CN107991493B - Application of anti-ENO 1 autoantibody in screening and predicting abortion risk of AIT pregnant woman - Google Patents
Application of anti-ENO 1 autoantibody in screening and predicting abortion risk of AIT pregnant woman Download PDFInfo
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Abstract
The invention belongs to the technical field of biomedicine, and particularly discloses application of detecting the level of α enolase (ENO1) specific autoantibody (ENO1Ab) in serum to predicting abortion risk of pregnant women suffering from autoimmune thyroiditis (AIT). The invention discovers that the existence of ENO1Ab is closely related to abortion and placenta dysfunction, and provides new clinical application for timely screening AIT pregnant women with high abortion risk.
Description
Technical Field
The invention belongs to the technical field of biomedicine, and particularly relates to application of an anti-ENO 1 autoantibody in screening and predicting abortion risk of AIT pregnant women.
Background
Autoimmune thyroiditis (AIT) is one of the most common endocrine diseases, with the most representative autoantibodies being thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb). The positive rate of the thyroid autoantibodies is 10-20% in the normal population during the childbearing period, and the positive rate of TPOAb or TgAb is 2-17% in the pregnant women, which varies with the ethnic group. Recent investigations in this group showed positive rates of TPOAb and TgAb in women at early gestation in areas of iodine abundance of 8.7% and 12.0%, respectively. This indicates that AIT is very common in pregnant women.
Numerous studies have shown that the risk of an AIT pregnant woman developing an adverse pregnancy outcome such as abortion, impaired mental and motor development, etc. is significantly increased, but there is still much controversy in terms of pathogenesis and preventive measures. Investigations have shown that 39% of married women have undergone more than one abortion, of which 26.4% of aborted women have AIT. Numerous studies have shown that the risk of abortion in pregnant women with AIT increases 2-3 times. Although 20-40% of TPOAb positive women developed hypothyroidism during pregnancy or postpartum, a systematic review and meta-analysis of 31 studies conducted by the university of London, Mary, England showed that treatment with supplemental levothyroxine (L-T4) only reduced the incidence of miscarriage by 52%. Factors other than hypothyroidism have been shown to be involved in the increased risk of abortion in pregnant AIT women, and in particular autoimmune factors may play an important role in the development of abortion. The problem with the prior art is that, although the latter has been of great interest, the mechanism is still unclear and there is a lack of an effective risk predictor of miscarriage in this regard.
α -enolase (ENO1) has been found to be expressed in cells of a variety of tissues (e.g., brain, thyroid, vascular endothelium, ovary, placenta, etc.) early on, although it was reported that various autoantibodies such as ENO1Ab could be detected in female patients with systemic lupus erythematosus and antiphospholipid syndrome who failed pregnancy, the clinical significance of its expression was unclear at that time.
The prior art has the technical problems that the correlation between the generation of ENO1Ab and the increase of the abortion risk of AIT pregnant women has not been studied yet, and the clinical application of the antibody is limited.
Disclosure of Invention
The invention provides application of an anti-ENO 1 autoantibody (ENO1Ab in serum) in screening and predicting abortion risk of AIT pregnant women, finds that a clear correlation exists between the generation of ENO1Ab and the abortion risk increase of the AIT pregnant women and placenta dysfunction, and increases the clinical application value of serum ENO1Ab detection.
The invention aims to provide application of an anti-ENO 1 autoantibody in preparation of a kit or a biomarker for screening and predicting abortion risk of an AIT pregnant woman.
Compared with the prior art, the invention discusses the relationship between a new non-traditional thyroid autoantibody-ENO 1Ab and the abortion occurrence of AIT pregnant women, provides a biomarker for predicting and screening the high abortion risk of AIT pregnant women by using ENO1Ab and the application in preparing a related kit, and has the following beneficial effects:
the relationship between autoantibodies generated by the autoimmune reaction aiming at ENO1 and the abortion and placental dysfunction processes of AIT pregnant women is found, and the detection of the ENO1Ab level in the serum of the AIT pregnant women can help to effectively predict the abortion risk, can be used as a biomarker for predicting and screening the abortion risk of the AIT pregnant women, can be used for preparing related kits for clinical application, can be used for preparing corresponding small-molecule interferents by taking the ENO1 autoantigen antibody reaction as a target spot, and can be used for developing new treatment means, so that the application prospect is wide.
We found that there was no data showing that L-T4 pregnant women had significantly reduced miscarriage than the non-pregnant women who had AIT; and ELISA determination is carried out by taking the recombinant full-length ENO1 protein as an antigen, and the result shows that whether AIT exists or not and whether L-T4 intervention is accepted or not, the ENO1Ab expression level of the pregnant woman suffering from abortion in the early pregnancy period is obviously higher than that of the pregnant woman not suffering from abortion; and high levels of ENO1Ab (OD) were present in AIT pregnant women who received L-T4 intervention450>0.8) are all significantly higher than in persons who have not experienced miscarriage: 64.7% vs 28.6%%, P<0.05; it was further shown, in particular by Logistic regression analysis, that an elevated level of ENO1Ab is an AIT pregnant woman abortionIndependent risk factor of, P<0.05, OR 3.114. These findings strongly suggest that detection of the serum ENO1Ab level of an AIT pregnant woman in the early stage of pregnancy can help to effectively predict the abortion risk, and provide clinical basis for early prevention and treatment.
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FIG. 1 detects the expression of ENO1 protein in the brain, thyroid and P0 day maternal placental tissues of normal CBA/J mice using multiple immunofluorescent staining;
wherein, fig. 1A is the expression result in the brain; FIG. 1B is the result of expression in thyroid; FIG. 1C is the results of expression in placental tissue;
FIG. 2 ENO1Ab levels in serum and amniotic fluid of a mother mouse immunized with ENO1 recombinant protein and Freund's adjuvant at day P0;
wherein FIG. 2A is a serum result and FIG. 2B is an amniotic fluid result;
FIG. 3 placental histology altered HE staining micrographs (40X) of serum ENO1Ab high expression mother mice;
wherein FIG. 3A is the placental results of control group mice that received adjuvant injection only, and FIG. 3B is the placental results of mice that received ENO1 recombinant protein immunized with Freund's adjuvant;
FIG. 4 retrospectively analyzes blood ENO1Ab levels in early pregnancy for non-AIT pregnant women with and without a history of miscarriage and for AIT pregnant women.
Detailed Description
The invention is described in detail below with reference to the figures and the specific embodiments, but the invention should not be construed as being limited thereto. The experimental methods in the following examples are conventional methods unless otherwise specified, and materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The invention provides application of an anti-ENO 1 autoantibody in preparation of a kit or a biomarker for screening and predicting abortion risk of an AIT pregnant woman.
It was determined whether the production of ENO1Ab is the causative factor in the development of abortion in AIT mothers. This is the key to discussing the increased risk of abortion in AIT pregnant women, but no effective prediction and prevention measures are available at present. Therefore, we conducted the following studies:
first, ENO1 has been found to be expressed in cells of a variety of tissues (e.g., brain, thyroid, vascular endothelium, ovary, placenta, etc.).
FIG. 1 is a graph of the expression of ENO1 protein in the brain, thyroid gland and P0 days of normal CBA/J mice in the placental tissue of the mother mouse by multiplex immunofluorescence staining, wherein FIG. 1A is the result of the expression in the brain, which is the confocal microscope observation (100X) of the double immunofluorescence staining of anti-ENO 1 (anti-antibody Aleax Fluor 555 marker, red) and DAPI (marker nucleus, blue), and the arrow indicates the vascular endothelial cell; FIG. 1B is the results of expression in the thyroid gland as observed by confocal microscopy (200X) of triple immunofluorescent staining against ENO1 (secondary antibody Aleax Fluor 555 marker, red), anti CD34 (secondary antibody FITC marker, green) and DAPI (marker nuclei, blue), arrows indicate vascular endothelial cells; FIG. 1C shows the expression in placental tissue as a result of confocal microscopy (200X) triple immunofluorescent staining of anti-ENO 1 (secondary antibody Aleax Fluor 555 marker, red), anti-CD 34 (secondary antibody FITC marker, green) and DAPI (marker nuclei, blue), with the arrows indicating vascular endothelial cells. From the graphs in FIG. 1, it was found that the expression was observed in thyroid follicular cells, nerve cells, and vascular endothelial cells of the brain, thyroid, and placenta. Furthermore, we further used the ENO1 recombinant protein to immunize CBA/J mice to induce a specific autoimmune response against ENO1, and found that there was high level of ENO1Ab expression in serum, and that it was maintained at a high level throughout the mouse gestation period, and that the antibody was able to pass through the placenta into the amniotic fluid, the results are shown in fig. 2. FIG. 2 shows the levels of ENO1Ab in serum and amniotic fluid of a mother mouse immunized with ENO1 recombinant protein and Freund's adjuvant at day P0, where FIG. 2A shows the serum results and FIG. 2B shows the amniotic fluid results; maternal mouse serum in figure 2: control group n-4, ENO1 group n-4; amniotic fluid: control group n-3, ENO1 group 3; the P <0.01 results indicate that specific autoimmune responses to ENO1 may act on sites such as placenta and cause dysfunction and affect pregnancy outcome. For this reason, we further examined the placental tissue changes of the mice immunized with the ENO1 recombinant protein, and found that the total placental area was reduced and the area of the periostracum region was also significantly reduced compared to the control group. A significant decrease in cell density was seen in the decidua, tight junction and labyrinth regions, and the results are shown in figure 3. FIG. 3 is a placenta histology change HE staining microscopic observation picture (40X) of a mother mouse with high-level expression of serum ENO1Ab, wherein FIG. 3A is a placenta result of a control mother mouse injected with only adjuvant (negative or low-level expression of serum ENO1Ab), FIG. 3B is a placenta result of a mother mouse immunized with ENO1 recombinant protein and Freund's adjuvant (high-titer ENO1Ab expression exists in serum), and the result of FIG. 3 shows that the existence of ENO1Ab may cause placenta dysfunction and may be involved in pregnancy complications. Particularly, as a key enzyme of glycolysis, the inhibition of the ENO1 function can affect the ovarian function and follicular development, interfere the production of progesterone in granulosa cells, cause insufficient production of corpus luteum, and affect the growth, development and quality of fertilized eggs. It has been shown to be an important autoantigen in the development of premature ovarian failure. ENO 1-specific autoimmune responses also exist in patients with endometriosis, suggesting that ENO1Ab may cause endometrial damage and thereby cause abortion. Moreover, studies have found that levels of ENO1 are significantly lower on placenta from unexplained abortion than on normal placenta. Furthermore, ENO1 is used as a plasminogen binding receptor, and ENO1Ab may interfere with the plasmin activation activity of ENO1 protein on the surface of a cell membrane, so that the function of a fibrinolytic system is disordered, embryo implantation disorder and placenta thrombosis are caused, and abortion is promoted.
Second, follow-up survey of clinical examples
1. Subject enrollment criteria: group entry criteria for pregnant women
(1) The inclusion standard includes ① women with gestation less than 8 weeks, ② women living in iodine-adapted area for more than 2 years, ③ single fetus.
(2) Exclusion criteria ① patients with existing nail function abnormalities (including subjects) at the time of pregnancy-specific diagnosis, ② patients with pregnancy-induced abortion due to no childbearing desire, known ovarian or uterine organic disease or accident, ③ patients with a history of wind-dampness immunity, ④ patients with severe chronic disease, ⑤ patients with personal or family history of genetic disease, ⑥ patients treated with excess iodine-containing preparation within nearly 3 months of illness, and ⑦ patients with history of iron deficiency or excess.
2. Study source and cohort:
46 non-AIT pregnant women with normal iron nutrition and nail work and urine iodine of 50-300 μ g/L are collected from 4425 pregnant women who meet the above-mentioned group standard subjects as a control group, and 90 pregnant women with positive total TPOAb are collected as an experimental group, wherein AIT1 is L-T4 non-dried group (not receiving L-T4 treatment) in 90 cases of the experimental group, and 38 cases; AIT2 group was L-T4 intervention group (treated with L-T4), 52 cases.
3. Relevant data collection and follow-up:
(1) sign "informed consent".
(2) Subjects were collected and recorded for general condition (including age, menstrual history, fertility history, smoking and drinking history, medication history, disease history, family history or occupational exposure history) and for preliminary physical examination results (including thyroid, height, weight, abdominal circumference, blood pressure, heart rate).
(3) ① the content of TSH, FT4, TPOAb, TgAb and serum ferritin is measured by Roche E601 full-automatic electrochemiluminescence immunoassay analyzer, urine iodine is measured by arsenic cerium catalytic spectrophotometry, ② the total length ENO1 (Beijing Yiwangshu Biotech limited, 1 ug/well) is used as coating antigen, and the total IgG ENO1 is measured by established indirect ELISA method (Zhang Hongmei, Qinlian, Ningyang, Lijing, Uniloyal, Tengzawing. anti- α enolase antibody is expressed in autoimmune thyroiditis 2016; 45(6): 499) 502) to obtain specific IgG ③ for all the above mentioned serum ENO1 and serum of pregnant women (recorded in hospital or hospital) without follow-up abortion in 12-14 weeks, 18-20 weeks, 24-20 weeks, 27 weeks.
(4) And (3) analyzing and processing the data by adopting statistical software SPSS 18.0, wherein ① shows whether the occurrence of the abortion is related to the blood ENO1 level of the pregnant woman, and ② analyzes whether the blood ENO1Ab level of the AIT pregnant woman is a risk factor of the occurrence of the abortion by using multivariate regression.
First, IWe analyzed the differences in blood ENO1Ab levels between these TPOAb-positive pregnant women and non-AIT pregnant women who were age, education, household income, smoking and drinking habits, weight, blood pressure, thyroid function, iodine nutrition, iron nutrition, etc. matched in all respects and thyroid antibody negative, and then we compared the differences between relevant indices including blood ENO1Ab levels between aborts and non-aborts in AIT pregnant women who were TPOAb-positive. We found that in early pregnancy, the levels of ENO1Ab in AIT pregnant women positive for TPOAb were significantly higher than in non-AIT pregnant women (mean titer 0.7086vs 0.5483, P titer) as determined by ELISA using recombinant full-length ENO1 protein as antigen<0.05; high level positive rate 33.3% vs 4.3%, P<0.05). FIG. 4 retrospectively analyzes the blood ENO1Ab levels in early pregnancy for non-AIT pregnant women with and without a history of abortion and for AIT pregnant women, in FIG. 4A shows non-AIT pregnant women with a history of abortion, B shows non-AIT pregnant women without a history of abortion, C shows AIT pregnant women without a history of abortion who received no L-T4 intervention, D shows AIT pregnant women without a history of abortion who received no L-T4 intervention, E shows AIT pregnant women with a history of abortion who received L-T4 intervention, and F shows AIT pregnant women without a history of abortion who received L-T4 intervention. The results in FIG. 4 were measured by ELISA using recombinant full-length ENO1 protein as antigen, as OD450>0.8 was determined to be high blood ENO1Ab expression, and the results in FIG. 4 show that the levels of ENO1Ab in miscarriage subjects were significantly higher than in non-miscarriage subjects, regardless of the presence or absence of AIT, and regardless of L-T4 treatment.
TABLE 1 comparison of blood ENO1Ab levels in non-AIT pregnant women with and without a history of miscarriage and in AIT pregnant women during early pregnancy
Note: ELISA assay with recombinant full-Length ENO1 protein as antigen, OD450>0.8 was determined as high level expression of blood ENO1 Ab.
TABLE 2 Single factor analysis of effects on AITD maternal abortion
Note: TPOAb to>300IU/ml was determined as high level expression; TgAb of>300IU/ml was determined as high level expression; ENO1Ab as OD450>0.8 was determined as high level expression. M is a median; IQR is the quartile spacing (25-75%).
TABLE 3 Logistic regression analysis of effects on AITD maternal abortion
| Variables of | Regression coefficient B | Standard error SE | Wald number | P value | OR(95％CI) |
| Age (age) | 0.099 | 0.055 | 3.199 | 0.074 | 1.104(0.991～1.230) |
| ENO1Ab | 1.136 | 0.476 | 5.684 | 0.017 | 3.114(1.224～7.921) |
Table 1 shows a comparison of blood ENO1Ab levels in non-AIT pregnant women with and without a history of miscarriage and in AIT pregnant women during early pregnancy, further finding that OD, if any, is used450>0.8 high expression of ENO1Ab as blood, high levels of ENO1Ab (OD) were present in the donors of AIT pregnant women (AIT2 group) receiving L-T4 intervention450>0.8) is also significantly higher than in persons who have not experienced miscarriage.
Age, weight early in pregnancy, history of smoking, iodine nutrition, administration of L-T4 intervention, thyroid antibody levels (blood TPOAb levels and TgAb levels), Tg levels, and ENO1Ab levels were then analyzed by single factor as a function of the occurrence of miscarriage in AIT pregnant women during pregnancy, with the results shown in table 2. Table 3 further performed multifactorial logistic regression analysis of the relevant factors that may affect abortion in AIT pregnant women, suggesting that elevated levels of ENO1Ab are independent risk factors for abortion in AIT pregnant women, P <0.05, OR 3.114.
By performing the above-described follow-up and test results on 90 collected AIT pregnant women with AIT and 46 non-AIT pregnant women with AIT and thyroid antibody negatives matching various conditions, we found that patients with AIT had different degrees of ENO1Ab expression; individuals who develop miscarriage experience elevated levels of ENO1Ab expression in their bodies during the early stages of pregnancy. Therefore, based on the problems found in clinical practice and theoretical mechanism analysis and human and animal research, the method firstly proposes that the autoimmune reaction induced by ENO1 as an autoantigen in AIT mothers may influence the functions of ovaries and placentas to cause abortion, and ENO1Ab can be used as an effective index and a biomarker for predicting the abortion risk of AIT pregnant women, and the development of a detection related kit thereof has important clinical application value.
While preferred embodiments of the present invention have been described, additional variations and modifications in those embodiments may occur to those skilled in the art once they learn of the basic inventive concepts. Therefore, it is intended that the appended claims be interpreted as including preferred embodiments and all such alterations and modifications as fall within the scope of the invention.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.
Claims (1)
1. Application of a reagent for detecting total IgG of an autoantibody of α -enolase ENO1 in serum in preparing a diagnostic reagent for predicting abortion risk of a pregnant woman with autoimmune thyroiditis AIT.
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