Pathogenesis of the obstetric antiphospholipid syndrome: the key role of beta 2 glycoprotein I

Antiphospholipid syndrome (APS) is defined by recurrent pregnancy morbidity and/or vascular thrombosis associated with the persistent presence of antibodies against anionic phospholipid-binding proteins. Beta 2 glycoprotein I (β2GPI) and prothrombin (PT) are the major antigens for antiphospholipid antibodies (aPL) detectable by functional coagulation [lupus anticoagulant (LA)] or solid-phase assays [anti-β2GPI-dependent cardiolipin (aCL) and anti-β2GPI]. β2GPI-dependent aPL are responsible for the positivity of the three classification laboratory criteria. While medium/high titers of antibodies against β2GPI are risk factors for both the vascular and the obstetric manifestations of APS, persistent low titers are also associated with pregnancy complications. There is evidence from animal models of aPL-dependent fetal loss and from in vitro systems that β2GPI-dependent aPL can be pathogenic. β2GPI is physiologically found in large quantities at the placental level being available for the specific antibodies circulating in the maternal blood. Once bound to the protein, the antibodies trigger a local inflammation via the activation of the complement cascade and affect trophoblast and decidual function. The final result is represented by defective placentation, while thrombotic events are apparently less important. β2GPI is a pleiotropic molecule with scavenging properties towards several molecules including apoptotic material and displays anti-oxidant activity. These functions may explain the β2GPI placental localization in an area of intensive tissue remodeling and low oxygen tension. Since β2GPI interacts also with the complement and the coagulation cascade, its binding with specific antibodies may affect the physiology of placentation in several ways

The Role of Ultrasonography in the Assessment of Skeletal Hand Involvement in Systemic Sclerosis

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Low levels of vitamin D are common in primary antiphospholipid syndrome with thrombotic disease.

The aim of this study was to assess vitamin D (vit.D) levels in patients with primary antiphospholipid syndrome (PAPS), the association between hypovitaminosis D and clinical manifestations, and the effect of vit.D supplementation on serum levels. Vit.D serum levels of 115 PAPS patients, classified according to the 2006 revised criteria at the Rheumatology Department, Brescia, and of 128 voluntary healthy donors (NHD) were tested in collaboration with DiaSorin (Saluggia, Italy) using the LIAISON® chemiluminescent immunoassay. Clinical data were derived from clinical charts. Vit.D deficiency was more prevalent in PAPS than NHD (17% vs 5%). During the summer, vit.D levels were lower in PAPS than NHD (median 28 vs 40.1 ng/mL, P<0.01). PAPS were subdivided according to clinical characteristics (thrombotic vs obstetric). Both groups had lower vit.D levels compared to NHD. Thrombotic PAPS had significantly lower levels than obstetric PAPS (median 20.8 vs 33.3, P<0.01). Sixteen patients (14%) received oral 25-OH vit.D supplementation (average 400 UI/die), but 63% of them did not reach serum levels above 30 ng/mL. PAPS showed significantly lower levels of vit.D than NHD. Hypovitaminosis D was seen to cluster in patients with thrombosis which may suggest that the lack of vit.D could be one of the many factors involved in the thrombotic process. Low-dose supplementation did not seem to be effective in a small group of patients

Adalimumab clinical efficacy is associated with rheumatoid factor and anti-cyclic citrullinated peptide antibody titer reduction: a one-year prospective study

Studies on autoantibody production in patients treated with tumor necrosis factor-α (TNF-α) inhibitors reported contradictory results. We investigated in a prospective study the efficacy of a treatment with human monoclonal anti-TNF-α antibody (adalimumab) in patients with rheumatoid arthritis (RA) and we evaluated the relationship between treatment efficacy and the incidence and titers of disease-associated and non-organ-specific autoantibodies. Fifty-seven patients with RA not responsive to methotrexate and treated with adalimumab were enrolled. Antinuclear, anti-double-stranded(ds)DNA, anti-extractable nuclear antigens, anti-cardiolipin (aCL), anti-β(2 )glycoprotein I (anti-β(2)GPI) autoantibodies, rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) autoantibodies were investigated at baseline and after 6 and 12 months of follow-up. Comparable parameters were evaluated in a further 55 patients treated with methotrexate only. Treatment with adalimumab induced a significant decrease in RF and anti-CCP serum levels, and the decrease in antibody titers correlated with the clinical response to the therapy. A significant induction of antinuclear autoantibodies (ANA) and IgG/IgM anti-dsDNA autoantibodies were also found in 28% and 14.6% patients, respectively, whereas aCL and anti-β(2)GPI autoantibodies were not detected in significant quantities. No association between ANA, anti-dsDNA, aCL and anti-β(2)GPI autoantibodies and clinical manifestations was found. Clinical efficacy of adalimumab is associated with the decrease in RF and anti-CCP serum levels that was detected after 24 weeks and remained stable until the 48th week of treatment. Antinuclear and anti-dsDNA autoantibodies, but not anti-phospholipid autoantibodies, can be induced by adalimumab but to a lower extent than in studies with other anti-TNF blocking agents

New insight into antiphospholipid syndrome: antibodies to \u3b22glycoprotein I-domain 5 fail to induce thrombi in rats

Clinical studies have reported different diagnostic/predictive values of antibodies to domain 1 or 4/5 of \u3b22glycoproteinI in terms of risk of thrombosis and pregnancy complications in patients with antiphospholipid syndrome. To obtain direct evidence for the pathogenic role of anti-domain 1 or anti-domain 4/5 antibodies, we analysed the in vivo pro-coagulant effect of two groups of 5 serum IgG each reacting selectively with domain 1 or domain 5 in LPS-treated rats. Antibody-induced thrombus formation in mesenteric vessels was followed by intravital microscopy and vascular deposition of \u3b22glycoproteinI, human IgG and C3 was analyzed by immunofluorescence. Five serum IgG with undetectable anti-\u3b22glycoproteinI antibodies served as controls. All the anti-domain 1 positive IgG exhibited potent pro-coagulant activity while the anti-domain 5 positive and the negative control IgG failed to promote blood clot and vessels occlusion. A stronger granular deposit of IgG/C3 was found on the mesenteric endothelium of rats treated with anti-domain 1 antibodies, as opposed to a mild linear IgG staining and absence of C3 observed in rats receiving anti-domain 5 antibodies. Purified anti-domain 5 IgG, unlike anti-domain 1 IgG, did not recognize cardiolipin-bound \u3b22glycoprotein I while able to interact with fluid-phase \u3b22glycoproteinI. These findings may explain the failure of anti-domain 5 antibodies to exhibit in vivo thrombogenic effect and the interaction of these antibodies with circulating \u3b22glycoproteinI suggest their potential competitive role with the pro-coagulant activity of anti-domain 1 antibodies. These data aim at better defining really at risk patients for more appropriate treatments to avoid recurrences and disability

1079-102 Correlation between norepinephrine and epinephrine myocardial spillover and tumor necrosis factor-alpha in conventional versus off-pump coronary artery bypass surgery

Background: Complete revascularization obtained by coronary artery bypass surgery does not prevent long term left ventricular remodeling and heart failure development. Periprocedural events linked to different surgical techniques, such as cardiopulmonary bypass with cardioplegic arrest (CABG) versus off-pump procedures may trigger an irreversible microvascular dysfunction or myocytes necrosis and apoptosis. Methods: To test this hypothesis we measured norepinephrine and epinephrine coronary sinus and aortic spillover before and after surgery, simultaneously with Tumor Necrosis Factor-alpha (TNF-alpha) measurements in 30 patients randomized to CABG (n=15), or off-pump (n=15) coronary surgery. Plasma catecholamines were assessed by high performance liquid chromatography and TNF-alpha by ELISA. Results: Norepinephrine and epinephrine spillover was similar in the two groups before surgery, being 1.38\ub10.62 and 1.08\ub10.45, respectively. After surgery norepinephrine spillover was 1.43\ub10.56, 0.72\ub10.49 in CABG and off-pump, respectively (P<0.05 CABG versus off-pump, means \ub1SD ). Epinephrine spillover was 1.27\ub10.16 and 0.65\ub10.15 respectively (P<0.05, CABG versus off-pump). TNF-alpha significantly increased only in CABG patients being 22.17\ub16.79 and 35.4\ub15.98, pg/mL, before and after surgery (P<0.05), respectively. After surgery norepinephrine spillover correlated with TNF-alpha levels (P=0.01, R=0.553). Conclusions: Patients undergoing off-pump interventions showed significantly lower catecholamines spillover as compared to CABG, suggesting that the off-pump technique may result less invasive, not only for a lower local and whole body inflammatory response but also for a lower sympathetic drive. For the first time in humans we have detected an increase in epinephrine-spillover after cardiac surgery. Further studies are necessary to evaluate if the short-term advantages observed after off-pump coronary surgery translate into a long-term attenuation of left ventricular remodeling and in the prevention of heart failure progression

Beta 2 glycoprotein I and neutrophil extracellular traps: Potential bridge between innate and adaptive immunity in anti-phospholipid syndrome

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by recurrent vascular thrombosis and miscarriages in the absence of known causes. Antibodies against phospholipid-binding proteins (aPL) are pathogenic players in both clotting and pregnancy APS manifestations. There is sound evidence that antibodies specific for beta2 glycoprotein I (β2GPI) trigger thrombotic and pregnancy complications by interacting with the molecule on the membranes of different cell types of the coagulation cascade, and in placenta tissues. In addition to the humoral response against β2GPI, both peripheral and tissue CD4+ β2GPI-specific T cells have been reported in primary APS as well as in systemic lupus erythematosus (SLE)-associated APS. While adaptive immunity plays a clear role in APS, it is still debated whether innate immunity is involved as well. Acute systemic inflammation does not seem to be present in the syndrome, however, there is sound evidence that complement activation is crucial in animal models and can be found also in patients. Furthermore, neutrophil extracellular traps (NETs) have been documented in arterial and venous thrombi with different etiology, including clots in APS models. Keeping in mind that β2GPI is a pleiotropic glycoprotein, acting as scavenger molecule for infectious agents and apoptotic/damaged body constituents and that self-molecules externalized through NETs formation may become immunogenic autoantigens, we demonstrated β2GPI on NETs, and its ability to stimulate CD4+β2GPI-specific T cells. The aim of this review is to elucidate the role of β2GPI in the cross-talk between the innate and adaptive immunity in APS