'Non-criteria antiphospholipid antibodies': bridging the gap between seropositive and seronegative antiphospholipid syndrome.

OBJECTIVE: We aimed to analyse the prevalence of non-criteria anti-phospholipid (aPL) antibodies and their role in the diagnosis, treatment and prognosis in a cohort of patients with clinical features consistent with a diagnosis of antiphospholipid syndrome (APS), but persistently negative for criteria aPL - anti-cardiolipin antibodies (aCL), anti-ß2-glycoprotein I antibodies (aß2-GPI) and lupus anticoagulant (LA) - named seronegative APS (SN-APS). METHODS: Sera from SN-APS patients were tested for aCL by TLC-immunostaining, anti-vimentin/cardiolipin (aVim/CL) and anti-phosphatidylserine/prothrombin (anti-PS/PT) by ELISA. Control groups of our study were APS patients and healthy controls. RESULTS: We enrolled 114 consecutive SN-APS patients, 69 (60.5%) resulted positive for at least one non-criteria test in two occasions 12 weeks apart. Among the persistently positive patients to these tests, 97% resulted positive for aCL by TLC-immunostaining, 52.3% for aVim/CL and 17.4% for aPS/PT. SN-APS patients with double positivity (aCL by TLC-immunostaining and aVim/CL) showed a likelihood positive ratio of 8 to present mixed thrombotic and obstetrical features. Among SN-APS patients tested positive, after the therapeutic changes, three cases of recurrent thrombosis were observed [median follow-up 41 months (IQR 39.5)]. Twenty pregnancies were recorded in 17 SN-APS patients after the detection of unconventional aPL and 12 of them (60%) experienced a good outcome under conventional treatment for APS. CONCLUSIONS: This is the largest monocentric study demonstrating that aCL tested by TLC-immunostaining and aVim/CL can detect aPL positivity in SN-APS. It may encourage clinicians to monitor and provide adequate targeted therapy, which improve SN-APS prognosis.

Antineutrophil properties of natural gingerols in models of lupus.

Ginger is known to have antiinflammatory and antioxidative effects and has traditionally been used as an herbal supplement in the treatment of various chronic diseases. Here, we report antineutrophil properties of 6-gingerol, the most abundant bioactive compound of ginger root, in models of lupus and antiphospholipid syndrome (APS). Specifically, we demonstrate that 6-gingerol attenuates neutrophil extracellular trap (NET) release in response to lupus- and APS-relevant stimuli through a mechanism that is at least partially dependent on inhibition of phosphodiesterases. At the same time, administration of 6-gingerol to mice reduces NET release in various models of lupus and APS, while also improving other disease-relevant endpoints, such as autoantibody formation and large-vein thrombosis. In summary, this study is the first to our knowledge to demonstrate a protective role for ginger-derived compounds in the context of lupus. Importantly, it provides a potential mechanism for these effects via phosphodiesterase inhibition and attenuation of neutrophil hyperactivity.

Antiphospholipid syndrome: An update on risk factors for pregnancy outcome.

BACKGROUND: The optimal treatment of women with primary antiphospholipid syndrome (APS) is still debated. About 20-30% of women with APS remain unable to give birth to healthy neonates despite conventional treatment, consisting of prophylactic-dose heparin and low-dose aspirin. These cases are defined "refractory obstetric APS". The early identification of risk factors associated with poor pregnancy outcome could be the optimal strategy to establish criteria for additional therapies, such as hydroxychloroquine, steroids, intravenous immunoglobulin, and plasma exchange. PURPOSE: The aim of the present study was to review current literature about risk factors for poor pregnancy outcome. SEARCH METHODS: The PubMed database was used to search for peer-reviewed original and review articles concerning risk factors for pregnancy outcome in APS from 1st January 1990 to 15th January 2018. OUTCOMES: History of pregnancy morbidity and/or thrombosis, the association with SLE and/or other autoimmune diseases are well known history-based predictive factors for obstetrical complications, such as miscarriage, maternal venous thromboembolism, intrauterine foetal demise, preeclampsia, and neonatal death. Moreover, laboratory findings associated with poor pregnancy outcome are:triple antiphospholipid antibodies aPL positivity, double aPL positivity, single aPL positivity, false-positive IgM for CMV, and hypocomplementemia. Triple positivity is confirmed as the most significant risk factor by a large body of evidence. Furthermore, the abnormal uterine arteries Doppler velocimetry results are confirmed to be strongly associated with poor pregnancy outcomes in APS. The good performance of the uterine arteries velocimetry, as a negative predictive factor, was reported by different studies. On the contrary, in case of abnormal uterine arteries results, the relevance of a careful surveillance is highlighted for the high risk of maternal-foetal complications. Nevertheless, this tool is a late indicator to suggest any additional treatments. CONCLUSIONS: In order to prevent obstetrical complications and establish the optimal combination therapy, the knowledge at preconception or at the beginning of pregnancy of risk factors associated with poor pregnancy outcome could be a crucial step for management and treatment of APS. In addition, in the preconception assessment a regimen with low-dose aspirin, folic acid, and vitamin D supplementation should be offered, and a treatment strategy has to be established (conventional vs additional therapy). In fact, additional treatment has to be tailored for each patient.

Anti-annexin A5 antibodies and 25-hydroxy-cholecalciferol in female patients with primary antiphospholipid syndrome.

Vascular antiphospholipid syndrome (VAPS) and obstetric (OAPS) are different entities because some patients only develop thrombosis (without recurrent pregnancy losses) and vice versa. Only two articles have reported that low 25-hydroxy-cholecalciferol (vitamin D3, VD3) levels were not correlated with the presence of conventional antiphospholipid antibodies (aPL Abs: anticardiolipin (aCL), anti-beta2glycoprotein I (aß2gpI), and lupus anticoagulant (LA)), but no article analyzed the association of VD3 and anti-annexin A5 (aanxA5) Abs. The aim of our study was to investigate the association between VD3, multiple positivity of conventional aPL and aanxA5 Abs levels only in female OAPS vs. VAPS. Our study included 62 consecutive female PAPS patients. Concentrations of Abs were measured by ELISA, while VD3 levels were determined by immunochemiluminescence. Only 10/62 (16.13%) had sufficient (≥ 30 ng/ml) VD3 levels, while 48/62 (77.42%) and 4/62 (6.45%) had insufficiency and VD3 deficiency, respectively. Statistically significant VD3 deficiency was noticed in VAPS (vs. OAPS, P = 0.013). A negative correlation between VD3 levels and the age of patients was noticed (r = - 0.493, P = 0.032) only in VAPS subgroup. Multiple positivity of aPL and aanxA5 Abs was not associated with VD3 deficiency. Newly emerging aPL Abs, such as aanxA5 Abs, or their combinations with classical aPL Abs are not associated with VD3 deficiency in neither OAPS nor VAPS patients. Due to its immunomodulatory roles in B-Ly homeostasis, supplementation with VD3 should be considered in APS, at least in subgroup with severe form of the disease, i.e., VAPS.

Omega-3 Fatty Acid Supplementation Improves Endothelial Function in Primary Antiphospholipid Syndrome: A Small-Scale Randomized Double-Blind Placebo-Controlled Trial.

Endothelial cells are thought to play a central role in the pathogenesis of antiphospholipid syndrome (APS). Omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation has been shown to improve endothelial function in a number of diseases; thus, it could be of high clinical relevance in APS. The aim of this study was to evaluate the efficacy of n-3 PUFA supplementation on endothelial function (primary outcome) of patients with primary APS (PAPS). A 16-week randomized clinical trial was conducted with 22 adult women with PAPS. Patients were randomly assigned (1:1) to receive placebo (PL, n = 11) or n-3 PUFA (ω-3, n = 11) supplementation. Before (pre) and after (post) 16 weeks of the intervention, patients were assessed for endothelial function (peripheral artery tonometry) (primary outcome). Patients were also assessed for systemic markers of endothelial cell activation, inflammatory markers, dietary intake, international normalized ratio (INR), and adverse effects. At post, ω-3 group presented significant increases in endothelial function estimates reactive hyperemia index (RHI) and logarithmic transformation of RHI (LnRHI) when compared with PL (+13 vs. -12%, p = 0.06, ES = 0.9; and +23 vs. -22%, p = 0.02, ES = 1.0). No changes were observed for e-selectin, vascular adhesion molecule-1, and fibrinogen levels (p > 0.05). In addition, ω-3 group showed decreased circulating levels of interleukin-10 (-4 vs. +45%, p = 0.04, ES = -0.9) and tumor necrosis factor (-13 vs. +0.3%, p = 0.04, ES = -0.95) and a tendency toward a lower intercellular adhesion molecule-1 response (+3 vs. +48%, p = 0.1, ES = -0.7) at post when compared with PL. No changes in dietary intake, INR, or self-reported adverse effects were observed. In conclusion, 16 weeks of n-3 PUFA supplementation improved endothelial function in patients with well-controlled PAPS. These results support a role of n-3 PUFA supplementation as an adjuvant therapy in APS. Registered at http://ClinicalTrials.gov as NCT01956188.

Antibodies to phosphatidylserine/prothrombin (aPS/PT) enhanced the diagnostic performance in Chinese patients with antiphospholipid syndrome.

BACKGROUND: Increasing evidence has highlighted the role of non-criteria antiphospholipid antibodies (aPLs) as important supplements to the current criteria aPLs for the diagnosis of antiphospholipid syndrome (APS). In this retrospective study, we evaluated the clinical relevance of antibodies to phosphatidylserine/prothrombin (aPS/PT) in Chinese patients with APS. METHODS: A total of 441 subjects were tested, including 101 patients with primary APS (PAPS), 140 patients with secondary APS (SAPS), 161 disease controls (DCs) and 39 healthy controls (HCs). Serum IgG/IgM aPS/PT was determined by ELISA. RESULTS: The levels of IgG/IgM aPS/PT were significantly increased in patients with APS compared with DCs and HCs. IgG and IgM aPS/PT were present in 29.7% and 54.5% of PAPS, and 42.1% and 53.6% of SAPS, respectively. For diagnosis of APS, IgG aCL exhibited the highest positive likelihood ratio (LR+) of 21.60, followed by LA (13.84), IgG aß2GP1 (9.19) and IgG aPS/PT (8.49). aPS/PT was detected in 13.3% of seronegative PAPS patients and 31.3% of seronegative SAPS patients. LA exhibited the highest OR of 3.64 in identifying patients with thrombosis, followed by IgG aCL (OR, 2.63), IgG aPS/PT (OR, 2.55) and IgG aß2GP1 (OR, 2.33). LA and IgG aCL were correlated with both arterial and venous thrombosis, whereas IgG aPS/PT and IgG aß2GP1 correlated with venous or arterial thrombosis, respectively. CONCLUSIONS: Our findings suggest that the inclusion of IgG/IgM aPS/PT may enhance the diagnostic performance for APS, especially in those in whom APS is highly suspected, but conventional aPLs are repeatedly negative. In addition, IgG aPS/PT may contribute to identify patients at risk of thrombosis.

Direct oral anticoagulants: an alternative treatment for thrombotic antiphospholipid syndrome?

Background Direct oral anticoagulants (DOACs) demonstrate a lower risk-benefit ratio than vitamin K antagonists (VKAs) for secondary thromboprophylaxis of thrombotic events. But there are no data on the efficacy of DOACs for the prevention of thrombotic recurrence in patients with antiphospholipid syndrome (APS). In this study, we evaluated the efficacy of DOACs to prevent recurrences of thrombotic events in patients with APS. Methods This was a single-center pilot, using a multi-step Fleming design. If seven or fewer patients presented treatment failure with rivaroxaban, the study could conclude efficacy. Results A total of 23 patients were included. APS involved the veins only ( n = 19), arteries only ( n = 2) or both ( n = 1) and 1 patient exhibited catastrophic antiphospholipid syndrome (CAPS). Overall, two patients were positive for lupus anticoagulant, anti-beta-2 glycoprotein I antibodies and anticardiolipid antibodies (triple positivity). The mean duration of follow up was 35.6 (range, 29-40) months. A total of six treatment failures were reported: one patient, with triple positivity, developed bilateral distal pulmonary embolism (PE) after 20 months of treatment with rivaroxaban, two patients refused to take rivaroxaban, the treatment was stopped in three other patients: two with adverse effects and one with chronic iron-deficiency anemia. Conclusions Rivaroxaban may represent an alternative for secondary thromboprophylaxis for thrombo-embolism in patients with APS, in particular, those with poor international normalized ratio (INR) control and those who are not at the highest risk of recurrent thrombosis, such as those with triple positivity.

Detection of lupus anticoagulant in the era of direct oral anticoagulants.

Lupus anticoagulant (LAC) is an in vitro phenomenon determining a phospholipid-dependent elongation of clotting times. The presence of LAC associated with anticardiolipin (aCL) and anti-ß2 glycoprotein I (anti-ß2GPI) antibodies is strongly associated with thrombosis and pregnancy morbidity. Direct oral anticoagulants (DOACs) targeting thrombin and factor Xa are currently widely use to prevent and treat venous and arterial thromboembolism. Some concern has, however, been expressed about the possibility of false laboratory results during LAC assessment in patients taking these drugs. Several in vitro studies, spiking DOACs into normal plasma as well as ex vivo at peak levels in treated patients, led in false-positive LAC. The dilute Russell Viper Venom time is the assay that is most influenced by rivaroxaban, edoxaban, dabigatran and less by apixaban. Both screening and confirmatory tests have resulted equally prolonged for activated partial thromboplastin time and have not led to false-positive results, but this may depend on the type of reagent used for the test. Taipan/Ecarin snake venoms ratios, has been recommend by some investigators as they do not seem to be affected by rivaroxaban or edoxaban, but these tests are neither standardized nor generally available in clinical practice. In conclusion, for the time being it does not seem advisable to carry out LAC testing during anti-factor Xa and anti-factor IIa treatment because of the risk of false-positive results. Whenever needed in deciding the suspension of DOACs or in case of recurrent thrombosis, LAC determination should be carried out at trough better if DOAC concentration is known.

Annexin A2, autoimmunity, anxiety and depression.

OBJECTIVES: Antiphospholipid syndrome (APS) is associated with neurological manifestations and one of the novel autoantigens associated with this disease is Annexin A2 (ANXA2). In this work we have examined the effect of high levels of autoantibodies to ANXA2 on the brain in a mouse model. METHODS: Recombinant ANXA2 emulsified in adjuvant was used to immunize mice while mice immunized with adjuvant only served as controls. At peak antibody levels the animal underwent behavioral and cognitive tests and their brains were examined for ANXA2 immunoglobulin G (IgG) and expression of ANXA2 and the closely linked protein p11. RESULTS: Very high levels of anti-ANXA2 antibodies (Abs) were associated with reduced anxiety in the open field 13.14% ± 0.89% of the time in the center compared to 8.64% ± 0.91% observed in the control mice (p < 0.001 by t-test). A forced swim test found significantly less depression manifested by immobility in the ANXA2 group. The changes in behavior were accompanied by a significant reduction in serum corticosteroid levels of ANXA2 group compared to controls. Moreover, higher levels of total IgG and p11 expression were found in ANXA2 group brains. Lower levels of circulating anti-ANXA2 Abs were not associated with behavioral changes. CONCLUSIONS: We have established an animal model with high levels of anti-ANXA2 Abs which induced IgG accumulation in the brain and specific anxiolytic and anti-depressive effects. This model promises to further our understanding of autoimmune disease such as APS and to provide better understanding of the role of the ANXA2-p11 complex in the brain.

Synthesis of Phospholipid-Protein Conjugates as New Antigens for Autoimmune Antibodies.

Copper(I)-catalyzed azide-alkyne cycloaddition, or CuAAC click chemistry, is an efficient method for bioconjugation aiming at chemical and biological applications. Herein, we demonstrate how the CuAAC method can provide novel phospholipid-protein conjugates with a high potential for the diagnostics and therapy of autoimmune conditions. In doing this, we, for the first time, covalently bind via 1,2,3-triazole linker biologically complementary molecules, namely phosphoethanol amine with human ß2-glycoprotein I and prothrombin. The resulting phospholipid-protein conjugates show high binding affinity and specificity for the autoimmune antibodies against autoimmune complexes. Thus, the development of this work might become a milestone in further diagnostics and therapy of autoimmune diseases that involve the production of autoantibodies against the aforementioned phospholipids and proteins, such as antiphospholipid syndrome and systemic lupus erythematosus.

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.

Management of refractory anti-phospholipid syndrome.

Anti-phospholipid syndrome (APS) is an autoimmune prothrombotic disorder characterised by the predisposition to venous and/or arterial thrombosis and obstetric morbidity. Management of APS centres on attenuating the procoagulant state whilst balancing the risks of anticoagulant therapy. Cases of recurrent thromboses and obstetric complications occur despite optimum therapy. Alternative therapies for refractory cases are subject to disparity among clinicians due to the current lack of clinical evidence present. This review aims to address the current management strategies for refractory thrombotic and obstetric cases and future therapeutic interventions. The role and current clinical evidence of using long term low molecular weight heparin (LMWH) as an alternative to warfarin therapy for refractory thromboses is evaluated. Potential alternatives for thromboses including statins, hydroxychloroquine, Rituximab are reviewed as well as the additional avenues to target in the future as the pathogenic mechanisms of APS are unveiled. The optimal management for refractory obstetric APS cases is subject to controversy. This review focuses and assesses the current evidence for the uses of low dose prednisolone, intravenous immunoglobulin and hydroxycholoroquine in obstetric cases. The treatment modalities for the management of refractory APS require further clinical evidence.

Effects of low-molecular-weight heparin on adhesion and vesiculation of phospholipid membranes: a possible mechanism for the treatment of hypercoagulability in antiphospholipid syndrome.

Heparins represent an efficient treatment of acute thrombosis and obstetric complications in antiphospholipid syndrome (APS). Enhanced microvesiculation of cell membranes, as detected by reduced membrane adhesion, can contribute to hypercoagulability in APS. Healthy donor IgG antibodies significantly increased beta2-glycoprotein I (beta2-GPI)-induced membrane adhesion, indicating that IgG antibodies might supplement the role of beta2-GPI in the regulation of membrane microvesiculation in healthy individuals. Anti-beta2-GPI IgG antibodies significantly reduced beta2-GPI-induced membrane adhesion, suggesting a direct role of anti-beta2-GPI antibodies in enhancing membrane microvesiculation in APS. Therapeutic concentration of nadroparin completely restored beta2-GPI-induced membrane adhesion in the presence of anti-beta2-GPI IgG antibodies. A novel anticoagulant mechanism of nadroparin in APS is suggested that supplements its direct effect on the coagulation cascade. Restoration of adhesion between negatively charged membranes in the presence of nadroparin might decrease shedding of microvesicles into the surrounding solution and could thus contribute to the efficacy of heparin treatment in APS.

Beta2-glycoprotein I and annexin A5 phospholipid interactions: artificial and cell membranes.

The aim of this report was an overview of beta2-glycoprotein I (beta2-GPI)- and annexin A5 (AnxA5)-phospholipid interactions including candidate beta2-GPI receptors, and their relevance to the investigation of physiological/pathological processes. Both beta2-GPI and AnxA5 have thrombomodulatory functions in vivo and their antigenicity is particularly important for thrombotic manifestations and pregnancy complications in antiphospholipid syndrome. Specific elements of beta2-GPI- and AnxA5-phospholipid interactions are different. The crucial elements for beta2-GPI are conformational change and dimerization, both of which are also required and necessary for receptor signaling, leading to the prothombotic state. AnxA5 differs in its ability to crystallize into a protective shield, the disruption of which seems to be the major prothrombotic mechanism. These differences may explain some of the functional consequences of both molecules seen in the pathological conditions. Future alternative therapies of antiphospholipid syndrome are proposed to be based on the expanding knowledge of beta2-GPI- and AnxA5-phospholipid interactions, specifically antagonizing beta2-GPI receptors, as well as inhibiting their signaling pathways.

Prophylactic therapy for patients with reproductive failure who were positive for anti-phospholipid antibodies.

PROBLEM: To elucidate the efficacy of the treatment using a Japanese-modified Chinese herbal medicine, Sairei-to, and low-dose aspirin with or without a corticosteroid hormone for the patients with adverse pregnancy histories positive for anti-phospholipid antibodies. METHOD OF STUDY: Fifteen cases positive for anti-phospholipid antibodies, who had experienced preterm delivery in which an extremely low birthweight infant (<1000 g) was born as a result of intrauterine growth restriction with or without severe preeclampsia, were treated with the medication according to the current protocol. Four cases with the same condition, who were treated with only low-dose aspirin, or without medication, were chosen as a control population. The pregnancy outcome was compared between the two groups. RESULTS: The rate of patients in whom the next pregnancy continued until the 36th week of gestation or later was significantly higher in treated patients (80.0%) compared with the control population (0%). CONCLUSIONS: In this series, we obtained case report data that Sairei-to may provide some benefit for patients with reproductive disorders positive for anti-phospholipid antibodies; however, randomized controlled trial evidence is needed before current treatment can be recommended.

Síndrome antifosfolípido catastrófico (SAFC): presentación de un caso clínico / Catastrophic antiphospholipid syndrome (CAPS): presentation of a clinical case

El síndrome antifosfolípidos (SAFL) es una trombofilia adquirida auto inmune, caracterizada por la ocurrencia de trombosis arteriales y/o venosas y abortos recurrentes. En raras ocasiones este cuadro puede tener una presentación catastrófica, con compromiso de microangiopatía y un curso grave de muy alta mortalidad. La frecuencia de este cuadro es menor al 1 por ciento de los SAFL, y cuando ocurre el compromiso de tres órganos se denomina síndrome antifosfolípido catastrófico (SAFC). Presentamos el caso de un paciente que debuta con una insuficiencia renal de rápida progresión, asociado a trombocitopenia y accidentes vasculares, en el cual se demuestra la presencia de anticuerpos antifosfolípidos. Se maneja con plasmaféresis, anticoagulación e inmunosupresión con excelente respuesta. Este caso es de interés por presentar un diagnóstico infrecuente de insuficiencia renal, cuyo manejo oportuno y agresivo puede cambiar el pronóstico sombrío publicado en la literatura.

Frequency and specificities of antiphospholipid antibodies (aPL) in volunteer blood donors.

In the State of Indiana, blood donors are screened by a written questionnaire prior to donation to identify potential exposures to infectious diseases and to assess medications. The potential donor is not asked about aPL-related events. Animal experiments have shown, however, that passive transfer of aPL can produce aPL-associated pathology in the recipient. We determined the incidence of antiphospholipid antibodies (aPL) in 775 volunteer blood donors in Indiana. Tubing segments containing 2 ml of anticoagulated blood were obtained from donor units. The average donor age was 43 years (range 17-82); 45% were female. Our in-house aPL ELISA tested for IgG, IgA and IgM to cardiolipin (aCL), phosphatidylserine (aPS), phosphatidylethanolamine (aPE) and phosphatidylcholine (aPC). The plasmas were tested with and without supplemental phospholipid (PL)-binding plasma proteins from adult bovine plasma (ABP). A total of 24 tests were performed for each donor. Normal ranges were determined for 98% of the donors by calculating multiples of the means (MoM) of OD values for each antigen-isotype combination. No decimals were used, all MoMs were rounded up to the next whole number. An additional two MoMs were added to the calculated cutoff values to eliminate borderline positive values. Results revealed that 63 (8.1 %) donors had positive findings for one or more aPL. The relatively high number of aPL-positive individuals reflects the observation that different donors were often in the highest 2% of each antigen-isotype combination tested. The aPL specificities, isotypes, and PL-binding protein dependence are summarized in this report.

Linseed oil suppresses the anti-beta-2-glycoprotein-I in experimental antiphospholipid syndrome.

The immunomodulatory potential of a diet enriched with n-3 polyunsaturated fatty acids was analysed in naïve mice with experimental antiphospholipid syndrome (APS) induced by active immunization with H-3, a human anti-beta-2-glycoprotein-I (anti-betaGPI) monoclonal antibody (mAb). Fetal loss and other clinical manifestations of APS were prevented in the group of APS mice upon exposure to the enriched n-3 diet compared to the control group. The titers of anti-betaGPI were significantly lower (in O.D. at 405 nm, 1.387+/-0.232 in comparison to non-treated mice 0.637+/-0. 111, P< 0.05). The reduced titer of anti-betaGPI antibodies in the sera of the treated mice was associated with a reduced number of anti-betaGPI forming cells in cultured splenocytes (84+/-14, antibody-forming cells (AFC)/10(5)cells in comparison to 37+/-4 AFC/10(5)cells (P< 0.02).In addition to the suppression of the humoral response in mice with experimental APS fed with linseed oil, we also observed an inhibitory effect on the cellular response. The T-cell response to anti-betaGPI was lower in comparison to mice immunized with H-3 anti-betaGPI mAB, which were kept on a normal diet. These results indicate that polyunsaturated fatty acids may improve clinical and laboratory parameters of APS. The beneficial effects of diets enriched with n-3 should be further examined as a potential mode of therapy for patients with APS.