REVIEW ARTICLE

Immunology of Pre-Eclampsia
Christopher W. G. Redman, Ian L. Sargent
Nufeld Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford, UK

Keywords HLA-C, immunoregulation, indoleamine 2,3dioxygenase, NK cells, placentation, regulatory T cells, systemic inammatory response Correspondence CWG Redman, Nufeld Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK. E-mail: christopher.redman@obs-gyn.ox.ac.uk Submitted February 1, 2010; accepted February 1, 2010. Citation Redman CWG, Sargent IL. Immunology of Pre-eclampsia. Am J Reprod Immunol 2010; 63: 534543 doi:10.1111/j.1600-0897.2010.00831.x

Pre-eclampsia develops in stages, only the last being the clinical illness. This is generated by a non-specic, systemic (vascular), inammatory response, secondary to placental oxidative stress and not by reactivity to fetal alloantigens. However, maternal adaptation to fetal (paternal alloantigens) is crucial in the earlier stages. A pre-conceptual phase involves maternal tolerization to paternal antigens by seminal plasma. After conception, regulatory T cells, interacting with indoleamine 2,3-dioxygenase, together with decidual NK cell recognition of fetal HLA-C on extravillous trophoblast may facilitate placental growth by immunoregulation. Complete failure of this mechanism would cause miscarriage, while partial failure would cause poor placentation and dysfunctional uteroplacental perfusion. The rst pregnancy preponderance and partner specicity of pre-eclampsia can be explained by this model. For the rst time, the pathogenesis of pre-eclampsia can be related to dened immune mechanisms that are appropriate to the fetomaternal frontier. Now, the challenge is to prove the detail.

Introduction Pre-eclampsia is relatively common, affecting about 3% of pregnancies. It originates in the placenta and causes variable maternal and fetal problems. At its worst, it may threaten maternal and perinatal survival. It is dened as a syndrome (a pattern of clinical features) and is probably heterogeneous in origin as it is in presentation. Placentation, the Uteroplacental Circulation and Staging of Pre-Eclampsia Pre-eclampsia results from imbalance between factors produced by the placenta and maternal adaptation to them. There are two broad classes of pre-eclampsia: maternal and placental, although many cases are a mix of the two.1 Placental pre-eclampsia is the outcome of poor placentation in
534

early pregnancy (weeks 818). It comprises failure to remodel spiral arteries supplying the uteroplacental circulation. Normal placentation requires that cytotrophoblast invade the placental bed where they come into contact with maternal tissues. The distal ends of the spiral arteries are then transformed into widely dilated, structureless conduits. Spontaneous miscarriage, especially if recurrent, is also associated with poor placentation2 and is the extreme end of a spectrum of compromise (Fig. 1). Pre-eclampsia has pre-clinical (symptomless) and clinical stages;1 until recently, only the nal phase could be detected by clinical screening. The latter is the outcome of placental dysfunction secondary to oxidative stress and a maternal inammatory reaction to its presence.3 Poor placentation is probably not the primary cause of pre-eclampsia. Changes in circulating trophoblastderived factors associated with an increased risk of pre-eclampsia can be
American Journal of Reproductive Immunology 63 (2010) 534543 2010 John Wiley & Sons A/S

IMMUNOLOGY OF PRE-ECLAMPSIA

Partners, Coitus, Sperm, and Semen A change of partner seems to restore the risk of preeclampsia to that of primiparity in multigravid women, for example Zhang and Patel 2007.9 But, a change of partner is also associated with a long inter-pregnancy interval.9,10 After correction for the latter, the association with the former disappears.11 However, a short interval between rst coitus and conception (coital interval) with the same partner also increases the risk of pre-eclampsia.12,13 In this context, there is clear evidence for partner specicity. These features suggest that exposure to paternal sperm or seminal plasma or both tolerizes the mother to fetopaternal alloantigens and failure of this immunoregulation increases the risk of preeclampsia (Stage 0 of pre-eclampsia). Immune priming, by coitus, has been demonstrated in mice.14 Seminal plasma appears to be more important than sperm. It contains paternal type I and type II MHC antigens and high concentrations of transforming growth factor-b (TGFb). TGFb induces regulatory T cells (T(reg)) or, in a more proinammatory environment, Th17 cells.15 In mice, exposure to seminal uid at mating induces tolerance to paternal alloantigens and an accumulation of T(reg) in the uterine draining lymph nodes, which may facilitate implantation.16 Pregnancy itself confers further protection to preeclampsia in later pregnancies by the same partner. This is probably true even after an abortion, although the evidence is inconsistent.17 Both forms of protection (before or after conception) appear to be relatively short lived, explaining the increased risk of pre-eclampsia after a long inter-pregnancy interval. The importance of pre-conceptual exposure to semen can explain why articial insemination with donor sperm, intracytoplasmic sperm injection, or barrier methods of contraception, summarized by Dekker (2002),18 are all associated with increased risks of pre-eclampsia (Fig. 2). Natures Transplant and MaternalPlacental Interfaces Reproductive immunology has focused on the concept of the semi-allogeneic fetus and its possible rejection by classical T-cell responses to alloantigens. But, the placenta not the fetus comprises the transplant. The placental cell of interest is trophoblast.

Fig. 1 Establishing the intervillous circulation. Before 8 weeks, the spiral arteries are plugged by cytotrophoblast and there is no intervillous perfusion. During the next 4 weeks, the arteries progressively unplug. With inadequate trophoblast invasion of the placenta bed, this happens prematurely. Then either miscarriage ensues or pregnancy continues with dysfunctional placental perfusion which leads on to pre-eclampsia. Adapted from Burton and Jauniaux (2004).2

detected before placentation is completed.4 It is probable that pre-eclampsia results from abnormal trophoblast growth and differentiation, at any time after the earliest stages of implantation.4 The primary dysfunction may be immunologic leading to the concept of a three-stage disease.5 This review is mainly focused on placental preeclampsia. The central issue is whether maternal immune responses to trophoblast generate normal or abnormal placentation? Throughout, we emphasize that, in overt preeclampsia, non-specic inammatory responses contribute to pathogenesis. Placentation in early pregnancy appears to involve specic maternal immune responses to fetal alloantigens, which generate partner specicity. Clinical and Epidemiological considerations Pre-eclampsia occurs mainly in rst pregnancies. This has been explained by invoking immune mechanisms linked to the belief that a genetically foreign fetus challenges the maternal immune system.6 The hypothesis is that the maternal immune system learns to accommodate the fetus. Such adaptation may be relatively defective in a rst pregnancy but less so in subsequent pregnancies. Furthermore, there may be partner specicity,7 which strengthens the argument that pre-eclampsia results from a relative failure to induce maternal tolerance of paternal alloantigens.8
American Journal of Reproductive Immunology 63 (2010) 534543 2010 John Wiley & Sons A/S

535

REDMAN AND SARGENT

Fig. 2 Maternal tolerance to fetal alloantigens. A longer pre-conception duration of coitus reduces the risk of pre-eclampsia by promoting maternal tolerance to paternal antigens. The tolerizing mechanism is not activated with some forms of assisted conception. Pregnancy itself enhances this tolerance which is slowly lost after delivery. Whether a change of partner increases the risk of pre-eclampsia depends on the coital interval with the new partner, not the duration of time since the last pregnancy. *IVF: in-vitro fertilisation; ICSI: intracytoplasmic sperm injection.

after 8 weeks. Before then, chorionic villi are bathed in uterine gland secretions histiotrophic nutrition to the rst-trimester fetus.19 By the end of the rst trimester, Interface I is replaced by three others: formed by invasive cytotrophoblast in the placental bed (Interface II), with the chorion leave (Interface III), and by syncytiotrophoblast bathed by maternal blood in the intervillous space (Interface IV). These concepts extend our earlier proposals.20 In the rst half of pregnancy, Interfaces I and II dominate. Interface II diminishes after 16 weeks,21 while Interface IV is activated with onset of the uteroplacental circulation at 89 weeks5 and enlarges with placental growth to become the dominant interface after 20 weeks. The early interfaces are concerned with implantation, placentation, and stages 1 and 2 of placental pre-eclampsia. Interface IV is largest and, at the end of pregnancy, generates the nal stage 3 of the disorder. Immune Mechanisms and Causes of Pre-eclampsia: Where, When, and How? If immune mechanisms are relevant, there must be maternal immune recognition of trophoblast, which regulates implantation, placental growth, and placentation. It needs to be partner specic and to generate immune memory. It should be consistent with the structure of the immune maternalfetal interfaces, with the types of maternal immune cells positioned at the interfaces and the antigens expressed by trophoblast. Partner specicity requires trophoblast expression of paternal alloantigens and their recognition by maternal immune cells.

Maternal immune cells are confronted by different trophoblast subtypes at multiple maternalplacental interfaces depending on gestational age and anatomic location (Table I). The interfaces may be in maternal tissues (decidua) or maternal blood (intervillous space). The earliest comprises syncytiotrophoblast of the implanting embryo (Interface I), the only time that syncytiotrophoblast lies at a tissue interface. The intervillous circulation is established

Table I The four maternal-fetal immune interfaces and preeclampsia

Alloantigen specic recognition of paternal antigens. Increasing maternal systemic inammatory response secondary to placental factors. a Weeks are calculated from last normal menstruation. Conception is assumed at the start of week 3.

American Journal of Reproductive Immunology 63 (2010) 534543

536

2010 John Wiley & Sons A/S

IMMUNOLOGY OF PRE-ECLAMPSIA

Immunoregulation implies a mechanism, which may partially fail to cause decient placentation or, by extension, fail completely to cause spontaneous abortion. Memory points to T-cell involvement. HLA (Human Leukocyte Antigen) Expression by Human Trophoblast Human trophoblast has limited expression of strong transplantation antigens (Fig. 3). These include nonpolymorphic HLA-E, F, and G which cannot signal paternal specicity whereas HLA-C, on extravillous (invasive) cytotrophoblast in Interface II, can. But this interface regresses in the second half of pregnancy.22 Stage 3, the clinical stage of pre-eclampsia, occurs when interface IV, the villous syncytium, is dominant. This is devoid of HLA expression. Immune mechanisms are of interest in the rst and second stages of pre-eclampsia. The clinical third phase is generated by a maternal systemic inammatory response, which is unlikely to be alloantigen driven. Stage 1 Pre-Eclampsia: Peri-implantation and the Histiotrophic Placenta At this stage, specic immune mechanisms in the placental bed are almost inaccessible to study. If immunoregulatory mechanisms fail completely, spontaneous abortion would ensue whereas partial failure might lead to continuing pregnancy with a

Fig. 3 HLA expression by subsets of human trophoblast. Adapted from van Maurik et al. (2009).21
American Journal of Reproductive Immunology 63 (2010) 534543 2010 John Wiley & Sons A/S

small placenta. This creates a continuum between abortion and pre-eclampsia.2,23 Indoleamine dioxygenase 2,3-dioxygenase (IDO), an enzyme involved in the catabolism of tryptophan, is an important immune regulator. It is activated in antigen-presenting cells by various inammatory stimuli including interferon-c. Tryptophan is an essential amino acid. Its depletion by catabolism starves T cells in the tissue micro-environment. This promotes their differentiation into regulatory T cells [T(reg)].24 IDO acts as a switch: in its presence, T(reg) are promoted; in its absence, T(reg) are reprogrammed to acquire a Th17 phenotype, with more T(reg) modulate pro-inammatory activity.25 immune responses in an antigen-specic way, hence their importance for allogeneic pregnancy, for which they are essential (see elsewhere in this issue). Pregnant mice treated with IDO inhibitor (4.5 days post conception) reject allogeneic but tolerate syngeneic fetuses.26 If the inhibitor is given later (6.5 days post conception), allogeneic pregnancies continue but signicant systolic hypertension develops compared to mice with syngeneic pregnancies.27 Proteinuria is inconsistently present but, in this report, the mice were killed relatively early (16.5 days) and the full evolution of the pregnancies was not dened. Hence in a mouse model, antigen- and stage-specic immune mechanisms are highly important. Early dysfunction leads to pregnancy loss; but dysfunction at a slightly later stage is associated with one feature of pre-eclampsia (hypertension) toward the end of a continuing pregnancy. Expression of IDO in human endometrium begins in the luteal phase in the glandular epithelium and stromal leukocytes. This pattern regresses during the second trimester when expression begins in trophoblast,28 particularly strongly in invasive cytotrophoblast,29 where it might be expected to modulate interactions with decidual immune cells. In short, its position at Interfaces I and II is highly relevant to potential immune mechanisms in stages 1 and 2 of pre-eclampsia. In summary, together with TGF-b, the components of an alloantigen-specic immunoregulatory mechanism [IDO and T(reg)] are located at interface I, are primed by pre-conceptual exposure to partners semen and, if dysregulated, could explain why primiparity and primipaternity are risk features for pre-eclampsia. However, there is little evidence available at the moment for two reasons. Interface I can only be
537

REDMAN AND SARGENT

studied before the outcome of pregnancy can be known. If the pregnancy is continuing, then the interface is accessible only to indirect measurements. Secondly, there is doubt about how best to identify and measure T(reg) during human pregnancy.30 No measurements have been reported in stages 1 and 2 of pre-eclampsia where they would be most likely to inuence allogeneic responses at interface II. Whether measures in peripheral blood are a good indicator of decidual activity is not known. Many authors look for concurrent expression of CD4 and CD25 or CD25bright to identify T(reg) and most nd that their proportions are increased in normal pregnancy, for example Somerset et al. (2004).31 However, the data are inconsistent, as are the methods used. T(reg) themselves are phenotypically and functionally heterogeneous32 so the relevant subset to study is not known. Recognition of HLA-C in the Early Human Decidua HLA-C is a key trophoblast molecule in relation to pre-eclampsia in stages 1 and 2. Both decidual T cells and the more abundant decidual NK cells can recognize paternal HLA-C. The importance of decidual NK cells is described elsewhere in this issue. They express killer immunoglobulin-like receptors (KIR) for which HLA-C is the dominant ligand. HLA-C has more than 100 alleles. Its KIR receptors are themselves extremely polymorphic. There are up to 17 different human KIR genes each with its own polymorphisms, some that activate, others that inhibit. The number of KIR genes in different genotypes varies. One genotype may itself be variably expressed by differential expression of KIR genes, xed by methylation with the phenotype passed to daughter cells.33 In other words, maternalfetal immune recognition at the site of placentation appears to be highly individualized by two polymorphic gene systems, maternal KIRs and fetal HLA-C molecules. KIR haplotypes fall into two groups, A and B, the latter distinguished by additional activating receptors. Uterine NK cells make chemokines and angiogenic cytokines, which promote trophoblast invasion. Their secretion is enhanced by ligation of a stimulatory KIR receptor (haplotype B) and reduced by ligation of haplotype A receptor as is summarized by Moffett and Hiby (2007).34 The former combination, in vivo, would be predicted to protect from preeclampsia. Possible maternal KIR genotypes could be AA (no activating KIR) or AB BB (presence of one or more activating KIRs).
538

HLA-C haplotypes can also be grouped as C1 and C2, depending on a single amino acid dimorphism in the alpha-1 domain. HLA-C2 interacts with KIRs more strongly than HLA-C135 so that maternal HLAC2 with fetal KIR B B could be the best combination for promoting adequate placentation and avoiding pre-eclampsia. This is what is observed. In a converse manner, Kir AA mothers confronted with HLA-C2 fetuses are the most susceptible to preeclampsia.36 Similar patterns occur in recurrent miscarriages which, as already mentioned, may share the same causation with pre-eclampsia, at the most extreme end of the spectrum.37 Although this form of maternalfetal immune recognition can explain the partner specicity for preeclampsia, it does not readily explain protection conferred by a previous pregnancy by the same partner. Pre-eclampsia and Immunologic Memory Protection from pre-eclampsia has relatively shortterm partner specicity. This could imply involvement of T cells and T-cell memory. The evidence is that paternal HLA-C is recognized by decidual T(reg), which can down regulate anti-paternal responses.38,39 The stability of T(reg) memory is still being determined. Natural T(reg) seem to be stable whereas those that are inducible probably are not.40 It is therefore likely that decidual T(reg) bestow, at least, short-term memory which could protect from pre-eclampsia in a second pregnancy with a short inter-pregnancy interval but this needs further investigation. The specic involvement of T(reg) in the genesis of pre-eclampsia is difcult to investigate; there are no data at the moment. Recently, it has become evident that NK cells themselves can sustain memory and mount the equivalent of a secondary immune response.41 Indeed, macrophages can generate a form of memory by epigenetic modication of specic TLR genes.42 Thus, an immune explanation for the primiparity and primipaternity effects of pre-eclampsia has become more plausible but awaits further investigation. The Third Stage of Pre-eclampsia and Maternal Systemic Inammation Poor placentation leads to small muscular spiral arteries which supply high pressure pulsatile ow to the intervillous space. Damage from rapid changes in oxygenation and hydrostatic stress ensues.43 The
American Journal of Reproductive Immunology 63 (2010) 534543 2010 John Wiley & Sons A/S

IMMUNOLOGY OF PRE-ECLAMPSIA

arteries retain responsiveness to vasoconstrictors, which can exacerbate oxidative stress further. Oxidative and ER stress are both features of the pre-eclampsia placenta.44 They are also powerfully pro-inammatory. We propose that the inammatory drive of pre-eclampsia results from the threeway interactions between these two stresses and inammatory responses3,45,46 in the placenta (Fig. 4). We further suggest that the third stage of pre-eclampsia is not caused by rejection of an allogeneic placenta but by a global maternal inammatory response to a damaged placenta. This is superimposed on a background of systemic inammatory response common to all normal pregnancies, which starts in the luteal phase of the menstrual cycle,47 when an allogeneic fetus cannot be implicated. The normal response intensies with advancing gestational maturity.48 We have emphasized the diverse and widespread nature of this sort of response (Fig. 5), which can explain the complex clinical presentations of severe pre-eclampsia, including endothelial, metabolic, coagulation, and complement abnormalities.49 We previously highlighted that pre-eclampsia is not an intrinsically different state from normal pregnancy but the extreme end of a continuous spectrum of responses that are a feature of pregnancy itself. Many physiological changes of normal pregnancy itself are simply less severe manifestations of the same changes in preeclampsia.

Fig. 5 The systemic inammatory network has metabolic components as well as involving the intravascular coagulation and complement systems. The main players are inammatory leukocytes and endothelium. All are activated in pregnancy relative to non-pregnancy and further activated in pre-eclampsia relative to normal pregnancy.3

Trophoblast Derived Factors and Pre-eclampsia Elsewhere we summarize the several possible trophoblast-derived factors that potentially contribute to maternal systemic inammation.3 These include growth factors, activin-A, corticotrophin-releasing hormone, and leptin, all of which have documented pro-inammatory actions. Another pro-inammatory placental factor has been recently described, namely free heme, which is strongly pro-oxidant and pro-inammatory.50 It is ectopically synthesised in the placenta and placental bed in pre-eclampsia. A nal candidate factor comprises placental microvesicles. Activated cells release microvesicles (200500 nm) by blebbing of the cell membrane. Apoptotic cells release larger microvesicles or apoptotic bodies. Cells can also secrete nanovesicles or exosomes (40100 nm). Microvesicles are shed from cell surfaces after activation, while nanovesicles are stored in multivesicular bodies and secreted constitutively. Microvesicles are normally detectable in blood from healthy individuals and are increased where there is vascular or inammatory stress. They are derived from various intravascular sources (platelets, leukocytes, endothelial cells, and so on) and can be identied by the specic markers they express. There is increasing awareness of their potential as markers for arterial, inammatory, and malignant diseases.51

Fig. 4 Three stages of pre-eclampsia. Stages 1 and 2 lead to dysfunctional uteroplacental perfusion and placental oxidative stress. This and the associated inammatory and endoplasmic reticulum stresses lead to abnormal placentalmaternal signalling and overt pre-eclampsia.
American Journal of Reproductive Immunology 63 (2010) 534543 2010 John Wiley & Sons A/S

539

REDMAN AND SARGENT

Micro- and nanovesicles are of interest in pre-eclampsia because they can be markers of inammatory and endothelial dysfunction, are immunoregulatory, and because there is a pregnancy-specic component derived from trophoblast. Syncytiotrophoblast microvesicles and nanovesicles are shed in normal pregnancy and in signicantly increased amounts in pre-eclampsia.5254 They have an anti-endothelial effect52 and are also pro-inammatory in vitro.53 Microvesicular shedding from the syncytial surface would be expected to increase in two situations. The rst is with increased placental size. Pre-eclampsia is predominantly a disorder of the third trimester when the placenta reaches its greatest size. Multiple pregnancies are associated with a higher risk of preeclampsia and also larger placentas. The second situation would be associated with placental oxidative stress in the most severe pre-eclampsia, typically of early onset. The placentas are usually abnormally small but may generate microvesicles with a more intense inammatory stimulus, for example, by an increased content of peroxidized lipids.55 Whether these microvesicles are a cause or consequence of systemic vascular stress is not known. Immunoregulation in Stage 3 Pre-eclampsia Only two aspects will be covered in detail: T(reg) and the role of IDO. Elsewhere in this issue, the concept of the Th2 bias of normal pregnancy and the need to update the Th1 Th2 paradigm in terms of Th17 and regulatory T cells [T(reg)] is discussed. Pre-eclampsia is associated with a Th1 bias; but this extends beyond Th cells to a type I bias of NK cells.56 However, in normal pregnancy, there may also be a bias away from IL-17 producing cells, which is not found in pre-eclampsia.57 Th17 stimulates autoimmunity and coordinates the inammatory response to infection. Its potential to harm pregnancy is not yet dened. The increase in circulating T(reg) found by some authors in normal pregnancy appears to be lost in pre-eclampsia (several authors, for example Sasaki et al. (2007).58 However, the available data are inconsistent. T(reg) are heterogeneous without specic markers59 so that their identication, for example by ow cytometry, is problematic. In addition, they function in tissues so that measures in peripheral blood are not easy to interpret. That Stage 3 pre-eclampsia is caused by loss of immune regulation
540

to an allogeneic fetus owing to T(reg) dysfunction is inconsistent with the evidence that the end-stage of the disease is a non-specic inammatory response to a damaged placenta. A simpler interpretation is that a Th1 environment tends to suppress the generation of T(reg).60 The interactions between IDO and T(reg) have already been mentioned, T(reg) differentiation being stimulated by IDO. Indirect measures suggest that IDO is less active in stage 3 pre-eclampsia.61 Given that 3rd stage pre-eclampsia involves maternal systemic inammation, it would be predicted that IDO would be activated. So this observation is unexplained. However, there is two way interaction between T(reg)62 and IDO such that underactive T(reg) responses could cause less IDO activity. The full detail awaits further analysis. Pre-eclampsia and Autoantibodies Certain function perturbing autoantibodies can increase the risk of pre-eclampsia most notably antiphospholipid and anti-angiotensin II type I receptor antibodies.63,64 It is difcult to argue that these are the specic cause of the syndrome even though the latter autoantibodies can generate a pre-eclampsialike disorder after administration to pregnant mice.65 In a casecontrol study, we found that such antibodies were relatively common in normal pregnancy controls and not present in a substantial minority of cases.66 Cross-reactivity with parvovirus B19 VP2 protein was demonstrated although serological evidence of previous parvovirus infection was not more common in pre-eclampsia cases. Th17 activity predisposes to autoimmunity.67 If the possible Th17 bias of pre-eclampsia is conrmed, this might amplify the induction of these antibodies in at least some cases, which might contribute to the pathology. Conclusion Different immune mechanisms operate at different interfaces during the three stages of pre-eclampsia. The diversity of the changes in the nal stage is well explained by a maternal systemic inammatory response secondary to oxidative placental damage. Now, for the rst time, there is the potential to explain the early phases of pre-eclampsia in terms of immune mechanisms that are appropriate and located at Interfaces I and II and account for the rst pregnancy preponderance of pre-eclampsia. The challenge is to turn potential into reality. A
American Journal of Reproductive Immunology 63 (2010) 534543 2010 John Wiley & Sons A/S

IMMUNOLOGY OF PRE-ECLAMPSIA

9
Fig. 6 Summary of immune events in pathogenesis of pre-eclampsia. The mechanisms of Stage 0 and Stage 1 have yet to be proved; the involvement of T(reg), dendritic cells, and Indoleamine dioxygenase 2,3-dioxygenase (IDO) is speculative but supported by experiments in mice. Stage 02 mechanisms largely concern uterine mechanisms. Stage 3 disease is a systemic inammatory disorder.

10

11

provisional scheme of the immune mechanisms of pre-eclampsia is in Fig. 6. Acknowledgments We acknowledge support from the Wellcome Trust Grant Ref GR079862MA. Our work is also supported by the Oxford Partnership Comprehensive Biomedical Research Centre with funding from the Department of Healths NIHR Biomedical Research Centres funding scheme. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health. References
1 Redman CW, Sargent IL: Latest advances in understanding preeclampsia. Science 2005; 308: 15921594. 2 Burton GJ, Jauniaux E: Placental oxidative stress: from miscarriage to preeclampsia. J Soc Gynecol Investig 2004; 11:342352. 3 Redman CW, Sargent IL: Placental stress and preeclampsia: a revised view. Placenta 2009; 30(Suppl A):S38S42. 4 Huppertz B: Placental origins of preeclampsia: challenging the current hypothesis. Hypertension 2008; 51:970975. 5 Jauniaux E, Watson AL, Hempstock J, Bao YP, Skepper JN, Burton GJ: Onset of maternal arterial blood ow and placental oxidative stress. A possible
American Journal of Reproductive Immunology 63 (2010) 534543 2010 John Wiley & Sons A/S

12

13

14

15

16

17

18 19

factor in human early pregnancy failure. Am J Pathol 2000; 157:21112122. Billington WD: The immunological problem of pregnancy: 50 years with the hope of progress. A tribute to Peter Medawar. J Reprod Immunol 2003; 60:111. Tubbergen P, Lachmeijer AM, Althuisius SM, Vlak ME, van Geijn HP, Dekker GA: Change in paternity: a risk factor for preeclampsia in multiparous women? J Reprod Immunol 1999; 45:8188. Saito S, Sakai M, Sasaki Y, Nakashima A, Shiozaki A: Inadequate tolerance induction may induce preeclampsia. J Reprod Immunol 2007; 76:3039. Zhang J, Patel G: Partner change and perinatal outcomes: a systematic review. Paediatr Perinat Epidemiol 2007; 21(Suppl 1):4657. Basso O, Christensen K, Olsen J: Higher risk of preeclampsia after change of partner. An effect of longer interpregnancy intervals? Epidemiology 2001; 12: 624629. Skjaerven R, Wilcox AJ, Lie RT: The interval between pregnancies and the risk of preeclampsia. N Engl J Med 2002; 346:3338. Robillard PY, Hulsey TC: Association of pregnancyinduced-hypertension, pre-eclampsia, and eclampsia with duration of sexual cohabitation before conception. Lancet 1996; 347:619. Kho EM, McCowan LM, North RA, Roberts CT, Chan E, Black MA, Taylor RS, Dekker GA: On behalf of the SCOPE Consortium: duration of sexual relationship and its effect on preeclampsia and small for gestational age perinatal outcome. J Reprod Immunol 2009; 82:6673. Robertson SA, Guerin LR, Moldenhauer LM, Hayball JD: Activating T regulatory cells for tolerance in early pregnancy the contribution of seminal uid. J Reprod Immunol 2009; 83:109116. Maitra U, Davis S, Reilly CM, Li L: Differential regulation of Foxp3 and IL-17 expression in CD4 T helper cells by IRAK-1. J Immunol 2009; 182: 57635769. Robertson SA, Guerin LR, Bromeld JJ, Branson KM, Ahlstro m AC, Care AS: Seminal uid drives expansion of the CD4 + CD25 + T regulatory cell pool and induces tolerance to paternal alloantigens in mice. Biol Reprod 2009; 80:10361045. Trogstad L, Magnus P, Skjaerven R, Stoltenberg C: Previous abortions and risk of pre-eclampsia. Int J Epidemiol 2008; 37:13331340. Dekker G: The partners role in the etiology of preeclampsia. J Reprod Immunol 2002; 57:203215. Burton GJ, Watson AL, Hempstock J, Skepper JN, Jauniaux E: Uterine glands provide histiotrophic

541

REDMAN AND SARGENT

20

21

22

23

24

25

26

27

28

29

30

31

nutrition for the human fetus during the rst trimester of pregnancy. J Clin Endocrinol Metab 2002; 87:29542959. Sargent IL, Borzychowski AM, Redman CWG: NK cells and human pregnancy - an inammatory view. Trends Immunol 2006; 27:399404. van Mourik MS, Macklon NS, Heijnen CJ: Embryonic implantation: cytokines, adhesion molecules, and immune cells in establishing an implantation environment. J Leukoc Biol 2009; 85: 419. Brosens IA, Robertson WB, Dixon HG: The role of the spiral arteries in the pathogenesis of preeclampsia. Obstet Gynecol Annu 1972; 1:177191. Wilczynski JR: Immunological analogy between allograft rejection, recurrent abortion and preeclampsia - the same basic mechanism? Hum Immunol 2006; 67:492511. Mellor AL, Munn DH: Creating immune privilege: active local suppression that benets friends, but protects foes. Nat Rev Immunol 2008; 8:7480. Baban B, Chandler PR, Sharma MD, Pihkala J, Koni PA, Munn DH, Mellor AL: IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J Immunol 2009; 183:24752483. Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL: Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 1998; 281:11911193. Nishizawa H, Hasegawa K, Suzuki M, Achiwa Y, Kato T, Saito K, Kurahashi H, Udagawa Y: Mouse model for allogeneic immune reaction against fetus recapitulates human pre-eclampsia. J Obstet Gynaecol Res 2008; 34:16. von Rango U, Krusche CA, Beier HM, Classen-Linke I: Indoleamine-dioxygenase is expressed in human decidua at the time maternal tolerance is established. Reprod Immunol 2007; 74:3445. Ho nig A, Rieger L, Kapp M, Su tterlin M, Dietl J, Ka mmerer U: Indoleamine 2,3-dioxygenase (IDO) expression in invasive extravillous trophoblast supports role of the enzyme for materno-fetal tolerance. J Reprod Immunol 2004; 61:7986. Mjo sberg J, Svensson J, Johansson E, Hellstro m L, Casas R, Jenmalm MC, Boij R, Matthiesen L, Jo nsson JI, Berg G, Ernerudh J: Systemic reduction of functionally suppressive CD4dim CD25high Foxp3+ Tregs in human second trimester pregnancy is induced by progesterone and 17beta-estradiol. J Immunol 2009; 183:759769. Somerset DA, Zheng Y, Kilby MD, Sansom DM, Drayson MT: Normal human pregnancy is associated with an elevation in the immune suppressive CD25

32

33

34

35

36

37

38

39

40

41

42

43

CD4 regulatory T-cell subset. Immunology 2004; 112:3843. Vignali DA, Collison LW, Workman CJ: How regulatory T cells work. Nat Rev Immunol 2008; 8: 523532. Parham P: MHC class I molecules and KIRs in human history, health and survival. Nat Rev Immunol 2005; 5:201214. Moffett A, Hiby SE: How does the maternal immune system contribute to the development of preeclampsia? Placenta 2007; 28(Suppl A):S51S56. Rajagopalan S, Long EO: Understanding how combinations of HLA and KIR genes inuence disease. J Exp Med 2005; 201:10251029. Hiby SE, Walker JJ, OShaughnessy KM, Redman CW, Carrington M, Trowsdale J, Moffett A: Combinations of maternal KIR and fetal HLA-C genes inuence the risk of preeclampsia and reproductive success. J Exp Med 2004; 200:957965. Hiby SE, Regan L, Lo W, Farrell L, Carrington M, Moffett A: Association of maternal killer-cell immunoglobulin-like receptors and parental HLA-C genotypes with recurrent miscarriage. Hum Reprod 2008; 23:972976. Tilburgs T, Roelen DL, van der Mast BJ, de GrootSwings GM, Kleijburg C, Scherjon SA, Claas FH: Evidence for a selective migration of fetus-specic CD4+ CD25bright regulatory T cells from the peripheral blood to the decidua in human pregnancy. J Immunol 2008; 180:57375745. Tilburgs T, Scherjon SA, van der Mast BJ, Haasnoot GW, Versteeg VD, Voort-Maarschalk M, Roelen DL, van Rood JJ, Claas FH: Fetal-maternal HLA-C mismatch is associated with decidual T cell activation and induction of functional T regulatory cells. J Reprod Immunol 2009; 82:148157. Komatsu N, Mariotti-Ferrandiz ME, Wang Y, Malissen B, Waldmann H, Hori S: Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc Natl Acad Sci USA 2009; 106: 19031908. Sun JC, Lanier LL: Natural killer cells remember: an evolutionary bridge between innate and adaptive immunity? Eur J Immunol 2009; 39:20592064. Foster SL, Hargreaves DC, Medzhitov R: Gene-specic control of inammation by TLR-induced chromatin modications. Nature 2007; 447:972978. Burton GJ, Woods AW, Jauniaux E, Kingdom JC: Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood ow during human pregnancy. Placenta 2009; 30:473482.
American Journal of Reproductive Immunology 63 (2010) 534543

542

2010 John Wiley & Sons A/S

IMMUNOLOGY OF PRE-ECLAMPSIA

44 Burton GJ, Yung HW, Cindrova-Davies T, CharnockJones DS: Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia. Placenta 2009; 30(Suppl A): S43S48. 45 Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, Johnson RS, Haddad GG, Karin M: NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature 2008; 453:807811. 46 Zhang K, Kaufman RJ: From endoplasmic-reticulum stress to the inammatory response. Nature 2008; 454:455462. 47 Willis C, Morris JM, Danis V, Gallery ED: Cytokine production by peripheral blood monocytes during the normal human ovulatory menstrual cycle. Hum Reprod 2003; 18:11731178. 48 Redman CW, Sacks GP, Sargent IL: Preeclampsia: an excessive maternal inammatory response to pregnancy. Am J Obstet Gynecol 1999; 180:499506. 49 Redman CW, Sargent IL, Roberts JM: Immunology of normal pregnancy and preeclampsia. In Chesleys Hypertensive Disorders of Pregnancy, MD Lindheimer, JM Roberts, FG Cunningham (eds). New York, Academic Press, 2009, pp 129142. ttir S, Stenfors I, 50 Olsson MG, Centlow M, Rutardo Larsson J, Hosseini-Maaf B, Olsson ML, Hansson SR, Akerstro m B: Increased levels of cell-free hemoglobin, oxidation markers, and the antioxidative heme scavenger alpha(1)-microglobulin in preeclampsia. Free Radic Biol Med 2010; 48:284291. 51 Cocucci E, Racchetti G, Meldolesi J: Shedding microvesicles: artefacts no more. Trends Cell Biol 2009; 19:4351. 52 Smarason AK, Sargent IL, Starkey PM, Redman CW: The effect of placental syncytiotrophoblast microvillous membranes from normal and pre-eclamptic women on the growth of endothelial cells in vitro. Br J Obstet Gynaecol 1993; 100:943 949. 53 Germain SJ, Sacks GP, Soorana SR, Sargent IL, Redman CW: Systemic inammatory priming in normal pregnancy and preeclampsia: the role of circulating syncytiotrophoblast microparticles. J Immunol 2007; 178:59495956. 54 Sabapatha A, Gercel-Taylor C, Taylor DD: Specic isolation of placenta-derived exosomes from the circulation of pregnant women and their immunoregulatory consequences. Am J Reprod Immunol 2006; 56:345355. 55 Cester N, Staffolani R, Rabini RA, Magnanelli R, Salvolini E, Galassi R, Mazzanti L, Romanini C:
American Journal of Reproductive Immunology 63 (2010) 534543 2010 John Wiley & Sons A/S

56

57

58

59 60

61

62

63

64

65

66

67

Pregnancy induced hypertension: a role for peroxidation in microvillus plasma membranes. MolCell Biochem 1994; 131:151155. Borzychowski AM, Croy BA, Chan WL, Redman CWG, Sargent IL: Changes in systemic type 1 and type 2 immunity in normal pregnancy and preeclampsia may be mediated by natural killer cells. Eur J Immnol 2005; 35:30543063. Santner-Nanan B, Peek MJ, Khanam R, Richarts L, Zhu E, Fazekas de St Groth B, Nanan R: Systemic increase in the ratio between Foxp3 + and IL-17producing CD4+ T cells in healthy pregnancy but not in preeclampsia. J Immunol 2009; 183:70237030. Sasaki Y, Darmochwal-Kolarz D, Suzuki D, Sakai M, Ito M, Shima T, Shiozaki A, Rolinski J, Saito S: Proportion of peripheral blood and decidual CD4(+) CD25(bright) regulatory T cells in pre-eclampsia. Clin Exp Immunol 2007; 149:139145. Corthay A: How do regulatory T cells work? Scand J Immunol 2009; 70:326336. Caretto D, Katzman SD, Villarino AV, Gallo E, Abbas AK: Cutting edge: the Th1 response inhibits the generation of peripheral regulatory T cells. J Immunol 2010; 184:3034. Kudo Y, Boyd CA, Sargent IL, Redman CW: Decreased tryptophan catabolism by placental indoleamine 2,3-dioxygenase in preeclampsia. Am J Obstet Gynecol 2003; 188:719726. Puccetti P, Grohmann U: IDO and regulatory T cells: a role for reverse signalling and non-canonical NFkappaB activation. Nat Rev Immunol 2007; 7:817823. Abrahams VM: Mechanisms of antiphospholipid antibody-associated pregnancy complications. Thromb Res 2009; 124:521525. Dechend R, Mu ller DN, Wallukat G, Homuth V, Krause M, Dudenhausen J, Luft FC: Activating autoantibodies against the AT1 receptor in preeclampsia. Autoimmun Rev 2005; 4:6165. Zhou CC, Zhang Y, Irani RA, Zhang H, Mi T, Popek EJ, Hicks MJ, Ramin SM, Kellems RE, Xia Y: Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice. Nat Med 2008; 14:855862. Herse F, Verlohren S, Wenzel K, Pape J, Muller DN, Modrow S, Wallukat G, Luft FC, Redman CW, Dechend R: Prevalence of agonistic autoantibodies against the angiotensin II type 1 receptor and soluble fms-like tyrosine kinase 1 in a gestational age-matched case study. Hypertension 2009; 53:393398. Korn T, Oukka M, Kuchroo V, Bettelli E: Th17 cells: effector T cells with inammatory properties. Semin Immunol 2007; 19:362371.

543