Specific Antiphospholipid Antibodies Research Articles

Chronic thromboembolic pulmonary hypertension in patients with antiphospholipid syndrome: Risk factors and management

Antiphospholipid syndrome (APS) may cause chronic thromboembolic pulmonary hypertension (CTEPH). Current knowledge regarding prevalence and risk factors for CTEPH among APS patients is limited. We sought to determine clinical features and biomarkers that could identify APS subjects suffering from CTEPH, and describe the prevalence, course and treatment outcomes of patients with APS-CTEPH. 504 APS patients were treated in our center during 2008 to 2019. We studied clinical and laboratory features of 69 APS patients, comparing 19 patients diagnosed with CTEPH (APS-CTEPH) and treated accordingly, with 50 consecutive age and gender matched patients with no evidence of pulmonary hypertension (APS-No-CTEPH). CTEPH prevalence was 3.8% in our APS cohort and was linked with the following parameters: primary APS (p < 0.05); prior pulmonary embolism (p < 0.001); recurrent venous thromboembolism (VTE) (p < 0.001); lower platelet counts (p < 0.001); triple anti-phospholipid antibodies positivity (p < 0.001), higher titers of anti-cardiolipin IgG (p < 0.001), anti-B2GPI IgG (p < 0.001), and high Russell viper venom time ratio (RVVT-ratio) (p < 0.05). Additionally, history of catastrophic APS was more prevalent in APS-CTEPH vs APS-No-CTEPH (p < 0.05). Of APS-CTEPH patients, 15/19 underwent pulmonary endarterectomy (PEA): In 12/15 the procedure was elective and resulted in good perioperative and long-term outcomes, while only 1 of 3 patients that underwent urgent PEA survived. CTEPH is relatively common in APS. Primary APS, prior PE, recurrent VTE, thrombocytopenia and specific anti-phospholipid antibodies predict CTEPH in APS. Active assessment for CTEPH in APS patients should be considered, as PEA was found to be effective and relatively safe, especially if electively performed.

Evaluation of the Diagnostic Value of Non-criteria Antibodies for Antiphospholipid Syndrome Patients in a Chinese Cohort.

ObjectiveAlthough specific anti-phospholipid antibodies (aPLs) have been used in the diagnosis of the antiphospholipid syndrome (APS) for years, new biomarkers are required to increase its diagnostic and risk-predictive power. This study aimed to explore the value of several non-criteria aPLs in a Chinese cohort.MethodsA total of 312 subjects, namely, 100 patients diagnosed with primary APS, 51 with APS secondary to SLE, 71 with SLE, and 90 healthy controls, were recruited. Serum anticardiolipin (aCL) IgG/IgM/IgA, anti-β2-glycoprotein I (aβ2GPI) IgG/IgM/IgA, anti-phosphatidylserine/prothrombin antibodies (aPS/PT) IgG/IgM, and anti-annexin A5 antibodies (aAnxV) IgG/IgM were tested using ELISA kits.ResultsOf the total number of patients, 30.46% and 6.62% with APS were positive for aCL or aβ2GPI IgA, respectively, while 39.07% and 24.50% were positive for aAnxV or aPS/PT for at least one antibody (IgG or IgM). The addition test of aCL IgA and aAnxV IgM assists in identifying seronegative APS patients, and IgG aPS/PT was linked to stroke.ConclusionDetection of aCL IgA, aβ2GPI IgA, aAnxV IgG/M, and aPS/PT IgG/M as a biomarker provides additive value in APS diagnosis and would help in risk prediction for APS patients in medical practice.

Antiphospholipid antibodies in patients with dysglycaemia: A neglected cardiovascular risk factor?

Background:Cardiovascular disease is a serious complication in patients with dysglycaemia, defined as either type 2 diabetes or impaired glucose tolerance. Research focusing on the identification of potential markers for atherothrombotic disease in these subjects is warranted. The antiphospholipid syndrome is a common acquired prothrombotic condition, defined by a combination of thrombotic events and/or obstetric morbidity and positivity of specific antiphospholipid antibodies. Available information on antiphospholipid antibodies in dysglycaemia is scarce.Objective:This study investigates the association between antiphospholipid antibodies and dysglycaemia.Patients/Methods:The PAROKRANK (periodontitis and its relation to coronary artery disease) study included 805 patients, investigated 6–10 weeks after a first myocardial infarction, and 805 matched controls. Participants without known diabetes (91%) underwent an oral glucose tolerance test. Associations between antiphospholipid antibodies (anti-cardiolipin and anti-β2 glycoprotein-I IgG, IgM and IgA) and dysglycaemia were analysed.Results:In total, 137 (9%) subjects had previously known type 2 diabetes and 371 (23%) newly diagnosed dysglycaemia. Compared with the normoglycaemic participants, those with dysglycaemia had a higher proportion with first myocardial infarction (61% vs 45%, p < 0.0001) and were more often antiphospholipid antibody IgG positive (8% vs 5%; p = 0.013). HbA1c, fasting glucose and 2-h glucose were significantly associated to antiphospholipid antibody IgG. Odds ratios (ORs) were 1.04 (95% confidence interval [CI] 1.02–1.06), 1.14 (95% CI 1.00 – 1.27) and 1.12 (95% CI 1.04 – 1.21), respectively, after adjustments for age, gender and smoking.Conclusions:This study reports an association between antiphospholipid antibody IgG positivity and dysglycaemia. Further studies are needed to verify these findings and to investigate if antithrombotic therapy reduces vascular complications in antiphospholipid antibody positive subjects with dysglycaemia.

Antiphospholipid antibodies and non-thrombotic manifestations of systemic lupus erythematosus

Objectives The aim of this study was to investigate the association between antiphospholipid antibodies and non-thrombotic and non-gestational manifestations of systemic lupus erythematosus. Methods Systemic lupus erythematosus patients with persistently positive antiphospholipid antibodies or lupus anticoagulant were identified and grouped as systemic lupus erythematosus with antiphospholipid syndrome (SLE-APS), systemic lupus erythematosus with positive antiphospholipid antibodies/lupus anticoagulant without antiphospholipid syndrome (SLE-aPL), and systemic lupus erythematosus with negative aPLs (SLE-No aPL). Groups were compared in terms of non-thrombotic systemic lupus erythematosus manifestations and laboratory features retrospectively. Results A total of 150 systemic lupus erythematosus patients, 26 with SLE-APS, 25 with SLE-aPL, and 99 with SLE-No aPL, were identified. Livedo reticularis, neurologic involvement, and thrombocytopenia were more common in antiphospholipid antibody positive systemic lupus erythematosus cases. Malar rash, arthritis, and pleuritis were more common in the SLE-No aPL, SLE-APS, and SLE-aPL groups, respectively. Positivity rates and titers of specific antiphospholipid antibodies did not differ between the SLE-APS and SLE-aPL groups. Conclusions Presence of antiphospholipid syndrome or persistent antiphospholipid antibodies may be related to non-thrombotic and non-gestational systemic lupus erythematosus manifestations. Patients with systemic lupus erythematosus plus antiphospholipid syndrome and persistent antiphospholipid antibodies without antiphospholipid syndrome also differ in terms of systemic lupus erythematosus manifestations.

Single test isolated lupus anticoagulant positivity is associated with increased plasma levels of inflammatory markers and dyslipidemia.

To investigate whether a single positive test for lupus anticoagulant (LA) is associated with levels of inflammatory markers and traditional cardiovascular risk factors, independent of autoimmune disease, thrombophilia and occurrence of other antiphospholipid antibodies. In a retrospective observational study we included persons referred for thrombophilia testing during 2011-2014. Persons with autoimmune disease, thrombophilia or presence of specific anti-phospholipid antibodies were excluded. Multivariate logistic regression analyses adjusted for age and sex was performed and odds ratios (ORs) with 95% confidence intervals (95% CI) calculated. Of 381 individuals tested, 271 fulfilled the criteria, of whom 22 (8%) were LA positive and 249 (92%) LA negative. LA positivity was associated with higher body mass index (BMI) (OR 1.12, 95% CI: 1.03-1.23, p = 0.01); C-reactive protein (OR 1.08 95% CI:1.04-1.11, p < 0.001); fibrinogen (OR 1.51 95% CI: 1.27-1.78, p < 0.001); coagulation factor VIII (FVIII) (OR 1.73 95% CI: 1.01-2.96, p = 0.046), low high density lipoprotein (HDL) (OR 0.03 95% CI: 0.00-0.19, p < 0.001) and high triglyceride (OR 1.81 95% CI: 1.12-2.92, p = 0.02) compared with LA negative individuals. This study shows that single test isolated LA positivity is associated with increased levels of inflammatory markers, low HDL cholesterol, elevated triglyceride and high BMI.

Histological antiphospholipid-associated nephropathy versus lupus nephritis in patients with systemic lupus erythematosus: an observational cross-sectional study with longitudinal follow-up.

IntroductionRenal involvement is a severe complication in systemic lupus erythematosus (SLE). Moreover, a subset of SLE patients develop the anti-phospholipid syndrome (APS), characterised by the occurrence of anti-phospholipid antibodies in combination with macro- and microvascular thrombotic manifestations, including acute and chronic antiphospholipid-associated nephropathy (APLN). Clinical presentations of lupus nephritis and APLN are similar and a renal biopsy is necessary to differentiate between the conditions. Our aim with this study was to investigate the occurrence of histopathological findings consistent with APLN (hAPLN) in renal biopsies from SLE patients and to investigate associations with anti-phospholipid antibody specificities, clinical manifestations, HLA-DRB1 alleles, and long-term renal outcome.MethodConsecutive renal biopsies from 112 SLE patients with renal involvement were investigated and evaluated for findings of hAPLN; in all there were 236 renal biopsies. Data from biopsy reports and clinical information were collected. Autoantibodies against cardiolipin and β2-glycoprotein-1 were measured by enzyme-linked immunosorbent assay. A lupus anticoagulant test was determined with a modified Dilute Russel Viper Venom method. HLA genotyping was performed by sequence-specific primer PCR. Renal outcome was determined at study end.ResultsThe prevalence of hAPLN was 14.3% among SLE patients with renal involvement. Compared to patients with pure lupus nephritis, occurrence of hAPLN was associated with intima changes (odds ratio (OR) = 24; 95% confidence interval (CI), 3.0 to 189.8; P < 0.0001), hypertensive vascular changes (OR = 7.8; 95% CI, 1.6 to 39.4; P = 0.01), inflammatory infiltrates (OR = 6.5; 95% CI, 1.7 to 25.1; P = 0.007) and tubular atrophy (OR = 13.1; 95% CI, 1.7 to 103.6; P = 0.002). hAPLN was associated with the presence of cardiolipin antibodies (OR = 3.3; 95% CI, 1.0 to 10.8; P = 0.05) and triple anti-phospholipid antibody positivity (OR = 4.2; 95% CI, 1.3 to 13.7; P = 0.02). Patients with hAPLN were more hypertensive (OR = 3.8; 95% CI, 1.2 to 12.3; P = 0.03) and had higher levels of creatinine as compared to lupus nephritis patients (median 116 versus 75 μmol/L; P < 0.0001). We found significantly higher frequency of HLA-DRB1*13 (OR = 5.1; 95% CI, 1.7 to 15.4; P = 0.03) and development of end-stage renal disease (OR = 5.8; 95% CI, 1.7 to 19.7; P = 0.008) in hAPLN compared with lupus nephritis.ConclusionhAPLN is a severe and often unrecognized condition in SLE patients with renal involvement. We have demonstrated an increased risk for development of renal impairment and a genetic predisposition in hAPLN patients compared to lupus nephritis patients.

Clinical accuracy for diagnosis of antiphospholipid syndrome in systemic lupus erythematosus: evaluation of 23 possible combinations of antiphospholipid antibody specificities

To evaluate the clinical accuracy of antiphospholipid antibody (aPL) specificities both individually and/or in combination, in a wide cohort of systemic lupus erythematosus (SLE) patients in an attempt to identify a panel of tests that may provide the best accuracy for diagnosing antiphospholipid syndrome (APS). This study included 230 patients (218 women, mean age 42.7 ± 11.9 years, mean disease duration 12.2 ± 8.7 years), all fulfilling the 1982 criteria for SLE. All patients were tested for lupus anticoagulant (LA), anti-cardiolipin (aCL), anti-β(2) glycoprotein I (anti-β2GPI), solid phase anti-prothrombin (aPT), anti-phosphatidylserine/prothrombin (aPS/PT), and anti-phosphatidylethanolamine (aPE) antibodies. Sensitivity, specificity and predictive values were calculated. The diagnostic accuracy for each combination of tests was assessed by ROC and their area under the curve analysis as well as by the Youden's index (YI). Testing for six aPL derived 23 possible combinations of results. Among them, LA + anti-β(2)GPI + aPS/PT had the best diagnostic accuracy for APS as a whole and individually for both thrombosis and pregnancy loss (AUC 0.712, OR 3.73 [95% CI 1.82-5.38], P = 0.0001, YI = 0.32 and AUC 0.709, OR 3.75 [95% CI 2.13-6.62], P = 0.0001, YI = 0.37 and AUC 0.677, OR 4.82 [95% CI 2.17-10.72], P = 0.0007, YI = 0.38, respectively) and the best specificity when compared with all the other obtainable combination of tests. Triple positivity for LA + anti-β(2)GPI + aPS/PT was more strongly associated with clinical events (thrombosis and/or PL) when compared with double or single positivity (OR 23.2 [95% CI 2.57-46.2] vs. OR 7.3 [95% CI 2.21-25.97], OR 5.7 [95% CI 2.12-17.01] or OR 3.11 [95% CI 1.56-7.8] for single positivity for LA, aPS/PT and anti-β(2)GPI, respectively). Combining LA, anti-β(2)GPI and aPS/PT improves the diagnostic power and helps in stratifying the risk for each patient, according to their aPL profile.

Molecular pathophysiology of the antiphospholipid syndrome: the role of oxidative post-translational modification of beta 2 glycoprotein I.

It has been well established that antiphospholipid antibodies and specifically those directed against beta 2 glycoprotein I (β2GPI) are pathogenic for the development of thrombosis in the antiphospholipid syndrome (APS). Several groups have shown that anti-β2GPI antibodies, in complex with β2GPI, elicit effects on blood cells and coagulation-fibrinolysis proteins, which prime the arterial and venous vasculature for the development of thrombosis. However, much less is known about the mechanism initiating the production of autoantibodies against β2GPI, a physiological abundant protein of blood. In the current review, novel findings are presented regarding the structure and oxidative post-translational modifications of β2GPI, which trigger the immune response. The majority of circulating β2GPI exists in a form containing unpaired cysteines (free thiols), which constitutes the reduced form of β2GPI. The free thiols exposed on β2GPI are involved in the interaction with platelets and endothelial cells. We propose that this abundant pool of free thiols may serve as an antioxidant reservoir protecting cells or critical molecules from oxidative stress. Oxidation of β2GPI confers an increase in its immunogenicity through a Th1 immunological mechanism. The clinical significance of these observations is that serum from patients with APS, assessed by a novel ELISA assay, have a significant increase in oxidised β2GPI. These findings hold promise, not only for the delineation of the role of β2GPI as an immunological target, but also for the development of improved diagnostic and prognostic assays for APS.

CD101 Expression and Function in Normal and Rheumatoid Arthritis-affected Human T Cells and Monocytes/Macrophages

It was recently reported that CD101 surface expression discriminates potency among CD4+CD25+ FoxP3+ regulatory T cells in the mouse. We investigated whether CD101 may also have a role in the suppressor function of regulatory T cells in humans given that the latter population may affect the autoimmune response in patients with rheumatoid arthritis (RA). Sorted T cells and monocyte/macrophage cell populations were analyzed by flow cyto metry using conjugated antibodies specific for cell-surface markers. T cell proliferation assays were conducted by [(3)H]thymidine incorporation and CD8(high) cytotoxicity measurements by Cyto-Scan-LDH cytotoxicity assays. ELISA were used to measure cytokines in cell culture supernatants and Western blotting was performed for profiling mitogen-activated protein (MAP) kinase activation using specific antiphospholipid antibodies. CD101 expression coincided with PMA-induced monocyte/leukocyte lineage differentiation. CD8(high)CD101- T cells exhibited greater cytotoxic activity than CD8(high)CD101+ T cells, while no difference was observed between CD4CD25(high)CD101+ and CD4CD25(high)CD101- Treg inhibitory activity through responder T cells. LPS-induced proinflammatory cytokine production and p38 MAP kinase activation were made possible by ligation of CD101 with an anti-CD101 antibody F(ab')(2) fragment. These results suggested a modulatory/coregulatory function of CD101 in the human immune system, in contrast to murine models, in which CD101 surface expression discriminates potency among FoxP3+ regulatory T cells. Cytotoxic CD8(high)CD101+ T cells were markedly less cytotoxic than CD8(high) T cells negative for the CD101 antigen and were conspicuously downregulated in patients with RA, suggesting a possible role for CD101 expression and function in the control of certain manifestations of RA pathology.

The association of anti-parvovirus B19-VP1 unique region antibodies with antiphospholipid antibodies in patients with antiphospholipid syndrome

Human parvovirus B19 (B19) infection has been identified as a trigger of antiphospholipid syndrome (APS). However, the precise role of B19-VP1 unique region (VP1u) in patients with antiphospholipid syndrome remains unclear. IgM and IgG against B19-VP, and serum levels of antibodies directed against cardiolipin (CL), beta2-glycoprotein-I (beta2GPI) and phospholipid (PhL) were determined using ELISA in 45 APS patients. Humoral responses of anti-B19-VP1u were assessed by Western blot and B19 DNA was detected by nested PCR. Absorption experiments were performed using B19-VP1u protein to determine the binding specificity of antiphospholipid antibodies (aPL). One and 18 of 45 APS patients had detectable levels of anti-B19-VP IgM and anti-B19-VP IgG, indicating recent and past infection respectively. All serum samples from APS patients with diagnostic pattern DNA(-)/IgM(-)/IgG(+) had anti-B19-VP1u activity. APS patients with anti-B19-VP1u antibody had a 4-fold increased risk for recurrent vascular thrombosis compared with those without anti-B19-VP1u antibody. The binding inhibition of CL, beta2GPI, and PhL by absorption with B19-VP1u ranged from 31.4% to 91.1%, 0.8% to 59.8% and 20.2% to 72.1% respectively. Significantly higher inhibition to beta2GPI by B19-VP1u absorption was observed in APS patients with anti-B19-VP1u antibody than in those without anti-B19-VP1u antibody. We show a close association of B19 infection with aPL production and suggest B19-VP1u may be of pathogenetic importance in some patients with APS.

The Association Between Antiphospholipid Antibodies and Adverse Pregnancy Outcomes: A Metaanalysis.

BACKGROUND: The Sapporo criteria for the diagnosis of the antiphospholipid syndrome (APS) are based on the presence of antiphospholipid antibodies (APLA) and clinical criteria. Although pre-eclampsia, intra-uterine growth restriction (IUGR), late fetal loss and placental abruption, collectively termed “placenta mediated complications”, are recognized as clinical criteria for the APS, their association with APLA remains controversial.OBJECTIVE: This review was conducted to evaluate the association between APLA (anticardiolipin antibodies, lupus anticoagulant, anti B2 glycoprotein 1 antibodies) and placenta mediated complications in untreated women without autoimmune diseases.METHODS: We performed a systematic review of published case-control, cohort and cross sectional studies using MEDLINE (1975 to October week 2 2007), EMBASE 16 (1980 to 2007 week 42) and all EBM Reviews (3rd quarter of 2007). For eligible studies, the rates of adverse pregnancy outcomes were compared between patients with and without specific APLA. Pooled odds ratios with 95% CI were generated using random-effects models.RESULTS: Our search strategy identified 1204 potentially relevant studies. Twenty five were included in the final analysis. Results are outlined in table 1.CONCLUSION: The association between various APLA and pregnancy complications is for the most part weak and inconsistent. There is currently insufficient data to support a significant link between anti-B2 glycoprotein 1 antibodies and pregnancy morbidity. Caution should be used when establishing a diagnosis of APS based on the presence of any APLA, particularly anti-B2 glycoprotein 1 antibodies, in the setting of late pregnancy complications. Table 1 Association Between APLA and Adverse Pregnancy OutcomesPre-eclampsia OR (95%CI) # studies / participantsIUGR OR (95%CI) # studies / participantsPlacental abruption OR (95%CI) # studies / participantsLate fetal loss OR (95%CI) # studies / participantsLA2.88 (1.42, 5.87) 11 / 60853.51 (1.38, 8.93) 4 / 32320.78 (0.13, 4.80) 2 / 2263.56 (0.12, 106.05) 3 / 3870aCL (IgG/IgM)1.71 (1.09, 2.70) 21 / 97222.31 (0.74, 7.17) 6 / 57531.35 (0.45, 4.02) 4 / 12743.86 (1.14, 13.07) 7 / 5963aCL IgG1.65 (0.84, 3.22) 15 / 36276.16 (2.50, 15.18) 2 / 10061.87 (0.21, 16.83) 2 / 50010.06 (0.88, 114.96) 2 / 1006aCL IgM1.36 (0.93, 1.97) 13 / 53970.75 (0.19, 2.93) 2 / 30020.96 (0.24, 3.85) 2 / 5001.37 (0.42, 4.46) 3 / 3212anti- B2GP1 (IgG/IgM)2.97 (0.47, 18.69) 4 / 222520.03 (4.59, 87.43) 1 / 11082.64 (0.14, 50.63) 1 / 5106.74 (0.24, 191.23) 3 / 1828anti- B2GP1 IgG0.87 (0.38, 2.01) 2 / 607N/A 0 / 0N/A 0 / 00.52 (0.02, 11.02) 1 / 212anti- B2GP1 IgM0.37 (0.16, 0.85) 1 / 400N/A 0 / 0N/A 0 / 01.32 (0.24, 7.42) 1 / 210LA: Lupus anticoagulant; aCL: Anticardiolipin antibodies; Anti-B2 GP1 antibodies: Anti-B2 glycoprotein 1 antibodiesitalic characters indicate statistically significant associations

Heterogeneity of binding reactivity to different phospholipids of antibodies from patients with systemic lupus erythematosus (SLE) and with syphilis

The binding specificities were investigated of anti-phospholipid antibodies derived from sera from 55 patients with SLE and related diseases, and from 33 patients with syphilis. Antibodies from both these groups of patients bind strongly to cardiolipin in solid-phase immunoassays, but only antiphospholipid antibodies from patients with autoimmune diseases are associated with thrombotic complications and recurrent spontaneous abortions. IgG anti-phospholipid antibodies from both groups of patients cross-reacted with a range of negatively charged phospholipids, but binding to neutral phospholipids was largely restricted to sera from patients with syphilis. A monoclonal IgM lambda anti-cardiolipin antibody, derived from a patient with autoimmunity, was used to inhibit binding of anti-phospholipid antibodies to cardiolipin and to phosphatidic acid. This antibody inhibited the binding of autoimmune sera to cardiolipin more strongly than sera from syphilis patients, but the converse pattern of inhibition of binding to phosphatidic acid was observed. The VDRL titre correlated with anti-phospholipid antibody activity in sera from syphilis patients, but not from those with autoimmunity. Lupus anti-coagulant activity correlated weakly with IgG antibody levels to each of the negatively charged phospholipids among the patients with autoimmunity. Lupus anticoagulant activity did not correlate uniquely with any anti-phospholipid antibody specificity. These results provide further documentation of the great heterogeneity of anti-phospholipid antibodies associated with autoimmune disease and syphilis.

Distinguished effects of antiphospholipid antibodies and anti-oxidized LDL antibodies on oxidized LDL uptake by macrophages

Several interpretations have been made regarding the specificity of antiphospholipid antibodies and antibodies against oxidized low-density lipoprotein (oxLDL), but these are still controversial. In the present study, we delineated specificity of these two types of antibodies and analyzed their regulatory effect on oxLDL and/or beta( 2)-glycoprotein I (beta(2)GPI) binding to macrophages. Scavenger receptor-mediated binding of oxLDL (or its beta(2)GPI complexes) to macrophages was observed and the binding was partly prevented by beta( 2)GPI. The IgG monoclonal anti-beta(2)GPI antibody (WB-CAL-1), which was derived from NZW x BXSB F1 mouse (a model of antiphospholipid syndrome), significantly increased the oxLDL/beta(2)GPI binding to macrophages. In contrast, IgM anti-oxLDL natural antibody, EO6 (derived from apoe( -/-) mouse), prevented the binding. Different antigenic specificity of these antibodies to oxLDL and its beta(2)GPI complexes was also confirmed in TLC-ligand blot and ELISA. Thus, IgG anti-beta(2) GPI autoantibodies contribute to lipid metabolism (housekeeping of oxLDL by macrophages) whereas IgM natural anti-oxLDL antibodies may protect against atherogenesis. In addition, in vitro data suggest that relatively high dose of intravenous immunoglobulin preparations (mainly contain IgG anti-oxLDL antibodies) might also prevent atherogenesis by inhibiting the oxLDL binding to macrophages.

Fine specificity of antibodies against phospholipids and beta-2-glycoprotein I in monoclonal gammopathy associated neuropathies

Phospholipids are abundantly represented within the nervous system. Aim of our study was to evaluate the presence and fine specificity of anti phospholipid antibodies (aPLAb) among patients with monoclonal gammopathy associated neuropathy. Thirty nine percent of these patients had high titers of aPLAb, mostly associated with low levels of anti beta2 glycoprotein I, which suggests different antibody specificity compared to patients with anti phospholipid syndrome. Further 6/48 patients with dysimmune neuropathy without monoclonal gammopathy had positive aPLAb titers. APLAb strongly cross-reacted with sulfatide. These findings suggest an adjuntive role of aPLAb on nerve damage and may help to better understand the nerve binding properties of anti-sulfatide antibodies.

Antiphospholipid syndrome: genetic review.

The possibility of a genetic predisposition to develop the antiphospholipid syndrome (APS) and to produce anticardiolipin antibodies and lupus anticoagulant has been addressed by family studies and by population studies. Various studies suggest a familial occurrence of anticardiolipin antibodies and lupus anticoagulant, with or without clinical evidence of APS. This familial tendency could be genetically determined. Multiple human leukocyte antigen-DR or -DQ associations with antiphospholipid antibodies have been described. Genetic studies of beta(2)-glycoprotein-1(GP1) polymorphisms have been determined and valine/leucine polymorphism could be a genetic risk for having anti-beta(2)-GP1 antibodies and APS. Compared with polymorphism of beta(2)-GP1 as a genetic risk factor for APS, beta(2)-GP1 deficiency is not associated with thrombosis and patients with APS usually have normal or somewhat elevated levels of beta(2)-GP1. The antigen specificity of antiphospholipid antibodies and the pathophysiology of thrombosis in APS are highly heterogeneous and multifactorial.

Specificity of anti-phospholipid antibodies in infectious mononucleosis: a role for anti-cofactor protein antibodies.

The antigen specificity of anti-phospholipid antibodies in infectious mononucleosis (IM) was studied using ELISA for the detection of anti-beta2-glycoprotein I (beta2-GPI), anti-annexin V, anti-protein S and anti-prothrombin antibodies and TLC immunostaining for the detection of anti-phospholipid antibodies. This technique enabled us to look at antibodies reacting to 'pure' phospholipid antigens in the absence of protein contamination. Sera from 46 patients with IM, 18 with systemic lupus erythematosus (SLE), 21 with primary anti-phospholipid antibody syndrome (PAPS), 50 with Helicobacter pylori infection and 30 healthy blood donors were tested. This study highlights anti-phospholipid antibodies in patients with IM as specific 'pure' anti-cardiolipin antibodies, while in PAPS and SLE patients anti-phosphatidylserine and anti-phosphatidylethanolamine antibodies were also found. This investigation also shows that the anti-cardiolipin antibodies found in IM can be present with anti-cofactor protein antibodies. The higher prevalence of anti-cofactor antibodies found in IM sera than in Helicobacter pylori sera may be due to the immunostimulatory effect and/or the polyclonal activation often observed in course of Epstein-Barr virus infection. However, anti-beta2-GPI and, to a lesser extent, anti-prothrombin antibodies occur with a significantly lower prevalence in IM than in PAPS patients. This finding suggests that these antibodies should be regarded as the expression of the broad autoimmune syndrome involving the phospholipid-binding plasma proteins.

Antiphospholipid antibodies and retinal thrombosis in patients without risk factors: a prospective case-control study

PURPOSE: To determine the prevalence of antiphospholipid antibodies and other immunologic abnormalities in patients with occlusive retinal vascular events, exempt from conventional risk factors of retinal thrombosis. METHODS: Forty patients with retinal vascular occlusion (26 with retinal vein occlusions, eight with arterial occlusions, two with combined venous and arterial occlusions, and four with venous occlusions plus vasculitis), free of main accepted risk factors for retinal thrombosis, were prospectively screened for antiphospholipid antibodies (anticardiolipin-antibodies and lupus anticoagulant) and other immunologic abnormalities. Fourteen patients were younger than 50 years. Prevalence and mean values of antiphospholipid antibodies (aPL) were compared with those in a homogeneous control group of 40 patients. RESULTS: The prevalence of antiphospholipid antibodies in the study group was 22.5% (nine of 40). Comparison with control group prevalence (5% [two of 40]) showed a statistically significant difference (P = .04). Six patients in the study group disclosed positivity for IgG-anticardiolipin antibodies, one patient for IgM anticardiolipin antibodies, and two patients for both isotypes IgG and IgM anticardiolipin antibodies. The antibody assay for lupus anticoagulant was negative for all patients. Three patients were diagnosed as having primary antiphospholipid antibody syndrome and are undergoing systemic anticoagulant therapy. Relevant immunologic abnormalities were also found (27.5% with antinuclear antibodies, 35% with elevation of circulating immune complexes, 35% with complement deficiency, 30% with positive rheumatoid factor, and 17.5% with positive C-reactive protein). Thirteen patients (32.5%) had more than four parameters altered. No significant association was found between prevalence or mean values of anticardiolipin antibody and patients younger than 50 years. CONCLUSIONS: The high prevalence of anticardiolipin antibodies in patients with vaso-occlusive retinopathy exempt from conventional risk factors, and the relevant diagnostic and therapeutic implications, lead us to recommend a systematic search for specific antiphospholipid antibodies in such patients.

Isolation and Characterization of Two Human Monoclonal Anti-Phospholipid IgG from Patients with Autoimmune Disease

The antigenic specificity of anti-phospholipid antibodies (APA) is a matter of intensive investigation. To further characterize these antibodies, we attempted to isolate human monoclonal APA. B-cells of patients with at least one positive test for antibodies against cardiolipin, phosphatidylserine, β2-glycoprotein I (β2-GPI) or the lupus anti-coagulant were immortalized by transformation with Epstein-Barr virus and screened for production of specific IgG. Positive pools were fused with a heteromyeloma cell line and APA-secreting clones were isolated by standard procedures. Two monoclonal APA, HL-5B from a 51-year-old man with primary anti-phospholipid syndrome and recurrent cerebral microinfarctions, and RR-7F from a 48-year-old women with systemic lupus erythematosus but no evidence for thrombotic events were obtained. HL-5B is of the IgG2 subtype with λ light chains, while RR-7F is IgG2 with κ light chains. Both monoclonals show reactivity against cardiolipin and phosphatidylserine but lack reactivity against β2-GPI or lupus anti-coagulant activity. To yield the same OD in the cardiolipin and phosphatidylserine ELISAs RR-7F must be used in an approximately 10-fold higher concentration than HL-5B, indicating a lower affinity towards these antigens. Interestingly, both mAPA can bind to cardiolipin in the absence of β2-GPI. They do not cross-react with dsDNA but show reactivity against oxidized low-density lipoproteins. Analysis of the heavy chain mRNA of HL-5B and RR-7F showed that both are members of the VH3 family. While HL-5B shows extensive somatic mutations in the CDR1 and 2 regions, indicating that it was derived by a T cell-dependent antigen driven process, RR-7F is apparently germline encoded. The two monoclonal APA can be used as tools in further structural and functional analyses.

Antiphospholipid syndrome--specificity of antiphospholipid antibodies and thrombosis

Antiphospholipid syndrome--specificity of antiphospholipid antibodies and thrombosis

Antiphospholipid antibodies and cerebral lupus.

Antiphospholipid antibodies probably play a minor role in cerebral lupus. They are associated primarily with stroke and transient ischemic attacks, which occur only in a minority of patients with central nervous system complications of SLE. However, ready demonstration of functional effects of antiphospholipid antibodies in the coagulation system as well as persuasive evidence that they can induce thrombosis and pregnancy loss in experimental mice lend credence to the belief that many autoantibodies play a direct role in disease pathogenesis. Hence the role of the many autoantibodies associated with CNS lupus is a legitimate field of inquiry. This review outlines the history of antiphospholipid antibodies, discusses the controversy concerning antiphospholipid antibody specificity, summarizes recent experimental data on their functional effects in the coagulation system, and describes animal models of the antiphospholipid syndrome in which antibodies with cardiolipin-binding activity have been shown to play a direct role in thrombosis and pregnancy loss.