoprotein (oxLDL) being the most significant. Both IgM and IgG antibodies to oxLDL are produced during atherosclerosis. Some studies have shown that elevated levels of antibody to oxLDL correlate with the degree of atherosclerosis. Other studies reported that immunization of experimental animals with oxLDL induces high levels of antibodies to oxLDL, with decreased atherosclerosis, suggesting that the immune response to oxLDL may be antiatherogenic. The accelerated development of atherosclerosis has been observed in patients with systemic autoimmune diseases. In patients with antiphospholipid syndrome (APS), β2-glycoprotein I (β2GPI) is a major antigenic target for anticardiolipin antibodies (aCLs). We recently reported that oxLDL interacts with β2GPI via oxLDL-derived specific ligands, such as 7- ketocholesteryl-9-caboxynonanoate (oxLig-1) to form complexes. In vitro, anti- β2GPI autoantibodies bind to oxLDL/β2GPI complexes that are actively taken up by macrophages via Fcγ receptors. Circulating oxLDL/β2GPI complexes were detected in patients with systemic lupus erythematosus (SLE) and APS, at higher levels than in healthy individuals. Autoantibodies against these complexes were also present; however, IgG anti-oxLig-1/β2GPI antibody levels in SLE patients with APS were significantly higher than those in SLE patients without APS and those in healthy individuals. [ABSTRACT FROM AUTHOR]

Antiphospholipid antibodies (aPLs) have been shown to induce thrombosis, activate endothelial cells, and induce fetal loss. The pathogenesis of aPL-induced thrombosis is incompletely understood, but it is thought to involve platelet and endothelial cell activation as well as pro-coagulant effects of aPL antibody directly on clotting pathway components. Recent studies have shown that uncontrolled complement activation leads to fetal death in aPLantibody treated mice. We hypothesized that aPL antibodies activate complement, generating split products that induce thrombosis. To test this hypothesis, we used an in vivo model of thrombosis in which aPL antibodies induce a significant increase in thrombus size and a mouse model of endothelial cell activation in which aPLs induce significant adhesion of leukocytes (WBCs) to endothelial cells. We found that mice deficient in complement components C3 and C5 were resistant to enhanced thrombosis and endothelial cell activation induced by aPL antibodies. Furthermore, inhibition of C5 activation using anti-C5 mAb prevented thrombophilia induced by aPL antibodies. Our data show that complement activation mediates two important effectors of aPL antibodies: induction of thrombosis and endothelial activation. [ABSTRACT FROM AUTHOR]