-
[show abstract]
[hide abstract]
ABSTRACT: An improved mechanistic understanding of the adaptational processes mounted during mammalian reproduction is emerging. Intricate pathways occurring at the fetomaternal interface, such as the formation of a functional synapse between invading fetal trophoblast cells, and the involvement of various maternal immune cell subsets and epigenetically modified decidual stromal cells have now been identified. These complex pathways synergistically create a tolerogenic niche in which the semiallogeneic fetus can develop. New insights into fetomaternal immune cross-talk may help us to understand the pathogenesis of pregnancy complications as well as poor postnatal health. Moreover, the effects of maternal immune adaptation to pregnancy on autoimmune disease activity are becoming increasingly evident. Thus, insights into fetomaternal immune cross-talk not only advance our understanding of pregnancy-related complications but also may be informative on how immune tolerance can be modulated in clinical settings outside the context of reproduction.
Nature medicine 05/2013; 19(5):548-56. · 27.14 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: STUDY QUESTION: Are maternal progesterone levels in early pregnancy associated with fetal birthweight? SUMMARY ANSWER: Low levels of first-trimester maternal progesterone are significantly associated with a reduction in birthweight in girls, but not boys. WHAT IS ALREADY KNOWN: Progesterone in the third trimester of pregnancy has previously been related to birthweight in humans. STUDY DESIGN, SIZE, DURATION: Pregnant women between gestational weeks 4 and 12 were recruited by 99 obstetricians in private practice and enrolled in a prospective cohort study. A follow-up took place at birth. Women younger than 18 years, who had undergone fertility treatments or were diagnosed with infectious diseases, were excluded from the study. A subgroup of 906 participants in whom progesterone had been measured was then selected retrospectively based on the following criteria: no miscarriages, elective abortions or pregnancy complications, infections or multiple births. Data from the follow-up were available for 623 women, who were included in the analyses. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was coordinated at the Charité University Medicine in Berlin, Germany. Anthropometric, medical and psychosocial information were collected and serum progesterone and estradiol levels were measured in women during the first trimester of pregnancy, followed by the documentation of the pregnancy outcome at birth. Univariable and multivariable regression analyses were performed to identify maternal markers, among them progesterone, affecting birthweight and to determine environmental and maternal factors that are associated with maternal progesterone levels during pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE: In the multivariable regression model, each increase in maternal progesterone by 1 ng/ml during the first trimester increased girls' birthweight by 10.17 g (95% CI: 2.03-18.31 g). If the mother carried a boy, maternal smoking and perceived worries during early pregnancy predicted a reduced birthweight, irrespective of progesterone levels. Maternal body mass index over 25 and maternal age <21 years significantly correlated with the reduced levels of progesterone. Correlations between environmental challenges and maternal progesterone did not reach levels of significance. Since the analyses were exploratory, the likelihood that results may be due to chance is increased. LIMITATIONS, REASONS FOR CAUTION: Due to the exploratory nature of the analyses, results need to be independently confirmed in a larger sample. Furthermore, our findings pertain to pregnant women without pregnancy complications or fertility treatments. WIDER IMPLICATIONS OF THE FINDINGS: Maternal progesterone during early pregnancy is an indicator of subsequent fetal development in female children. Future studies should confirm this relationship and determine whether maternal progesterone is a useful tool in predicting pregnancies at risk resulting in the birth of a girl with low birthweight. Detailed identification of environmental factors modulating maternal progesterone levels should be addressed in future studies. STUDY FUNDING/POTENTIAL COMPETING INTERESTS: Financial support was provided by the Alexander von Humboldt Foundation, Excellence Initiative of the Hamburg Foundation for Research and the Association for Prevention and Information for Allergy and Asthma (Pina e.V.). The authors have no conflict of interest.
Human Reproduction 10/2012; · 4.47 Impact Factor
-
Allergy Asthma and Clinical Immunology 05/2012; 6:1-1.
-
[show abstract]
[hide abstract]
ABSTRACT: PROBLEM: T cells are present at the feto-maternal interface, but their function during pregnancy has not been fully elucidated. T cells bearing γλ T-cell receptor (TCR) may be particularly important, as some subsets can react to trophoblast cells by producing cytokines, such as interleukin-2 (IL-2).METHOD: We depleted T cells bearing the γλ receptor by injecting monoclonal antibodies (mAB) into females of the abortion-prone animal model CBA x DBA/2. We investigated the percentage and number of γλ T-cell receptor positive (TCR)+ cells in decidua and spleen during pregnancy in control and γλ-depleted female mice. Pregnant females were also exposed to ultrasonic sound stress to boost the abortion rate.RESULTS: Stress failed to increase the abortion rate in the γλ TCR-depleted mice. FACScan analysis show that the ratio of cells bearing the γλ TCR dramatically decreased after injection of mAB to the γλ TCR in spleen and decidua, these cells recovered six days after depletion, showing a change in cytokine pattern. Levels of TNF-α in decidual γλ T cells decreased; similar effects of decreasing Th1 cytokines could be observed in splenic γλ T cells. We further identified increased levels of intracellular TNF-α in the Vλ4 subset in the decidua, compared to spleen.CONCLUSIONS: Trophoblast recognition by the Vλ4 T-cell subset in the decidua may cause the release of abortogenic cytokines such as TNF-α. Depletion of such γλ TCR T cells during early pregnancy may promote successful pregnancy outcome in normal pregnancy and prevent stress-induced abortions.
American Journal Of Reproductive Immunology 09/2011; 37(1):87 - 93. · 2.17 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Maternal stress can cause loss of both histocompatible (syngeneic) and histoincompatible (semiallogeneic) embryos in pregnant mice. Stress increases abortogenic Th1 cytokines and reduces levels of anti-abortogenic Th2 cytokines, progesterone levels, and T regulatory cell activity. While physiological levels of interferon-γ promote vascular remodeling at the feto-maternal interface, an overshooting Th1 cytokine response requires a Toll-like receptor (TLR)-mediated "danger signal" such as lipopolysaccharide (LPS). Interestingly, stress can enhance permeability of mucosal membranes to entry of bacterial products and promote transmucosal migration of commensal bacteria. We hypothesized that bacterial component such as LPS may provide the danger signal through which stress triggers maternal immune activation, subsequently resulting in fetal rejection. Blocking the TLR4 receptor for LPS or neutralization of LPS using bactericidal permeability increasing protein abrogate fetal loss due to sonic stress challenge in DBA/2J-mated CBA/J mice. These treatments prevented stress-triggered immune responses in the decidua, upregulated Treg cells, and reduced the frequency of mature dendritic cells in uterine-draining lymph nodes but not in the uterus. Interestingly, anti-TLR4 treatment only partly ameliorated stress-induced endocrine responses, such as increased hypothalamic corticotropin releasing hormone and vasopressin mRNA expression but not decrease of serum progesterone. Galectin-1 knock-out mice were more susceptible to stress-triggered complete implantation failure rather than fetal loss, which was also abolished by LPS neutralization. Insights provided in this paper shed new light on the mechanisms by which stress affects pregnancy outcome and introduce microbial-derived LPS as a mediator within the cascade of stress-triggered immune and endocrine events during pregnancy.
Journal of Molecular Medicine 03/2011; 89(7):689-99. · 4.67 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Different conventional anti-asthmatic and anti-allergic drugs are commonly used in pregnancy, including inhaled corticosteroids, long- and short-acting β-agonists, leukotriene modifiers, cromolyn, and theophylline. Alternatively, immunotherapy with allergens before and during pregnancy is accepted as a causal treatment of allergies, but the allergy specifity and severity in combination with a variety of application protocols and procedures cause wide heterogenity of this treatment principle. Furthermore, the pharmacokinetic characteristics and the US Food and Drug Administration (FDA) classification of conventional anti-allergic drugs and immunological implications of immunotherapy are summarized in this review, and insights on fetal programming of allergies are introduced. We propose a potential perspective of treatment with anti-inflammatory and pro-resolving mediators, such as lipoxins, resolvins and protectins; these are lipid mediators physiologically generated during the immune response from arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid. This proposal fits with the recently appreciated approaches to allergy prevention for the newborn child by a balanced maternal nutrition and omega-3 long-chain polyunsaturated fatty acid consumption.
Current pharmaceutical biotechnology 02/2011; 12(5):758-64. · 3.40 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Endometriosis is a common gynaecological disease that is characterized and defined as the presence of endometrial tissue outside the uterus, causing painful periods and subfertility in approximately 10% of women. After more than 50 years of research, little is known about the mechanisms underlying the development and establishment of this condition. Animal models allow us to study the temporal sequence of events involved in disease establishment and progression. Also, because this disease occurs spontaneously only in humans and non-human primates and there are practical problems associated with studying the disease, animal models have been developed for the evaluation of endometriosis. This review describes the animal models for endometriosis that have been used to date, highlighting their importance for the investigation of disease mechanisms that would otherwise be more difficult to elucidate, and proposing new alternatives aimed at overcoming some of these limitations.
Journal of Reproductive Immunology 11/2010; 86(2):141-7. · 2.97 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Previous data have shown that 'danger' signals, such as bacterial lipopolysaccharide (LPS) acting via toll-like receptors (TLR), are conditions antecedent to early pregnancy failure in several murine abortion models. Indeed, the abortion rate increased in the CBA x DBA/2 model after injection of tumor necrosis factor-alpha (TNF-alpha) + interferon (IFN-gamma) on gestation day (GD) 7.5 only if the LPS-TLR signaling pathway was intact. High rates of cytokine-boosted abortion >80% loss can be demonstrable in certain animal colonies that have a high endogenous (spontaneous) rate of resorption (30-50%). A specific role for LPS on GD 0.5 determines the endogenous loss rate and on GD 6.5 the responsiveness to cytokine boosting of losses. Th1 cytokines (or the stress that induces these cytokines) increase intestinal permeability and absorption of luminal contents. It was predicted that intestinal availability of LPS was a major factor in the endogenous and cytokine-boosted resorption rates.
A fixed weight of fresh mouse droppings from CBA/J female mice house in a high-abortion-rate (30-40%) colony at Clamart, France was homogenized and filtered. Fresh mouse droppings from a low-abortion-rate (10-15%) colony in Berlin, Germany were similarly processed. LPS was assayed using the Limulus amoebocyte lysate bioassay.
To our surprise, there was no significant difference in LPS content of fecal samples from the two colonies.
A high endogenous rate of abortion and cytokine (or stress) boosted abortion in the CBA x DBA/2 model is not explained by the LPS content of feces. Possible explanations include: fecal LPS does not reflect small intestinal LPS, there are additional TLR signals besides LPS that are important and endogenous stress levels may be higher in high-abortion-rate colonies, so permeability of the intestine (and Th1 cytokine levels) may be already higher. These data have implications for studies on the role of flora in human pregnancy problems.
American Journal Of Reproductive Immunology 01/2009; 60(6):529-33. · 2.17 Impact Factor
-
Nature medicine 12/2008; 14(11):1184-5. · 27.14 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The aim of the study was to identify if (i) psychosocial factors differ in endometriosis; (ii) related psychosocial aspects alter immune markers of depression/sickness behaviour; and (iii) serum immune marker may be indicative for endometriosis.
We enrolled 103 women in a case-control study. Psychosocial data were obtained, serum levels of interleukin (IL)-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, interferon (IFN)-gamma, TNF-alpha, IFN-alpha and soluble intercellular adhesion molecule-1 (sICAM-1) were analysed.
Among 69 eligible patients, endometriosis was diagnosed in 38 women. Patients with endometriosis reported reduced quality of life, increased stress perception/depressive symptoms; the Th1/Th2 ratio was in favour of Th1, accompanied by the increased levels of IFN-alpha. sICAM-1 levels were unaffected. No correlation could be confirmed between psychosocial and immune markers.
Women with endometriosis may benefit from strategies contributing to reduction of stress and development of coping mechanisms, thus helping to break the vicious circle of inflammation, sickness behaviour and depression.
American journal of reproductive immunology (New York, N.Y.: 1989) 12/2008; 60(5):449-61. · 3.05 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Problem The aim of the study was to identify if (i) psychosocial factors differ in endometriosis; (ii) related psychosocial aspects alter immune markers of depression/sickness behaviour; and (iii) serum immune marker may be indicative for endometriosis.Method of study We enrolled 103 women in a case–control study. Psychosocial data were obtained, serum levels of interleukin (IL)-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, interferon (IFN)-γ, TNF-α, IFN-α and soluble intercellular adhesion molecule-1 (sICAM-1) were analysed.Results Among 69 eligible patients, endometriosis was diagnosed in 38 women. Patients with endometriosis reported reduced quality of life, increased stress perception/depressive symptoms; the Th1/Th2 ratio was in favour of Th1, accompanied by the increased levels of IFN-α. sICAM-1 levels were unaffected. No correlation could be confirmed between psychosocial and immune markers.Conclusion Women with endometriosis may benefit from strategies contributing to reduction of stress and development of coping mechanisms, thus helping to break the vicious circle of inflammation, sickness behaviour and depression.
American Journal Of Reproductive Immunology 10/2008; 60(5):449 - 461. · 2.17 Impact Factor
-
Sandra M Blois,
Gabriela Barrientos,
Mariana G Garcia,
Arif S Orsal,
Mareike Tometten,
Rosalia I Cordo-Russo,
Burghard F Klapp,
Angela Santoni,
Nelson Fernández,
Peter Terness, Petra C Arck
[show abstract]
[hide abstract]
ABSTRACT: A complex regulation of innate and adaptive immune responses at the maternal fetal interface promotes tolerance of trophoblast cells carrying paternally derived antigens. Such regulatory functions involve uterine dendritic cells (uDC) and natural killer (uNK) cells. The existence of a NK and DC "cross talk" has been revealed in various experimental settings; its biological significance ranging from cooperative stimulation to cell lysis. Little is known about the presence or role of NK and DC cross talk at the maternal fetal interface. The present study shows that mouse NK and DC interactions are subject to modulation by trophoblast cells in vitro. This interaction promotes a tolerogenic microenvironment characterized by downregulation of the expression of activation markers on uNK cells and uDC and dominance of Th2 cytokines. NK and DC interactions would also influence uterine cell proliferation and this process would be strongly modulated by trophoblast-derived signals. Indeed; while low proliferation rates were observed upon regular coculture allowing direct contact between uterine cells and trophoblasts, incubation in a transwell culture system markedly increased uterine cell proliferation suggesting that soluble factors are key mediators in the molecular "dialog" between the mother and the conceptus during the establishment of mouse pregnancy. Our data further reveal that the regulatory functions of trophoblast cells associated with tolerance induction are impaired in high abortion murine matings. Interestingly, we observed that secretion of interleukin-12p70 by uDC is dramatically abrogated in the presence of uNK cells. Taken together, our results provide the first evidence that a delicate balance of interactions involving NK cells, DC, and trophoblasts at the mouse maternal fetal interface supports a successful pregnancy outcome.
Journal of Molecular Medicine 08/2008; 86(7):837-52. · 4.67 Impact Factor
-
Petra C Arck,
Mirjam Rücke,
Matthias Rose,
Julia Szekeres-Bartho,
Alison J Douglas,
Maria Pritsch,
Sandra M Blois,
Maike K Pincus,
Nina Bärenstrauch,
Joachim W Dudenhausen,
Katrina Nakamura,
Sam Sheps,
Burghard F Klapp
[show abstract]
[hide abstract]
ABSTRACT: Many pregnancies are lost during early gestation, but clinicians still lack tools to recognize risk factors for miscarriage. Thus, the identification of risk factors for miscarriage during the first trimester in women with no obvious risk for a pregnancy loss was the aim of this prospective cohort trial. A total of 1098 women between gestation weeks 4 and 12 in whom no apparent signs of a threatened pregnancy could be diagnosed were recruited. Demographic, anamnestic, psychometric and biological data were documented at recruitment and pregnancy outcomes were registered subsequently. Among the cases with sufficiently available data, 809 successfully progressing pregnancies and 55 subsequent miscarriages were reported. In this cohort, risk of miscarriage was significantly increased in women at higher age (>33 years), lower body mass index (< or =20 kg/ m(2)) and lower serum progesterone concentrations (< or =12 ng/ml) prior to the onset of the miscarriage. Women with subsequent miscarriage also perceived higher levels of stress/demands (supported by higher concentrations of corticotrophin-releasing hormone) and revealed reduced concentrations of progesterone-induced blocking factor. These risk factors were even more pronounced in the subcohort of women (n = 335) recruited between gestation weeks 4 and 7. The identification of these risk factors and development of an interaction model of these factors, as introduced in this article, will help clinicians to recognize pregnant women who require extra monitoring and who might benefit from therapeutic interventions such as progestogen supplementation, especially during the first weeks of pregnancy, to prevent a miscarriage.
Reproductive biomedicine online 07/2008; 17(1):101-13. · 2.04 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A neurogenic component in atopy and allergy is evident and potentially of great pathogenic relevance. Stress was recently shown to activate elements of this component and is vividly discussed as a cause of exacerbation. However, to date, scientific proof of stress-induced neuronal plasticity and neuro-immune interaction in atopy or allergy remains lacking. Here we show early evidence that exposure to sound stress and atopic dermatitis-like allergic dermatitis (AD) equipotently raise the number of cutaneous nerve fibers containing the prototypic stress neuropeptide substance P (SP) in mice. Stress increases AD readout parameters by at least 30% (eosinophil infiltration, vascular cell adhesion molecule-positive blood vessels, epidermal thickness). This dramatic pathologic exacerbation is associated with increased neurogenic inflammation (degranulated mast cells; interstitial neuropeptidergic dense core granules, mast cell apoptosis, endothelial gaping). Key features of AD exacerbation could not be induced in mice lacking the neurokinin-1 SP receptor (NK1). Interestingly, stress had no significant additional effect on CD4+ cell number, but shifted the cytokine profile toward TH2 in skin. Thus, we conclude that stress primarily exacerbates AD via SP-dependent cutaneous neurogenic inflammation and subsequent local cytokine shifting and should be considered as a therapeutic target, while it offers a convincing pathogenic explanation to affected patients and their frustrated physicians alike.
Journal of Investigative Dermatology 03/2008; 128(2):434-46. · 6.31 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Successful mammalian pregnancy relies on the action of sophisticated regulatory mechanisms that allow the fetus (a semi-allograft) to grow and develop in the uterus in spite of being recognized by maternal immune cells. Among several immunocompetent cells present at the maternal fetal interface, dendritic cells (DC) seem to be of particular relevance for pregnancy maintenance given their unique ability to induce both antigen-specific immunity and tolerance. Thus, these cells would be potentially suitable candidates for the regulation of local immune responses within the uterus necessary to meet the difficult task of protecting the mother from infection without compromising fetal survival. Current evidence on decidual DC phenotype and function, and their role in the regulation of the maternal immune system during mouse and human pregnancy are discussed and reviewed herein; highlighting novel DC functions that seem to be of great importance for a successful pregnancy outcome.
Immunological Investigations 02/2008; 37(5):499-533. · 1.47 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Stress alters murine hair growth, depending on substance P-mediated neurogenic inflammation and nerve growth factor (NGF), a key modulator of hair growth termination (catagen induction). Whether this is of any relevance in human hair follicles (HFs) is completely unclear. Therefore, we have investigated the effects of substance P, the central cutaneous prototypic stress-associated neuropeptide, on normal, growing human scalp HFs in organ culture. We show that these prominently expressed substance P receptor (NK1) at the gene and protein level. Organ-cultured HFs responded to substance P by premature catagen development, down-regulation of NK1, and up-regulation of neutral endopeptidase (degrades substance P). This was accompanied by mast cell degranulation in the HF connective tissue sheath, indicating neurogenic inflammation. Substance P down-regulated immunoreactivity for the growth-promoting NGF receptor (TrkA), whereas it up-regulated NGF and its apoptosis- and catagen-promoting receptor (p75NTR). In addition, MHC class I and beta2-microglobulin immunoreactivity were up-regulated and detected ectopically, indicating collapse of the HF immune privilege. In conclusion, we present a simplistic, but instructive, organ culture assay to demonstrate sensitivity of the human HF to key skin stress mediators. The data obtained therewith allow one to sketch the first evidence-based biological explanation for how stress may trigger or aggravate telogen effluvium and alopecia areata.
American Journal Of Pathology 01/2008; 171(6):1872-86. · 4.89 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Emerging research indicates that central-nervous stress perception is translated to peripheral tissues such as the skin not only via classical stress hormones but also via neurotrophins and neuropeptides. This can result in neurogenic inflammation, which is likely to contribute to the triggering and/aggravation of immunodermatoses. Although the existence of such a "brain-skin connection" is supported by steadily increasing experimental evidence, it remains unclear to which extent perceived stress affects the sensory "hardwiring" between skin and its afferent neurons in the corresponding dorsal root ganglia (DRG). In this paper, we provide experimental evidence in a murine model of stress (exposure of C57BL/6 mice to sound stress) that stress exposure, or intracutaneous injection of recombinant nerve growth factor (NGF) to mimic the skin's response to stress, up-regulate the percentage of substance P (SP)+ or calcitonin gene-related peptide (CGRP)+ sensory neurons in skin-innervating DRG. Further, we show that the number of SP+ or CGRP+ sensory nerve fibers in the dermis of stressed C57BL/6 mice is significantly increased. Finally, we document that neutralization of NGF activity abrogates stress-induced effects on the percentage of SP+ and CGRP+ sensory neurons in skin-innervating DRG as well as on dermal sensory nerve fibers. These data suggest that high stress perception results in an intense cross talk between the skin and skin-innervating DRG, which increases the likelihood of NGF-dependent neurogenic skin inflammation by enhancing sensory skin innervation.
Journal of Molecular Medicine 01/2008; 85(12):1369-78. · 4.67 Impact Factor
-
Sandra M Blois,
Juan M Ilarregui,
Mareike Tometten,
Mariana Garcia,
Arif S Orsal,
Rosalia Cordo-Russo,
Marta A Toscano,
Germán A Bianco,
Peter Kobelt,
Bori Handjiski,
Irene Tirado,
Udo R Markert,
Burghard F Klapp,
Francoise Poirier,
Julia Szekeres-Bartho,
Gabriel A Rabinovich, Petra C Arck
[show abstract]
[hide abstract]
ABSTRACT: A successful pregnancy requires synchronized adaptation of maternal immune-endocrine mechanisms to the fetus. Here we show that galectin-1 (Gal-1), an immunoregulatory glycan-binding protein, has a pivotal role in conferring fetomaternal tolerance. Consistently with a marked decrease in Gal-1 expression during failing pregnancies, Gal-1-deficient (Lgals1-/-) mice showed higher rates of fetal loss compared to wild-type mice in allogeneic matings, whereas fetal survival was unaffected in syngeneic matings. Treatment with recombinant Gal-1 prevented fetal loss and restored tolerance through multiple mechanisms, including the induction of tolerogenic dendritic cells, which in turn promoted the expansion of interleukin-10 (IL-10)-secreting regulatory T cells in vivo. Accordingly, Gal-1's protective effects were abrogated in mice depleted of regulatory T cells or deficient in IL-10. In addition, we provide evidence for synergy between Gal-1 and progesterone in the maintenance of pregnancy. Thus, Gal-1 is a pivotal regulator of fetomaternal tolerance that has potential therapeutic implications in threatened pregnancies.
Nature medicine 01/2008; 13(12):1450-7. · 27.14 Impact Factor
-
Sandra M Blois,
Ulrike Kammerer,
Catalina Alba Soto,
Mareike C Tometten,
Valerie Shaikly,
Gabriela Barrientos,
Richard Jurd,
Daniel Rukavina,
Angus W Thomson,
Burghard F Klapp,
Nelson Fernández, Petra C Arck
[show abstract]
[hide abstract]
ABSTRACT: Pregnancy is a unique event in which a fetus, despite being genetically and immunologically different from the mother (a hemi-allograft), develops in the uterus. Successful pregnancy implies avoidance of rejection by the maternal immune system. Fetal and maternal immune cells come into direct contact at the decidua, which is a highly specialized mucous membrane that plays a key role in fetal tolerance. Uterine dendritic cells (DC) within the decidua have been implicated in pregnancy maintenance. DC serve as antigen-presenting cells with the unique ability to induce primary immune responses. Just as lymphocytes comprise different subsets, DC subsets have been identified that differentially control lymphocyte function. DC may also act to induce immunologic tolerance and regulation of T cell-mediated immunity. Current understanding of DC immunobiology within the context of mammalian fetal-maternal tolerance is reviewed and discussed herein.
Biology of Reproduction 11/2007; 77(4):590-8. · 4.01 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Beta-2 microglobulin (B2M) plays a pivotal role in the biology of mammals, including its association with major histocompatibility complex (MHC) Class I gene products. The latter molecules have been shown to affect reproduction in both mice and humans, although the exact mechanism is still unknown. Here we report the results of a longitudinal study of the reproductive performance of a genetically modified B2m deficient mouse strain with low MHC Class I expression. Our data show that this mouse strain has an impaired reproductive performance. However, the mice superovulate well and show a normal estrous cycle. Breeding studies from crosses between the transgenic mice and the wild-type parental strain show that B2m deficient mice have a significantly lower frequency of mating than the control B2m+/+ mice. In addition, the litter size and weaning success of B2m deficient mice were lower than the control. Perinatal lethality of the B2m deficient offspring was also inflicted by cannibalism of the young pups by the B2m deficient female. The impaired breeding phenotype (IBP) can be reversed by reintroducing the B2m gene in F1 heterozygous B2m+/- animals; thus the presence of B2M confers a normal breeding pattern. The acquisition of an impaired breeding phenotype (IBP) as a result of the knockout of B2m directly implicates B2M in the reproductive cycle of mice and raises the possibility of an effect of B2M on the reproduction of other mammals.
Biology of Reproduction 09/2007; 77(2):274-9. · 4.01 Impact Factor
