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Background Estrogen and progesterone have been associated in women with symptoms that include asthma, migraine, dermatitis and pain. Objective We suggest a connection between symptoms associated with hormone changes to a hormone antibody response. Methods For IgG, IgM and IgE antibodies to progesterone, blood samples were obtained from 288 healthy control subjects by a commercial lab in California. Blood from 270 patients in Texas with changes in symptoms associated with menstrual cycles was examined. For IgE antibodies to both progesterone and estrogen, blood samples were obtained from an additional 32 healthy control subjects who had no symptoms related to menses and from 98 patients with symptoms associated with menstrual cycles. The symptoms were asthma, migraines and joint pain. Results At 2 S.D. above the mean values of control subjects, a significant number of patients show high levels of IgG, IgM and IgE antibodies to progesterone and estrogen. Conclusions This paper describes evidence of antibodies to the hormones estrogen and progesterone. Progesterone, estrogen and their metabolites, after binding to human tissue proteins, such as albumin or globulin, may act as antigens and promote Type 2 helper cell development, thereby regulating antibody synthesis and allergy. This leads to the possibility of treating a wide variety of disorders by determining hormone allergy and initiating desensitization. Two obvious applications for determination and treatment of hormone allergies are pre-menstrual asthma and menstrual migraines. [ABSTRACT FROM AUTHOR]

Problem: Previous studies document an association between mode of delivery (MOD) and allergic conditions in children. Immunoglobulin (Ig) concentrations at birth may play a role. The goal of this study is to assess the impact of MOD on Ig concentrations at delivery from newborn dried blood spots (DBS). Method of study: The Upstate KIDS Study (2008–2010) is a prospective cohort of mother‐child pairs recruited from New York State, excluding New York City. Ig subtypes IgA, IgE, IgG1, IgG2, IgG3, IgG4, and IgM were measured in residual NDBS from the Newborn Screening Program (N = 3274 infants). MOD was categorized as vaginal delivery (VD), emergency cesarean delivery (ECD) or planned cesarean delivery (PCD). Associations between MOD and Ig levels were assessed using ANOVA and multiple regression, with models adjusted for gestational age, birth weight, maternal race, plurality, and smoking status. Results: IgA, and the IgG subtypes IgG3 and IgG4 were found to be significantly lower in PCD neonates relative to VD neonates in adjusted regression models: 3.57 mg/ml, (95% CI: 3.51, 3.63) compared to 3.64 mg/ml (95% CI: 3.59, 3.69); 8.95 ng/ml (95% CI: 8.88,9.03) compared to 9.03 ng/ml (95% CI: 8.98, 9.08) and 8.05 ng/ml (95% CI: 7.91, 8.20) compared to 8.22 ng/ml (95% CI: 7.91,8.20), respectively. Conclusions: MOD may thus be related to neonatal immune profile. Results were found to be robust to sensitivity testing based on maternal complications and indication for CD. Clinical implications are unclear given the small levels of association found in newborns, but the result suggests greater susceptibility to infection, and further study is warranted. [ABSTRACT FROM AUTHOR]

Problem: Endometriosis (EM) is a chronic immunoinflammatory disease associated with an abnormal immunotolerant microenvironment. Myeloid‐derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that play a major role in immunosuppression in cancer, inflammation and other diseases. This paper aims to elucidate whether or not MDSCs are involved in regulating this microenvironment in EM and how this regulation occurs. Method of Study: Immunochemistry (IHC) and qPCR were conducted to measure CD11b and ARG1 expression in the ectopic endometrium samples from EM patients. CCL25 levels in EM PF and the expression of CCR9 on M‐MDSCs were measured by ELISA. M‐MDSC migration was determined towards rhCCL25, α‐CCR9, α‐CCL25 and EM PF through in vitro chemotaxis assay. CD33+CD14+CD11b+HLA‐DR‐ M‐MDSCs isolated from EM PBMCs were added to CD8+ T cells stimulated with α‐CD3/α‐CD28 antibody. After 72 hours of co‐culture, proliferation was measured to rate the immunosuppressive function of M‐MDSCs. Finally, levels of IL‐10, GM‐CSF and arginase activity in the cultured supernatants were detected. Results: IHC and qPCR results revealed higher CD11b and ARG1 expression in EM endometrium than normal endometrium. MDSCs accumulated in the EM microenvironment, in which M‐MDSCs were the predominant type. CD33+CD14+CD11b+HLA‐DR− M‐MDSCs expressed high CCR9 levels and were recruited through CCL25. M‐MDSCs from EM PBMCs inhibited proliferation and activity in autologous T cells. rhCCL25 promoted IL‐10 and GM‐CSF secretion and arginase enzymatic activity in CD33+CD14+CD11b+HLA‐DR− M‐MDSCs. Conclusion: CD33+CD14+CD11b+HLA‐DR− M‐MDSCs recruited and activated by CCR9/CCL25 play a crucial role in the pathogenic progression of endometriosis, thus providing a potential target for EM treatment. [ABSTRACT FROM AUTHOR]

The article discusses results of a cohort-controlled study of intravenous immunoglobulin (IVIG) and anti-tumor necrosis factor (TNF)-alpha or Humita in patients with recurrent in vitro fertilization (IVF) failure and elevated cytokine production ratio. The method of the study is described, including an analysis of evidence for causation. The study suggests a potential mechanism by improving the physiology during follicle development.

Reproductive failures include infertility and recurrent pregnancy loss (RPL). Although the relative importance of immunological factors in human reproduction remains unclear, there may be immune‐mediated reproductive failures in a portion of unexplained infertility and RPL. As a cause of immunological factor, anti‐sperm antibodies (ASA) are produced both in men and women. There have been reported several antigens in the surface of sperm that are especially foreign to women. The presence of ASA, especially sperm‐immobilizing antibodies, in the sera of infertile women has been shown to inhibit sperm migration in the female genital tract. Therefore, the effectiveness of the treatments for infertile women with sperm‐immobilizing antibodies by timed intercourse or intra‐uterine insemination is limited. Such antibodies can also exert inhibitory effects on various stages of sperm‐egg interaction and subsequent embryo development in vitro. It is suggested that ASA testing for infertile women should be performed before proceeding IVF. The manipulation of gametes and embryos from patients having sperm‐immobilizing antibodies should be carefully carried out especially to avoid contaminating patient's serum and follicular fluid in the culture medium in order to overcome the immunological causes of female infertility by ASA, and satisfactory results under suitable conditions for gametes and embryos have been obtained. The relationship between ASA and RPL was controversially reported. Increased miscarriage rates in women with ASA were demonstrated by some authors. In contrast, lack of association between ASA and RPL was reported. In this manuscript, we are focusing the roles of ASA in women with reproductive failures. [ABSTRACT FROM AUTHOR]

Problem: HLA‐C is the only classical HLA‐I antigen expressed on trophoblast. We hypothesized that the alloimmune response to paternal HLA‐C plays a role in unexplained recurrent miscarriage. Method of study: In a case‐control design, we included 100 women with at least three unexplained consecutive miscarriages along with their partners and children. For the first control group, we included 90 women with an uneventful singleton pregnancy without pregnancy complications in their history along with their children. The second control group consisted of 425 families. HLA‐C*07 and HLA‐C*17 frequencies, which are the most immunogenic HLA‐C antigens, along with HLA‐C mismatches, and the presence of specific HLA antibodies in the mother were determined. Results: HLA‐C and HLA‐C*07 mismatches were significantly increased in couples with recurrent miscarriage compared to control subjects (P = .016, P = .008, respectively). The incidence of child‐specific HLA‐C*07/HLA‐C*17 antibodies was increased in women with recurrent miscarriage (P = .007). Conclusion: The results show that HLA‐C incompatibility between couples is significantly associated with unexplained recurrent miscarriage. [ABSTRACT FROM AUTHOR]

Problem Chronic histiocytic intervillositis ( CHIV) is a rare type of placental pathology that is associated with reproductive loss at all gestational ages. The aim of the study was to investigate the relationship between the severity of CHIV and the outcome of pregnancy and to compare the immune response between CHIV patients and controls to explore an immunological origin of CHIV. Method of study Microscopic slides were reviewed and scored according to a previously published grading system in 30 pregnancies of 22 CHIV patients. Partner-specific mixed lymphocyte reactions, cytotoxic T-lymphocyte precursor frequencies ( CTLpf), and anti- HLA antibodies were determined in four patients and seven controls. Results Higher CHIV scores are associated with worse pregnancy outcome. CHIV patients demonstrated a higher CTLpf against their partner compared to non-complicated pregnancies ( P = 0.03). The CTLpf was extremely high in 75% of the patients. Antipaternal HLA antibodies were only present in 75% of the CHIV patients compared to none of the controls ( P = 0.02). Conclusion CHIV scores seem to be associated with the severity of adverse pregnancy outcome. High antipaternal cellular (T-cell) and humoral (B-cell) response to partner-specific CTLpf and the presence of anti- HLA antibodies directed to the partner suggest an immunologic origin of CHIV. [ABSTRACT FROM AUTHOR]

Problem During pregnancy, antibodies are induced that target the paternal human leukocyte antigens of the semi-allogeneic fetus. The level and presence of these antibodies have been reported increased as well as decreased for a variety of pregnancy complications; the clinical relevance and consequences of these antibodies are not very clear. Therefore, the objective of this review is to determine whether the presence of antipaternal antibodies influences pregnancy outcome. Method We performed a systematic search of studies that described the effect of antipaternal antibodies on pregnancy complications. The primary outcome was the risk ratio for HLA class I and class II antibodies on pregnancy complications. Furthermore, we calculated the risk for first- and third-trimester complications. Results The seventeen studies that were selected for meta-analysis showed high level of statistical and clinical heterogeneity. In the meta-analysis, we found no significant effect of HLA class I or class II antibodies on pregnancy outcome. Conclusion No consistent conclusions can be drawn from the meta-analysis. Discrepancies in the meta-analysis are the result of different screening techniques, varying time points of screening, and use of incorrect control groups. Furthermore, more detailed analyses of the characteristics and specificity of the antibodies involved are essential. [ABSTRACT FROM AUTHOR]

After defining the term 'foreign embryonic isoantigens', the author describes the experimental sequence which has allowed this new fetoprotein class to be identified. Experiments have followed three different directions, namely (i) passive immunization, by which conceptus antibodies raised in another animal species are transferred to the female animal, the effects on the offspring becoming apparent after pregnancy; (ii) laboratory techniques, where the presence of conceptus antibodies in serum from aborting women has been demonstrated by use of analytical techniques or by testing the serum on cultured embryos; and (iii) active isoimmunization, by which the female animal is immunized against a conceptus extract from the same species, and the effects on the offspring are observed after pregnancy. The immunologic basis for autoantigenicity in these fetoproteins, and its significance to materno-fetal medicine, are explained. Finally, some fetoproteins not yet unambiguously classed as foreign embryonic isoantigens are presented. [ABSTRACT FROM AUTHOR]

Citation Winger EE, Reed JL, Ashoush S, El-Toukhy T, Ahuja S, Taranissi M. Elevated preconception CD56+16+ and/or Th1:Th2 levels predict benefit from IVIG therapy in subfertile women undergoing IVF. Am J Reprod Immunol 2011; 66: 394-403 Problem We sought to answer two questions: First, is there a group of patients who benefit from intravenous immunoglobulin (IVIG) in IVF? Second can this group of patients be identified by preconception blood testing? Method of study A total of 202 IVF cycles in subfertile women were divided into four groups. Group I: 62 cycles with preconception Th1:Th2 ratio and/or % CD56+ cell elevation using IVIG; Group II: 27 cycles with similar Th1:Th2 and/or % CD56+ cell elevation not using IVIG; Group III: 71 cycles with normal Th1:Th2 and/or % CD56+ cell levels using IVIG; Group IV: 42 cycles with normal Th1:Th2 and % CD56+ levels not using IVIG. These groups were similar with regard to patient age, diagnosis, and past failure history. Results The implantation rate (number of gestational sacs per embryo transferred, with an average of two embryos transferred per cycle) was 45% (55/123), 22% (12/54), 54% (75/139), and 48% (40/84) for Groups I-IV, respectively. The clinical pregnancy rate (fetal heart activity per IVF cycle started) was 61% (38/62), 26% (7/27), 69% (49/71), and 71% (30/42), respectively. The live birth rate was 58% (36/62), 22% (6/27), 61% (43/71), and 71% (30/42), respectively, and the live birth per embryo transferred was 40% (49/123), 13% (7/24), 43% (60/139), and 48% (40/84), respectively. There was a significant improvement in implantation, clinical pregnancy, live birth rate and live birth rate per embryo transferred for Group I versus Group II ( P = 0.0032, 0.0021, 0.0017, and 0.0002, respectively) and for Group II versus Group IV ( P = 0.0021, 0.0002, <0.0001 and <0.0001, respectively). There was no significant difference in success rates between Groups I and III ( P = 0.085, 0.23, 0.45, 0.34, respectively) and between Groups III and IV ( P = 0.22, 0.48, 0.17, 0.31, respectively). Conclusion In subfertile women with preconception Th1:Th2 and/or % CD56+ cell elevation, IVF success rates are low without IVIG therapy but significantly improve with IVIG therapy. In patients with normal Th1:Th2 and normal CD56+ cell levels, IVF success rates were not further improved with IVIG therapy. IVIG may be a useful treatment option for patients with previous IVF failure and preconception Th1:Th2 and/or NK elevation. Preconception immune testing may be a critical tool for determining which patients will benefit from IVIG therapy. Prospective controlled studies (preferably double-blind, stratified, and randomized) are needed for confirmation. [ABSTRACT FROM AUTHOR]

Citation Khan SA, Jadhav SV, Suryawanshi AR, Bhonde GS, Gajbhiye RK, Khole VV. Evaluation of contraceptive potential of a novel epididymal sperm protein SFP2 in a mouse model. Am J Reprod Immunol 2011; 66: 185-198 Problem Sperm flagellar protein 2 (SFP2), which was earlier identified using a novel combinatorial approach, was evaluated for its contraceptive potential in mice. Method of study Male mice were actively immunized with two synthetic peptides of SFP2. Antipeptide antibody was characterized by Western blot and indirect immunofluorescence. Immune response was monitored, and mating studies were performed 6 and 22 weeks post-immunization. Result Antibodies to the SFP2 peptide 1 recognized a doublet at 220- to 230-kDa region only in the epididymal protein extract. Peptide 1 antibody recognized the cognate protein on spermatozoa from mouse, rat, and human. Histological analysis of testis and epididymis of the immunized mice indicated no deleterious effect. Incubation of sperm with the immune sera of peptide 1 caused significant reduction in motility and viability but did not agglutinate sperm. Only synthetic peptide 1 gave rise to high-level antibodies in all the immunized mice, which on mating resulted in reduced fertility rate (20%) when compared with PBS control animals (100%). The antibody levels in the immunized males declined by 22 weeks post-immunization, resulting in 100% reinstatement of fertility. Conclusion These data provide an experimental basis for the development of effective contraceptive vaccine based on new epididymal target. [ABSTRACT FROM AUTHOR]

Problem Women with antiphospholipid antibodies (aPL) are at risk for recurrent miscarriage, pre-eclampsia, and pre-term labor. aPL target the placenta directly by binding to beta2-glycoprotein I (β2GPI) expressed on the surface of trophoblast cells. The objective of this study was to determine the effects of aPL on trophoblast function and the mechanisms involved. Method of study First trimester trophoblast cells were treated with anti-β2GPI monoclonal antibodies and patient-derived aPL, after which cell survival and function was evaluated. Results We report that anti-β2GPI antibodies trigger an inflammatory response in trophoblast, characterized by increased secretion of interleukin (IL)-8, MCP-1, GRO-α, and IL-1β, and that this occurs in a TLR-4/MyD88-dependent manner. At high concentrations, these antibodies also induce caspase-mediated cell death. This was attenuated upon disabling of the MyD88 pathway, suggesting that anti-β2GPI-induced inflammatory mediators compromise trophoblast survival by acting in an autocrine/paracrine manner. Enhanced IL-8, GRO-α, and IL-1β secretion also occurred when trophoblast cells were incubated with antibodies from patients with antiphospholipid syndrome. Heparin, which acts as a pro-survival factor in human trophoblast, attenuated the anti-β2GPI antibody-mediated cell death, and also the pro-inflammatory response, but only at high concentrations. Conclusion These findings demonstrate that aPL triggers a placental inflammatory response via the TLR-4/MyD88 pathway, which in turn compromises trophoblast survival. Thus, the TLR-4/MyD88 pathway may provide a new therapeutic target to improve pregnancy outcome in antiphospholipid syndrome patients. [ABSTRACT FROM AUTHOR]

Problem The purpose of this study was to investigate whether treatment with TNF-α inhibitors and/or intravenous immunoglobulin (IVIG) increases in vitro fertilization (IVF) success rates among young (<38 years) women with infertility and T helper 1/T helper 2 cytokine elevation. Method of study Seventy-five sub-fertile women with Th1/Th2 cytokine elevation were divided into four groups: Group I: Forty-one patients using both IVIG and Adalimumab (Humira®), Group II: Twenty-three patients using IVIG, Group III: Six patients using Humira®, and Group IV: Five patients using no IVIG or Humira®. Results The implantation rate (number of gestational sacs per embryo transferred, with an average of two embryos transferred by cycle) was 59% (50/85), 47% (21/45), 31% (4/13) and 0% (0/9) for groups I, II, III and IV respectively. The clinical pregnancy rate (fetal heart activity per IVF cycle started) was 80% (33/41), 57% (13/23), 50% (3/6) and 0% (0/5) and the live birth rate was 73% (30/41), 52% (12/23), 50% (3/6) and 0% (0/5) respectively. There was a significant improvement in implantation, clinical pregnancy and live birth rates for group I versus group IV ( P = 0.0007, 0.0009, and 0.003, respectively) and for group II versus group IV ( P = 0.009, 0.04 and 0.05, respectively). Conclusion The use of a TNF-α inhibitor and IVIG significantly improves IVF outcome in young infertile women with Th1/Th2 cytokine elevation. [ABSTRACT FROM AUTHOR]

Problem Comparison of two types of immunocompromised mouse strains (SCID and NOD/SCID) for production of human antisperm antibodies (AsA). Method of study Human peripheral blood lymphocytes (PBL) were grafted to mouse peritoneal cavity and sensitized with natively glycosylated and N-deglycosylated sperm extracts. Results and conclusion NOD/SCID mice inoculated with hu-PBLs exhibited higher AsA titres with a tendency for greater sperm agglutination than human AsA raised in SCID mouse model. A comparison between ‘native’ and deglycosylated sperm extracts revealed higher agglutination titres by sera induced with the latter ones. Inhibitory effect of human polyclonal AsA in sperm penetration assay, however, produced opposite results to that for agglutination. Western immunoblotting was used to evaluate reactive sperm antigens prior to and after in situ sensitization showing multiple bands different from positive reactions brought by original sera of in vivo primed AsA-positive males. It seems that in situ generated AsA recognized sperm entities different from those revealed by blood donor’s sera samples. [ABSTRACT FROM AUTHOR]

Problem Anti-beta2-Glicoprotein-1 antibodies (anti-β2GPI-ab) have been related to recurrent miscarriage (RM) with conflicting results. The aim was to evaluate the role of anti-β2-GPI-ab as unique biological marker in RM related to antiphospholipid (aPL). Method of study A cohort study that included 59 cases, divided in two groups, was designed: group 1 comprised 43 pregnant women with ‘obstetric’ antiphospholipid syndrome (APS) and group 2 included 16 cases with similar complaints but only having repeatedly anti-β2-GPI-ab. Previous thrombosis and/or inherited thrombophilia were excluded. Lupus anticoagulant, anticardiolipin antibodies (aCA), anti-β2-GPI-ab, and other autoantibodies were analyzed. Miscarriages, premature births, pre-eclampsia, live births, placental and systemic thromboses were studied. Results No differences in previous obstetric complications were detected ( P = 1.00–0.164). After the treatment, differences in number of obstetric complications were not seen ( P = 1.00). Live births were similar in two groups (88.4% and 93.7%; P = 1.00). Placental thrombosis was equal in both groups, 93.3% versus 80% ( P = 1.00). Conclusion These results suggest that anti-β2-GPI-ab may be considered a biological marker for obstetric APS. [ABSTRACT FROM AUTHOR]

Problem The authors review embryofetal pathologies in humans caused by antibodies to maternal autoantigens and paternal alloantigens. They consider the variable percentages of miscarriages, developmental delays, intrauterine growth retardation, perinatal deaths and birth defects of unknown etiology, because a part of these percentages may be caused by analog human isoantibodies to the studied ones in the chick embryos. Method of study A total of 81 chick embryos whose dams had been immunized against soluble foreign transitory antigens and soluble paternal alloantigens from chick embryos have been macroscopically analyzed. The development was interrupted at random to know anomalies then existing; but 29/81 eggs (35.8%) were incubated until hatching. Each class of anomaly was analyzed by statistical methods; 66 control embryos were studied using the same methods. Results Transmission of the induced isoantibodies to the embryos caused: monstrosity 8.6%; death by functional abnormality 3.7%; digested embryos 7.4%; malformation 1.2%; developmental delay 30.8%; developmental delay together with intraovo growth retardation 11.1; intraovo growth retardation 15.1%; normal 25.9%. Of the mentioned 29 eggs, 19 embryos died before being born, six died in under 1 week, but only four poults survived more than 1 week. Three chicks exhibited congenital abnormalities: transitory ataxia and dysphagia, and one of them also scoliosis, while a fourth remained healthy. Conclusion If pathogenic activity by these isoantibodies can be shown to occur naturally in humans, as has been postulated, it could account for some miscarriage, developmental delay, fetal and perinatal death and birth defects of currently unknown etiology. [ABSTRACT FROM AUTHOR]

Problem Mannose-binding lectin (MBL) is an important component of the innate immunity, present at the mucosal level in vagina: a common pathogen’s entry point. Method of study We used a rapid genotyping method based on melting temperature assay to search for three single nucleotide polymorphisms (SNPs) located in the first exon of the MBL2 gene and we also measured MBL serum levels in patients with recurrent bacterial vaginosis (rBV) and recurrent vulvovaginal candidiasis (rVVC). Results Detected frequencies of MBL2 SNPs were comparable to the ones already reported for the Italian population and no significant differences were found between rVVC, rBV and controls. MBL serum levels did not show significant differences between the studied groups. Conclusion No correlation for the screened mutations has been found neither in protecting nor in favoring the infection in rVVC and rBV patients. Our data demonstrate a lack of association between functional polymorphisms in the first exon of MBL2 gene, MBL deficiency,VVC and rBV. [ABSTRACT FROM AUTHOR]

Problem The present study was conducted to examine the efficacy of immunotherapy for unexplained primary recurrent aborters using paternal lymphocytes. Method of study Two hundred and twenty-eight recurrent aborters were prospectively followed up regarding immunotherapy. Of the 228 patients, 165 underwent immunotherapy using freshly prepared paternal lymphocytes and pregnancy outcome was analyzed. No mixed lymphocyte culture reaction-blocking antibodies (MLR-BAbs) were observed in these patients prior to vaccinations. Pregnancy outcome was also analyzed in such as those patients positive for MLR-BAbs and who did not undergo immunotherapy, and in patients negative for MLR-BAbs and who had become pregnant without immunotherapy. Results Of the 140 newly pregnant patients after immunotherapy, the pregnancy continued successfully in 110 (78.6%), and the pregnancy continued successfully in 24 of 32 patients (75.0%) who were positive for MLR-BAbs. The success rate of pregnancy was 30.0% in 18 non-immunized patients. Thus, the success rate was significantly higher among patients with immunotherapy and patients positive for MLR-BAbs than in non-immunized patients, negative for MLR-BAbs. Conclusion Immunotherapy using paternal lymphocytes is considered to be effective for unexplained primary recurrent aborters negative for MLR-BAbs. [ABSTRACT FROM AUTHOR]

Problem Patients with elevated blood natural killer (NK) cells may be offered intravenous immunoglobulin (IVIG) treatment, but there is controversy about the utility of blood NK cell testing. Human CD56+ NK cells include several subpopulations that include the putatively cytotoxic CD56+ CD16+ subset. In mouse models of pregnant failure, NKT cells appear to be important. However, a mouse model may only be pertinent to a subset of patients, as recurrent pregnancy failure is a heterogenous group. Method of study An ethics-approved observational study was done to observe the effect of treatment on total blood lymphoid cells, and subsets of CD56+ blood lymphocytes including CD56+ CD3+ NKT cells determined by flow cytometry, and to correlate with pregnancy outcome. Fifteen fertile women with a history of successful pregnancy and thirty-one women suffering from repeated implantation failure or recurrent spontaneous abortion provided serial blood samples during one menstrual cycle or prior to and during treatment. IVIG was administered to the latter group with or without heparin/aspirin. Results Eight of thirty infertile women presented with high numbers of CD56+ CD3+ NKT cells, which declined after treatment with IVIG. The elevated NKT cell group with or without concomitant autoimmunity achieved a significantly higher successful pregnancy rate over the course of the study, as compared to women with average numbers of NKT cells and no evidence of autoimmunity ( P = 0.018). Elevated NKT levels alone was an independent predictor of success on treatment ( P = 0.003). Conclusion Elevated NKT cells in recurrent pregnancy loss or implantation failure can be ameliorated with IVIG treatment, and result in successful pregnancy. Assay of NKT cell numbers may idengif"y patients who are more likely to benefit from IVIG therapy and merits further examination in randomized phase II studies. [ABSTRACT FROM AUTHOR]

Problem Progesterone-induced blocking factor (PIBF) induces Th2 biased cytokine production; therefore, this study investigates the effects of PIBF on the protein kinase C (PKC)/Ca++ system – which plays a key role in Th1/Th2 differentiation. Method of study Proteins from PIBF-treated cells were reacted on Western blots with phospho-specific antibodies recognizing different PKC izoforms. Intracellular free calcium was measured by flow cytometry. Results Both interleukin (IL)-4 and PIBF induced PKC phosphorylation, which was abrogated by anti-IL-4R α or anti-PIBF immunoglobulin G pre-treatment. PIBF treatment did not alter intracellular Ca++ levels. Inhibition of PKC ζ or PKC θ phosphorylation, but not that of PKC α/ β resulted in the loss of STAT6 and Jak1 phosphorylation by PIBF. Conclusions Our data show that PIBF phosphorylates PKC via binding to the IL-4R, without affecting intracellular Ca++. Phosphorylation of PKC ζ and PKC θ is required for Jak1 and STAT6 activation, whereas PKC α/ β is not involved. These findings explain the mechanism by which PIBF supports a Th2 dominant cytokine pattern. [ABSTRACT FROM AUTHOR]

In this review, a novel and unifying pathophysiologic mechanism of preeclampsia is presented whereby a minimal excess of placental immune complex production versus removal causes a proinflammatory autoamplification cascade of trophoblast apoptosis/necrosis and oxidative stress, culminating in clinical preeclampsia. This concept immediately leads to a plethora of new and robust therapeutic strategies. [ABSTRACT FROM AUTHOR]

PROBLEM: To determine the ability of monoclonal antibodies (MoAbs) against acrosomal antigens to detect physiology and pathology of human spermatozoa and to detect spermatids in ejaculates of infertile male with azoospermia. METHOD OF STUDY: Sperm antigens detected with prepared MoAbs were partially characterized by biochemical and immunocytochemical methods. The acrosomal status of spermatozoa was compared in men with normal and pathological spermiograms and in sperm before and after induced acrosome reaction (AR). Ejaculates from patients were tested for the presence of spermatids. RESULTS: MoAbs specifically bind to intra-acrosomal sperm antigens with quantitative difference between ejaculates with normal and pathological spermiograms. These antigens are released from the acrosome after induced AR. MoAbs labeled acrosomal proteins in round and elongated spermatids in the ejaculates of patients with azoospermia. CONCLUSION: MoAbs against intra-acrosomal sperm antigens are useful for human sperm diagnosis and prediction of spermatogenesis. The spermatids can be utilized in assisted reproduction. [ABSTRACT FROM AUTHOR]

PROBLEM: Prevention of spontaneous abortion by allogeneic mononuclear leukocyte immunotherapy has proven ineffective in the CBA x DBA/2 murine abortion model if the leukocytes are stored overnight before inoculation. The mechanism and generality of the phenomenon has not been elucidated. METHODS: As prevention of recurrent abortion in the CBA x DBA/2 model requires allogeneic BALB/c lymphoid cells bearing paternal antigens and the tolerance-signaling molecule CD200 (OX-2), we evaluated effects of cell storage on cell surface CD200 expression using flow cytometry of fresh or stored cells stained with monoclonal anti-CD200 antibody. Release of putative CD200 molecules into culture supernatant during storage was tested by the ability of supernatants to block binding of anti-CD200 to freshly isolated cells. Similar studies were done using human peripheral blood mononuclear leukocytes. Possible binding of soluble CD200 to immunoglobulin G (IgG) molecules in plasma as a basis for the anti-abortive effect of intravenous immunoglobulin G (IVIG) was tested using the standard peripheral blood lymphocyte (PBL) natural killer (NK) cell lysis of 51Cr-labeled K562 cells and monoclonal anti-human CD200 antibodies. RESULTS: Loss of anti-abortive effect of BALB/c cells with overnight storage at 4°C and blocking of protective effect of freshly isolated cells with anti-CD200 antibody was confirmed. Supernatants of stored cells acquired a low level of protective activity against abortion in the CBA x DBA/2 model. Cell surface CD200 was lost with overnight storage at 4 or 22 C, and supernatants acquired the ability to block binding of anti-CD200 antibody to fresh cells. Similar results were obtained using human PBL. However, if cells were stored overnight in IgG containing plasma, binding was not blocked. Suppression of NK cell lysis by PBL was abrogated if anti-CD200 antibody was added to the assay. CONCLUSIONS: Loss of the tolerance signal CD200 from allogeneic cel... [ABSTRACT FROM AUTHOR]

PROBLEM: We have shown that CD200Fc, a chimeric molecule including the extracellular domain of CD200 and a murine immunoglobulin (Ig)G2a Fc region, regulates immune responses and prevents T helper (Th)1 cytokine-triggered spontaneous abortions in mice. CD200 is expressed on a subpopulation of uterine decidua cells and on trophoblast, both in the mouse and human. The receptor(s) for CD200, CD200R(s), was not previously well-characterized. METHODS: 5′-rapid amplification of cDNA ends (RACE), cDNA and genomic DNA clone analysis were used to identify a family of CD200Rs on mouse chromosome 16, juxtaposed to the CD200 gene, named CD200R1, R2, R3, and R4. Northern blot and reverse transcriptase polymerase chain reaction (RT-PCR) analysis was used to detect expression of different CD200R subtypes in different organs. Rabbit polyclonal and rat monoclonal antibodies (mAbs) to CD200R isoforms was used for fluoresence-activated cell sorter (FACS) analysis, to test for immunomodulatory effects on allogeneic mixed-lymphocyte responses in vitro, and for immunohistochemistry. RESULTS: The CD200Fc was able to interact physically with each of the CD200Rs expressed on the cell surface. Northern blot and RT-PCR analyses indicated distinct patterns of CD200R isoform mRNA expression in different tissues and FACS analyses confirmed unique cell-and tissue-specific expression of the different CD200Rs. mAbs directed against the different isoforms modified the development of in vitro alloimmune responses. The addition of anti-CD200R1/R4 elicited immunomodulatory responses in vitro comparable to findings with CD200Fc, but different from the effects of anti-CD200R2. CONCLUSIONS: These data provide evidence for a family of CD200R molecules in the mouse genome and defines the existence of previously unrecognized diversity in the CD200/CD200R immunomodulatory gene member family. Although this gene member family is clustered in the... [ABSTRACT FROM AUTHOR]

Domagała A, Kurpisz M. Immunoprecipitation of sperm and somatic antigens with antibodies from sera of sperm-sensitized and anti-sperm antibody-free individuals. AJRI 2004; 51:226–234 © Blackwell Munksgaard, 2004 Immune infertility may result from the presence of anti-sperm antibodies (ASA) in sera of sensitized individuals or in their genito-urinary millieu. According to some authors, sera of pre-pubertal boys with genital disorders may contain ASA, too. When identified and characterized, sperm antigenic components can be employed for diagnostic and/or for immunocontraceptive purposes. Sperm auto- and isoimmune reactive surface antigens were identified by means of immunoprecipitation. Comparative immunoprecipitations of somatic antigens by using antibodies, contained in polyclonal sera of fertile and (immunologically) infertile adults as well as pre-pubertal boys with gonadal failures were performed. Antibodies contained in sera of the all studied populations reacted with a number of sperm as well as somatic antigens. However, we distinguished a panel of antigens localized exclusively on the surface of sperm cells, reacting with ASA positive sera (in the range of molecular weight between 15 and 115 kDa), some of them seem to present novel entities as can be judged by the molecular weight. [ABSTRACT FROM AUTHOR]

Analyzes whether progesterone and estrogen affect asymmetric antibody synthesis by modulating interleukin-6 production in hybridoma cells. Contribution of sex hormones (SHs) in the immune system; List of the immunomodulatory actions of SHs; Significance of blocking and protective asymmetric antibodies during pregnancy.

The author comments on the manuscript "Treatment with tumor necrosis factor (TNF) inhibitors and intravenous immunoglobulin (IVIG) improves live birth rates in women with recurrent spontaneous abortion (RSA)," by Edward E. Winger and Jane L. Reed. According to the author, the manuscript provides the views of the Alan Beer Reproductive centres and is welcomed because it deals with IVIG, not lymphocyte allo-immunization as a technique for treatment of recurrent pregnancy loss.