Journal of Reproductive Immunology RSS feed: Articles in Press. The aim of the Journal of Reproductive Immunology is to provide the critical forum for the dissemination of results from high quality research in all aspects of experimental, animal and clinical reproductive immunobiology. This encompasses normal and pathological processes of: * Male and Female Reproductive Tracts * Gametogenesis and Embryogenesis * Implantation and Placental Development * Gestation and Parturition * Mammary Gland and Lactation INCLUDING: * Infectious disease, including STDs * Inflammation * Autoimmunity * Mucosal Immunology * Cytokines and Other Immune Mediators * Immunoendocrinology * Reproductive Immunotherapies * Immunogenetics * Developmental Immunology * Immunology of Reproductive Cancers * Application of Immunological Techniques in Eluciation of Reproductive Processes or Dysfunction The international character of the Journal is reflected in the breadth of its Editorial Board and commitment to publish new and outstanding studies in different aspects of reproductive immunobiology from all five continents. Within the Journal, the Editors wish to bridge the gap between basic and clinical studies in all subareas of research relevant to reproductive immunobiology.http://www.jrijournal.org//inpress?rss=yesElsevier Inc.en © 2010 Published by Elsevier Inc. Journal of Reproductive Immunology0165-03782010-03-08 © 2010 Published by Elsevier Inc. healthpermissions@elsevier.comhttp://www.jrijournal.org/article/PIIS0165037810000409/abstract?rss=yesAbstract: Self and non-self recognition is the key mechanism by which the immune system determines whether or not to mount an immune response. During pregnancy the maternal immune system must tolerate the persistence of non-self semi-allogeneic fetal cells in the maternal tissue. Although many mechanisms have been shown to contribute to the prevention of a destructive maternal immune response to fetal cells, the immune acceptance of the allogeneic fetus in pregnancy largely remains an immunological paradox (). The aim of this review is to describe the expression of the polymorphic histocompatibility antigens at the fetal–maternal interface, their interaction with maternal leukocytes and their possible roles in immune regulation at the fetal–maternal interface during human pregnancy.Major histocompatibility complex (MHC)-mediated immune regulation of decidual leukocytes at the fetal–maternal interface - Uncorrected ProofTamara Tilburgs, Sicco A. Scherjon, Frans H.J. Claas10.1016/j.jri.2010.01.005Journal of Reproductive Immunology (2010)2010-03-08Journal of Reproductive Immunology2010-03-08http://www.jrijournal.org/article/PIIS0165037810000410/abstract?rss=yesAbstract: The conceptus is considered a semi-allograft because of the presence of paternal HLA-C molecules. These alloantigens can be processed by maternal antigen presenting cells, which present them to specific maternal CD4+ T cells. After activation, the maternal CD4+ T cells can become effector decidual CD4+ T cells, which are able to release various cytokines. Th1-type cytokines (IFNγ) that promote allograft rejection may compromise pregnancy, whereas the Th2-type cytokines (IL-4, IL-10) that inhibit Th1 responses, promote allograft tolerance and therefore may improve fetal survival. A collaborative interaction between the decidual natural regulatory T cells, CD4+ CD25+ Foxp3 T cells and NKT cells in preventing fetal allograft rejection is suggested.T cell tolerance towards the fetal allograft - Uncorrected ProofMarie-Pierre Piccinni10.1016/j.jri.2010.01.006Journal of Reproductive Immunology (2010)2010-03-08Journal of Reproductive Immunology2010-03-08RESEARCH ARTICLEhttp://www.jrijournal.org/article/PIIS0165037810000422/abstract?rss=yes Radslav Kinsky died peacefully and quietly on 12 October 2008 after a long disease, which he fought with lucidity and courage until the end in his beloved land of Ž’dár nad Sázavou, Czech Republic.Radslav Kinsky (1928–2008) - Uncorrected ProofGerard Chaouat10.1016/j.jri.2009.12.007Journal of Reproductive Immunology (2010)2010-03-08Journal of Reproductive Immunology2010-03-08OBITUARYhttp://www.jrijournal.org/article/PIIS0165037810000434/abstract?rss=yesAbstract: Increased production of Th1 cytokines such as TNFα plus IFNγ compared to the Th2 cytokine IL-10 is linked to infertility and recurrent spontaneous abortion (RSA). In murine models, direct evidence of pathogenic mechanisms has been elucidated, and these have been validated where possible by correlation with human data. Although there are a number of potential targets that could be utilized for therapeutic benefit, TNFα is currently the most feasible and uncorrected abnormality. Two recently published observational cohort-controlled studies of the addition of anti-TNFα agents to treatment with heparin plus aspirin, with or without IVIG, in RSA and in infertile (repeat IVF failure) patients are reviewed with respect to methodological and biological rigor, and literature supporting the reliability, feasibility, and value of observational cohort-controlled trials compared to double-blind randomized controlled trials is outlined. For those who do not believe the existing data is sufficiently strong for adoption of anti-TNFα therapy, a hybrid approach is outlined for validation of efficacy in specific subsets of pregnancy failure patients. Potential side effects and key issues in informed consent are set out. Anti-TNFα drugs may offer a new safe and effective approach to treating patients with Th1-cytokine-dependent infertility and recurrent miscarriages.Anti-TNFα therapy in immune-mediated subfertility: State of the art - Uncorrected ProofDavid A. Clark10.1016/j.jri.2010.01.007Journal of Reproductive Immunology (2010)2010-03-08Journal of Reproductive Immunology2010-03-08RESEARCH ARTICLEhttp://www.jrijournal.org/article/PIIS0165037810000446/abstract?rss=yesAbstract: Women pregnant with a male fetus often generate cellular and humoral immune responses against male-specific minor histocompatibility (HY) antigens—however, the importance of these responses for pregnancy outcome is unclear. Epidemiologic studies have shown that the birth of a boy compared with a girl prior to a series of miscarriages significantly reduces the chance of a subsequent live birth and pregnancies with boys have an increased risk of placental abruption. This paper aims to review the current knowledge about the impact of anti-HY immunity on pregnancy outcome in terms of miscarriage and placental abruption. Our knowledge primarily comes from studies of the impact on pregnancy outcome of HLA class II alleles known to restrict CD4 T cell mediated anti-HY responses among 358 secondary recurrent miscarriage (SRM) patients and 203 of their children born prior to the miscarriages and investigation of these HLA alleles in 8 patients with recurrent severe placental abruptions. The chance of a subsequent live birth in SRM patients with firstborn boys compared to firstborn girls was significantly lower in women with HY-restricting HLA class II alleles [OR: 0.17 (0.1–0.4), p=0.0001]. Most patients with recurrent placental abruptions had firstborn boys and significantly more of these patients carried HLA haplotypes with HY-restricting class II alleles compared with controls (p=0.009). These findings are strongly indicative of aberrant maternal immune reactions against fetal HY antigens playing a role in recurrent miscarriage and placental abruption. We propose pathogenetic pathways for these conditions that in our view best explain the findings.The impact of anti-HY responses on outcome in current and subsequent pregnancies of patients with recurrent pregnancy losses - Uncorrected ProofOle Bjarne Christiansen, Rudi Steffensen, Henriette Svarre Nielsen10.1016/j.jri.2009.12.008Journal of Reproductive Immunology (2010)2010-03-08Journal of Reproductive Immunology2010-03-08http://www.jrijournal.org/article/PIIS0165037810000458/abstract?rss=yesAbstract: Mucosal tissues of the genital tracts and the distal intestinal tract are portals of entry for infectious agents of sexually transmitted diseases, including HIV-1. Although the genital and intestinal tracts share a common embryologic origin and remain in anatomical proximity, these two sites display remarkably different immunologic features, including the levels, isotypes and molecular forms of immunoglobulins, and magnitudes and qualities of humoral and cellular immune responses. Thus, viral and bacterial infections of the genital tract or intravaginal immunizations induce, in the absence of mucosal adjuvants, minimal immune responses. Consequently, to induce relevant immune responses in the genital tract, alternative immunization routes have been explored, including systemic, intranasal, oral, or rectal immunization and their combinations. In limited studies performed in animals, systemic immunization with a subsequent mucosal (intranasal) immunization proved to be effective in the induction of humoral immune responses in genital tract secretions. The approaches have been explored to a limited extent in humans.Antibody-mediated protection and the mucosal immune system of the genital tract: relevance to vaccine design - Uncorrected ProofJiri Mestecky, Milan Raska, Jan Novak, Rashada C. Alexander, Zina Moldoveanu10.1016/j.jri.2010.02.003Journal of Reproductive Immunology (2010)2010-03-08Journal of Reproductive Immunology2010-03-08REVIEW ARTICLEhttp://www.jrijournal.org/article/PIIS016503781000046X/abstract?rss=yesAbstract: Several lines of evidence suggest that the human leukocyte antigen (HLA)-G play a key role in the regulation of human pregnancy. A sub-population of cells highly represented at the decidua belong to the myeloid-derived monocyte/macrophage lineage, which potentially interact with HLA-G expressing cells. It is proposed that HLA-G protects decidual trophoblasts from lysis by blocking the effector function of decidual monocyte/macrophages. The interaction between HLA-G and monocyte/macrophages may therefore contribute to a successful pregnancy. Here we examine existing knowledge on the convergent role of HLA-G and monocyte/macrophages in pregnancy and define the synergy that exists between these two elements in the decidua. Key features of the HLA-G gene product are discussed followed by the main characteristics of decidual monocyte/macrophages. A hypothetical model for the interaction between HLA-G and monocyte/macrophage cells at the fetal–maternal interface is proposed.Interaction between HLA-G and monocyte/macrophages in human pregnancy - Uncorrected ProofAyesha Shakhawat, Valerie Shaikly, Essam Elzatma, Emmanouil Mavrakos, Asma Jabeen, Nelson Fernández10.1016/j.jri.2010.02.004Journal of Reproductive Immunology (2010)2010-03-08Journal of Reproductive Immunology2010-03-08http://www.jrijournal.org/article/PIIS0165037810000392/abstract?rss=yesAbstract: While proof of concept that the immune system can be harnessed to attack cancer cells has been established, only a minority of patients are cured with immunotherapeutic regimens designed to enhance host autologous immunity. Recently acquired knowledge indicates that the low response rates associated with conventional cancer immunotherapy could be attributed, at least in part, to the processes of immunosenescence and replicative senescence, which consequently render the anti-tumor T cell clones of the aged host quantitatively insufficient and qualitatively impaired to elicit an effective anti-cancer response. Therefore, it is anticipated that the efficacy of adoptive T cell cancer immunotherapy can be dramatically improved by utilizing “young” T cells with targeted antigen specificity derived from umbilical cord blood, instead of current practice using autologous senescent T cells derived usually from aged cancer patients. Functionally competent CD8+ T cells specific against tumor antigens (e.g. Her2/neu and MAGEA3) as well as against viral antigens have been recently generated from cord blood mononuclear cells suggesting that cord blood can be a source of “young” anti-tumor T cells for adoptive cancer immunotherapy. Moreover, cord blood can give rise to antigen non-specific effector cells including NK cells and dendritic cells. Finally, umbilical cord blood anti-tumor specific T cell clones are unlikely to have participated in tumor immunoediting, making them more efficient than host T cells in eradicating tumor cells.Cord blood as a source of non-senescent lymphocytes for tumor immunotherapy - Uncorrected ProofAnastasios E. Germenis, Vaios Karanikas10.1016/j.jri.2010.02.002Journal of Reproductive Immunology (2010)2010-03-04Journal of Reproductive Immunology2010-03-04RESEARCH ARTICLEhttp://www.jrijournal.org/article/PIIS0165037810000343/abstract?rss=yesAbstract: Glycoproteins expressed at the fetal–maternal interface have been shown to exert immunomodulating effects. Glycodelin, hCG and transferrin have been used in in vitro experiments as ligands to block E-selectin-mediated cell adhesion. We found that glycodelin is a strong inhibitor of the E-selectin-mediated cell adhesion with a 103-fold increase in potency compared to the monovalent tetrasaccharide sialyl Lewis X. HCG with distinct carbohydrate expression is also an effective selectin antagonist, whereas the potency of transferrin is low. This could indicate a possible role of glycodelin, hCG and transferrin in preventing leukocyte adhesion to the fetal trophoblast. In decidual tissue of abortion patients, glycodelin expression was significantly reduced compared to normal gestation. These results were confirmed by in situ hybridization. Moreover, glycodelin expression in endometrial cells in vitro could be stimulated by addition of hCG. Because hCG is down-regulated in women with abortion, we speculate that hCG could be one of the factors regulating glycodelin expression. Galectins are structurally related proteins with the ability to bind β-galactosides through a conserved carbohydrate recognition domain. Galectin-1 (Gal-1) expression in the syncytiotrophoblast is down-regulated in early pregnancy loss. Gal-1 recognizes the Thomsen–Friedenreich disaccharide (Galβ1-3GalNAc-) on the syncytiotrophoblast and extravillous trophoblast. Gal-1 also inhibited trophoblast cell proliferation but did not induce apoptosis in BeWo cells. Ligation of Gal-1 on trophoblast cells may have regulatory effects on trophoblast cell differentiation. Decreased expression of Gal-1 may partly explain disturbed trophoblast differentiation during early placentation leading to early pregnancy loss.Glycoprotein and carbohydrate binding protein expression in the placenta in early pregnancy loss - Uncorrected ProofU. Jeschke, B. Toth, C. Scholz, K. Friese, A. Makrigiannakis10.1016/j.jri.2009.10.012Journal of Reproductive Immunology (2010)2010-03-02Journal of Reproductive Immunology2010-03-02http://www.jrijournal.org/article/PIIS0165037810000355/abstract?rss=yesAbstract: The success of implantation depends on a receptive endometrium, a normal blastocyst and synchronized cross-talk at the maternal–fetal interface. The progression of pregnancy then requires immunological tolerance which allows conceptus survival. A cascade of cytokines mediates this dialogue and is crucial in the cross-talk between the immune and endocrine systems. The first known human embryo-derived signal is chorionic gonadotropin (hCG) by which the embryo profoundly influences immunological tolerance and angiogenesis at the maternal–fetal interface. hCG levels coincide with the development of trophoblast tolerance. Indeed, it increases the number of uterine natural killer cells that play a key role in the establishment of pregnancy. hCG also intervenes in the development of local immune tolerance through the cellular system of apoptosis via Fas/Fas-Ligand. It modulates the Th1/Th2 balance and acts on complement C3 and C4A/B factors modulating decidual immunity. The transient tolerance evident during gestation is at least partially achieved via the presence of regulatory T cells which are attracted by hCG at the fetal–maternal interface. Finally, hCG treatment of activated dendritic cells results in an up-regulation of MHC class II, IL-10 and IDO expression, reducing the ability to stimulate T cell proliferation. Successful implantation requires an extensive endometrial angiogenesis in the implantation site. Recent data demonstrate angiogenic effects of hCG via its interaction with endometrial and endothelial LH/hCG receptors. Our review focuses on these functions of hCG, giving new insight into the endocrine–immune dialogue that exists between the conceptus and immune cells within the receptive endometrium at the time of implantation.Human chorionic gonadotropin: A hormone with immunological and angiogenic properties - Uncorrected ProofMarie Tsampalas, Virginie Gridelet, Sarah Berndt, Jean-Michel Foidart, Vincent Geenen, Sophie Perrier d’hauterive10.1016/j.jri.2009.11.008Journal of Reproductive Immunology (2010)2010-03-02Journal of Reproductive Immunology2010-03-02http://www.jrijournal.org/article/PIIS0165037810000367/abstract?rss=yesAbstract: Taking a cue from the recent workshop ‘Preeclampsia—A Pressing Problem’ sponsored by the National Institutes of Child Health and Human Development, this review article takes a fresh look at hypoxia and a dysfunctional immune system as the key contributors to the etiology of preeclampsia and the mechanisms involved therein. In the context of epidemiological research on the intricate and multifactorial nature of preeclampsia, we focus on hypoxia as an upstream regulator of preeclampsia and its consequences in a model compromised by a deficiency in key pregnancy compatible immune modulators. It has been proposed that placental hypoxia releases cytotoxic factors produced at the maternal–fetal interface into the circulation to manifest the maternal symptoms associated with preeclampsia. However, it is not clear how this mechanism is empowered in pregnant women. Does systemic hypoxia exert preeclampsia-like effects on pregnancy? Are these effects further manifested by intrinsic inflammation in the absence of key immune modulators such as IL-10? Thus, it is of paramount importance that in vivo models be developed wherein the role of systemic hypoxia can be evaluated for preeclampsia-causing events. We present a discussion on whether prolonged exposure to hypoxia can lead to a perpetual cycle of compartmentalized uteroplacental tissue damage, release of anti-angiogenic and vasoconstrictive factors that impair trophoblast invasion and promote systemic vascular resistance resulting in the maternal syndrome.Beyond the threshold: an etiological bridge between hypoxia and immunity in preeclampsia - Uncorrected ProofSurendra Sharma, Wendy E. Norris, Satyan Kalkunte10.1016/j.jri.2010.01.002Journal of Reproductive Immunology (2010)2010-03-02Journal of Reproductive Immunology2010-03-02REVIEW ARTICLEhttp://www.jrijournal.org/article/PIIS0165037810000379/abstract?rss=yesAbstract: Whether the embryo develops normally or not depends not only on the mechanisms regulating embryonic development, but also on the mechanisms acting to resist and repair injures in the embryo due to harmful maternal stimuli or exposure to developmental toxins. The key role of p53 in the regulation of the embryo's response to embryopathic stress inducing DNA damage is beyond doubt. Yet the question why p53 in some cases acts as a suppressor of teratogenesis, whereas in other cases it induces teratogenesis, remains unanswered. In this minireview we analyze studies in which organogenesis-stage embryos were exposed to various developmental toxins and suggest a model unifying the teratogenesis-suppressing and teratogenesis-promoting role of p53. This model predicts that p53 protects embryos from developmental toxins inducing oxidative stress and promotes the process of maldevelopment induced by developmental toxins activating apoptotic machinery. Certainly, many questions must be answered before concluding the extent to which this model is correct. Yet, it does allow us to explain some discrepancies obtained in studies performed to date. Also, the model might be useful in choosing molecular targets for further studies addressing p53-controlled and p53-independent mechanisms, which determine the embryo's resistance to embryopathic stress.Mechanisms of the embryo's response to embryopathic stressors: a focus on p53 - Uncorrected ProofArkady Torchinsky, Vladimir Toder10.1016/j.jri.2010.01.003Journal of Reproductive Immunology (2010)2010-03-02Journal of Reproductive Immunology2010-03-02REVIEWhttp://www.jrijournal.org/article/PIIS0165037810000380/abstract?rss=yesAbstract: We report a new morphometric method for measurement of the amount of cell death in three-dimensional multicellular spheroids of the trophoblast-like cell line AC1-M59 and of cultured pieces of decidua tissue (decidua spheroids) in response to a cytotoxic agent. The viability of the spheroids was assessed by adding propidium iodide to the culture medium at the end of the toxic treatment. On fluorescence and brightfield images of serial cryosections the areas of propidium iodide fluorescence and the entire corresponding spheroids were measured by applying digital image processing and ratiometrical quantification. As an example, we evaluated the cytotoxic effect of hydrogen peroxide on both types of spheroids. The relative potency of hydrogen peroxide to induce tissue damage was assessed quantitatively for determination of the minimal concentration that leads to an increase in cytotoxicity. The method presented suggests general applicability for in vitro determination of toxicity against tissues.Measurement of cell death by oxidative stress in three-dimensional spheroids from trophoblast and in fragments of decidua tissue - Uncorrected ProofRegine-Susanne Theuerkauf, Helmut Ahammer, Monika Siwetz, Christine Helige, Gottfried Dohr, Wolfgang Walcher, José Ramón Palacio, Paz Martinez, Peter Sedlmayr10.1016/j.jri.2010.01.004Journal of Reproductive Immunology (2010)2010-03-02Journal of Reproductive Immunology2010-03-02http://www.jrijournal.org/article/PIIS0165037810000331/abstract?rss=yesAbstract: Issues concerning the beginning of life and medical intervention in the onset of human existence are very delicate in their nature; they involve multi-dimensional knowledge, they are difficult to comprehend and sensitive to handle. When pure scientific elements are combined with profound emotions, when the genius of technological discoveries touches upon human dignity and sanctity, when passion for the technological achievement intervenes in basic human rights, then the sense of inadequacy and ignorance becomes intense and critical. Silence seems more sought-after than words, and willingness to learn more prudent than the desire to speak. Fear of the inconceivable consequences and even more so the inability to assess them, experiments with the unknown, the likelihood that basic historical, ethical and social values may change forever, but mainly the replacement of God in His wondrous work of creation – the onset of human life – places the ethics of reproductive technologies on the frontline of contemporary bioethics. This opinion paper does not deal with dangers, insults, fears, threats, “speed limits” or ethical controversies, but rather with the very mystery of life. Although there are no generally accepted replies to the various questions being posed, some thoughts and reservations, which can shed some light upon complicated dilemmas are presented. Firstly, the content of reproductive technologies, the problem of infertility today, the methods of fertility treatment, and of prenatal and pre-implantation testing are described, and then the social impact of IVF, complicated cases, deontological dilemmas and some ethical concerns are discussed.The ethics of assisted reproduction - Uncorrected ProofNikolaos Chatzinikolaou10.1016/j.jri.2010.02.001Journal of Reproductive Immunology (2010)2010-02-26Journal of Reproductive Immunology2010-02-26http://www.jrijournal.org/article/PIIS0165037810000148/abstract?rss=yesAbstract: Although recurrent miscarriage (RM) affects only 1–3% of couples, it has a major influence on the wellbeing and psychosocial status of patients. Therefore, research into improved diagnosis and development of new treatment strategies is essential. In this review, we summarize current concepts on diagnosis and treatment in RM, drawing upon research reports and international guidelines to provide insights into the pathophysiology of pregnancy disrupted by repeated miscarriage. Anatomical malformations, infectious diseases, endocrine disorders, autoimmune defects as well as acquired and inherited thrombophilia are established risk factors in RM. In addition, our recent findings indicate an impact on miscarriage incidence of glycoproteins such as glycodelin, and nuclear hormone receptors such as the peroxisome proliferator-activated receptors (PPARs). Significantly reduced glycodelin expression is associated with miscarriage, whereas up-regulation of PPARs appears to compensate for either the activated immune response or the disturbed cytotrophoblast differentiation in RM patients. There is also evidence that circulating placental microparticles are increased in a subgroup of RM patients, indicating an acquired procoagulant state even outside pregnancy. Treatment strategies like aspirin and low molecular weight heparin (LMWH) are standard medications in RM, although only a few placebo-controlled trials have proven their benefit in respect to live birth rate. There is emerging evidence that new treatment options, including drugs like TNFα inhibitors and granulocyte colony-stimulating factor (G-CSF) might be beneficial in some cases of RM. However, larger clinical trials must be completed to further prove or disprove benefits of these drugs in the treatment of RM patients.Recurrent miscarriage: current concepts in diagnosis and treatment - Corrected ProofBettina Toth, Udo Jeschke, Nina Rogenhofer, Christoph Scholz, Wolfgang Würfel, Christian J. Thaler, Antonis Makrigiannakis10.1016/j.jri.2009.12.006Journal of Reproductive Immunology (2010)2010-02-11Journal of Reproductive Immunology2010-02-11REVIEWhttp://www.jrijournal.org/article/PIIS016503780900552X/abstract?rss=yesAbstract: Stress profoundly compromises reproduction, particularly when experienced in early gestation. One outcome is pregnancy failure: although glucocorticoids have adverse effects it is not clear what their role in pregnancy failure is. However, secretion of vital hormones such as progesterone and prolactin are reduced and this unbalances the delicate and important pregnancy-protective cytokine milieu. Complex interaction between glucocorticoids, progesterone/prolactin and the immune system evidently precipitate the loss, although early loss may confer reproductive advantage by preserving maternal energy stores and facilitating ongoing maternal care for other offspring. If pregnancy failure is not induced another, perhaps more profound, outcome of maternal stress is fetal programming. Much is known about the role of elevated glucocorticoids during late gestation in fetal programming, but in early gestation their role is less clear, though likely. Other key pregnancy hormones and immune factors also contribute to fetal programming. Undoubtedly integrated action of glucocorticoids, progesterone/prolactin and the immune system is crucial for optimal pregnancy outcome and is highly susceptible to environmental conditions.Stress in early pregnancy: maternal neuro-endocrine-immune responses and effects - Corrected ProofVictoria J. Parker, Alison J. Douglas10.1016/j.jri.2009.10.011Journal of Reproductive Immunology (2009)2009-12-28Journal of Reproductive Immunology2009-12-28http://www.jrijournal.org/article/PIIS016503780900549X/abstract?rss=yesAbstract: In mammalian reproduction, two immunologically disparate entities, the mother and her fetus, co-exist in close proximity and mutually tolerate each other. The maternal immune system plays a major contributing role in the reproductive outcome. A coordinated set of immunological events takes place between the maternal and fetal cells to ensure fetal survival. Among these, cytokines secreted by proximal maternal immune cells as well as fetal trophoblast cells play a major role in feto-maternal tolerance. In this review, we describe the role of the vacuolar ATPase (and more specifically the a2 isoform, a2V-ATPase) in controlling the expression of these vital cytokines. a2V-ATPase is a key enzyme that controls the acidification of intracellular vesicles and the extracellular environment, processes that play a major role in cellular function. The localization of a2V-ATPase in tissues and immune cells of the reproductive tract which are essential for pregnancy will be described. Information will be provided on the role of a2V-ATPase on aspects of cell development in pregnancy, from fertilization to implantation and fetal growth. Particular emphasis will be placed on the role of a2V-ATPase in (a) regulating parts of the cytokine network at the implantation site and (b) attenuating the potentially harmful maternal immune response against trophoblast cells.The a2 isoform of vacuolar ATPase is a modulator of implantation and feto-maternal immune tolerance in early pregnancy - Corrected ProofEvangelos Ntrivalas, Rita Levine, Christina Kwong, Alice Gilman-Sachs, Kenneth Beaman10.1016/j.jri.2009.10.010Journal of Reproductive Immunology (2009)2009-12-16Journal of Reproductive Immunology2009-12-16http://www.jrijournal.org/article/PIIS0165037804001251/abstract?rss=yesThis article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.WITHDRAWN: Effects of implantation and early pregnancy on the expression of cytokines and vascular surface molecules in the sheep endometrium - Corrected ProofAbu Nasar Md., Aminoor Rahman, Kenneth J. Snibson, Chee Seong Lee, Els N.T. Meeusen10.1016/j.jri.2004.08.006Journal of Reproductive Immunology (2009)2009-03-23Journal of Reproductive Immunology2009-03-23http://www.jrijournal.org/article/PIIS0165037807001714/abstract?rss=yesProgram - Uncorrected Proof10.1016/j.jri.2007.06.050Journal of Reproductive Immunology (2007)2007-07-09Journal of Reproductive Immunology2007-07-09