IgG anti-laminin-1 autoantibody and recurrent miscarriages

PROBLEM: The present study assesses the clinical significance of anti-laminin-1 auto-antibodies (auto-Abs) in recurrent miscarriages. METHOD OF STUDY: A total of 207 recurrent aborters with a history of two or more consecutive first-trimester miscarriages were tested for the presence of anti-laminin-1 Abs, beta2-glycoprotein I-dependent anticardiolipin Abs, lupus anticoagulants, anti-DNA Abs, and anti-nuclear Abs, before they had conceived again. Recurrent aborters then were followed up during subsequent pregnancies and their outcomes were evaluated relative to their blood test results prior to pregnancy. RESULTS: Fifty-five (31.1%) women out of 177 recurrent aborters were positive for IgG anti-laminin-1 auto-Abs. The levels of IgG anti-laminin-1 auto-Abs in recurrent aborters were significantly higher than those in healthy pregnant women and in healthy non-pregnant women (P = 0.0043 and 0.0073, respectively). The live birth rate of subsequent pregnancies in IgG anti-laminin-1 auto-Abs-positive recurrent aborters was significantly lower than the IgG anti-laminin-1 auto-Abs-negative recurrent aborters (P = 0.0320). There were no specifically significant relationships observed between IgG anti-laminin-1 auto-Abs and other tested auto-Abs. CONCLUSION: IgG anti-laminin-1 auto-Abs are associated with recurrent miscarriages and the subsequent pregnancy outcome of recurrent aborters.     

Antiphospholipid antibody syndrome in adverse pregnancy

As a single test beta 2-glycoprotein I-dependent anticardiolipin antibody(beta 2GPI-dependent aCL) appears to be superior to cofactor-independent anticardiolipin antibody or any other single conventional antiphospholipid antibody for the detection of autoantibody-associated conditions of reproductive failure. beta 2GPI-dependent aCL are significantly highly associated with adverse pregnancy outcomes in healthy pregnant women and can be used for prediction, whereas beta 2GPI-independent aCL can not. Anticardiolipin antibodies and Lupus anticoagulant(LAC) define two distinct but partly related populations. LAC and anti beta 2GPI antibodies appear to be associated with pregnancy loss, with LAC being linked not only to spontaneous abortions in the first trimester but also to miscarriages in the second trimester. The live birth rate in patients strongly positive for antiphospholipid antibody(aPL) is lower than that in patients with moderate aPL production even if treatment with prednisolone, heparin, high-dose immunoglobulin, and/or low-dose aspirin is performed during pregnancy. However, low-dose aspirin is useful to treat cases of moderate aPL so that distinction between the two groups is warranted.     

Prevalence of autoantibodies in patients with recurrent miscarriages

PROBLEM: It is well known that the prevalence of several autoantibodies is higher in patients with recurrent miscarriages than in normal women. However, links between individual autoantibodies are unclear. The present study focuses on the possible association between beta 2-glycoprotein I (beta 2-GPI)-dependent anticardiolipin antibody (aCL), lupus anticoagulant (LA), and antinuclear antibody (ANA) in patients with recurrent miscarriages. METHOD OF STUDY: Three hundred and one patients, with a history of two or more unexplained miscarriages, were studied. The titers of beta 2-GPI-dependent aCL and LA were then compared between single-antibody-positive and three-antibody-positive groups. RESULTS: The prevalences of beta 2-GPI-dependent aCL, LA, and ANA were 3.3, 10.0, and 25.2%, respectively. Four of the 301 patients had all three antibodies. The LA titers in patients with positive values for three antibodies was significantly higher than in cases with only LA. CONCLUSION: beta 2-GPI-dependent aCL, LA, and ANA define three distinct, but partly related populations in patients with recurrent miscarriage. We should test at least two kinds of autoantibodies in recurrent aborters, because it has been found that, e.g., beta 2-GPI-dependent aCL and LA are predictors for miscarriages.     

Th1 and Th2 cytokine profiles in recurrent aborters with successful pregnancy and with subsequent abortions

BACKGROUND: This study compared Th1-Th2 cytokine profiles in a subgroup of recurrent aborters who had an abortion with those in a subgroup of recurrent aborters who had a successful pregnancy. METHODS: Fifty-four women with a history of at least three normal pregnancies, 24 women with a history of recurrent spontaneous abortion (RSA) followed by abortion (RSA-->A) and 39 women with a history of RSA followed by normal pregnancy (RSA-->N) were studied. Blood samples and placentas were obtained at the time of delivery or abortion; peripheral blood mononuclear cells were stimulated separately with phytohaemagglutinin and with autologous placental cells, and the secreted cytokines estimated. RESULTS: Peripheral blood mononuclear cells from the RSA-->N subgroup secreted higher concentrations of Th1-type cytokines as compared with normal pregnant women, indicating a higher Th1 bias in these women. However, women in the RSA-->N subgroup had significantly higher concentrations of Th2 cytokines as compared with women in the RSA-->A subgroup. A comparison of Th1:Th2 cytokine ratios indicated a higher Th2 bias in RSA-->N women as compared with RSA-->A women. CONCLUSIONS: We conclude that abortion-prone women who proceed to have successful pregnancy are more Th2-biased than abortion-prone women who abort, and that recurrent aborters who undergo spontaneous abortion have a stronger Th1 bias than aborters who have normal pregnancy.     

Secretion of Interleukin-2 from Unstimulated Peripheral Blood Mononuclear Cells Is a Possible Pathogenic Mechanism in Recurrent Abortion

PROBLEM: The objective of this study was to evaluate the activated status of helper T cells in women with recurrent abortion. METHOD OF STUDY: The spontaneous secretion of interleukin (IL)-2 from peripheral blood mononuclear cells (PBMCs) obtained from 12 women with primary partner-specific recurrent abortion and 7 normal females and 10 normal males was measured. RESULTS: IL-2 concentrations in medium conditioned with PBMCs from the recurrent abortion group were 1.44 ± 0.32 (mean ± standard deviation) U/ml, whereas those from the normal female and male groups were below the minimum detectable concentration. CONCLUSION: The fact that PBMCs from recurrent aborters spontaneously secrete IL-2 suggests that helper T cells are activated in recurrent aborters.     

Human reproductive failure is not a clinical feature associated with beta(2) glycoprotein-I antibodies in anticardiolipin and lupus anticoagulant seronegative patients (the antiphospholipid/cofactor syndrome)

It has been suggested that patients with clinical features suggestive of antiphospholipid syndrome but being lupus anticoagulant (LA) and anticardiolipin (aCL) negative, should be tested for antibodies to beta(2) glycoprotein-I (abeta(2)GP-I), a protein involved in the binding of antiphospholipid antibodies (aPL) to phospholipid surfaces. This was investigated in the present study where a total of 385 women aged 相似文献   

Peripheral Blood Mononuclear Cells from Women with Recurrent Abortion Exhibit an Aberrant Reaction to Release Cytokines upon the Direct Contact of Human Leukocyte Antigen-G-Expressing Cells

PROBLEM: In search for pathogenesis of recurrent abortion, we examined whether lymphocytes/macrophages from women with recurrent abortion exhibited an aberrant ability to release cytokines upon the direct contact of human leukocyte antigen (HLA)-G. METHOD OF STUDY: The amounts of cytokines released from peripheral blood mononuclear cells (PBMCs) from women with recurrent abortion were compared with those from normal multiparous women or normal nulligravidous women when cocultured with or without HLA-G-expressing target cells. RESULTS: When cocultured with HLA-G-expressing target cells, the amount of interleukin-1β released from PBMCs was increased in recurrent aborters whereas it decreased in both normal multiparous and nulligravidous women. The amount of interleukin-3 released from PBMCs did not differ with or without HLA-G-expressing cells in recurrent aborters, whereas it increased in the presence of HLA-G-expressing cells in normal controls. The amount of tumor necrosis factor-α released from PBMCs was decreased in the presence of HLA-G-expressing cells in both recurrent aborters and normal controls. CONCLUSION: The aberrant reaction of maternal lymphocytes/macrophages in releasing cytokines upon the contact of HLA-G expressed on trophoblasts may impact negatively on trophoblastic growth, which may be pathogenic in recurrent abortion.     

抗生殖免疫抗体与不明原因反复自然流产的关系

目的：为探讨抗生殖免疫抗体与不明原因反复自然流产的关系。方法：采用ELISA法检测52例不明原因反复自然流产(流产组)血清抗精子抗体(AsAb)、抗子宫内膜抗体(EmAb)、抗卵巢抗体(AovAb)、抗心磷脂抗体(AcAb)和抗绒毛膜促性腺激素抗体(AhcGAb)的含量。结果：流产组AsAb阳性26．92％,EmAb阳性42．30％,AovAb阳性30．76％,AcA阳性46．15％和AhcGAb阳性48．07％;流产组的各项抗生殖免疫抗体检出率均明显高于对照组。结论：以上5种抗生殖免疫抗体可干扰卵的发育成熟、排卵、受精、胚泡着床和胚胎发育等过程。抗生殖免疫抗体与不明原因反复自然流产关系十分密切。     

Molecular genetic studies of HLA-DRB1 alleles in patients with unexplained recurrent abortion in the Japanese population

BACKGROUND: Recently, evidence that HLA antigens are markers for recurrent spontaneous abortion has gained increased attention. Although the association between HLA class II antigens and patients with unexplained recurrent abortion was elucidated by a large population study in a Caucasian population, such analyses have been conducted in only a small Japanese population. The aim of the present study was to determine whether HLA-DR antigens are associated with patient populations with unexplained recurrent abortion in the Japanese population. METHODS: HLA-DRB1 genotypes were determined using a PCR-restriction fragment length polymorphism (PCR-RFLP) method in 93 patients with unexplained recurrent abortion (79 primary recurrent aborters and 14 secondary recurrent aborters) and in 115 normal fertile women. The rate of possession of each HLA-DRB1 genotype was compared among the three populations. RESULTS: The rate of possession of the HLA-DRB1*1502 in patients with secondary recurrent abortion was significantly higher (P < 0.01 after correction for multiple comparisons) compared with the control, fertile women. The rate of possession of HLA-DRB1*1502 was also higher in patients with primary recurrent abortions than in controls, but the difference was not statistically significant after correction. CONCLUSIONS: These findings suggest that HLA-DRB1*1502 might be a risk allele for unexplained recurrent abortion in the Japanese population.     

Anticardiolipin, other antiphospholipid antibody tests and diagnosis of the antiphospholipid syndrome

The frequent occurrence of false positive results in the anticardiolipin (aCL) enzyme linked immunosorbent assay (ELISA) hampers its application in identifying the antiphospholipid syndrome (APS), a condition characterized by a myriad of clinical presentations. This study highlights some of the pitfalls in the use of assays for antiphospholipid (aPL) antibody in clinical practice. The aCL ELISA, commercially prepared anti-beta2-gylcoprotein 1 (beta2-GP1) and antiphospholipid (APhL) assays were evaluated in the diagnosis of antiphospholipid syndrome (APS) in 94 pregnant women who had spontaneous abortion and a group of 177 healthy blood donors. Serological tests were used to rule out syphilis as the cause of false positive results in the aCL ELISA. The prevalences of positive aCL ELISA results (29/94, 31% v 26/177, 14%; p = 0.001) and aCL antibodies of the IgM isotype (19/94, 20% v 6/177, 3%; $p = 0.001$) were significantly higher in aborters compared to healthy subjects. The majority of the sera which were positive in the aCL ELISA were shown to be false positives as 93% (27/29) of aCL positive aborters and 67% (8/24) of aCL positive healthy subjects were negative in the anti-beta2-GP1 assay. Similarly, the sensitivity of the APhL ELISA was low and only 1% (1/94) of the sera of aborters and 6% (11/177) of healthy subjects were positive in this assay. The frequent occurrence of anticardiolipin antibodies of the authentic non-autoimmune variety and the low sensitivity of the other more specific aPL assays make the positive aCL ELISA difficult to interpret. We recommend that the diagnosis APS be made with strict adherence to the preliminary criteria for classification of APS.     

Polymorphism of human leukocyte antigen-E gene in the Japanese population with or without recurrent abortion

PROBLEM: The aim of this study was to investigate the gene frequencies and shared alleles of human leukocyte antigen (HLA)-E gene in Japanese couples with or without recurrent abortion. METHOD OF STUDY: Polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis was carried out to detect polymorphism in exon 3 of the HLA-E gene in 30 Japanese couples with recurrent abortion and 38 normal Japanese couples with proven fertility. RESULTS: No point mutation was detected in exon 3 of HLA-E in both recurrent aborters and normal controls. HLA-EG and HLA-ER alleles were detected with frequencies of 66.7% and 33.3% in couples with recurrent abortion and 69.2% and 30.8 in normal couples, respectively. The gene frequency of HLA-EG was higher than that of HLA-ER, which is contrary to that found in Caucasian, African-American and Hispanic people but similar to Chinese people. The frequency of each allele was not significantly different between recurrent aborters and normal controls. The number of shared alleles between each couple with recurrent abortion is not significantly different from that with normal controls. CONCLUSION: Allele frequencies of HLA-E were suggested to be different in Asian people from those in other ethnic people. In light of no specific distribution pattern in recurrent aborters, HLA-E polymorphism does not seem to play a role in the pathogenesis of recurrent abortion.     

Antiphospholipid antibodies

OBJECTIVE: To review the role of lupus anticoagulants in the pathogenesis of both venous and arterial thromboembolic events, as well as in recurrent spontaneous abortions. The pathophysiology of lupus anticoagulants and associated antiphospholipid antibodies (eg, anticardiolipin antibodies) is also discussed. DATA SOURCES: Review of the recent medical literature. DATA EXTRACTION AND SYNTHESIS: Key articles in the recent medical literature dealing with lupus anticoagulants and their role in pathogenesis of thromboembolic events were reviewed. Plasma proteins that have an affinity for binding to "perturbed cellular membranes" have been identified as the antigenic targets for antiphospholipid antibodies. Thus, the concept of antiphospholipid antibodies needs to be reevaluated. Perhaps a better term is antiprotein-phospholipid antibodies. The principal antigenic protein targets are beta(2)-glycoprotein I, prothrombin, and a wide range of additional proteins that interact with activated cellular membranes, including protein C, protein S, annexin V, etc. Most research reported in the literature has focused on beta(2)-glycoprotein I and human prothrombin.     

抗子宫内膜抗体和抗精子抗体在临床中的价值探讨

目的探讨抗精子抗体和抗子宫内膜抗体在临床上检测原发性不孕和复发性自然流产的价值。方法回顾性分析2018年1月至2018年12月在复旦大学附属妇产科医院诊治的原发性不孕患者及复发性自然流产患者病史,以同期进行常规检查的孕妇作为对照,对比研究对象抗子宫内膜抗体、抗精子抗体的水平,分析抗子宫内膜抗体、抗精子抗体在原发性不孕和复发性自然流产中可能的相关性。结果收集到原发性不孕患者170例及复发性自然流产患者238例病史资料,以同期进行常规检查的孕妇208例作为对照组。原发性不孕患者抗精子抗体检测阳性例数显著高于对照组,但抗子宫内膜抗体并无显著改变;复发性自然流产患者抗子宫内膜抗体检测阳性率显著高于对照组,但抗精子抗体并无明显不同;早孕期流产患者抗精子抗体检测阳性率显著高于对照组;发生复发性自然流产在4次以上的病人,其体内抗子宫内膜抗体和抗精子抗体的水平均显著高于对照组。结论抗子宫内膜抗体和抗精子抗体检测在复发性自然流产和原发性不孕患者中具有相关的临床价值,应加强备孕人群的筛查工作,及早干预。     

Antineutrophil cytoplasmic antibodies and other immunologic abnormalities in patients with habitual abortion.

PROBLEM: The immunologic mechanisms of pregnancy loss in habitual aborters with antiphospholipid and antinuclear antibodies have not been fully clarified. The possible association of antineutrophil cytoplasmic antibodies (ANCAs) with recurrent miscarriage was examined. METHOD OF STUDY: In a prospective, controlled trial of 59 women with recurrent abortion, the prevalence of pANCA (antimyeloperoxidase), cANCA (antiproteinase-3), and immunoserologic abnormalities of systemic lupus erythematosus (SLE) anti double-stranded DNA, anti-SSA, anti-SSB, anti-U1RNP, anti-Sm, anticardiolipin and antinuclear antibodies, LE-cell, lupus anticoagulant, and complement-3 were investigated. RESULTS: pANCA occurred in 2, and cANCA in 6 of 59 case patients, but neither was observed in the controls (P = 0.09 for cANCA). cANCA levels were significantly higher in patients than in controls (P = 0.028). Six recurrent aborters were identified as having a group of immunoserologic abnormalities characteristic of SLE. CONCLUSIONS: Immunologic mechanisms detectable in SLE may operate in a subgroup of habitual aborters with suspected immunologic cause. ANCAs occur more frequently in patients with recurrent miscarriage than in controls.     

Association between infertility and spontaneous abortion.

Women experiencing recurrent spontaneous abortion have a higher frequency of infertility than that expected in the general population. To further define the relationships between infertility and spontaneous abortion, the obstetrical histories of 43 women with unexplained secondary infertility were evaluated for the frequency of spontaneous abortion. Of the 88 pregnancies studied, 39 (44%) resulted in spontaneous abortion. Women with unexplained secondary infertility experienced a three-fold increase (P less than 0.0001) in the frequency of spontaneous abortions and half the number of live births (P less than 0.0001) compared with the general population. We conclude that the association between infertility and spontaneous abortion includes a higher frequency of spontaneous abortion among infertile couples as well as a higher prevalence of infertility among recurrent spontaneous aborters compared with the general population.     

Antiphospholipid and other autoantibodies in a cohort of habitual aborters and healthy multiparous women in Jamaica

Blood samples from 50~women who had had recurrent spontaneous abortions and 135 healthy multiparous women were investigated for anticardiolipin (aCL) antibodies and anti-β? Glycoprotein 1 (anti-β? GP1) dependent aCL antibodies by enzyme-linked immunosorbent assays (ELISA), lupus anticoagulant activity was measured by activated partial thromboplastin time, antinuclear antibodies, rheumatoid factors and thyroid antibodies using standard techniques. Serological tests for syphilis were performed on all sera and thyroid function was evaluated. There was no significant difference in the prevalence of autoantibodies in habitual aborters and control subjects (60% and 44%, respectively). Habitual aborters differed from controls only in the prevalence of positive aCL antibody tests (15/50, 30% vs. 15/135, 11%; χ2 = 8.5, P= 0.01); medium/high concentrations of aCL antibodies (9/50, 18% vs. 9/135, 7%; χ2 4.3, P= 0.05); aCL antibodies of the IgM isotype (8/50, 16% vs. 7/135, 5%; χ2 = 4.5, P= 0.05) and anti-β?- GPI antibodies (7/50, 14% vs. 3/135, 2%; χ2 6.1, P= 0.05). We recommend aCL antibody screening in habitual aborters and the performance of the anti-β? GP1 antibody tests to identify those most at risk.     

Antiphospholipid antibodies and thrombosis: the putative mechanisms of hypercoagulable state in patients with anticardiolipin antibody

Antiphospholipid antibodies are well recognized as associated with serious clinical complications such as arterial and venous thrombosis and recurrent spontaneous abortion. These complications are collectively called antiphospholipid syndrome(APS). The mechanisms responsible for the thrombosis are unclear. We reported three mechanisms. beta 2-glycoprotein I(beta 2GPI) inhibited activated protein C(APC) activity and, furthermore, APC activity decreased by the addition of monoclonal aCL and beta 2GPI. Monoclonal anticardiolipin antibodies(aCL) seemed to enhance the inhibition of APC procoagulant activity caused by beta 2GPI. Monoclonal aCL in the presence of beta 2GPI also increased the activity of plasminogen activator inhibitor(PAI)-1 in the mixture of tissue-plasminogen activator(t-PA) and PAI-1 by inhibiting the function of beta 2GPI, which increased the remaining t-PA activity in the mixture. The formation of thrombin-antithrombin complexes(TAT) in APS was impaired. The level of TAT in APS did not increase, however the level of prothrombin fragment 1 + 2 (F1 + 2) increased. Therefore, free thrombin present in patients' blood may contribute to thrombosis in APS. These reports indicate that thrombosis in APS may be caused by several thrombogenic factors that stimulate aCL.     

封闭抗体的抗独特型抗体在反复自然流产中的应用价值

为了观察在反射自然流产（ＲＳＡ）中独特型抗体－抗独特型抗体网络的作用，分别测定正常生育组、原发性ＲＳＡ、继发性ＲＳＡ的封闭抗体效率（Ａｂ１）和抗独特型抗体（Ａｂ２），以及原发性ＲＡＳ免疫治疗前后Ａｂ２的变化。结果发现：正常生育组的Ａｂ２分别为７．５３％和１０．７０％；而原发性ＲＳＡ分别为－５５．５１％和－４２．６８％；继发性ＲＳＡ则分别为２９．９８％和－３０．００％，免疫治疗前后，原发性ＲＳＡ患者     

HLA-E and immunobiology of pregnancy

Recently, it has been suggested that non-classical antigens such as human leukocyte antigen (HLA)-G and HLA-E may interact with KIR receptors of NK cells which results into downregulation of immune response and helps in the maintenance of pregnancy. In the present study, we have investigated HLA-E polymorphism in normal fertile women and recurrent spontaneous aborters to assess the effect of HLA-E alleles on the success of pregnancy. Allele E*0101 was found to be significantly higher in patients with recurrent spontaneous abortion (chi(2) = 4.097 and P = 0.0430). Differential expression, peptide affinity, and stability of E*0101 may be one of the reasons.     

Natural killer cell activity and cytokine production after in vitro immunoglobulin treatment of lymphocytes derived from pregnant women with or without risk for spontaneous abortion

OBJECTIVE: To investigate the possible mechanism of action effective in immunoglobulin G (IgG) treatment of recurrent spontaneous abortion (RSA). The effect in vitro of a commercially available intravenous immunoglobulin (IvIg) on the rate of interleukin (IL)-10 and IL-12 positive cells (Th1/Th2 balance) and on natural killer (NK) cell activity in populations of peripheral lymphocytes of healthy pregnant women and women at risk for premature pregnancy termination was studied. Primary habitual aborters as well as women showing clinical symptoms (bleeding or regular uterine contractions) of threatened premature pregnancy termination were included. METHODS: Lymphocytes of 20 pregnant women were tested. Five different batches of an IvIg with reported immunomodulatory potential were used at a concentration of 10 mg/mL. Cytokine profiles of the lymphocytes were determined by immunocytochemistry. For testing of NK cell activity, the 4 hr single cell cytotoxicity assay was used. RESULTS: Incubation with IgG of lymphocytes from recurrent spontaneous aborters concomitantly and significantly decreased the rate of IL-12 positive cells (P < 0.01) and increased the rate of IL-10 positive cells (P < 0.01), whereas such treatment had no significant effect on lymphocytes of pregnant women not at risk of abortion. Dialysis or heat treatment (56 degrees C, 30 min) of the IgG preparations did not modify the effect. Elevated NK cell activity of women at risk for premature pregnancy termination significantly decreased after IgG incubation of cells in all cases, whereas NK cell activity of normal pregnancy lymphocytes was not altered. CONCLUSION: This study suggests that incubation of peripheral lymphocytes from RSA patients with polyclonal polyspecific IgG alters cytokine profiles and NK activity while the same treatment does not affect lymphocytes of healthy pregnant women. These data might add to the understanding of mechanisms of action of IvIg in prevention of recurrent pregnancy loss.