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Correlation between oral sex and a low incidence of preeclampsia: A role for soluble HLA in seminal fluid?
Abstract
The involvement of immune mechanisms in the aetiology of preeclampsia is often suggested. Normal pregnancy is thought to be associated with a state of tolerance to the foreign antigens of the fetus, whereas in preeclamptic women this immunological tolerance might be hampered. The present study shows that oral sex and swallowing sperm is correlated with a diminished occurrence of preeclampsia which fits in the existing idea that a paternal factor is involved in the occurrence of preeclampsia. Because pregnancy has many similarities with transplantation, we hypothesize that induction of allogeneic tolerance to the paternal HLA molecules of the fetus may be crucial. Recent data suggest that exposure, and especially oral exposure to soluble HLA (sHLA) or HLA derived peptides can lead to transplantation tolerance. Similarly, sHLA antigens, that are present in the seminal plasma, might cause tolerance in the mother to paternal antigens. In order to test whether this indeed may be the case, we investigated whether sHLA antigens are present in seminal plasma. Using a specific ELISA we detected sHLA class I molecules in seminal plasma. The level varied between individuals and was related to the level in plasma. Further studies showed that these sHLA class I molecules included classical HLA class I alleles, such as sHLA-A2, -B7, -B51, -B35 and sHLA-A9. Preliminary data show lower levels of sHLA in seminal plasma in the preeclampsia group, although not significantly different from the control group. An extension of the present study is necessary to verify this hypothesis.
... This exaggerated inflammatory response may be partially due to absence of some immunomodulators that down-regulates the immune response to invading fetal antigens, Chambers, et al., 2001. Soluble HLA (sHLA) is one of the main immunomodulatory molecules, its presence in seminal plasma has been controversial Anderson, 1996, Schaller et al, 1993and Koelman et al, 2000. The presence of sHLA-I and/or sHLA-II in seminal fluid of husbands may be associated P with less risk of developing abnormal immune response in their pregnant wives as these molecules may have an immunomodulatory function, Pollanen and Cooper, 1994. ...
... Because pregnancy has many similarities with transplantation, we hypothesize that induction of allogeneic tolerance to the paternal HLA molecules of the fetus may be crucial. Schaller et al, 1993, in a partial contrast to our results and those obtained by Koelman, 2000, reported lack of HLA-I and HLA-II in seminal plasma using an ELISA technique and monoclonal antibodies. Our study validates ELISA technique for sHLA I & II as a screening method to detect couples with high tendency to develop preeclampsia, so that treatment can be initiated as early as possible. ...
The involvement of immune mechanisms in the etiology of pre-eclampsia has been suggested in a number of publications. Basically, a state of tolerance to the half-foreign antigens of the fetus during normal pregnancy is widely accepted to explain the success of pregnancy and non-rejection. In pre-eclampsia, this immunological tolerance might not occur. Free HLA molecules or the so called "soluble HLA (sHLA)" molecules are known to have an immunomodulatory function. As sHLA antigens are present in the seminal plasma, they might cause tolerance in the mother to paternal antigens. In order to test this hypothesis, we used western blotting technique to qualitatively investigate whether sHLA class I and/or sHLA-II antigens are present in seminal plasma(sp) of husbands of pre-eclamptic women and compared the results with those from a matching group of husbands of wives with normal pregnancy. We also measured the levels of sHLA class I and sHLA class II molecules in sp from husbands of pre-eclamptic and normal pregnant controls by ELISA. sHLA class I and sHLA class II were detected in all pre-eclamptic and control groups. However, the levels of sHLA class I and sHLA class II were significantly lower in seminal plasma of husbands of preeclamptic women as compared to those of normal pregnancy control group.
... Moreover, first pregnancy, first pregnancy after partner change, and long interval between pregnancies increase PE risk [98,99]. The reduced opportunities for exposure to seminal plasma, and pregnancy by sperm or oocyte donation or pregnancies with donated greatly increase PE risk [100][101][102][103]. ...
... To maintain immunotolerance at the feto-maternal interface, between dendritic cells (DCs) and Tregs [115], the cross-presentation of paternal antigens to maternal cytotoxicity T CTLs and CD4 + T cells [115,116] is altered by fetal antigen-specific Tregs at the feto-maternal interface [117][118][119][120][121]. Seminal plasma components such as TGF-β, prostaglandins, MHCs, and minor antigens also functionally affect maternal antigen-presenting cells (APC). These functional changes were maintained by EVTs [103,122]. In mice, these functional changes favor fetal-antigen-specific Tregs cell expansion in the uterus and uterine drainage lymph nodes [123][124][125]. ...
Pregnancy is a particular physiologic stage during which immune regulation is essential. A successful placentation and subsequent fetal development depend on the delicate balance between moderate pro-inflammatory response and immune tolerance. Findings have pointed out a crucial role for regulatory B cells (Bregs) in establishing an immunomodulatory (IM) environment relevant to pregnancy. In a steady state, Bregs represent 10% of B cells in peripheral blood, a proportion that increases during pregnancy, with the highest rate being observed in post-partum. In the context of pregnancy, Bregs seem to be well positioned to perform the mechanisms that accommodate the growing semi-allogenic fetus and also allow the adequate immune response to pathogen. This chapter discusses the mechanism of action of Bregs during human pregnancy. Also, we will evoke interactions between maternal immune cells and fetal annexes that result in hijacking the naïve B cells to educate and to differentiate them into Bregs.
... Some researches indicate that class I-a HLA antigens and TGF-β are present in large quantities in seminal fluid [20,21], that can induce Th2 immune response and immune tolerance with the stimulation of TGF-β, endometrium recruit antigen presenting cells and inhibit T cell, so that the maternal shows low response to the paternal antigen. TGF-β in seminal fluid leads to immune tolerance through multiple stimulation to the endometrium [22]. ...
... Research of Koelman included 41 PE primiparas and 44 non-PE primiparas, collected whether they had oral sex and spermatophagy before pregnancy. The result showed that oral sex and spermatophagy reduced the risk of PE [21]. A systematic review contains 7 researches including 7125 pregnancies, showed that the incidence of PE was significantly reduced in primiparas with higher overall sperm exposure [26]. ...
Purpose
This study aimed to evaluate the incidence of preeclampsia after a long duration or a short duration of sperm exposure with the biological father.
Methods
Analyze the clinical and follow-up data of 502 single birth primigravid women in Women’s Hospital, School of Medicine, Zhejiang University. They were divided into two groups according to the duration of sperm exposure with the biological father, short duration of sperm exposure (≤ 3 months) and long duration of sperm exposure (≥ 12 months). Basic information and clinical characteristics in each group were evaluated.
Results
A total of 502 patients were followed, included 122 long duration of sperm exposure and 380 short duration of sperm exposure. Patients in the long duration group were younger than the short group (aged 31.49 ± 3.21 vs 27.49 ± 3.21 years, P < 0.001). These two groups had no statistical significant in patient’s body mass index, education level, gestational age, birth weight, fetal birth weight, fetal sex and delivery mode (P > 0.05). Stratified analysis with the cutoff of 30 year-old suggested that the incidence of pregnancy-induced hypertension (PIH)/preeclampsia (PE) of short duration group was significantly higher than the long duration group (OR 2.82; 95% CI 1.08–7.41), so as PE (OR 10.28; 95% CI 1.01–105.02). Stratified analysis suggested no significantly increased or decreased risk for PIH (OR 1.59; 95% CI 0.54–4.68), gestational diabetes mellitus (OR 0.6; 95% CI 0.31–1.18), intrahepatic cholestasis of pregnancy (OR 2.49; 95% CI 0.34–18.48) or fetal anomaly (OR 0.4; 95% CI 0.14–1.20).
Conclusion
A long duration of sperm exposure with the biological father may reduce the incidence of PE.
... Asimismo, diversos autores han señalado su eficacia en pacientes transplantados en modelos murinos y humanos. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] Se realizó una revisión de la literatura sobre la inducción de la tolerancia oral, los mecanismos inmunológicos, el papel celular regulador ante antígenos expuestos y los resultados experimentales de la tolerancia oral en trasplantes de órganos y tejidos con el objetivo de demostrar que el uso de esta alternativa terapéutica es viable en pacientes trasplantados. ...
... 55-57Estudios y utilidad en trasplantes [T2]El primer trasplante renal en Colombia se realizó en 1963 en el Hospital San Juan de Dios en Bogotá. 58 A partir de entonces, las prácticas de intervención y la cobertura de los sitios donde se practican estos procedimientos han mejorado y en la actualidad se cuenta con cerca de 25 instituciones hospitalarias habilitadas para realizar trasplantes de órganos sólidos en el país; 59 sin embargo, son varios los obstáculos que se deben enfrentar para lograr trasplantes exitosos, por ejemplo el rechazo del injerto por falta de tolerancia inmunológica.Como ya se describió, uno de los métodos para lograr la tolerancia inmunológica es la vía oral, ya que la ingesta de aloantígenos o de antígeno leucocitario humano soluble del donante permite que el sistema inmune haga un primer reconocimiento por medio de las CPA y del complejo mayor de histocompatibilidad presentes en el tracto gastrointestinal; de esta forma, cuando se haga el trasplante, el sistema inmune del receptor no respuesta de rechazo, pues ya se habrá generado tolerancia ante los antígenos del donante.Uno de los resultados más prometedores en la inducción de tolerancia a un injerto trasplantado se encontró en un estudio de Kelman et al.,14 quienes describen lo que ocurre a nivel inmunológico durante el embarazo. Estos autores indican que existe tolerancia entre las moléculas del sistema del antígeno leucocitario humano del feto y el sistema inmune de la madre y reportan una correlación entre la ingesta de semen por sexo oral y una menor incidencia de preeclampsia, resultados que permiten presumir que la vía oral es un mecanismo útil para inducir tolerancia.La mayoría de la evidencia encontrada proviene de modelos murinos con trasplante de corazón, riñón, córnea y médula ósea, tal como se evidencia en la Tabla 2. ...
Introduction:
Oral tolerance is defined as the suppression of the immune response to antigens that have been previously administered orally. The purpose of inducing oral tolerance is to avoid using immunosuppressive drugs since, considering that they are not antigen-specific, they make the host more susceptible to acquire infections and develop neoplasms.
Objective:
To carry out a literature review on the most relevant theoretical references regarding oral tolerance induction in organ and tissue transplantation to prove that oral tolerance is a viable alternative therapy in transplant patients.
Materials and methods:
A literature review was conducted in the PubMed, MEDLINE, LILACS and Embase databases using the following search strategy: publication time: no limits; publication language: English and Spanish; type of studies: case-control studies, literature and systematic reviews; search terms: "T-Lymphocytes, Regulatory", "Autoimmunity", Immunosuppression", "Immune system" and "Immune Tolerance", and their equivalents in Spanish.
Results:
After the initial search was completed, 719 records were retrieved; however, only 99 addressed oral tolerance induction. Once duplicate records and articles without full-text access were removed, 75 studies were included for analysis.
Conclusions:
Oral administration of antigens is an effective way to induce immune tolerance in transplant patients (murine models) as it eliminates the adverse effects associated with immunosuppressive therapy, which currently is the standard therapy to treat these patients worldwide.
... Semen contains various immunomodulatory factors, such as chemokines and cytokines, 1 but also soluble human leukocyte antigens (sHLA), which together can induce a local immune response in an immune regulatory environment. 2 The presence of seminal plasma (SP) in the female reproductive tract after coitus can lead to an influx of immune cells, for example, the number of CD14+ macrophages and CD1a + dendritic cells were shown to be approximately 2-fold increased upon semen exposure. 3 Immune recognition of paternal antigens may play a role in pregnancy complications: change of partner is a risk factor for intrauterine growth restriction, preterm birth, low birth weight and infant mortality, and it counteracts the protective effect of multiparity against preeclampsia. ...
... [4][5][6] Additionally, the length of unprotected sexual cohabitation affects the incidence of pregnancy-induced hypertensive disorders, 7,8 and oral exposure to semen is correlated with a diminished occurrence of preeclampsia. 2 Furthermore, preeclampsia occurs more frequently in pregnancies induced by artificial insemination with donor semen. 9 Combined, these findings indicate that exposure to paternal antigens prior to gestation has a beneficial effect on pregnancy outcome. ...
Soluble HLA‐G (sHLA‐G) levels in human seminal plasma (SP) can be diverse and may affect the establishment of maternal‐fetal tolerance and thereby the outcome of pregnancy. We investigated whether sHLA‐G levels in SP are associated with polymorphisms in the 3'‐untranslated region (UTR) and UTR haplotypes of the HLA‐G gene. Furthermore, we compared the HLA‐G genotype distribution and sHLA‐G levels between men, whose partner experienced unexplained recurrent miscarriage (RM), and controls. Soluble HLA‐G levels (n=156) and HLA‐G genotyping (n=176) were determined in SP samples. The concentration of sHLA‐G was significantly associated with several single nucleotide polymorphisms (SNPs): the 14 base pair (bp) insertion/deletion (indel), +3010, +3142, +3187, +3196, and +3509. High levels of sHLA‐G were associated with UTR‐1 and low levels with UTR‐2, UTR‐4 , and UTR‐7 (P<0.0001). HLA‐G genotype distribution and sHLA‐G levels in SP were not significantly different between the RM group (n=44) and controls (n=31). In conclusion, seminal sHLA‐G levels are associated with both singular SNPs and 3’UTR haplotypes. HLA‐G genotype and sHLA‐G levels in SP are not different between men whose partner experienced RM and controls, indicating that miscarriages are not solely the result of low sHLA‐G levels in SP. Instead it is more likely that these miscarriages are the result of a multifactorial immunologic mechanism, whereby the HLA‐G 3’UTR 14 bp ins/ins genotype plays a role in a proportion of the cases. Future studies should look into the functions of sHLA‐G in SP and the consequences of low or high levels on the chance to conceive. This article is protected by copyright. All rights reserved.
... Cell surface expression of HLA-DR in syncytiotrophoblasts and the presence of HLA-DR in syncytiotrophoblast-derived extracellular vesicles were observed in preeclampsia (69). Seminal plasma also contains soluble HLA molecules (70)(71)(72). Additionally, human EVTs express minor histocompatibility antigens, such as HY, HA, and ACC (73). ...
... First pregnancy, pregnancy following a partner change, and a pregnancy interval of more than ten years raise the risk of preeclampsia (94)(95)(96). Long-term condom usage and AID pregnancy also elevate the risk of preeclampsia, suggesting insufficient paternal antigen-specific tolerance mediated by seminal plasma priming (70,97,98). OD pregnancy, in which the fetus is completely allogenic and no priming effect has occurred, is associated with a high risk of preeclampsia (6,98). ...
Semi-allogenic fetuses are not rejected by the maternal immune system because feto-maternal tolerance induced by CD4⁺CD25⁺FoxP3⁺ regulatory T (Treg) cells is established during pregnancy. Paternal antigen-specific Treg cells accumulate during pregnancy, and seminal plasma priming plays an important role in expanding paternal antigen-specific Treg cells in mouse models. Although paternal-antigen specific Treg cells have not been identified in humans, recent studies suggest that antigen-specific Treg cells exist and expand at the feto-maternal interface in humans. Studies have also revealed that reduction of decidual functional Treg cells occurs during miscarriage with normal fetal chromosomal content, whereas insufficient clonal expansion of decidual Treg cells is observed in preeclampsia. In this review, we will discuss the recent advances in the investigation of mechanisms underlying Treg cell-dependent maintenance of feto-maternal tolerance.
... The same author compared patients with simple PIH versus those with preeclampsia and eclampsia and observed that the sexual cohabitation times are shorter (9.5 months) compared to those of unaffected women (26.3 months) (Robillard and Hulsey, 1996). Koelman et al. (2000) found a lower frequency of oral sex in women with preeclampsia compared to healthy pregnant women (p = 0.0003), suggesting a protective role. The authors report lower amounts of soluble HLA A and HLA B in the seminal fluid, in partners of preeclamptic women (Koelman et al., 2000). ...
... Koelman et al. (2000) found a lower frequency of oral sex in women with preeclampsia compared to healthy pregnant women (p = 0.0003), suggesting a protective role. The authors report lower amounts of soluble HLA A and HLA B in the seminal fluid, in partners of preeclamptic women (Koelman et al., 2000). In Robertson et al. (2003) proposed how repeated semen exposure protects preeclampsia, based on four lines of evidence: (1) the semen contains antigens shared by the conception; (2) after the seminal contact, the maternal mucosa can mount a regulated immune response to semen antigens; (3) semen contains among others, high amounts of TGFb that can inhibit type 1 immunity; and (4) TGFb-dependent changes in T-lymphocytes allow a hyporesponsiveness to paternal antigens. ...
Preeclampsia is a condition associated with high rates of maternal-fetal morbidity and mortality. It usually occurs in 3–10% of nulliparous women and 18% of previously affected women. Different lines of evidence have demonstrated the role of the father in the onset of preeclampsia. The placenta is the cornerstone of preeclampsia and poses important paternal genetic determinants; in fact, the existence of a “paternal antigen” has been proposed. Nulliparity is a well-known risk factor. Change of partner to a woman without history of preeclampsia increases the risk; however, this change decreases in women with history of the condition. High interval between pregnancies, short sexual intercourse before pregnancy, and conception by intracytoplasmic sperm injection suggest a limited exposure to the so-called paternal antigen. A man who was born from a mother with preeclampsia also increases the risk to his partner. Not only maternal but also paternal obesity is a risk factor for preeclampsia. Fetal HLA-G variants from the father increased the immune incompatibility with the mother and are also significantly associated with preeclampsia in multigravida pregnancies. An analysis of a group of Swedish pregnant women showed that the risk for preeclampsia is attributable to paternal factors in 13% of cases, which could be related to genetic interactions with maternal genetic factors. This review aimed to evaluate the evidences of the father’s contribution to the onset of preeclampsia and determine the importance of including them in future studies.
... Later in life he explored the T cell signature and monocyte fingerprint in the human placenta, investigating their correlation with pregnancy outcomes [17][18][19][20][21]. Also in this research line, immunogenetics was of interest, as his team showed that some degree of HLA matching, similar to the natural situation, is beneficial for a successful pregnancy after oocyte donation [22,23]. In his research, Frans boldly tackled controversial topics, which is exemplified by a paper that revealed a correlation between oral sex and a lower incidence of the pregnancy complication preeclampsia [24]. They proposed that soluble HLA in seminal fluid might play a role in inducing immunological tolerance [25]. ...
... The removal of the seminal vesicle, which produces seminal plasma, results in no increase in paternal antigen-specific Treg cells or a decrease in the number of implantations, suggesting that seminal plasma plays an important role in the differentiation of paternal antigenspecific Treg cells 42,44,72 (Figure 1). Seminal plasma contains transforming growth factorβ and prostaglandin E2, which induce Treg cells,72 as well as soluble paternally derived HLA-class I antigen.73 ...
Background
Immune cells play an important role in the establishment of pregnancy, and abnormalities in the immune system can cause implantation failure and miscarriage.
Methods
Previous papers have been summarized and the role of immune cells in reproduction is reviewed.
Results
The immune environment in the uterus changes drastically from before implantation to after pregnancy to maintain pregnancy. In allogeneic pregnancies, immature dendritic cells (DCs) that induce immune tolerance from outside the uterus flow into the uterus, and mature DCs that remain in the uterus express programmed cell death ligand 2, which suppresses the immune response. Macrophages are classified into M1‐macrophages, which induce inflammation, and M2‐macrophages, which suppress inflammation; M1‐macrophages are required for luteinization, and M2‐macrophages induce the differentiation of endometrial epithelial cells to enable implantation. Regulatory T cells, which suppress rejection, are essential for the implantation and maintenance of allogeneic pregnancies. Implantation failure and fetal loss are associated with decreased numbers or qualitative abnormalities of DCs, macrophages, and regulatory T cells. The clinical usefulness of immunomodulatory therapies in patients with repeated implantation failure and recurrent pregnancy loss has been reported.
Conclusion
The provision of individualized medical care in cases of implantation failure or miscarriage may improve clinical outcomes.
... Because poor placentation is the basis of PE, especially in early onset PE (diagnosed before 34 weeks), immune maladaptation has been proposed to underlie the development of PE (9,10), and this relationship is supported by many reports. Epidemiologically, the risk of developing PE is higher in cases with inadequate exposure to paternal antigens (first partner pregnancy, long interpregnancy interval, oocyte donation, etc.), possibly due to inadequate induction of paternal antigen-specific immune tolerance (11)(12)(13)(14)(15). In addition, quantitative and functional impairment of Tregs has been reported during PE (6,(16)(17)(18)(19)(20). FOXP3 + Tregs are a heterogeneous population with multiple subsets. ...
A balance between pro-inflammatory decidual CD4⁺ T cells and FOXP3⁺ regulatory T cells (FOXP3⁺ Tregs) is important for maintaining fetomaternal tolerance. Using single-cell RNA-sequencing and T cell receptor repertoire analysis, we determined that diversity and clonality of decidual CD4⁺ T cell subsets depend on gestational age. Th1/Th2 intermediate and Th1 subsets of CD4⁺ T cells were clonally expanded in both early and late gestation, whereas FOXP3⁺ Tregs were clonally expanded in late gestation. Th1/Th2 intermediate and FOXP3⁺ Treg subsets showed altered gene expression in preeclampsia (PE) compared to healthy late gestation. The Th1/Th2 intermediate subset exhibited elevated levels of cytotoxicity-related gene expression in PE. Moreover, increased Treg exhaustion was observed in the PE group, and FOXP3⁺ Treg subcluster analysis revealed that the effector Treg like subset drove the Treg exhaustion signatures in PE. The Th1/Th2 intermediate and effector Treg like subsets are possible inflammation-driving subsets in PE.
... Across different parts of the world, the rate of oral sex practices has been progressively increasing over the decades [3]. In the largest and most recent multi-continental survey on Furthermore, oral sex has been associated with the reduction of risk of multiple gynaecological and obstetric problems such as vaginal and/or anal sexually transmitted infections, unwanted pregnancy, anxiety over becoming pregnant, pre-enclampsia, miscarriage and endometriosis [5,[19][20][21]. ...
This study aimed to conduct a mixed-methods SR of the literature investigating the experiences (knowledge, attitudes, practices, and effects of use) concerning dental dam and cling film use. The SR methodology was informed by the Preferred Reporting Items for SRs and Meta-analysis framework, the Cochrane Handbook for SR of Interventions, the Joanna Briggs Institute guideline for conducting mixed-methods SRs, and the PICO (population, intervention (or exposure), comparison, and outcome) framework. Using a set of inclusion criteria, relevant studies in the literature were obtained for the review from 11 electronic databases, Teesside University Library, websites of multilateral health organisations, and reference lists of eligible literature. The included literature was appraised for quality using the Mixed Methods Appraisal Tool version 2018 and the AAOCDS Tool. Only those studies in the literature with sufficient quality were finally included for data extraction (using an adapted version of the JBI Quality Assessment and Review Instruments) and synthesis. Best evidence synthesis was performed for the quantitative data, while meta-aggregation was performed for the qualitative data. The synthesised data were then configured using the segregated approach. A total of 529 studies from the literature were obtained from the searched databases, while only four were obtained from the other sources. After de-duplication, screening, and quality appraisal, a total of 17 studies were found eligible and included in this review. Sixteen studies were non-grey literature while, one was grey literature, and only a few reported a finding on cling film and heterosexual populations. A total of 5516 adolescents and adults were investigated in the analysed literature. Overall, the reported knowledge of dental dams was generally poor, while no study reported knowledge of cling film. The attitudes towards dental dams/cling film were complex and predominantly negative, with very few participants using dental dams/cling film for oral sex. No study reported any finding on the effect(s) of dental dam/cling film use. In conclusion, there is a need for robust and strategic public health interventions for sexual health and safer oral sex practices.
... Oral sex has its benefits and risks. Oral sex had been found to improve the sexual satisfaction, intimacy, and relationship quality among sexual partners [7,8]; also, it reduces the risk of endometriosis, miscarriage, the sexually transmitted infections of the anus or genitalia, and pre-eclampsia [7,[9][10][11]. However, if carried out unprotected, it is possible to contract sexually transmitted oral infections (STOIs) through oral sex [12,13]. ...
Oral sex, a risky sexual behaviour, is now a common sexual behaviour in Nigeria. Nigerian clinicians play crucial roles in the promotion of healthy sexual behaviours among the lay public. This study seeks to identify those factors that determine the willingness of Nigerian clinicians to recommend protected oral sex to patients with history of oral sex practice. This study surveyed 330 clinicians in Nigeria, using an e-questionnaire circulated via WhatsApp and Telegram. The collected data were analysed using SPSS version 21 software. The majority (89.1%) of the respondents were willing to recommend protected oral sex for patients engaging in oral sex. Amidst all of the factors (sociodemographic factors, sexual history, etc.) investigated, only one factor (which was the uncertainty about the risk level of oral sex) was found to predict the willingness to recommend protective measures to patients on oral sex (OR = 3.06, p = 0.036). In conclusion, only few factors were found to influence Nigerian clinicians in engaging in patient education on safer oral sex practices.
... These results suggest that paternal antigen-specific Tregs are induced by paternal antigens in seminal plasma, and that these cells accumulate in the uterine regional lymph nodes to prepare for implantation. In support of this hypothesis, soluble HLA antigens are contained in semen [25]. It has also been reported that the number of oral sex sessions that induce oral immune tolerance is low in cases of preeclampsia (PE), which is also thought to be a breakdown of immune tolerance to paternal antigens during pregnancy [26]. ...
It is well recognized that immune tolerance is important to prevent semiallografted fetuses from rejection by maternal immunocompetent cells; however, immune activation also plays an important role in placental development and fetal growth. Basic and clinical studies have shown that an imbalance between immune activation and regulation can lead to implantation failure, miscarriage, and preeclampsia. Here, the balance between immunostimulation and immunoregulation in reproduction will be reviewed.
... However, a variety of immunoregulatory processes are known to be induced by pregnancy as reviewed by Abu-Raya et al. (11), which may limit child-HLA-specific antibody responses. Despite that only women with no prior record of major alloimmunization events were enrolled in the study and given the presence of soluble HLA in seminal plasma (32,33), prior HLA-specific immunization, e.g., by unprotected sex (34), cannot be fully ruled out in the present cohort due to the unavailability of pre-pregnancy samples. Conversely, Kakaiya et al. (35) reported an HLA antibody prevalence of only 1.6% in healthy female blood donors, suggesting a limited impact of preformed antibodies on the study. ...
Predicted Indirectly ReCognizable Human Leukocyte Antigen (HLA) Epitopes (PIRCHE) are known to be a significant risk factor for the development of donor HLA-specific antibodies after organ transplantation. Most previous studies on PIRCHE limited their analyses on the presentation of the HLA-DRB1 locus, although HLA-DRB3/4/5, -DQ, and -DP are also known for presenting allopeptides to CD4+ T cells. In this study, we analyzed the impact of predicted allopeptides presented by these additional loci on the incidence of HLA-specific antibodies after an immunization event. We considered pregnancy as a model system of an HLA immunization and observed child-specific HLA antibody (CSA) development of 231 mothers during pregnancy by samples being taken at delivery. Our data confirm that PIRCHE presented by HLA-DRB1 along with HLA-DRB3/4/5, -DQ, and -DP are significant predictors for the development of CSA. Although there was limited peptidome overlap observed within the mothers’ presenting HLA proteins, combining multiple presenting loci in a single predictor improved the model only marginally. Prediction performance of PIRCHE further improved when normalizing scores by the respective presenters’ binding promiscuity. Immunogenicity analysis of specific allopeptides could not identify significant drivers of an immune response in this small cohort, suggesting confirmatory studies.
... Koelman et al. [51] demonstrated the presence of soluble class I human leukocyte antigen (HLA) molecules in seminal plasma representing a potential straightforward way of endometrial exposition. Interestingly, soluble HLA molecules have been demonstrated to induce apoptosis in human cytotoxic T cells [52]; induction of apoptosis may be a mechanism in inducing specific tolerance against the partners HLA cell membrane molecules. ...
The maternal syndrome preeclampsia is triggered by syncytiotrophoblast (STB) stress; the heterogeneity of the syndrome is caused by the different pathways leading to this STB stress. Inflammation plays a pivotal role in the pathogenesis of preeclampsia. While, the immune system at large is therefore intimately involved in the causation of this heterogeneous syndrome, the role of the adaptive immune system is more controversial. The classic paradigm placed preeclampsia as the disease of the nulliparous pregnant women. Up to the later part of the 20th century, human reproduction, particularly in Western societies, was characterised by a low rate of pre-marital sex, and the great majority of children being born within one stable sexual relationship. More prolonged periods of regular sexual intercourse within a stable relationship have been demonstrated to reduce the risk of preeclampsia and fetal growth restriction. Primarily animal studies have indeed shown that repetitive sperm exposure leads to partner specific mucosal tolerance. Societal changes made partner change over the reproductive period of individual women extremely common. For the adaptive immune system of multiparous women, being pregnant in a new sexual relationship (primipaternity) would represent being faced with a new “hemi-allograft”. In these pregnancies, potential couple-specific immune “maladaptation” could lead to the superficial cytotrophoblast invasion of the spiral arteries, known to be associated with early-onset preeclampsia. Having a new pregnancy in a different relationship does indeed increase the risk for this type of preeclampsia. Large epidemiologic population studies identified prolonged birth interval but not “primipaternity” as a risk factor for preeclampsia in multiparous women. This apparent contradiction is explained by the fact that the great majority of preeclampsia cases in these population studies involve term preeclampsia. In late-onset preeclampsia, the far more common phenotype of the syndrome, STB stress is not caused by lack of proper spiral artery modification, but involves maternal genetic predisposition to cardiovascular and metabolic disease, with in particular obesity/metabolic syndrome representing major players. Partner or couple specific issues are not detectable in this disease phenotype.
... Regardless, Th3 Treg was first described to have an important role in oral tolerance (182). Interestingly, exposure to semen through oral sex has been proposed to be beneficial for subsequent pregnancy outcomes in couples experiencing PE or RPL (186)(187)(188), providing a possible mechanistic explanation for this effect. ...
Objectives: Maintenance of immunological tolerance towards the semi-allogeneic fetus is important for successful pregnancy outcome. However, some women experience unexplained recurrent pregnancy losses (uRPL). It has been described that regulatory T-cell (Treg) percentages are decreased at the maternal-fetal interface (decidua) during miscarriage compared to elective termination pregnancies. We hypothesized that in women with uncomplicated term pregnancy after a previous history of uRPL a higher level of immune regulation is required at the fetal-maternal interface compared to women with uncomplicated pregnancy without any miscarriage in history.
Methods: We developed two antibody panels for in-depth immune profiling by mass cytometry using a total of 59 unique immune markers. The first panel focused on all immune lineages while the second had a focus on T cells, including intracellular markers. We analysed decidual immune cells isolated from placentas of 6 women with historic uRPL (cases) and 3 women without miscarriage history (controls).
Results: Analysis and visualization of the high-dimensional data was performed by applying HSNE and t-SNE for the case- and control groups combined. For this first analysis we focused on Tregs. In clustering analysis based on marker expression, FoxP3+ and FoxP3- Treg-like cells (CD25+CD127-CTLA-4+) clustered together. We observed a significantly higher Treg-like cell percentage in the decidua parietalis of cases compared to controls (2.35% vs. 0.18% within CD45+ cells, P=0.024). For both the decidua basalis and parietalis, 50% of cases had an increased Treg-like cell percentage compared to controls.
Conclusion: A proportion of women with an history of uRPL display increased Treg-like cell levels at the fetal-maternal interface, suggesting a possible compensatory role allowing for a successful pregnancy. We aim to further elucidate the immunological context of this potential regulatory compensation mechanism by analyzing the other immune cell types in the decidua.
... This is a particularly interesting (and probably unexpected) finding, that is relatively easily understood from an immunological point of view, and it is hard to conceive of alternative explanations. (Note, however, that in the index study [245], the correlation or otherwise of oral and vaginal sex was not reported, so it is not entirely excluded that more oral sex also meant more vaginal sex.) ...
Although it is widely recognised as involving two stages (poor placentation followed by oxidative stress/inflammation), the precise originating causes of pre-eclampsia (PE) remain elusive. We have previously brought together some of the considerable evidence that a (dormant) microbial component is commonly a significant part of its aetiology. However, apart from recognising, consistent with this view, that the many inflammatory markers of PE are also increased in infection, we had little to say about immunity, whether innate or adaptive. In addition, we focussed on the gut, oral and female urinary tract microbiomes as the main sources of the infection. We here marshall further evidence for an infectious component in PE, focussing on the immunological tolerance characteristic of pregnancy, and the well-established fact that increased exposure to the father's semen assists this immunological tolerance. As well as these benefits, however, semen is not sterile, microbial tolerance mechanisms may exist, and we also review the evidence that semen may be responsible for inoculating the developing conceptus with microbes, not all of which are benign. It is suggested that when they are not, this may be a significant cause of pre-eclampsia. A variety of epidemiological and other evidence is entirely consistent with this, not least correlations between semen infection, infertility and PE. Our view also leads to a series of other, testable predictions. Overall, we argue for a significant paternal role in the development of PE through microbial infection of the mother via insemination.
... Interestingly, this exposure does not have to be local. Exposure to paternal antigen via nonvaginal routes can also prime the endometrium immunologically [77]. Although the mechanism responsible for this priming effect is not clear, seminal fluid contains soluble and exosome-borne signaling agents that promote leukocyte recruitment and generation of regulatory T cells (Treg cells) which suppress inflammation, promote vascular adaptation, and foster tolerance towards fetal antigens [78]. ...
Interventions to prevent pregnancy complications have been largely unsuccessful. We suggest this is because the foundation for a healthy pregnancy is laid prior to the establishment of the pregnancy at the time of endometrial decidualization. Humans are one of only a few mammalian viviparous species in which decidualization begins during the latter half of each menstrual cycle and is therefore independent of the conceptus. Failure to adequately prepare (decidualize) the endometrium hormonally, biochemically, and immunologically in anticipation of the approaching blastocyst—including the downregulation of genes involved in the pro- inflammatory response and resisting tissue invasion along with the increased expression of genes that promote angiogenesis, foster immune tolerance, and facilitate tissue invasion—leads to abnormal implantation/placentation and ultimately to adverse pregnancy outcome. We hypothesize, therefore, that the primary driver of pregnancy health is the quality of the soil, not the seed.
... The risk of preeclampsia increases in women at the first pregnancy following a partner change and after pregnancy intervals of more than 10 years (41)(42)(43). Increased risk of preeclampsia has also been reported in association with long-term condom usage and artificial insemination by donor, indicating that insufficient paternal antigen-specific tolerance mediated by seminal plasma priming may underlie preeclampsia (44)(45)(46). Pregnancy following oocyte donation, in which the fetus is completely allogeneic, associates with a significantly high risk of preeclampsia (45,47). These epidemiological data demonstrate that the failure or lack of paternal antigen-specific tolerance may be responsible for preeclampsia. ...
CD8⁺ T cells, the most abundant T cell subset in the decidua, play a critical role in the maintenance of pregnancy. The majority of decidual CD8⁺ T cells have an effector memory phenotype, while those in the peripheral blood display a naive phenotype. An increased amount of highly differentiated CD8⁺ T cells in the decidua indicates local antigen stimulation and expansion, albeit these CD8⁺ T cells are suppressed. In decidual CD8⁺ T cells, co-inhibitory molecules such as PD-1, TIM-3, LAG-3, and CTLA-4 are upregulated, reflecting the suppression of cytotoxicity. Previous studies established the importance of the PD-1/PD-L1 interaction for feto-maternal tolerance. CD8⁺ T cells could directly recognize fetal-specific antigens, such as HLA-C, expressed by trophoblasts. However, although fetal-specific CD8⁺ T cells have been reported, their TCR repertoires have not been identified. In this study, we analyzed the TCR repertoires of effector memory CD8⁺ T cells (CD8⁺ EM cells) and naive CD8⁺ T cells (CD8⁺ N cells) in the decidua and peripheral blood of women with normal or complicated pregnancy and examined PD-1 expression at a single-cell level to verify whether antigen-specific CD8⁺ T cells accumulate in the decidua and to identify immunological differences related to the suppression of antigen-specific CD8⁺ T cells between normal pregnancy, miscarriage, and preeclampsia. We observed that some TCRβ repertoires, which might recognize fetal or placental antigens, were clonally expanded. The population size of clonally expanded CD8⁺ EM cells was higher in the decidua than in the peripheral blood. CD8⁺ EM cells began to express PD-1 during the course of normal pregnancy. We found that the total proportion of decidual CD8⁺ EM cells not expressing PD-1 was increased both in miscarriage and in preeclampsia cases, although a different mechanism was responsible for this increase. The amount of cytotoxic CD8⁺ EM cells increased in cases of miscarriage, whereas the expression of PD-1 in clonally expanded CD8⁺ EM cells was downregulated in preeclampsia cases. These results demonstrated that decidual CD8⁺ EM cells were able to recognize fetal-specific antigens at the feto-maternal interface and could easily induce fetal rejection.
... Sperm exposure was defined as: sexual cohabitation >12 months; 14 either sexual cohabitation >12 months or oral sex before pregnancy; 15 either sexual cohabitation >12 months or no use of barrier methods before pregnancy; 17 no use of barrier methods before pregnancy; 16,18,20 oral sex before pregnancy. 19 The quality of the studies included in our meta-analysis was assessed by the MINORS' tool for assessing the risk of bias (Figure 2A, Figure 2B). All studies had low risk of bias in "aim," and the majority in "rate". ...
Objective
The aim of this systematic review was to evaluate the role of paternal sperm exposure before pregnancy on the risk of preeclampsia.
Study design
The search was conducted using electronic databases from inception of each database through October 2019. Review of articles also included the abstracts of all references retrieved from the search. Only studies evaluating exposure to paternal sperm before pregnancy on the risk of preeclampsia in the subsequent pregnancy were included. Exposure group was defined as significant exposure to paternal sperm, either measured by sexual cohabitation, oral sex habit, or by absence of barrier methods. Control groups was defined as minimal exposure to paternal sperm, either measured by lack of sexual cohabitation or oral sex habit, or by use of barrier methods. Sperm exposure identifiable before pregnancy that may be suspected to modify the risk of preeclampsia was examined. The primary outcome was the incidence of preeclampsia. Subgroup analyses by parity and type of sperm exposure were planned. All analyses were carried out using the random effects model. The pooled results were reported as the OR with 95% confidence interval (CI). Heterogeneity was measured using I-squared (Higgins I²).
Results
Seven studies including 7,125 pregnant women were included in this systematic review. Overall, the incidence of preeclampsia was similar in women with a higher overall sperm exposure compared to controls, 774/5,512 (14%) vs 220/1,619 (13.6%); OR 1.04, 95% CI 0.88 to 1.22, respectively. The incidence of preeclampsia was significantly reduced in women with a higher overall sperm exposure when including only nulliparous women, 643/3,946 (16.1%) vs 170/725 (23.4%); OR 0.63, 95% CI 0.52 to 0.76. Significant lower rate of preeclampsia was also found for ≥12-month sexual cohabitation, 494/3,627 (13.6%) vs 123/691 (17.8%); OR 0.73, 95% CI 0.59-0.90. Significantly higher rate of preeclampsia was reported in women not using barrier methods, 315/1,904 (16.5%) vs 103/962 (10.7%); OR 1.65, 95% CI 1.30 to 2.10.
Conclusions
Paternal sperm exposure in nulliparous women and sexual cohabitation > 12 months before pregnancy are associated with a decreased risk of preeclampsia.
... Regardless, Th3 Treg was first described to have an important role in oral tolerance (182). Interestingly, exposure to semen through oral sex has been proposed to be beneficial for subsequent pregnancy outcomes in couples experiencing PE or RPL (186)(187)(188), providing a possible mechanistic explanation for this effect. ...
In pregnancy, the semi-allogeneic fetus needs to be tolerated by the mother's immune system. Regulatory T cells (Tregs) play a prominent role in this process. Novel technologies allow for in-depth phenotyping of previously unidentified immune cell subsets, which has resulted in the appreciation of a vast heterogeneity of Treg subsets. Similar to other immunological events, there appears to be great diversity within the Treg population during pregnancy, both at the maternal-fetal interface as in the peripheral blood. Different Treg subsets have distinct phenotypes and various ways of functioning. Furthermore, the frequency of individual Treg subsets varies throughout gestation and is altered in aberrant pregnancies. This suggests that distinct Treg subsets play a role at different time points of gestation and that their role in maintaining healthy pregnancy is crucial, as reflected for instance by their reduced frequency in women with recurrent pregnancy loss. Since pregnancy is essential for the existence of mankind, multiple immune regulatory mechanisms and cell types are likely at play to assure successful pregnancy. Therefore, it is important to understand the complete microenvironment of the decidua, preferably in the context of the whole immune cell repertoire of the pregnant woman. So far, most studies have focused on a single mechanism or cell type, which often is the FoxP3 positive regulatory T cell when studying immune regulation. In this review, we instead focus on the contribution of FoxP3 negative Treg subsets to the decidual microenvironment and their possible role in pregnancy complications. Their phenotype, function, and effect in pregnancy are discussed.
... The risk is increased in case of twin pregnancy with a risk of multiplication by three and in case of primipaternity (first pregnancy of a given couple). This primipaternity evokes a possible reaction mechanism to sperm, supported by other arguments (11). The notion of high blood pressure in the family increases the risk of occurrence by 3. In our patient who was in her third gestation, only twinning was found to be a risk factor for pre-eclampsia. ...
In general, the term "preeclampsia" refers to the presence of hypertension associated with proteinuria occurring after 20 weeks of gestation in a previously non-proteinuric and normotensive woman. A 24-year-old woman, known to be non-hypertensive, carried two pregnancies and lost two babies. In 2011, as she was carrying the third (twin) pregnancy at 17 weeks of amenorrhea, she was admitted to the hospital for an 8-kilogram excess weight gain between two antenatal visits spaced 4 weeks apart. The clinical examination revealed 140 mmHg systolic blood pressure and 80 mm Hg diastolic blood pressure. The following days, the systolic blood pressure ranged between 110 and 120 mm Hg. Furthermore, the presence of bilateral and symmetrical pitting edema of the lower limbs was reported. The laboratory assessment upon admission showed the following results, proteinuria; 3.3 g/24 h, total albumin; 1.7 g/dL, total protein; 5.4 g/dL and total calcium was 75 g/L. The test results for HIV serology, HBs antigen and HCV antibodies as well as antinuclear and native anti-DNA antibodies were negative. The treatment consisted of iron, folic acid and calcium supplementation. Cesarean section was scheduled for the 38th week. The immediate aftermath was simple. Formula feeding was recommended for the newborns and ramipril 1.25 mg was initiated in the mother once daily. The evolution was marked by a progressive reduction in proteinuria around 500 mg/24 h six months after delivery, and below 200 mg/24 h one year later. Pre-eclampsia before 20 weeks of gestation is rare. Hypertension, which is its main clinical sign, may be exceptionally absent at this stage.
... Since its discovery, sHLA has been determined in different body fluids, including blood, plasma, amniotic fluid, seminal plasma, synovial fluid, sweat, urine and peritoneal dialysate. Levels of sHLA have been studied in the context of acute and chronic graft-versus-host disease, preeclampsia, rheumatoid arthritis and chronic renal failure [22][23][24][25][26]. In patients with varicella meningitis, sHLA was detected in the cerebrospinal fluid (CSF); in patients with AIDS, the concentration of sHLA in both serum and CSF directly correlated to the stage of the disease, with a higher concentration in more advanced cases [27]. ...
A high HLA expression in uveal melanoma (UM) is part of the prognostically unfavorable inflammatory phenotype. We wondered whether the presence of soluble HLA (sHLA) in the aqueous humour is associated with clinical, histopathological or genetic tumour characteristics, and represents tumour HLA expression and intratumoural inflammation. Aqueous humour from 108 UM patients was analysed for the presence of sHLA, using a Luminex assay specific for HLA Class I. Clinical and genetic parameters were compared between sHLA-positive and negative eyes. A qPCR analysis was performed on tumour tissue using a Fluidigm assay. In 19/108 UM-containing eyes, the sHLA level in the aqueous was above the detection limit. Tumours in sHLA-positive eyes were significantly larger, more frequently involved the ciliary body, and more often showed monosomy 3, gain of chromosome 8q and loss of BAP1 staining. Melanoma-related survival was worse in patients with sHLA-positive aqueous humour. sHLA in the aqueous did not represent the tumour’s HLA expression and did not relate to immune cell infiltration in the tumour. We conclude that UM-containing eyes may contain sHLA in the aqueous humour, where it is a prognostically-unfavourable sign and may influence local immune responses.
... However, the biological rationale of this paper is not well substantiated. The articles that are being referred to in the introduction provide no more than hypotheses (Robertson and Sharkey, 2001, Koelman et al., 2000). Other referenced research is only carried out in mice, which is not a good model for early pregnancy loss in humans, since mice absorb embryos rather than miscarrying them (Clark et al., 2013, Moldenhauer et al., 2009, Ho et al., 1994. ...
... Even though there is no evidence yet that these memory cells are paternal-antigen specific, this could be a mechanism that contributes to tolerance toward paternal-fetal antigens. This mechanism is supported by existing epidemiologic data showing an association between a longer period of exposure to seminal fluid of the future father and a lower risk of preeclampsia (142)(143)(144). Generating paternal specific memory T cells as a therapeutic target, through paternal cell immunization before conception seems obvious and has indeed been carried out by several studies (145,146). ...
Adaptations of the maternal immune response are necessary for pregnancy success. Insufficient immune adaption is associated with pregnancy pathologies such as infertility, recurrent miscarriage, fetal growth restriction, spontaneous preterm birth, and preeclampsia. The maternal immune system is continuously exposed to paternal-fetal antigens; through semen exposure from before pregnancy, through fetal cell exposure in pregnancy, and through microchimerism after pregnancy. This results in the generation of paternal-fetal antigen specific memory T cells. Memory T cells have the ability to remember previously encountered antigens to elicit a quicker, more substantial and focused immune response upon antigen reencounter. Such fetal antigen specific memory T cells could be unfavorable in pregnancy as they could potentially drive fetal rejection. However, knowledge on memory T cells in pregnancy has shown that these cells might play a favorable role in fetal-maternal tolerance rather than rejection of the fetus. In recent years, various aspects of immunologic memory in pregnancy have been elucidated and the relevance and working mechanisms of paternal-fetal antigen specific memory T cells in pregnancy have been evaluated. The data indicate that a delicate balance of memory T cells seems necessary for reproductive success and that immunologic memory in reproduction might not be harmful for pregnancy. This review provides an overview of the different memory T cell subtypes and their function in the physiology and in complications of pregnancy. Current findings in the field and possible therapeutic targets are discussed. The findings of our review raise new research questions for further studies regarding the role of memory T cells in immune-associated pregnancy complications. These studies are needed for the identification of possible targets related to memory mechanisms for studies on preventive therapies.
... plus de risque que des primipares (OR ajusté = 2,5 ; 95 % IC[1,8 -3,5])226 , l'effet protecteur de l'antécédent d'avortement pourrait disparaitre après un changement de partenaire de la grossesse en cause 147 et les femmes auraient plus de risque si leur partenaire est né d'une grossesse prééclamptique227 . ...
Impact des facteurs environnementaux sur la survenue d'une pré-éclampsie » Thi-Chiên TRAN Titre : Impact des facteurs environnementaux sur la survenue d'une pré-éclampsie sévère Mots clés : Date de conception, Facteur environnement, Grossesse, Météorologie, Placenta, Pré-éclampsie Résumé Introduction : La pré-éclampsie (PE) est caractérisée par une hypertension associée à une protéinurie appa-raissant après la 20 ième semaine de grossesse. Elle est l'une des complications les plus fréquentes (pouvant aller jusqu'à 10 % des grossesses).
... 51 Additionally, the use of barrier contraceptives increases the incidence of pre-eclampsia, while oral sex acts as another mechanism to increase maternal mucosal tolerance to paternal antigens decreasing the risk of pre-eclampsia. [51][52][53] The risk of preeclampsia is lower with Asian paternity, although discordance of parental ethnicity increases the risk. 54 Furthermore, studies on paternal family history of genetic thrombophilia, hypertension, and cardiovascular disease reflect genes passed through the feto-placental unit via the father, which are associated with a number of adverse pregnancy outcomes. ...
The role of fathers prior to conception, during pregnancy, and in the post-partum period has generally not been a key consideration for Obstetric Physicians. However, this view may need challenging. This paper outlines the key importance of fathers in all phases of obstetric medical care. We review the contribution of paternal factors such as genetics, health, and lifestyle to fetal development, pregnancy complications, and maternal and neonatal wellbeing. The role of fathers in complex care decisions during pregnancy is also reviewed. Postpartum, fathers have a substantial role in shaping the future of the family unit through encouraging breastfeeding and creating a supportive environment for motherhood. This review proposes areas for future research and recommends an evidence-based change in practice in obstetric medicine that focuses on recognizing the role of fathers in the pregnancy journey.
Autophagy is a bulk degradation system that maintains cellular homeostasis by producing energy and/or recycling excess proteins. During early placentation, extravillous trophoblasts invade the decidua and uterine myometrium, facing maternal immune cells, which participate in the immune suppression of paternal and fetal antigens. Regulatory T cells will likely increase in response to a specific antigen before and during early pregnancy. Insufficient expansion of antigen‐specific Treg cells, which possess the same T cell receptor, is associated with the pathophysiology of preeclampsia, suggesting sterile systemic inflammation. Autophagy is involved in reducing inflammation through the degradation of inflammasomes and in the differentiation and function of regulatory T cells. Autophagy dysregulation induces protein aggregation in trophoblasts, resulting in placental dysfunction. In this review, we discuss the role of regulatory T cells in normal pregnancies. In addition, we discuss the association between autophagy and regulatory T cells in the development of preeclampsia based on reports on the role of autophagy in autoimmune diseases.
Historically, oral sex is part of human sexual behaviour even though some consider it taboo, and its expression is deemed inappropriate. Human rights also stand out as technology becomes more sophisticated, leading to its practice disclosure in the 21 st century. The large-scale oral sex discussion in media encourages people to express it, and there is feedback on whether it is right or not. It all depends on each person’s values. We found this sexual behaviour occurs everywhere regardless of religion, culture and race.
Pop culture influences this behaviour considerably. It can be seen in music, movies and television programmes that allude to oral sex. Numerous motivations underlying this behaviour include sexual pleasure for the sake of psychological well-being. It is undeniable that this behaviour is still controversial. There is a risk of it causing disease, but it reportedly provides many benefits.
Oral sex is not a new behaviour crossing boundaries, according to our theory. It is an old behaviour that has been highlighted because of the factors that support it. This behaviour, still considered taboo, has its disadvantages, such as sexually transmitted disease and oral cancer, but also has benefits, such as preventing preeclampsia.
Background:
Nowadays pathogenesis of preeclampsia is still unknown. Among the different etiological hypotheses, some authors proposed that it might be due to an abnormal immunologic response to foreign fetal antigen derived from the father's sperm. Indeed, the fetus is considered a semi allograft, being one half paternally derived in its antigenicity, and the first pathogenic insult of preeclampsia may be an abnormal maternal immune response towards this semi-allogenic implant. In the context of Artificial Reproductive Techniques, it has been shown that the use of donor and surgically retrieved spermatozoa (e.g. Testicular Sperm Extraction) increases the risk of preeclampsia, confirming the protective effect of sperm exposure on maternal complications.
Objective:
Determining whether the lack of exposure to sperm antigens is associated with worse maternal and neonatal outcomes in pregnancies obtained through intracytoplasmic sperm injection after testicular sperm extraction for obstructive azoospermia.
Material and methods:
This is a single-center case-control retrospective study, focusing on all first pregnancies obtained through intracytoplasmic sperm injection after testicular sperm extraction for obstructive azoospermia at Humanitas Fertility Center between January 1st, 2010 and December 31st, 2019. Controls included patients that achieved their first pregnancy with intracytoplasmic sperm injection and ejaculated sperm, for a diagnosis other than azoospermia, in the same time period. Cases were matched with controls in a 1:2 ratio, considering female age, female BMI and year of controlled ovarian stimulation. The primary outcome measure was the delivery rate, defined as the number of deliveries divided by the total number of clinical pregnancies. Secondary outcome measures focused on maternal and neonatal complications, such as miscarriage rate, rate of main obstetric complications, prematurity rate and rate of congenital malformations.
Results:
By analyzing overall 113 pregnancies among cases and 214 pregnancies among controls, this study showed that the delivery rate was higher in controls with respect to cases (92.06% vs 84.07%, p = 0.026); among deliveries, live births were respectively 98.95% and 100%, while only one stillbirth occurred in cases. The first trimester miscarriage rate was higher in the cases than controls (13.27% vs 6.07%, p = 0.027), while no difference was found among rate of second trimester miscarriages, therapeutic abortions and ectopic pregnancies. There was no difference regarding the rate of maternal complications, including gestational hypertension, preeclampsia, HELLP syndrome, gestational diabetes, placenta previa, placental abruption and premature rupture of the membranes. Considering neonatal complications, it was shown that twins belonging to controls had a higher prematurity rate with respect to cases (65.79% vs 50.00%) but without a statistical relevance. Lastly, the rate of congenital malformations did not differ among the two groups.
Discussion:
This study showed that, once couples diagnosed with obstructive azoospermia achieve a pregnancy, they have a much higher risk of miscarriage in the first trimester in respect to non-azoospermic patients. Moreover, controls had a higher delivery rate in respect to cases; however, when the fetal status at birth was compared, no difference was found between live births and stillbirths.
Conclusions:
Differently from the findings in the literature, no association with preeclampsia was found. This might be related to a collider bias/left truncation bias: since azoospermic patients are at higher risk of early termination of pregnancy, it results that they do not have the possibility to develop preeclampsia and other adverse outcomes. This article is protected by copyright. All rights reserved.
Since thousands of years ago, oral sex has become part of sexual behavior among humans. Oral sex is considered taboo. Its taboo does not lie in the behavior, but its expression is deemed inappropriate. As technology becomes more sophisticated, human rights also stand out, leading to the disclosure of the practice in the 21 st century. The oral sex that is discussed on a large scale in media encourages people to express it as feedback whether within right or not. It all depends on the value of each people. We found that this sexual behavior is found everywhere regardless of religion, culture, and race.
Pop culture influences this behavior so much, it can be seen from music, movies, and television programs that provoke oral sex. Many motivations underlying this behavior include getting sexual pleasure for the sake of psychological well-being. But it is undeniable that this behavior is still controversial. It could be at risk of causing disease and, on the other hand, is reported to provide many benefits.
According to our theory, oral sex is not a new behavior crossing boundaries. It is just an old behavior that surfaces because of the factors that support it. This behavior, which is still considered taboo, has its disadvantages such as sexually transmitted disease and oral cancer but has also benefits such as preventing preeclampsia.
Since thousands of years ago, oral sex has become part of sexual behavior among humans. Oral sex is considered taboo. Its taboo does not lie in the behavior, but its expression is deemed inappropriate. As technology becomes more sophisticated, human rights also stand out, leading to the disclosure of the practice in the 21 st century. The oral sex that is discussed on a large scale in media encourages people to express it as feedback whether within right or not. It all depends on the value of each people. We found that this sexual behavior is found everywhere regardless of religion, culture, and race.
Pop culture influences this behavior so much, it can be seen from music, movies, and television programs that provoke oral sex. Many motivations underlying this behavior include getting sexual pleasure for the sake of living well-being. But it is undeniable that this behavior is still controversial. It could be at risk of causing disease and, on the other hand, is reported to provide many benefits.
According to our theory, oral sex is not a new behavior crossing boundaries. It is just an old behavior that surfaces because of the factors that support it. This behavior, which is still considered taboo, has its disadvantages such as sexually transmitted disease but has also benefits such as preventing preeclampsia.
Fetal antigen-specific tolerance is important for maintaining allogeneic pregnancies. Maternal conventional T cells recognize fetal antigens; however, regulatory T (Treg) cells suppress immune reactions against the fetus. Fetal antigen-specific Treg cells are induced in the decidua upon contact with antigen-presenting cells and extravillous trophoblasts (EVTs). Functional alteration of cytotoxic T cells (CTLs) in the decidua also contributes to maintaining the pregnancy. Reduced, dysfunctional, and imbalanced Treg cell distribution likely contributes to the pathogenesis of pregnancy complications, such as miscarriage and preeclampsia. Recent studies have revealed differences in Treg cell characteristics during preeclampsia and miscarriage. Treg cell reduction in the decidua is likely associated with miscarriage. Insufficient expansion of fetal antigen-specific Treg cells in the decidua probably plays a role in preeclampsia pathogenesis. In addition, the balance between Treg cell-mediated tolerance and functional alteration of CTLs is important. Further investigations of functional molecules in Treg cells will contribute to the development of immunotherapy for pregnancy complications.
Regulatory T cells (Treg cells) are an immunosuppressive subset of helper T cells, which are crucial to maintaining immune homeostasis, self-tolerance, and feto-maternal tolerance. Fetal alloantigens are recognized by conventional T cells; however, Treg cells, directly and indirectly, suppress their cytotoxic activities against fetuses. Murine models show that paternal antigen-specific Treg cells (PA-Treg cells) expand at the feto-maternal interface during pregnancies and seminal plasma-priming is important to this process. In humans, extensive epidemiological data of preeclampsia suggest that insufficient PA-specific tolerance relates to its development, but some epidemiological studies suggest the relationship between PA-specific tolerance and miscarriages. Recent basic research studies imply the immunological differences between miscarriages and preeclampsia from the standpoint of PA-Treg cells, which support epidemiological evidence. In this section, we review the latest understanding of Treg cell-mediated tolerance and prospects of clinical applications of immunological therapies and preventions for miscarriages and preeclampsia.
Cytokine secretion by NK cells is abnormal in some women with recurrent pregnancy loss (RPL). Cytokine production is usually evaluated after stimulation with PMA and ionomycin. However, stimulation of uterine NK cells with semen corresponds more closely to physiological conditions at the time of conception. As seminal plasma has immunomodulatory properties, we aimed to elucidate compatibility between uterine NK cells and semen. Endometrial samples were stimulated with PMA/ionomycin, semen, seminal plasma, or spermatozoa. Thereafter, cytokine production by NK (CD56bright) cells was evaluated using flow cytometry and compared between women with and without a history of RPL associated with abnormal NK cell distribution in the endometrium or unexplained RPL. The ratios (%) of NK cells producing IFN-γ and TNF-α (NK1 phenotype), IL-4 (NK1/NK2 phenotype), and IL-10 (NK1/NKr1 phenotype) were significantly lower after stimulation with semen than with PMA/ionomycin (P < 0.01). After exposure to semen, ratios (%) of NK cells producing IL-4 and IL-10 in patients with unexplained RPL were significantly lower (P < 0.05), whereas those of NK1/NK2 and NK1/NKr1 were significantly higher (P < 0.01) than those in controls. The shift of endometrial NK cells to the NK2 phenotype was more pronounced when stimulated by semen than by PMA/ionomycin. However, a semen-induced shift to NK1 in women with unexplained RPL could induce miscarriage. Couple-specific immunological compatibility tests through semen stimulation in vitro might provide important information to avoid RPL.
Oral administration of antigen is a potent route for induction of systemic tolerance. Regulatory T cells and TH3 cellsare generated at intestinal mucosal sites. Oral exposure to antigens in seminal plasma has been suggested to be ableto generate ‘tolerance’ at the materno-fetal interface that may reduce the risk of pre-eclampsia and recurrent miscarriage. Issues relating to assessing the applicability of oral exposure to seminal plasma antigens in recurrentmiscarriage are discussed. Such tolerance could represent an unappreciated confounder in immunotherapy trials.
Using a variety of different and often provocative examples, this chapter illustrates how evolutionary theory can be used to think about things in new and sometimes even counterintuitive ways. Examples include how semen sampling may be an evolved mate-choice mechanism, why pubic hair removal may promote pedophilia, why we owe our existence to the moon, why the risk of conception is higher as a result of being raped, why bottle-feeding your previous child may put your next child at risk of becoming autistic, and why smart people are attracted to evolutionary studies. The chapter argues that evolutionary theory enables people to think about human behavior and human existence in ways that are outside the box.
A possible way of immunomodulation of the maternal immune system before pregnancy would be exposure to paternal antigens via seminal fluid to oral mucosa. We hypothesized that women with recurrent miscarriage have had less oral sex compared to women with uneventful pregnancy.
In a matched case control study, 97 women with at least three unexplained consecutive miscarriages prior to the 20th week of gestation with the same partner were included. Cases were younger than 36 years at time of the third miscarriage. The control group included 137 matched women with an uneventful pregnancy. The association between oral sex and recurrent miscarriage was assessed with conditional logistic regression, odds ratios (ORs) were estimated. Missing data were imputed using Imputation by Chained Equations.
In the matched analysis, 41 out of 72 women with recurrent miscarriage had have oral sex, whereas 70 out of 96 matched controls answered positive to this question (56.9% vs. 72.9%, OR 0.50 95%CI 0.25−0.97, p = 0.04). After imputation of missing exposure data (51.7%), the association became weaker (OR 0.67, 95%CI 0.36–1.24, p = 0.21).
In conclusion, this study suggests a possible protective role of oral sex in the occurrence of recurrent miscarriage in a proportion of the cases. Future studies in women with recurrent miscarriage explained by immune abnormalities should reveal whether oral exposure to seminal plasma indeed modifies the maternal immune system, resulting in more live births.
Pregnancy-induced hypertension affects at least 10% of all pregnancies. An association with first pregnancy or a change in paternity for subsequent pregnancies has been suggested. We studied the duration of sexual cohabitation with the father prior to conception and the incidence of pregnancy-induced hypertension. During a five-month period, 1011 consecutive women who delivered in an obstetric unit were interviewed about paternity and duration of sexual cohabitation before conception. Obstetric charts were abstracted to identify three groups: those with pregnancy-induced hypertension, chronic hypertension, and normal blood pressure. The incidence of pregnancy-induced hypertension was 11.9% among primigravidae, 4.7% among same-paternity multigravidae, and 24.0% among new-paternity multigravidae. For both primigravidae and multigravidae, length of sexual cohabitation before conception was inversely related to the incidence of pregnancy-induced hypertension (p < 0.0001). Similar results were observed after control for race, education, maternal age, marital status, and number of pregnancies. Pregnancy-induced hypertension may be a problem of primipaternity rather than primigravidity. Furthermore, an extended duration of sexual cohabitation before conception may protect against pregnancy-induced hypertension.
Few authors have published investigations regarding a possible association between preeclampsia and changing paternity. This study employs an epidemiological approach to explore the relationship between severe preeclampsia and changes in paternity patterns among multigravidae in a Caribbean community (Guadeloupe, French West Indies). Multiparae who were diagnosed with preeclampsia or eclampsia with fetal complications (transfer of their infants in the Neonatal Department) and controls were examined (134 mothers' interviews). Information concerning paternity for the index and previous pregnancies was collected from three groups: women with pregnancy-induced hypertension (PIH); women with chronic hypertension (CH); and a control group consisting of women without hypertension during pregnancy. In 21/34 (61.7%) of PIH mothers, the father of the current pregnancy was different than that of the former, compared to 4/40 (10%) among CH and 10/60 (16.6%) in the controls (P < 0.0001). Moreover, considering three and four consecutive pregnancies, there was a significant trend (P < 0.005 and P < 0.02) for an increase in PIH with having a different father in each successive pregnancy. Patterns of changing paternity were significantly correlated with pregnancy-induced hypertension in multiparae but not with chronic hypertension and controls.
The ability to predict the likely occurrence of graft-versus-host-disease (GVHD) after BMT would be extremely valuable. We performed a retrospective study on the correlation between soluble HLA class I (sHLA-I) levels and GVHD in the sera of 34 patients receiving an allogeneic BMT and in the sera of 12 patients receiving an autologous BMT. sHLA-I levels measured pre- and at different times post-BMT were correlated with the occurrence of post-BMT complications, ie acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD), infections and relapse. No changes in sHLA-I levels (delta sHLA-I) occurred in autologous and allogeneic BMT patients without GVHD. In contrast, sHLA-I reached high levels in patients suffering from GVHD. Increased sHLA-I levels correlated strongly with episodes of both acute and chronic GVHD (P = 0.004 and P = 0.005, respectively). Also during relapse increased sHLA-I levels were found (P = 0.032). During infections sHLA-I levels increased, although not significantly. Kinetic studies gave no evidence that the increase in sHLA-I levels preceded the clinical occurrence of aGVHD or of cGVHD. A slight, but significant correlation was found between total blood bilirubin levels and sHLA-I levels in patients suffering from GVHD (P = 0.037), indicating the contribution of the liver as a source of sHLA-I. We conclude that measurements of sHLA-I levels do not function as a predictive parameter for GVHD, but can be valuable for the monitoring of GVHD after BMT.
The microlymphocytotoxicity test is universally employed for serological HLA-A, -B, -C, -DR, and -DQ typing. Peripheral blood lymphocytes (PBL) (consisting of approximately 80% T and 10-15% B cells in healthy subjects) or T cells are generally used as targets for HLA-A, -B, and -C typing. B cell enriched suspensions are used for typing HLA-DR and -DQ antigens which are not expressed on resting T cells. Lymphocytes are tested with a set of HLA specific alloantibodies which are polyclonal antisera or monoclonal antibodies (see Chapter 2) each selected to react with one (monospecific), or sometimes two or more (polyspecific/ multispecific) HLA antigens. For full HLA typing the antibody set should cover as many of the various HLA antigens as possible. Reagents for HLA typing should ideally be selected to give strong reliable positive and negative results.
Large numbers of maternal lymphocytes are present in breast milk. We asked whether exposure of an infant to maternal lymphocytes during the process of breast feeding would have an effect on the subsequent reactivity of a patient to a maternal-donor related renal transplant. We studied the posttransplant course of 55 patients who had received a primary maternal-donor transplant. Twenty-seven recipients had been breastfed during infancy and 28 recipients had not been breast-fed. A history of breast feeding was associated with a more favorable posttransplant course as measured by the percentage of patients who had no rejection episodes during the first posttransplant year (P [less than or greater than] .006). The one-year graft function rate for breast-fed recipients was 82%; this was statistically significantly better than the 57% measured for non-breast-fed recipients (P [less than or greater than] .05). Statistical significance of differences between groups was not attained when results were evaluated over a five-year interval. A difference between breastfed and non-breast-fed recipients was not apparent when we evaluated a somewhat smaller group of patients who had received a paternal donor transplant. From these observations we conclude that the process of breast feeding during infancy may result in a measurable immunologic benefit to the recipient of a subsequent maternal-donor related renal transplant.
The primary hypothesis of this study was that contraceptive methods that prevent exposure to sperm and seminal fluid (condoms, diaphragms, spermicides, withdrawal) are associated with an increased risk of developing preeclampsia during the subsequent pregnancy. A case-control study was conducted comparing the contraceptive and reproductive histories of 110 primiparous women with preeclampsia with 115 pregnant women without preeclampsia, aged 15 to 35 years, who gave birth at North Carolina Memorial Hospital, Chapel Hill, between 1984 and 1987. Controls were frequency matched to cases by age, race, and distance from the hospital. Unconditional logistic regression analysis indicated a 2.37-fold (95% confidence interval, 1.01 to 5.58) increased risk of preeclampsia for users of contraceptives that prevent exposure to sperm. A dose-response gradient was observed, with increasing risk of preeclampsia for those with fewer episodes of sperm exposure. These results were supportive of the hypothesis that birth control methods that prevent sperm exposure may play a role in the etiology of preeclampsia.
(JAMA. 1989;262:3143-3147)
Increased levels of both donor and recipient derived HLA molecules can be found in serum and plasma of transplanted patients during rejection. Recent data suggest that levels of donor specific soluble HLA Class I (sHLA-1) correlate better with graft rejection than total sHLA Class I [1, 2]. Therefore, quantification of donor specific soluble counterparts of HLA Class I in the serum of the recipient may be a new way for non-invasive monitoring of rejection after organ transplantation. Up to now, only a limited number of mouse monoclonal antibodies (alpha HLA-A2, and alpha HLA-B7) has been used in enzyme linked immunosorbent assays (ELISAs) to detect donor specific HLA molecules in the plasma of transplant recipients. To monitor other donor-recipient combinations, we tested some of our HLA Class I specific human monoclonal antibodies, routinely used in complement dependent cytotoxicity, for their suitability in ELISA based assays. In the present model system, we used alpha HLA-A9 (BvK5C4) or alpha HLA-A3 (OK2F3) hybridoma-supernatant to set up a sHLA-A9 and sHLA-A3 specific ELISA. In a pilot study we show that these assays were sensitive enough to detect an increase of donor specific sHLA-I during rejection in the plasma of two heart transplant recipients. Use of a large set of human hybridoma's will enable monitoring most recipient/donor combinations in the near future.
Successful transplantation depends on the minimization of immunological differences between the donor and recipient tissues. These differences are based on polymorphisms of the human major histocompatibility complex and play a major role in determining the acceptance or rejection of allografts during transplantation. Histocompatibility Testing: A Practical Approach describes methods for the investigation of these polymorphisms at the gene and protein levels and their application to the clinical transplanation of human organs and bone marrow. There is currently no other text available covering these up-to-date serological and molecular techniques in this area of immunogenetics, despite their importance to fundamental research, clinical practice and forensic medicine. This book will therefore be of great interest to researchers in many subject areas, irrespective of whether they are in established laboratories or are entering this field for the first time.
The incidence of pre-eclampsia in 125 primigravidas who had previously received blood-transfusions was significantly less than in a matched series of controls--i.e., 12.8% compared with 23.2%. This suggests that immunological factors may be involved in the aetiology of pre-eclampsia.
Evidence for immunologic processes taking part in the pathogenesis of what until now has been called the "essential" form of EPH gestosis is cited. The name of immunogestosis (IG) is introduced. The data of this preliminary study suggest that regular "inoculation" of the female genital tract with allogeneic spermatozoal histocompatibility antigens reduces the incidence of IG. Information about preconceptional sexual habits and contraceptive measures was obtained from 83 selected primigravid patients. Twenty-eight women had mild to moderate IG (Group B);55 did not (Group A). Women in Group B had had less contact with spermatozoa of partners than did women in Group A. Oral contraceptive consumption was less in Group B than in Group A. Women in Group B were younger than women in Group A. All these differences were statistically significant. A new immunoetiologic hypothesis referring to IG, as well as the theoretic and clinical implications arising from it, are discussed. This hypothesis is based on the assumption that spermatozoal histocompatibility antigens can either induce immunologic tolerance or be responsible for the phenomenon of immunologic enhancement in the maternal immunosystem. As the fetus inherits paternal histocompatibility antigens, it is concluded that pre-existing tolerance (or enhancement) exerts an IG-preventive function in a subsequent pregnancy.
The incidence and natural history of serum anti-paternal cytotoxic antibody (APCA) in normal pregnancy and spontaneous abortion was investigated prospectively in 306 women (64 primigravidae and 242 multigravidae), in order to establish whether serum APCA is a useful screening test in the diagnosis, treatment and prognosis for patients with recurrent pregnancy loss. Pre-pregnancy, serial pregnancy and post delivery serum samples were tested against partner's lymphocytes, using a microdroplet lymphocytotoxicity assay. The incidence of serum APCA in the 256 pregnancies successfully completed was 32%, compared with 10% amongst the 50 pregnancies ending in spontaneous abortion. The lower incidence of positive APCA tests in unsuccessful pregnancies was explained by our finding that positive APCA tests are related to the gestational age of the pregnancy and are rarely demonstrable before 28 weeks gestation. Since APCA usually disappears between pregnancies, its usefulness as a diagnostic test for immunotherapy against recurrent abortion should be questioned.
Oocyte donation was performed by gamete intrafallopian transfer in 61 women, 34 of whom were amenorrhoeic. The mean age of the donors was 32 years (range 23-38). Seventy-five treatment cycles gave 29 clinical pregnancies, of which 21 reached term, 3 continue, and 5 were lost (3 miscarriages, 1 tubal, and 1 cervical). 11 (38%) of the women who became pregnant were over 42 years old. When more than four oocytes were transferred, many of the pregnancies were multiple. 8 (38%) of the pregnancies that came to term were complicated by pre-eclamptic toxaemia. When oocytes are obtained from young women, the fertility potential is high irrespective of the recipient's age.
A simplified enzyme linked immunosorbent assay utilizing an HLA class I framework-specific monoclonal antibody and a polyclonal enzyme linked beta-2 microglobulin specific antiserum has been established for the quantitative measurement of soluble HLA class I molecules. A total of 219 unrelated healthy individuals and 137 members of 28 families typed for HLA were analyzed for their non-membrane bound, i.e. soluble HLA-A,B,C antigens (sHLA-A,B,C). As reported by others, we observed associations of higher or lower sHLA-A,B,C values to particular HLA antigens: High plasma values were observed in probands positive for HLA-A23, A24, A29, Aw33, Bw65, and Cw8 and low values in HLA-B27 and B37 positive individuals. However, as shown by family studies, levels of sHLA-A,B,C were apparently not controlled by the MHC haplotypes alone, since no significant difference between HLA identical siblings and two haplotype different individuals could be detected. Thus, additional non-MHC linked gene(s) may be involved in the release of class I gene products.
The primary hypothesis of this study was that contraceptive methods that prevent exposure to sperm and seminal fluid (condoms, diaphragms, spermicides, withdrawal) are associated with an increased risk of developing preeclampsia during the subsequent pregnancy. A case-control study was conducted comparing the contraceptive and reproductive histories of 110 primiparous women with preeclampsia with 115 pregnant women without preeclampsia, aged 15 to 35 years, who gave birth at North Carolina Memorial Hospital, Chapel Hill, between 1984 and 1987. Controls were frequency matched to cases by age, race, and distance from the hospital. Unconditional logistic regression analysis indicated a 2.37-fold (95% confidence interval, 1.01 to 5.58) increased risk of preeclampsia for users of contraceptives that prevent exposure to sperm. A dose-response gradient was observed, with increasing risk of preeclampsia for those with fewer episodes of sperm exposure. These results were supportive of the hypothesis that birth control methods that prevent sperm exposure may play a role in the etiology of preeclampsia.
In a paired sequential double-blind trial of immunological treatment of recurrent spontaneous abortion successful outcome of the next pregnancy was significantly more common in women injected with purified lymphocytes prepared from their husbands' blood than in those injected with their own lymphocytes. 17 of 22 women given paternal cells had successful pregnancies, compared with 10 of 27 given their own cells.
The relation between pregnancy-induced hypertension and reproductive history was assessed in 29,484 women receiving obstetric care at Parkland Memorial Hospital. The incidence of pregnancy-induced hypertension was 25.4% in primigravid women, somewhat lower (22.3%) in women whose only previous pregnancy terminated in abortion, and much lower (10%) in women who carried two or more successive pregnancies to viability.
A total population of pregnant women from Aberdeen City District 1967-1978 has been studied. There were 29 851 pregnancies and 6637 women had a first recorded pregnancy between 1967 and 1978 and had two or more pregnancy events. As expected the incidence of pre-eclampsia in a second pregnancy was less than that in a first pregnancy, but it was dependent on the outcome of the first pregnancy. If the first pregnancy was complicated by proteinuric pre-eclampsia than the incidence of the condition in the second pregnancy was similar to that in a first pregnancy, but women who were normotensive in the first pregnancy had a reduced incidence of the condition in the second pregnancy. The incidence of proteinuric pre-eclampsia after early abortion (less than 13 weeks), either spontaneous or induced was similar to the population incidence in a first pregnancy, but after a late spontaneous abortion the risk of proteinuric pre-eclampsia was significantly reduced. Change of civil status of the offspring from first to second pregnancy did not affect the incidence of pre-eclampsia in a second pregnancy. There was an effect of birthweight in that women who had proteinuric pre-eclampsia in conjunction with a low-birthweight baby (less than 2500 g) in their first pregnancy had double the incidence of proteinuric pre-eclampsia in their second pregnancy. Only a pregnancy of 37 weeks or more is likely to offer protection or 'immunity' to pre-eclampsia in a second pregnancy and even then the effect is moderated by the development of pre-eclampsia in the first pregnancy.
Three women, each with a history of three spontaneous abortions, were typed for A, B, C, and DR histocompatibility (HLA) antigens and found to share antigens with their husbands. The women were repeatedly transfused throughout pregnancy with leucocyte-enriched plasma from at least sixteen different erythrocyte-compatible donors. The pregnancies were normal and each mother produced a healthy baby. The presence of trophoblast/lymphocyte cross-reactive (TLX) antigens, which stimulate the mother to mount a response with blastocyst protective factors and which prevent maternal rejection of the antigenically unique embryo, might explain these results.
Large numbers of maternal lymphocytes are present in breast milk. We asked whether exposure of an infant to maternal lymphocytes during the process of breast feeding would have an effect on the subsequent reactivity of a patient to a maternal-donor related renal transplant. We studied the posttransplant course of 55 patients who had received a primary maternal-donor transplant. Twenty-seven recipients had been breast-fed during infancy and 28 recipients had not been breast-fed. A history of breast feeding was associated with a more favorable posttransplant course as measured by the percentage of patients who had no rejection episodes during the first posttransplant year (P less than or equal to .006). The one-year graft function rate for breast-fed recipients was 82%; this was statistically significantly better than the 57% measured for non-breast-fed recipients (P less than or equal to .05). Statistical significance of differences between groups was not attained when results were evaluated over a five-year interval. A difference between breast-fed and non-breast-fed recipients was not apparent when we evaluated a somewhat smaller group of patients who had received a paternal donor transplant. From these observations we conclude that the process of breast feeding during infancy may result in a measurable immunologic benefit to the recipient of a subsequent maternal-donor related renal transplant.
The combination of the Propidium Iodide method and automatic reading and scoring with a microscope fluorimeter is an accurate, reproducible and stable procedure for HLA-DR, MB and MT typing.
A review of 34, 201 multigravid deliveries found 47 patients who had severe pre-eclampsia after previous normotensive, non-albuminuric pregnancies. In 13 of these patients the affected pregnancy was apparently by a new father compared with 3 matched controls (P less than 0.01). This evidence supports the idea of a paternal immunogenetic factor in pre-eclampsia; immunogenetics.
Three consecutive eclamptic patients seen by me at the Ikedife Hospital within one week were multiparous. Routine history taking revealed changes in paternity in the first two cases. This led me to make confidential inquiries about the actual paternity in the pregnancies of other eclamptic multiparous patients.
The First International Workshop on Soluble HLA antigens focused on the comparison of immunoassay procedures for quantitation of soluble HLA (sHLA) class I antigens and the selection of a sHLA class I antigen international standard. Several sets of serum, plasma, and cell culture supernatant specimens were assayed blindly for levels of sHLA class I antigens by 15 participating laboratories using different immunoassay formats. The sandwich ELISA using (i) for antigen capture: an anti-HLA class I heavy chain monoclonal antibody (mAb) specific for a monomorphic epitope, and (ii) for antigen detection: an anti-beta 2 microglobulin antibody-enzyme conjugate, was the assay format of choice. There was a high inter-laboratory correlation among the majority of laboratories. All serum and plasma specimens from normal donors, and from a single transplant patient, had detectable levels of sHLA class I antigens. Paired serum and plasma specimens had similar levels of sHLA class I antigens, although plasma sHLA antigens seemed more stable than serum sHLA antigens. sHLA-A2 and sHLA-B7 antigens were detected in all specimens from HLA-A2 and HLA-B7 donors, respectively, using allele-specific ELISAs. No difference in reactivity was observed for quantitation of native sHLA class I antigens whether the capture mAb was TP25.99 (alpha 3 domain-specific) or W6/32 (alpha 2 + alpha 3-specific). However, a human-mouse chimeric sHLA class I antigen reacted weakly in assays which used TP25.99 mAb. The wide variation among laboratories in their reporting of micrograms/ml units pointed to the need for an inter-laboratory standardization based on a calibrated sHLA antigen preparation. T.sB7, an sHLA-B7 antigen derived from a cell line transfected within human beta 2 microglobulin and HLA-B7 genes, was accepted as the First sHLA class I Antigen International Standard at the workshop meeting.
Pre-eclampsia is a frequent, unpredictable syndrome which is dangerous for both mother and foetus. The concept of placental ischemia has gained wide acceptance among the numerous theories put forward to explain the illness. The setting up of preeclampsia seems to be scheduled in two steps: (1) an absolute or relative placental ischemia due to vascular diseases or hypertrophic placenta, or most often secondary to implantation defect, particularly anomaly with the invasive trophoblast; (2) a diffuse endothelial disease. The connection between these two steps is incompletely disclosed. The authors demonstrate that the maternal immune system which is strongly stressed during all the stages of normal gestation is implicated in pre-eclampsia. Its role is probably not univocal. Foeto-trophoblastic antigens could be poorly recognised. This defect of recognition could lead to the abnormalities of trophoblastic invasion observed in pre-eclampsia. Pre-eclampsia does not seem to be accompanied by an immunological rejection of the foetus. Some genetically predisposed patients do not have a sufficiently competent immune system to neutralise one or more of the toxic products released by the ischemic placenta. Certain types of pre-eclampsia could be auto-immune, with the auto-antibodies directed against certain types of phospholipids or trophoblastic constituents. A disequilibrium between oxidation and anti-oxidation mechanisms involving neutrophils could lead to aggression of the endothelium which is observed in pre-eclampsia. Pre-eclampsia could represent a form of immuno-dystrophy, with the excessive production of adverse cytokines locally, directed against the trophoblast. Without directly implicating the immune system as the trigger of pre-eclampsia, it seems that its role is unclear. In some cases it develops protective mechanisms which, when overwhelmed or inadequate, allows pre-eclampsia to occur. In other cases it can form part of the cascade of aggressions leading to the abnormalities encountered. The integration of these abnormalities in the pathophysiological models, could help improve the classification of pre-eclampsia. This attempt will lead to a more adapted preventive and therapeutic management of pre-eclampsia.
The identification of immunomodulatory approaches that allow the induction of antigen-specific unresponsiveness is required for long-term graft survival without the complications of chronic immunosuppression. Recent novel strategies based upon treatment with synthetic peptides corresponding to linear sequences of MHC class I and II molecules reproducibly induce tolerance to alloantigens. Although the mechanisms involved are still not completely understood, the phenomenology reported makes these approaches promising for evaluation in clinical trials.
The induction of oral tolerance by oral immunization has been well recognized. Accumulated evidence shows that oral tolerance can be mediated by orally activated humoral and cellular factors. In animal models, the development of several T cell-mediated autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, uveitis and diabetes type 1 can be inhibited by oral immunization of the respective antigens. In allergy, oral administration of certain allergens can prevent and reduce both contact and atopic dermatitis. Oral tolerance to alloantigen also reduces graft rejection. In spite of these encouraging results, the usefulness of this approach for an alternative immunotherapy in humans needs to be investigated further.
The lack of expression of HLA antigen on immature germ cells from ejaculates with antisperm antibodies has been reported.
The expression of human leukocyte antigens on immature germ cells from ejaculates with antisperm antibodies (ASA) was investigated by indirect immunofluorescence using a panel of monoclonal antibodies (MAb) and automated flow cytometry. Patients were divided into two groups: fertile (prevasectomic; N = 10), and ejaculates with ASA (10 samples with IgG and IgA ASA, and five semen samples with only IgG ASA). ASA were detected on sperm using the direct immunobead test. After centrifuging semen samples on a Ficoll-Hypaque gradient, round cells obtained at the gradient interface were gated by a flow cytometer. The "immature germ cell window" was defined in terms of cellular volume and granularity.
The percentage of gated round cells from semen samples that reacted with anti-CD45 was always less than 5%, and with anti-CD44 less than 3%. This lack of reactivity of gated round cells with MAb specific for leukocytes and epithelial cells suggests that they were immature germ cells. Immature germ cells were unreactive with W6/32 and anti-beta-2-microglobulin MAb, which suggests that these cells do not express HLA class I molecules. Similarly, no reactivity of the immature germ cells with the MAb that recognize HLA class II molecules was found. No significant differences were observed in the expression of HLA molecules on immature germ cells between the different semen samples studied: fertile, and ejaculates with ASA.
The presence of ASA in ejaculate is not associated with abnormal HLA antigen expression on immature germ cells.
The expression of human leukocyte antigens (HLA) on ejaculated spermatozoa and on lymphocytes was compared by flow cytometry using monoclonal antibodies towards HLA class I (pan-HLA-A, -B, -C) and class II (DR) antigens. Soluble antigens of HLA class I (s HLA-A, -B, -C) in seminal plasma and in blood plasma were monitored with an ELISA technique. Lymphocytes showed specific fluorescence after incubation with the antibodies against HLA class I and class II (DR), whereas, on spermatozoa no positive immunofluorescence could be detected. No antibodies were bound to any significant extent either after modifications of sperm preparation (density gradient centrifugation, swim up-technique, addition of azide, foetal calf serum or benzamidine chloride) or after treatment of spermatozoa with detergents. Furthermore, different concentrations of soluble HLA-A, -B, -C in seminal plasma and in blood plasma were detected. The latter one showed soluble HLA about four-fold more concentrated than the seminal plasma (means +/- SD: 262.5 +/- 144.4 nmol l-1 vs. 62.5 +/- 27.1 nmol l-1). These results suggest, that the HLA-expression differs between human spermatozoa and somatic cells.
Recent evidence indicates that MHC peptides play an important role in T-cell recognition of alloantigen. We studied the tolerogenicity of orally administered synthetic MHC allopeptides in the rat model. Initially, we demonstrated that oral administration of synthetic class II MHC allopeptides significantly inhibited the DTH response to the peptides as well as to donor-derived cells. The tolerogenic effect was antigen specific and was induced by immunogenic, but not by nonimmunogenic, allopeptides. Immunohistological studies of DTH skin lesions showed that oral tolerance is associated with a state of "immune deviation" to a predominance of Th2 cell function in the lesions. We recently extended the above observations and examined the tolerogenic effect of orally administered synthetic MHC allopeptides on MLR and CTL generation. We found that oral administration of the class II allopeptides effected significant reduction of MLR proliferation and CTL generation, which was antigen specific. In addition, similar to the DTH results when we compared the tolerogenicity of the immunogenic versus the nonimmunogenic peptides, MLR and CTL suppression was significantly higher with the immunogenic peptides. The gut immune system play an important role in oral tolerance by MHC peptides. Initial experiments showed that intestinal epithelial cells pulsed in vitro with immunogenic MHC allopeptides, or in vivo by oral administration of immunogenic peptides, were capable of presenting these peptides to primed T cells in vitro. Whether such presentation by intestinal epithelial cells or other gut antigen-presenting cells leads to preferential activation of Th2 regulatory cells, which ultimately suppress Th1 alloimmune responses, remains to be determined.
Mucosal immunity depends on antigen stimulation in specialized lymphoepithelial structures such as the Peyer's patches. Although these inductive compartments were discovered more than 300 years ago, their functional role has become clear only over the last few decades. Research on homing of primed lymphoid cells to the intestinal mucosa began with animal experimentation in the 1960s and 1970s and has recently been brought to the molecular level. The major effector substance of mucosal immunity is secretory IgA (SIgA). The first evidence for its local antibody activity was obtained in humans in 1922, but its unique properties were not defined until the mid-1960s. Several models were subsequently proposed for selective external transport of IgA involving the secretory component (SC). In the early 1970s SC was suggested to act as a transmembrane polymeric Ig receptor common for dimeric IgA and pentameric IgM; this transport mechanism has now been confirmed by detailed studies at the level of cellular/molecular biology. Although SIgA antibodies performing immune exclusion are the main goal for exploitation of the mucosal immune system by oral vaccination, little is known about the precise mechanisms for induction of mucosal immunity against soluble proteins and chemicals. A peripheral immunosuppressive effect of oral immunization with such substances was apparently exploited by ancient people, and "oral tolerance" has since 1910 been subjected to numerous feeding experiments in rodents. The basis for the whole phenomenon appears to be intact epithelial barrier. Mucosal induction of suppression may in the future be exploited not only to modulate autoimmune diseases through the gut but also to prevent the development of IgE-mediated allergy and other untoward immune reactions by way of the respiratory tract.
Soluble HLA class I molecules (sHLAs) have been identified in the serum of patients with inflammatory diseases, allografts and autoimmune diseases and in serum of healthy individuals. The biological significance of these molecules, particularly after allogeneic organ transplantation, has been enigmatic. Here we show that primary alloreactive CD8+ T cells interact with sHLA and undergo apoptosis in the absence of a second signal. Ligation of CD28 rescued T cells from death, implying that sHLAs induce apoptosis through selective stimulation of the T-cell receptor. CD95-L was upregulated after cytotoxic T lymphocytes were incubated with sHLAs, and cell death was blocked by a neutralizing anti-CD95-L antibody, suggesting that sHLAs induce endogenous mutual killing of activated T cells. These results provide a molecular basis for the capacity of sHLAs to downregulate T-cell responses, which may be especially relevant to organ transplantation.
Our aim was to seek evidence for circulating leukocyte activation in preeclampsia.
Whole blood flow cytometric techniques were used to analyze surface markers of activation (CD11b, CD14, CD23, CD49d, CD62L, CD64, CD66b, HLA-DR) and intracellular reactive oxygen species. Samples were taken from 21 women with preeclampsia, 21 matched normal pregnant women, 21 healthy nonpregnant controls, and 6 nonpregnant patients with septicemia. Ten preeclamptic cases were followed up 6 weeks post partum.
The leukocytes of healthy pregnant women differed substantially and significantly from those of nonpregnant women (increased CD11b, CD14, and CD64 and increased intracellular reactive oxygen species). In preeclampsia there was, in addition to these changes, reduced expression of L-selectin and further increases in intracellular reactive oxygen species. The changes found in normal pregnancy and preeclampsia were similar, but not identical, to those found in sepsis.
Normal third-trimester pregnancy is characterized by remarkable activation of peripheral blood leukocytes, which is further increased in preeclampsia.
During pregnancy and nursing, a baby's developing immune system is intimately exposed to the mother's antigens. To determine whether this exposure is of clinical benefit to patients who later receive an allograft as an adult, we analyzed the outcome of primary renal transplantations from sibling donors.
We retrospectively studied graft survival and rejection episodes in 205 patients who had received renal transplants at nine centers between 1966 and 1996 from sibling donors bearing maternal or paternal HLA antigens not inherited by the recipient. The sibling donors were categorized by analysis of family HLA-typing data.
In the multicenter analysis, graft survival was higher at 5 years and at 10 years after transplantation in recipients of kidneys from siblings expressing maternal HLA antigens not inherited by the recipient than in recipients of kidneys from siblings expressing paternal HLA antigens not inherited by the recipient (86 percent vs. 67 percent at 5 years and 77 percent vs. 49 percent at 10 years, P=0.006 for both). Paradoxically, there was a higher incidence of early rejection in the former group, suggesting that fetal and neonatal exposure to maternal antigens results in immunologic priming. Pretransplantation transfusions of donor blood reduced the incidence of acute rejection while preserving the beneficial effect of tolerance to noninherited maternal antigens on graft survival. Since 1986, new immunosuppressive drugs have lessened the short-term, but not the long-term, survival advantage of grafts expressing maternal HLA antigens not inherited by the recipient.
In the transplantation of a kidney from a sibling donor who is mismatched with the recipient for one HLA haplotype, graft survival is higher when the donor has maternal HLA antigens not inherited by the recipient than when the donor has paternal HLA antigens not inherited by the recipient.
To clarify the controversial results in the literature regarding the role of donor-specific transfusion (DST) on allograft survival, we have examined the influence of the following on DST-induced allograft survival in a 2C transgenic mouse model: varying the time between DST and transplantation; the role of MHC disparities between donor and recipient; whether tolerance induced by DST spreads to skin allografts expressing other alloantigens; and whether cyclosporine (CsA) treatment could further modulate skin allograft tolerance after DST.
The studies were performed in both 2C anti-Ld (MHC class I) transgenic and normal (nontransgenic) mice. Our data demonstrate that a single infusion of Ld-mismatched lymphocytes 7 days before transplantation leads to permanent acceptance of donor-specific skin allografts in both transgenic (58/58) and nontransgenic (8/8) mice in the absence of any other nonspecific immunosuppressive treatment. Pretransplantation DST from donors mismatched for more than one MHC antigen (Ag) has no beneficial effect on subsequent donor skin allograft survival. However, Ld plus multiple minor histocompatibility (mH) Ag-mismatched DST induced permanent acceptance of donor-specific skin allografts. Tolerance induced by one-locus Ld-mismatched DST spreads to skin allografts expressing either two-locus Ld or one-locus Ld plus multiple mH Ags. Administration of CsA after DST diminished skin allograft survival, rather than enhancing it, suggesting that tolerance in this model system is established by an active immunological process sensitive to CsA.
(1) Pretransplantation infusion of Ld-mismatched lymphocytes in the presence or absence of multiple mH mismatches induces permanent survival of donor-specific skin allografts. (2) CsA abrogates DST-induced transplantation tolerance.
Heart transplant rejection is routinely defined by histological evaluation of endomyocardial biopsies (EMB). As elevated levels of donor derived sHLA (dsHLA) can be detected in the serum of transplanted patients just before or during rejection, quantification of donor specific soluble counterparts of HLA Class I (sHLA-I) in the serum of the recipient may be a new way for non-invasive monitoring of graft rejection. However, not all patients show an increase of dsHLA at time of rejection. A reason for this might be that anti-donor-HLA antibodies, which are formed by the patient, form complexes with donor sHLA-I molecules. This masking or blocking of sHLA-I binding sites might cause false-negative results of tests detecting donor specific sHLA. Using HLA-antigen specific ELISA tests we could demonstrate that most anti-HLA antibodies block the detection of sHLA antigens in plasma, even in high dilutions of the antibody when the antibodies were not detectable in a CDC test. In general, HLA-antigen specific antibodies block the detection of sHLA molecules, while broadly-reactive antibodies, recognizing another epitope on the molecule, do not. The implication of these findings is that more than one dsHLA allotype within one patient should be tested to monitor graft rejection. In addition, sHLA monitoring must be combined with an HLA-antibody screening.
Preeclampsia is often thought of as being a disease of first pregnancies. The incidence of preeclampsia in subsequent pregnancies, after a previous normal pregnancy is lower. However, it has been reported that this beneficial effect of multiparity is lost with a change in paternity. The aim of this study was to assess the impact of change in paternity on the incidence of preeclampsia in Dutch multiparous pregnant women.
364 Multiparous patients with hypertension (diastolic blood pressure > or = 100 mmHg) were identified in the obstetric database of the Academic Hospital Vrije Universiteit Amsterdam for the period 1989-1996. The diagnosis in their obstetrical history (Preeclampsia, HELLP-syndrome, chronic hypertension) was defined in a pragmatic way in view of the retrospective nature of the study. The control group consisted of 281 multiparous women from a midwife clinic, with normotensive pregnancies in the same period. Patients and controls were asked, by telephone, if the index pregnancy was from the same partner as the previous pregnancy and what the sex of the newborns had been in each pregnancy. Fisher's Exact test was used for statistical analysis and P < 0.05 was considered significant.
The final study group consisted of 333 multiparous patients with hypertension. The control group consisted of 182 multiparous women without hypertension. The prevalence of new paternity was significantly higher (P < 0.0001) both for preeclamptic and HELLP patients in comparison with the controls, with an odds ratio of 8.6 (95%CI: 3.1-23.5) and 10.9 (95%CI: 3.7-32.3), respectively.
This study confirms that change of partner raises the risk for preeclampsia in subsequent pregnancies. Immune maladaptation on the fetal maternal interface could be an underlying mechanism. Multiparous women with a new partner should be approached as being primigravid women.
Succesful strategy for the large scale development of HLA-human monoclonal antibodies Genetic Diversity of HLA: Functional and Medical Implications
- A Mulder
- M J Kardol
- J G S Niterink
- J H Parlevliet
- M Marrari
- J Tanke
Mulder, A., Kardol, M.J., Niterink, J.G.S., Parlevliet, J.H., Marrari, M., Tanke, J., et al., 1997. Succesful strategy for the large scale development of HLA-human monoclonal antibodies. In: Charron, D. (Ed.), Genetic Diversity of HLA: Functional and Medical Implications. EDK Publishers, Sevres, pp. 354 – 356.
Automated reading of propidium iodide lymphocytotxicity tests for HLA-DR, MB, and MT typing. Tissue Antig Effect of blood transfusions on subsequent kidney transplants Tissue Antig
- A Naipal
- D Amaro
- J Bruning
- J W Van Leeuwen
- A Van Rood
- J J Opelz
- G Sengar
- D P S Mickey
- M R Terasaki
Naipal, A., D'Amaro, J., Bruning, J.W., van Leeuwen, A., van Rood, J.J., 1984. Automated reading of propidium iodide lymphocytotxicity tests for HLA-DR, MB, and MT typing. Tissue Antig. 24, 302. Opelz, G., Sengar, D.P.S., Mickey, M.R., Terasaki, P.I., 1973. Effect of blood transfusions on subsequent kidney transplants. Transplant Proc. 5, 253. Pouletty, P., Ferrone, S., Amesland, F., Cohen, N., Westhoff, U., Charron, D., et al., 1993. Summary report from the first international workshop on soluble HLA antigens. Paris, August 1992. Tissue Antig. 42, 45 – 54.
Similarly, by combining the data of the individual sHLA antigens HLA-References Astin, Pre-eclampsia/eclampsia: the fatal father factor History of oral tolerance and mucosal immunity
- M Scott
- J R Worley
fold higher concentration in blood plasma compared to the level in seminal plasma. Similarly, by combining the data of the individual sHLA antigens HLA-References Astin, M., Scott, J.R., Worley, R.J., 1981. Pre-eclampsia/eclampsia: the fatal father factor. Lancet II, 533. Brandtzaeg, P., 1996. History of oral tolerance and mucosal immunity. Ann. NY Acad. Sci. 13, 1–27.
Clinical typing by cytotoxicity Histocompatibility Testing, A Practical Approach
- C Darke
- P Dyer
Darke, C., Dyer, P., 1993. Clinical typing by cytotoxicity. In: Dyer, P., Middleton, D. (Eds.), Histocompatibility Testing, A Practical Approach. Oxford University Press, Oxford, pp. 51–80.
Change in paternity: a risk factor for preeclampsia in multiparous women Quantification of soluble HLA class I gene products by an enzyme linked immunosorbent assay
- G A Dekker
- P Tubbergen
- M Valk
- S M Althuisius
- A M A Lachmeijer
Dekker, G.A., Tubbergen, P., Valk, M., Althuisius, S.M., Lachmeijer, A.M.A., 1998. Change in paternity: a risk factor for preeclampsia in multiparous women. Am. J. Obstet. Gynecol. 178, S120. Doxiadis, I., Westhoff, U., Grosse-Wilde, H., 1989. Quantification of soluble HLA class I gene products by an enzyme linked immunosorbent assay. Blut 59, 449 – 454.
Succesful strategy for the large scale development of HLA-human monoclonal antibodies
- Mulder