SLE患者抗载脂蛋白A-I抗体的检测及其对细胞内胆固醇外流的影响

研究系统性红斑狼疮(SLE)患者血中抗载脂蛋白A-I(Apo A-I)抗体的阳性率及其可能的致动脉粥样硬化的机制。采用酶联免疫吸附法(ELISA)检测175例SLE患者抗Apo A-I抗体,以64例正常人为对照;用抑制试验研究Apo A-I aa74- 105肽段能否抑制抗ApoA-I多抗和单抗IS4与Apo A-I的结合;并观察抗Apo A-I多抗和单抗对细胞内胆固醇流出的影响。结果显示,在SLE患者中存在抗Apo A-I抗体,阳性率为16.6%;肽段aa74-105能够抑制抗Apo A-I抗体与Apo A-I的结合;抗Apo A-I抗体在体外能抑制细胞内胆固醇的流出。实验表明,SLE患者的抗Apo A-I抗体可能通过和Apo A-I功能区中的部分氨基酸结合,影响Apo A-I的功能而抑制细胞胆固醇流出,促进SLE患者动脉粥样硬化的发生。     

Anti-phospholipid antibodies in HIV infection and SLE with or without anti-phospholipid syndrome: comparisons of phospholipid specificity, avidity and reactivity with beta2-GPI.

Increased prevalence of anti-phospholipid antibodies (aPL) and increased levels of lipid peroxidation have been described in patients with HIV infection. To assess the binding specificity and avidity of aPL antibodies in HIV infection, sera from 44 HIV-1 infected patients were evaluated for antibodies to cardiolipin (aCL), phosphatidyl serine (aPS), phosphatidyl inositol (aPI) and phosphatidyl choline (aPC) using enzyme linked immunosorbent assay (ELISA) methods. Sera from 30 patients with systemic lupus erythematosus (SLE), but without features of anti-phospholipid syndrome (APS) (SLE/non APS), six with SLE and secondary APS, (SLE/APS) and 11 with primary APS (PAPS) were also evaluated as controls. The resistance of the aPL antibody binding to dissociating agents was evaluated by treating the ELISA wells, after serum incubation with 2 M urea or 0.6 M NaCl for 10 min. An anti-beta2-glycoprotein-I (beta2-GPI) ELISA was used to assess serum reactivity against beta2-GPI, a plasma protein considered as the true antigen of aCL antibodies occurring in APS and SLE patients. The prevalence of aCL, aPS, aPI and aPC antibodies in HIV-1 infection was 36%, 56%, 34% and 43% respectively, which was comparable to that found in SLE/APS and PAPS patients and significantly higher than that observed in SLE/non-APS patients. Anti-beta2-GPI antibodies occurred in 5% of HIV-1 infected vs. 17% in SLE/non-APS (P=0.11), 50% in SLE/APS (P=0.009) and 70% in PAPS patients (P=0.0014). A significant decrease of aPL binding after urea and NaCl treatment was observed in the sera of HIV-1-infected, compared to that of APS patients, indicating that aPL antibodies from HIV-1 infected individuals have low resistance to dissociating agents. In conclusion, aPL antibodies (1) occur in HIV-1 infection; (2) tend to recognize various phospholipids but not beta2-GPI; and (3) are of low resistance to dissociating agents-a finding probably reflecting low antibody avidity. Finally, these, like the autoimmune-type aCL antibodies, tend to recognize the oxidized CL-a finding probably indicating autoantibody generation as a result of neoepitope formation by oxidized PLs.     

IgG autoantibodies against beta2-glycoprotein I complexed with a lipid ligand derived from oxidized low-density lipoprotein are associated with arterial thrombosis in antiphospholipid syndrome

We recently reported [J. Lipid Res. 42 (2001), 697; 43 (2002), 1486; 44 (2003), 716] that [beta2-glycoprotein I (beta2GPI) forms complexes with oxidized LDL (oxLDL) and autoantibodies against these complexes are present in patients with SLE and antiphospholipid syndrome (APS). The relationship of beta2GPI/oxLDL complexes and IgG autoantibodies against beta2GPI complexed with oxLig-1 (an oxLDL-derived ligand) with clinical manifestations of APS was studied in 150 APS and SLE patients. The beta2GPI/oxLDL levels of APS patients were similar to those of SLE patients without APS, but they were significantly higher than healthy individuals. There was no difference in the complex levels among the patients with arterial, venous thrombosis, or pregnancy morbidity. IgG anti-beta2GPI/oxLig-1 levels of APS were significantly higher than those of SLE without APS and healthy individuals. Further, antibody levels of APS patients with arterial thrombosis were significantly higher than those patients with venous thrombosis and pregnancy morbidity. Thus, oxidation of LDL leads the complex formation with beta2GPI in SLE and APS patients. In contrast, anti-beta2GPI/oxLig-1 autoantibodies were generated only in APS and were strongly associated with arterial thrombosis. These results suggest that autoantibodies against beta2GPI/oxLDL complexes are etiologically important in the development of atherosclerosis in APS.     

Validation of Autoantibody Assays in Type 1 Diabetes: Workshop Programme

Antiphospholipid syndrome (APS) was firstly described in systemic lupus erythematosus (SLE), but it was recognized also as a primary APS (PAPS) form. These forms are not always distinguishable, since they show some common clinical/serological manifestations. We actually may deal with: (1) patients initially classified as PAPS gradually developing SLE; (2) patients with SLE and associated APS, whose complications generally affect morbidity and mortality; (3) patients with SLE and positive antiphospholipid antibodies without APS manifestations; the relevant issue in such patients is to provide effective prophylaxis. The close relationship between PAPS and SLE is also supported by: (i) nuclear autoimmunity and (ii) complement activation at least in animal models of APS. Future studies on the genetic background and/or on regulatory suppressive mechanisms may clarify how and why PAPS can evolve into SLE.     

Incidental discovery of high systemic lupus erythematosus disease activity associated with cytomegalovirus viral activity

We try to find the association of cytomegalovirus (CMV) infection and anti-β2 glycoprotein 1 autoantibodies (anti-β2 GP1), a key antibody in antiphospholipid syndrome (APS), among systemic lupus erythematosus (SLE) and cerebral vascular accident (CVA) patients. This retrospective study enrolled serum samples obtained from 87 SLE and 97 CVA patients who have been checked for the existence of anti-β2 GP1. First, the prevalence rate of anti-CMV IgG and IgM in patients with and without anti-β2 GP1 were compared. Second, the prevalence of anti-CMV IgG and IgM were compared between SLE and CVA patients. Last, this study analyzed the clinical characteristics and disease activity in SLE patients with positive anti-CMV IgM and IgG. No difference existed in the prevalence rate of anti-CMV IgG and IgM between positive or negative anti-β2 GP1 serum samples in both SLE and CVA patients. However, the prevalence of anti-CMV IgM was significantly higher in the SLE group than in the CVA group. Severity of clinical features and SLEDAI scores were considerably higher in patients with positive anti-CMV IgM than in SLE patients with negative anti-CMV IgM. Very impressively, all IgM-positive SLE samples (9/9) carrying highest levels of anti-CMV IgG, indicated reactivation of the latent CMV infection. Hence, it suggests that CMV reactivation might contribute toward the disease flare in some SLE patients. In future, a prospective and longitudinal study is stongly indicated.     

Autoantibodies against monomeric C-reactive protein in sera from patients with lupus nephritis are associated with disease activity and renal tubulointerstitial lesions

Serum levels of C-reactive protein (CRP) often remain low despite high disease activity in systemic lupus erythematosus (SLE). Sera from 96 patients with renal biopsy-proven active lupus nephritis, 24 of 96 patients in remission, and 49 patients with SLE with negative urinalysis (nonrenal SLE) was collected. Immunoglobulin G autoantibodies against monomeric CRP (mCRP) were screened by enzyme-linked immunosorbent assay with purified human CRP. Associations with clinical features, pathological data, and laboratory findings were investigated. The prevalence of mCRP autoantibodies in active lupus nephritis (57/96, 59.4%) was significantly higher than that in patients with SLE without clinical evidence of kidney involvement (20/49, 40.8%, p = 0.034). For the 13 patients with positive mCRP autoantibodies and sequential sera, their positive mCRP autoantibodies in active phase turned negative in remission (13/13, 100%). Patients with mCRP autoantibodies had significantly higher SLEDAI scores than patients without mCRP autoantibodies (18.3 +/- 5.2 vs 15.8 +/- 4.0, p = 0.013), who were more likely to experience acute renal failure (14/55 vs 2/33, p = 0.022), oral ulcer (15/57 vs 3/39, p = 0.022), and delayed activated partial thromboplastin time (18/52 vs 2/38, p = 0.001). Positive correlations between levels of mCRP autoantibodies and semiquantitative scores of renal histologic features were first observed in lupus nephritis as follows: interstitial inflammation (r = 0.328), tubular atrophy(r = 0.276), interstitial fibrosis (r = 0.211), and chronicity index score (r = 0.243). Autoantibodies against mCRP are prevalent in patients with lupus nephritis and are associated with disease activity and renal tubulointerstitial lesions.     

血浆前蛋白转化酶枯草溶菌素9 与钙化性主动脉瓣疾病的关联机制

目的:探讨血浆前蛋白转化酶枯草溶菌素9(PCSK9)与钙化性主动脉瓣疾病(CAVD)的相关性。方法:经心脏彩超筛选CAVD 患者120 例及阴性对照组患者40 例,通过CT 定量评分系统分4 组:AVC 1、2、3 和4 级,并通过软件计算主动脉瓣钙化积分。检测血浆总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、三酰甘油(TG)、载脂蛋白A1(Apo A1)及载脂蛋白B(Apo B)、脂蛋白(a){LP(a)}和高敏C 反应蛋白(hsCRP)水平以及PCSK9 水平。结果:4组患者LDL-C、Apo B 和Lp(a) 水平差异有显著性(P<0.05),AVC2-4 级患者明显高于AVC1 级,而TG、HDL-C、apo A1 和hsCRP 组间差异无统计学意义。AVC3 级和AVC 4 级的TC 水平高于AVC1 组(P<0.05)。同时,AVC2-4 组血浆PCSK9 水平高于AVC1 组(P<0.05)。将所有人群的主动脉瓣钙化积分与TC(r =0.248,P =0.026),LDL-C (r =0.222,P =0.048),Lp(a)(r =0.276,P =0.013),Apo A1(r =0.245,P =0.012),Apo B(r =0.212,P =0.019)和PCSK9(r =0.309,P =0.005)均存在明显相关性,ApoA1,Apo B 呈正相关。结论:CAVD 患者PCSK9 水平明显高于对照组,PCSK9 与CAVD 的发生存在相关性。     

Levels of antibodies against C1q and 60 kDa family of heat shock proteins in the sera of patients with various autoimmune diseases

Previously a strong positive correlation was found between antibodies to C1q (C1qAb) and antibodies against human heat shock protein (hsp60) and mycobacterial hsp65 in HIV infected patients. Here the levels of these antibodies were measured in the sera of patients with different autoimmune diseases (122 systemic lupus erythematosus (SLE), 55 systemic sclerosis, 33 undifferentiated connective tissue disease (UCTD), 27 primary Raynaud syndrome, 21 rheumatoid arthritis (RA), 14 polymyositis/dermatomyositis (PM/DM), and 192 healthy blood donors. The prevalence of IgG C1qAb was found to be high (P<0.0001 as compared to the healthy controls) only in the SLE group. The levels of the anti-hsp60 (P=0.0094) and anti-hsp65 (P=0.0108) antibodies were high only in the UCTD patients. No correlation was found between the C1qAb and anti-hsp antibodies in any group except a significant (P=0.011) positive correlation between C1qAb and hsp65 antibodies in the patients with UCTD. These findings indicate that the autoantibodies against C1q are heterogeneous: in different diseases different types of C1qAb may dominate.     

Oxidized low-density lipoprotein/beta2-glycoprotein I complexes and autoantibodies to oxLig-1/beta2-glycoprotein I in patients with systemic lupus erythematosus and antiphospholipid syndrome

Oxidized low-density lipoprotein (oxLDL) interacts with beta2-glycoprotein I (beta2-GPI) via oxLDL-derived specific ligands (oxLig-1) forming complexes. The prevalence and significance of oxLDL/alpha2-GPI complexes and antibodies to oxLig-1/alpha2-GPI were evaluated in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). The oxLDL/beta2-GPI complex was 69% positive (above mean + 3 SD of control subjects) in 97 consecutive patients with SLE, 62% in 40 patients with SLE with secondary APS, and 60% in 50 control patients with SLE without APS. IgG anti-oxLig-1/beta2-GPI antibody was positive in 31 (32%) of 97 consecutive patients with SLE, in 26 (65%) of 40 patients with SLE with secondary APS, and in 6 (19%) of 32 control patients with SLE. Anti-oxLig-1/beta2-GPI antibodies were 93.7% specific with a positive predictive value of 90.0% for APS, better than anticardiolipin antibodies (80.0% specific, 71.4% predictive value). These results confirm that oxLDL/beta2-GPI complexes are common in SLE and suggest a possible immunogenic role in APS. In contrast, IgG anti-oxLig-1/beta2-GPI antibodies not only are associated with but also are clinically useful risk factors for APS.     

Pregnancy outcomes in patients with systemic autoimmunity

The impact of maternal systemic autoimmune diseases on pregnancy outcome is not unequivocally defined. We analysed the pregnancy outcome of 221 pregnancies from 181 autoimmune patients, consecutively followed in a single Italian reference centre from 2001 to 2009. All patients were prospectively followed with monthly visits. Pregnancy outcome was compared with the previous obstetrical history. The patient population comprised five groups: primary antiphospholipid syndrome (PAPS, 39 pregnancies), antiphospholipid syndrome associated with a rheumatic disease (APS/RD, 17 pregnancies), other RD (92 pregnancies), isolated autoantibodies (autoAbs) in the absence of a definite autoimmune disease (aAbs, 38 pregnancies) and reactive arthritis or spondyloarthropathies (35 pregnancies). Of these patients, 50.6% had previous pregnancy complications with an anamnestic live-birth rate of 43.4%. In these patients, complications dropped to 28.2% (44/156). This percentage was very similar to that observed in the 221 pregnancies (29.9%, 66/221) with a live-birth rate of 87.3%. Mean neonatal weight was 3018 ± 611 g; mean gestational age at delivery was 38.17 ± 2.79 weeks. Thus, 10.4% of pregnancies resulted in preterm delivery and 10.9% newborns had low weight at delivery. APS/RD patients had the worse outcome: 17.6% resulted in miscarriage, 14.3% resulted in growth restriction and 50% resulted in preterm delivery. This result was mainly due to patients with APS/systemic lupus erythematosus (SLE) that had the lowest gestational age at delivery (30.8 ± 3.56 weeks) and the lowest newborn weight (1499 ± 931 g). Results confirm that a strict follow-up and targeted treatments significantly improve pregnancy outcomes in autoimmune patients with PAPS, SLE and isolated autoAbs. The pregnancy outcome in patients with APS/SLE remains unsatisfactory.     

Pregnancy outcomes in patients with systemic autoimmunity

The impact of maternal systemic autoimmune diseases on pregnancy outcome is not unequivocally defined. We analysed the pregnancy outcome of 221 pregnancies from 181 autoimmune patients, consecutively followed in a single Italian reference centre from 2001 to 2009. All patients were prospectively followed with monthly visits. Pregnancy outcome was compared with the previous obstetrical history. The patient population comprised five groups: primary antiphospholipid syndrome (PAPS, 39 pregnancies), antiphospholipid syndrome associated with a rheumatic disease (APS/RD, 17 pregnancies), other RD (92 pregnancies), isolated autoantibodies (autoAbs) in the absence of a definite autoimmune disease (aAbs, 38 pregnancies) and reactive arthritis or spondyloarthropathies (35 pregnancies). Of these patients, 50.6% had previous pregnancy complications with an anamnestic live-birth rate of 43.4%. In these patients, complications dropped to 28.2% (44/156). This percentage was very similar to that observed in the 221 pregnancies (29.9%, 66/221) with a live-birth rate of 87.3%. Mean neonatal weight was 3018 ± 611 g; mean gestational age at delivery was 38.17 ± 2.79 weeks. Thus, 10.4% of pregnancies resulted in preterm delivery and 10.9% newborns had low weight at delivery. APS/RD patients had the worse outcome: 17.6% resulted in miscarriage, 14.3% resulted in growth restriction and 50% resulted in preterm delivery. This result was mainly due to patients with APS/systemic lupus erythematosus (SLE) that had the lowest gestational age at delivery (30.8 ± 3.56 weeks) and the lowest newborn weight (1499 ± 931 g). Results confirm that a strict follow-up and targeted treatments significantly improve pregnancy outcomes in autoimmune patients with PAPS, SLE and isolated autoAbs. The pregnancy outcome in patients with APS/SLE remains unsatisfactory.     

TSGA10 - A target for autoantibodies in autoimmune polyendocrine syndrome type 1 and systemic lupus erythematosus

Autoimmune polyendocrine syndrome type 1 (APS1) is a rare monogenic autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene. High-titre autoantibodies are a characteristic feature of APS1 and are often associated with particular disease manifestations. Pituitary deficits are reported in approximately 7% of APS1 patients, with immunoreactivity to pituitary tissue frequently described. Using APS1 patient serum to immunoscreen a pituitary cDNA expression library, testis specific, 10 (TSGA10) was isolated. Immunoreactivity against TSGA10 was detected in 5/99 (5.05%) patients with APS1, but also in 5/135 (3.70%) systemic lupus erythematosus (SLE) patients and 1/188 (0.53%) healthy controls. TSGA10 autoantibodies were not detected in the serum from patients with any other autoimmune disease. Autoantibodies against TSGA10 were detectable from a young age in 4/5 positive APS1 patients with autoantibody titres remaining relatively constant over time. Furthermore, real-time PCR confirmed TSGA10 mRNA to be most abundantly expressed in the testis and also showed moderate and low expression levels throughout the entire body. TSGA10 should be considered as an autoantigen in a subset of APS1 patients and also in a minority of SLE patients. No recognizable clinical phenotype could be found to correlate with positive autoantibody reactivity.     

Protective Molecules–C-Reactive Protein (CRP), Serum Amyloid P (SAP), Pentraxin3 (PTX3), Mannose-Binding Lectin (MBL), and Apolipoprotein A1 (Apo A1), and Their Autoantibodies: Prevalence and Clinical Significance in Autoimmunity

Apoptotic defects and impaired clearance of cellular debris are considered key events in the development of autoimmunity, as they can contribute to autoantigen overload, and may initiate an autoimmune response. The pentraxins are a group of highly conserved proteins including the short pentraxins, C-reactive protein (CRP) and serum amyloid-P (SAP), and the long pentraxin-3 (PTX3), which are all involved in innate immunity and in acute-phase responses. Mannan-binding lectin (MBL) is an activator of the complement system, and Apolipoprotein A-1 (Apo A-1) is pivotal in the cholesterol homeostasis and has anti-inflammatory properties. In addition to their role in innate immunity and inflammation, each of these five proteins participates in the removal of damaged and apoptotic cells. In this review, we discuss the clinical significance of different levels of these proteins, their role in the induction or protection from autoimmunity, and the presence of specific autoantibodies against them in the different autoimmune diseases.     

Isotype distribution and clinical relevance of anti-beta2-glycoprotein I (beta2-GPI) antibodies: importance of IgA isotype.

The aim of this study was to evaluate the prevalence of IgG, IgA and IgM anti-beta2-GPI antibodies in anti-phospholipid syndrome (APS), and to establish the clinical significance of IgA type antibodies compared with the other isotypes. Anti-beta2-GPI antibodies were measured in the sera of 70 patients by solid-phase enzyme immunoassay in gamma-irradiated polystyrene plates coated with human purified beta2-GPI. Thirty-three out of the 70 patients were classified as having APS: three of them had primary, and 30 had secondary APS related to systemic lupus erythematosus (SLE). The remaining 37 patients had SLE without APS. Anti-beta2-GPI antibodies of IgG, IgA and IgM isotypes were present in 84.8%, 59.3% and 51.5% of patients with APS. Both the frequency and the level of each isotype were significantly higher in patients with APS. This association was very strong for IgA (P = 0.0004 for the antibody frequency and P < 0.0001 for the antibody level), as well as for IgG type antibodies (P < 0.0001 and P < 0.0001), whereas it was weaker for IgM (P = 0.01 and P = 0.04). A strong relationship was demonstrated between increased IgA anti-beta2-GPI antibody levels and a history of venous thrombosis, thrombocytopenia, heart valve disease, livedo reticularis and epilepsy. IgG anti-beta2-GPI antibodies were associated with the presence of lupus anticoagulant (LA) in addition to the main features of APS. However, antibodies of IgM isotype were related only to thrombocytopenia and heart valve disease. We recommend the evaluation of anti-beta2-GPI antibodies of IgA isotype in addition to IgG in patients with clinical suspicion of APS.     

Anti-beta 2-glycoprotein I and antiphosphatidylserine antibodies are predictors of arterial thrombosis in patients with antiphospholipid syndrome

The predictive value (PV) and association of 4 antiphospholipid antibodies with clinical manifestations of the antiphospholipid syndrome (APS) were evaluated in 90 patients with systemic lupus erythematosus (SLE) and 100 with APS. Patients with APS were classified into arterial thrombosis, venous thrombosis, and pregnancy morbidity subgroups. IgG, IgM, and IgA anticardiolipin (aCL), antiphosphatidylserine (aPS), anti-beta 2-glycoprotein I (anti-B2GPI), and antiprothrombin (aPT) antibodies were determined by enzyme-linked immunosorbent assay. Individually, anti-B2GPI and aPS antibodies had the strongest PV for APS (86.4%-94.1%; P < .001) in patients with SLE. The PV for APS reached 100% when 2 or more antibodies were present. Similarly, anti-B2GPI and aPS antibodies had a stronger PV and association for arterial thrombosis (87%-95%; P < .001) compared with venous thrombosis (80%-92%; P = .01). Weak PV and association with pregnancy morbidity were seen with all antibodies. These results suggest an important pathogenic role of anti-B2GPI antibodies in arterial thrombosis. In addition, anti-B2GPI and aPS antibodies seem to provide the best diagnostic value for the laboratory assessment of APS.     

Antiphospholipid antibodies and atherosclerosis

Antiphospholipid antibodies (APA) are present in a variety of autoimmune disorders, including systemic lupus erythematosus (SLE) and the antiphospholipid syndrome (APS). Increasing evidence suggests that a subset of APA can also be detected in patients with atherosclerosis. In this review, we discuss the specificities of the autoantibodies that are present during both APS and atherosclerosis. A critical and unresolved question is whether these APA are specific for epitopes that result from lipid oxidation. Despite the fact that APA are present in patients with systemic autoimmunity and that they may participate in the pathogenesis of APS, recent studies have paradoxically proposed a beneficial role for some APA in atherosclerosis. We review the evidence that some APA specificities may be protective against plaque formation, and we discuss the putative mechanisms by which some APA could be useful in the prevention of atherosclerosis.     

Epstein Barr Virus Transformation of Peripheral Blood B Cells Secreting Antibodies Reactive with Cell Surface Antigens

The natural structuring of the immune system is responsible for the functional physiological state of the body. The development of natural autoantibodies involved in homeostasis relies on the ability to distinguish between exposed/masked and altered/non-altered self antigens. The objectives of this article were to address the relationships between antigen and autoantibodies against serum amyloid A (SAA), define SAA protein concentrations in 219 blood donor (BD) sera and determine their autoantibody levels and search for possible clinical associations with autoimmune and thrombotic diseases. Just recently, an increasing number of reports have indicated significantly decreased levels of autoantibodies against pro-inflammatory molecules, such as anti-TNF-alpha, anti-IL-6, or anti-CRP found in diseased conditions, as compared to healthy donors, or even to less severe disease conditions. In accord with this line of thought, our data indicate a predominant presence of anti-SAA autoantibodies in healthy BDs (above 95% as tested by the immunoblot analysis, n = 41). Using ELISA, high levels of anti-SAA antibodies were confirmed with a median OD = 0.996 for the BD group (n = 219). This suggests that anti-SAA antibodies might have a physiological role in homeostasis and/or the innate immune system and could actually be a part of the natural antibody repertoire. Significantly, lower median levels were found in patients with arterial thrombosis. Based on 219 BD sera, we could establish a new median value of 20 μg/ml for SAA antigen and a cut-off value of 114.7 μg/ml (97.5th percentile). Significantly, higher concentrations of SAA were observed for antiphospholipid syndrome, rheumatoid arthritic, and SLE patients.     

Thrombotic microangiopathic hemolytic anemia with reduction of ADAMTS13 activity: initial manifestation of childhood-onset systemic lupus erythematosus

Severe manifestations of systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and thrombotic thrombocytopenic purpura (TTP) are characterized by multiorgan thrombotic microangiopathy. We describe reduction of ADAMTS13 activity and the development of systemic autoimmunity in all 8 children initially diagnosed with acquired noncongenital TTP during an 8.5-year period. Median age at diagnosis was 12.0 years (range, 2.6-17.3 years). ADAMTS13 activity was absent (<5%) in 6 patients; 3 patients had a detected inhibitor. SLE was diagnosed concurrently in 3 patients, and 4 patients were diagnosed within 5 years. Six of the children diagnosed with SLE had absent ADAMTS13 activity at diagnosis. In 6 patients with SLE, immune-mediated nephritis developed by 46 months. All surviving patients with SLE developed antiphospholipid antibodies, including some with a lupus anticoagulant. Patients with SLE did not have TTP recurrences once daily immunosuppressive regimens were started. An evaluation for SLE/APS is warranted in children and adolescents with reduced ADAMTS13 activity and thrombotic microangiopathy.     

Anti-thyroid antibodies and antiphospholipid syndrome: evidence of reduced fecundity and of poor pregnancy outcome in recurrent spontaneous aborters

PROBLEM: To determine the presence of anti-thyroid antibodies in patients with primary antiphospholipid syndrome (APS) [antiphospholipid antibodies (aPL) + recurrent spontaneous abortion (RSA)], compare APS alone with APS and thyroid autoimmunity for fecundity and for pregnancy outcome. METHOD OF STUDY: A total of 203 non-pregnant women affected with primary APS were evaluated for anti-thyroid antibodies; 162 non-pregnant women affected with RSA and thyroid autoimmunity alone served as controls. RESULTS: Anti-thyroid antibodies were found in 27% of APS patients studied. Patients with aPL alone had higher percentages of spontaneous pregnancies (P < 0.0001) and live births (P = 0.0003), when compared with patients positive for anti-thyroid antibodies alone or with aPL. CONCLUSIONS: Thyroid autoimmunity is frequently present in APS recurrent aborters and is often associated with either reduced fecundity or with poor pregnancy outcome. Thyroid antibodies should always be evaluated in women with RSA including those with aPL.     

Detection of 'antiphospholipid' antibodies: a single chromogenic assay of thrombin generation sensitively detects lupus anticoagulants, anticardiolipin antibodies, plus antibodies binding beta(2)-glycoprotein I and prothrombin

The diagnosis of the antiphospholipid syndrome (APS) requires both a typical clinical event plus a persistently positive test in an assay for either anticardiolipin (aCL) antibodies or a lupus anticoagulant (LA). Enzyme linked immunosorbent assays (ELISA) specific for autoantibodies against beta(2)-glycoprotein I (beta(2)GPI) or prothrombin are also used, but none of the tests are adequately sensitive or specific. A chromogenic assay was developed that measures the effect of test antibody or plasma samples on in vitro thrombin formation. It is able to detect both LA and beta(2)GPI-dependent aCL antibodies and may have greater specificity for APS than currently available tests. Using this method various monoclonal antibodies (MoAbs) were examined, from mice immunized with beta(2)GPI, mice with a spontaneous animal model of APS, and from three humans with APS. Plasma and affinity purified antibodies from patients with APS and control groups were also examined. Thrombin inhibition was more sensitive to perturbation by MoAbs than a combination of tests for LA (P < 0.05) and at lower antibody concentrations (12.5 microg/ml versus 100 microg/ml). There was a significant correlation between inhibition of thrombin generation and the level of MoAb reactivity to beta(2)GPI (r = 0.90; P < 0.001) but not to CL (r = 0.06; P = 0.76). Plasma and affinity purified antibodies from patients with APS also inhibited thrombin generation, and significantly more so than patients with aPL from causes other than APS. APS patient samples showed thrombin inhibition in the presence of anti-beta(2)GPI or antiprothrombin antibodies. All MoAbs binding beta(2)GPI showed inhibition of thrombin generation, while MoAbs binding domain I of beta(2)GPI had more LA effect.