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The immunology of preeclampsia
The Immunology of Preeclampsia Gustaaf A. Dekker and Baha M. Sibai
The immune maladaptation hypothesis of preeclampsia is concordant with cytokine-mediated oxidative stress, chronology of endothelial activation, lipid changes, adverse effect of changing partners, and the protective effect of sperm exposure. Genetic factors may involve underlying hereditary thrombophilic disorders and hyperhomocysteinemia, essential hypertension and/or obesity, or control of the Thl/Th2 balance and thus affect the maternal response against fetal antigens. Placental ischemia and increased syncytiotrophoblast deportation are probably end-stage disease phenomena. Copyright 9 1999 by W.B. Saunders Company p
reeclampsia occurs in 3% to 5% of pregnancies and is a major cause (15% to 20%) of maternal mortality in developed countries and a leading cause of preterm birth and intrauterine growth retardation. 1 In this review, relevant endotheliai and immunologic aspects of normal pregnancy will be discussed and compared with those occurring in preeclampsia. In addition, current hypotheses regarding the etiology of preeclampsia as they relate to the primary hypothesis of immunologic maladaptation will be summarized.
Normal Pregnancy A Vasodilatory State Generalized vasodilatation is the primary hemodynamic change of normal pregnancy and is already present d u r i n g the luteal phase in women who subsequently become pregnant. 2 In the 1980s, pregnancy-associated biological dominance of prostacyclin over thromboxane-A 2 was t h o u g h t to cause vascular refractoriness to vasoconstrictors and thus vasodilation. ~ More recently, it was demonstrated that vasodilator prostaglandins do not mediate the attenuation of systemic and renal pressor responsiveness in pregnancy. 4,5 A n u m b e r of peptide regulatory factors (cytokines, binding proteins, growth factors) released in an appropriate steroid environFrom the Department of Obstetrics and Gynaecology, Free University Hospital, Amsterdam, The Netherlands; and the Department of Obstetrics and Gynecology, University of Tennessee, Memphis, TN. Address reprint requests to Baha M. Sibai, MD, Maternal-Fetal Medicine, University of Tennessee, Memphis, 853 Jefferson Ave, Suite El02, Memphis, TN 38103. Copyright 9 1999 by W.B. Saunders Company O146-0005/99/2301-0004510. 00/0 24
ment appear to play an integral part in this mediation, and nitric oxide may be important as final messenger. 6 In pregnant animals, pharmacological inhibition of nitric oxide synthesis produces a preeclampsia like syndrome. 7 An endothelium-derived hyperpolarizing vasodilatory factor is also involved in pregnancy-associated vasorelaxation, s
The Uteroplacental Circulation in Normal Pregnancy During the initial phases of placental development, cytotrophoblasts stream out of the tips of the anchoring villi, penetrate the overlying syncytiotrophoblast to form cytotrophoblast columns that develop into t h e cytotrophoblast shell. Cytotrophoblasts continue to migrate into the decidua and eventually invade the spiral arterioles. Endovascnlar cytotrophoblasts replace the endothelium of spiral arteries and then invade the media, with resulting destruction of the medial elastic, muscular, and neural tissue. The medial musculoelastic layer is replaced by a fibrinoid matrix in which cytotrophoblasts are embedded. Eventually, cytotrophoblasts become incorporated into the wall of the vessel, and the endothelium appears to be reconstituted. These physiological changes create a low resistance to flow and absence of maternal vasomotor control, which allows an enormous increase in blood supply to the growing fetus. 9 During invasion, cytotrophoblasts are not cytolytic but secrete plasminogen activator and metalloproteinases that effect the extracellular matrix. Activity of these enzymes is influenced by mediators such as beta-human chorionic gonadotropin (/3HCG) and cytokines2 Onset of trophoblast invasive behavior is associated with a shift in ex-
Seminars in Perinatology, Vol 23, No 1 (February), 1999: pp 24-33
The Immunology of Preeclampsia
pression of cell surface adhesion molecules, necessary for adhesion to extracellular matrix proteins for anchorage and traction. Endovascular cytotrophoblasts transform their adhesion receptor phenotype so as to resemble the endothelial cells they replace, t~ Local concentrations of cytokines may be involved in this phenomenon. Vascular endothelial growth factor, an angiogenic growth factor, is among the possible candidates because it is expressed at high levels during placentation. H Vascular endothelial growth factor induces the expression of av/3a integrin on cytotrophoblasts, an adhesion molecule associated with angiogenic invasion, and with the de novo expression of endothelial characteristics by invading cytotrophoblasts. 1~Decidual macrophages are a major source of vascular endothelial growth factor, whereas the receptor for vascular endothelial growth factor has been localized on cytotrophoblasts. Vascular endothelial growth factor is upregulated by hypoxia, which may provide a mechanism through which the placenta develops according to its metabolic requirements, especially in the first 10 weeks of pregnancy when oxygen tension of trophoblast villi is low.11
Immunology of Normal Pregnancy The placenta is essentially an allograph; its implementation involves an allogenetic recognition system based on natural killer cells rather than T cells. 12 About 75% of decidual cells express CD45 reflecting their bone marrow origin. In the late secretory phase of the endometrium, a population also expressing CD56 (a marker of peripheral blood large granular lymphocytes) becomes dominant. As pregnancy progresses, the number of decidual macrophages and T cells remain constant, but the number of large granular lymphocytes declines dramatically, la These lymphocytes resemble natural killer cells. Cells of the natural killer lineage, such as uterine large granular lymphocytes, destroy target cells that are deficient in class I human leukocyte antigens (HLA) expression rather than recognizing the presence of foreign HLA. This is the basis of the "missing self" hypothesis for natural killer cell cytolysisA~ Syncytiotrophoblasts are devoid of classical class I and II HLA. Although this prevents recognition by maternal T lymphocytes, the lack of
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class I molecules leaves these cells susceptible to attack by natural killer cells. Binding of a maternal IgG antibody to an 80-kDa protein present on syncytiotrophoblast may be important in preventing natural killer cell attack. 14 Invading cytotrophoblasts, which are the cells in direct contact with maternal tissues, express the relatively nonpolymorphic class I molecule HLA-G, which protects them from recognition by natural killer cells. ~,1~ Several HLA-G alleles have been described, but most of these polymorphisms are some distance from the peptide-binding groove, a6 Invasive cytotrophoblasts also express HLA-C. Considering positions important in peptide binding, HLA-C is also less polymorphic when compared with HLA-A and -B. a2,t7 Natural killer cells express killer inhibitory and killer activatory receptors capable of recognizing HLA class I molecules. Interestingly, the repertoire of the above receptors expressed by uterine large granular lymphocytes differs between women. HLA-C appears to be the most pertinent in influencing natural killer cell function. The two killer inhibitory receptors that are specific for all HLA-C alleles also recognize HLA-G, suggesting that HLA-G is the universal inhibitor of cytolysis by natural killer cells. 1~,1s Trophoblast invasion may actually be dependent on appropriate cytokines being produced by uterine large granular lymphocytes and other decidual CD45 cells in response to HLA-G expressed on cytotrophoblasts. This phenomenon is called immunotrophism. Several cytokines, in a close and complex interaction with steroids and prostaglandins, are essential to early pregnancy development. 19 For instance, tumor necrosis factor-a (TNF-~), interferon-~ (IFN-ot), IFN-/3, IFN-T, and transforming growth factor-I/3 (TGF-1/3) inhibit trophoblast growth. Conversely, interleukin-1 (IL-1), vascular endothelial growth factor, granulocyte-macrophage colony-stimulating factor and IL-6 stimulate tro-
phoblast growth. 19,20 Overall natural killer cell and T lymphocyte activity is downregulated in normal pregnancy3 ~ In 1986, two distinct and mutually inhibitory types o f T helper cells were described3 ~ The first type of cell, termed Thl, secretes IL-2, IFN-T, and lymphotoxin. This contrasts with Th2 cells, which secrete IL-4, IL-6, and IL-103 ~ Thl cytokines are associated with cell-mediated immunity and delayed hypersensitivity reactions,
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whereas Th2 cytokines foster antibody responses and allergic reactions. Pregnancy is characterized by Th2 switch. During pregnancy, expression of both CD4 and CD8 is transiently down regulated on 0~/3 TcR+ splenic T cells specific for a paternal major histocompatibility complex class I antigen, which represents a reduced T h l response. 23 HLA-G expressed on cytotrophoblast induces a Th2 response in decidual leukocytes. 24,25 Several substances such as prostaglandin E2, progesterone, TGF-/32, granulocyte-macrophage colony-stimulating factor, and IL-10 ~1,25,26 play a part in the immunoendocrine network in pregnancy maintenance. Placental and decidual cells produce Th2-specific cytokines, including IL-4, IL-5, and ID10. IL-10 acts as a cytokine synthesis inhibitory factor and as an inducer of adrenocorticotropin.1~,21,26,27 The importance of the Th2 switch is supported by the finding that decidual CD4 and CD8 T-cell clones of recurrent abortion patients show reduced IL-4 and IL-10 production. Also, when measured in peripheral leukocytes, normal pregnancy is characterized by a Th2 cytokine profile, whereas spontaneous miscarriages are characterized by a T h l cytokine profile. 2s However, just considering successful pregnancy as a Th2 p h e n o m e n o n is probably an oversimplification, because cytokine expression in pregnancy is very complex and changes t h r o u g h o u t gestation. 29,3~
Preeelampsia A Vasoconstrictory State Development of preeclampsia begins with a loss of vascular refractoriness to vasoactive agents followed by vasoconstriction. Increased vascular sensitivity and subsequent vasoconstriction results in a decrease in intravascular volume. Intravascular volume is shunted, across the "leaky" capillaries, to extravascular spaces. Until recently, absence of normal stimulation of the renin-angiotensin aldosterone system, despite significant hypovolemia and the increased sensitivity to vasoconstrictors, was explained by an impaired endothelial production of prostacyclin and an overproduction of thromboxane-A 2 by platelets. 31-33 Currently, we know that preeclampsia is not simply a state of prostacyclin deficiency. Preeclampsia is characterized by a generalized dysfunction of the maternal endo-
thelium, as is demonstrated by increased levels of factor VIII:R ag, total and cellular fibronectin; thrombomodulin, endothelin, growth factor activity, and a disturbance of the tPA/PAI-1 and prostacyclin/thromboxane-A 2 balance. 34 Preeclampsia is associated with an impairment of endothelium-dependent relaxation in maternal resistance arteriesY Initial studies on actual nitric oxide production in preeclampsia yielded controversial results, 36 mostly because these studies looked at plasma levels of various byproducts. However, two i n d e p e n d e n t studies found a decrease in urinary excretion of nitric oxide metabolites in preeclampsia (which represents a better indicator of overall decreased nitric oxide production) .~6.37 In preeclampsia, platelet activation in the Spiral arteries results in the release of thromboxane-A 2 and serotonin, contributing to platelet aggregation and inducing the formation of fibrin to stabilize the platelet thrombus that may occlude maternal blood flow to a placental cotyledon, thus leading to placental infarction. 3s,39
The Uteroplacental Circulation in Preeclampsia In preeclampsia, physiological changes in the spiral arteries are confined to the decidual portion of the arteries. About one third to one half of spiral arteries escape entirely from endovascular trophoblast invasion. Myometrial segments remain anatomically intact and do not dilate; adrenergic nerve supply to the spiral arteries remains intact. In addition, many vessels are occluded by fibrinoid material and exhibit adjacent foam cell invasion (acute atherosis). 9 Change in expression of adhesion molecules by invasive cytotrophoblasts is abnormal i n preeclampsia and results in decreased trophoblast attachment on extracellular matrix proteins. In preeclampsia, cytotrophoblasts fail to mimic a vascular adhesion phenotype. 9,10This abnormal cytotrophoblast differentiation is not necessarily a primary feature of preeclampsia, but may be a consequence of cytokines produced by activated decidual leukocytes. 1~176
The Origin of Preeclampsia The origin of preeclampsia remains unknown, but three hypotheses are currently the subject of extensive investigation.
The Immunology of Preeclampsia
The Placental Ischemia Hypothesis According to this hypothesis, preeclampsia starts with the process that affects the spiral arteries, which results in a deficient blood supply to the placenta. The ensuing placental ischemia results in increased deportation of syncytiotrophoblast microvillous membrane particles. Such particles from normal and preeclamptic placentae disturb endothelial function, 41 thus, increased deportation of syncytiotrophoblast microvillous membrane particles may cause endothelial dysfunction in preeclampsia. 41,4~ Increased syncytiotrophoblast microvillous membrane particles deportation in established preeclampsia can be explained by the presence of elongated syncytial sprouts 4a representing evidence of placental repair mechanisms. Although placental ischemia is an attractive hypothesis, several concerns dispute its validity. Chronology of the maternal components of preeclampsia do not fit with the placental ischemia hypothesis. Endothelial involvement is present in the first trimester, 43-45 which is difficult to reconcile with the first conceivable stages of placental ischemia. The normal environment for trophoblast in the first trimester is low in oxygen, 1~ and this relative "hypoxia" is likely to be of physiological importance because signs of increased intervillous flow are associated with adverse pregnancy outcome. 46 Decreased placental vascular endothelial growth factor mRNA and maternal plasma vascular endothelial growth factor levels in preeclampsia argue against the placental ischemia concept, 47,48 and structural differences of terminal villi in severe preeclampsia are consistent with an increased oxygen content within terminal villi rather than hypoxia. 49 Thus, increased syncytiotrophoblast microvillous membrane particles deportation as a consequence of placental ischemia is probably a feature of end-stage disease.
Immune Maladaptation Hypothesis Genuine preeclampsia is a disease of first pregnancies. ~ A previous normal pregnancy is associated with a markedly lowered incidence of preeclampsia; even a previous abortion provides some protection in this respect, v~The protective effect of multiparity is, however, lost with change of partner. The adverse impact of having a new partner, first described by Needp 1 has since
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been found by several investigators. ~,53 Thus, preeclampsia appears to be a problem of primipaternity rather than of primigravidity. 53 Repeated sperm exposure may prevent preeclampsia. 54 Users of barrier contraceptives are at a twofold increased risk of preeclampsia. 55 Robillard et a156 interviewed 1,011 consecutive women about paternity and duration of sexual cohabitation before conception. For both primigravidae and multigravidae, length of sexual cohabitation before conception was inversely related to the incidence of pregnancy-induced hypertension. In concordance with the effects of short sperm exposure and altered paternity, artificial d o n o r insemination results in a substantial increase in the risk of preeclampsia. 57,5s Oral antigens stimulating the gut-associated lymphoid tissue preferentially generate a Th2-type responseP 9 Based on this concept, Dekker 6~ asked 41 primiparous women with a history of proteinuric preeclampsia and a control group of 44 primiparous women if they had oral sex (intraoral ejaculation) with their partner before pregnancy. In the preeclamptic group, significantly less women (44%) had oral sex with their partner before the index pregnancy as compared with the control group (82%). The protective effects of sperm exposure are not fully understood. This may be because of T cells in the genital tract with special receptors that may recognize antigens without the usual requirement for simultaneous binding to class I HLA on the antigen-presenting cell. This could then pave the way to recognition of trophoblast lacking classical HLA. 61 In addition, TGF-~I in seminal plasma initiates endometrial leukocyte infiltration by up-regulating expression of granulocyte-macrophage colony-stimulating factor, but expression of IL-2 is reduced. This results in a transient state of T lymphocyte hyporesponsiveness to paternal class I HLA. 62 In addition to the epidemiological studies, there are numerous reports of immunologic p h e n o m e n a in preeclampsia. These include antibodies against endothelial cells; increased circulating i m m u n e complexes; c o m p l e m e n t activation; complement and i m m u n e complex deposition in spiral arteries, placenta, liver, kidney, and skin; enhanced activity of certain cytokines; and lower proportion of T helper cells in the second trimester of future preeclamptic women. Acute atherosis is histopathologicalty
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similar to lesions seen in organ i m m u n e rejection. 63 Thus, there is no d o u b t that preeclamptic patients manifest immunopathology, but the question remains as to whether such immunopathology causes (or results from) preeclampsia. I m m u n e complex, complement, and fibrin deposits in decidual vessels may occur in response to rather then be the cause o f vascular occlusion; analogous results described in chorionic villous tissue may have resulted from placental ischemia. C o n c e r n i n g the pivotal role of HLA-G on invasive cytotrophoblasts in escaping maternal imm u n e surveillance, Colbern et a164 were the first to observe a lower level o f mRNA for HLA-G in trophoblasts in preeclampsia as c o m p a r e d with normal pregnancy. But normalization to mRNA for cytokeratin showed that this could be caused by the smaller n u m b e r of trophoblast cells present in preeclamptic placentae. Hara et a165 f o u n d that invading cytotrophoblasts, which were stained for cytokeratin, normally all expressed HLA-G, whereas in preeclampsia, clusters o f cytotrophoblasts were insularly devoid of HLA-G. Similar findings were reported by Lim et al. 66 Attenuated HLA-G expression on invading cytotrophoblasts could be of obvious importance in the pathogenesis of preeclampsia, 67 but whether this p h e n o m e n o n is caused by aberrant trophoblast differentiation or the result of structural gene mutation has not yet been elucidated. If preeclampsia is caused by i m m u n e maladaptation, what are the mediators causing endothelial activation? Decidual leukocytes, when activated, can release a host of mediators that may interact with endothelial cells. Cytokines. Prime candidates for the putative circulating endothelium-activating molecules in preeclampsia are the cytokines. The majority of studies r e p o r t e d so far f o u n d increased TNF-a and IL-1 levels, and increased levels o f soluble TNF-a receptors and IL-1 receptor antagonist. 6s,69 Serum levels of IL-2 (an important cytokine in the T-cell pathway) are also increased in preeclampsia. 7~ Increases in plasma ceruloplasmin, c o m p l e m e n t activity, aa-antitrypsin and haptoglobin, and reduced albumin and transferrin in preeclampsia, are characteristic of an acute phase reaction that may be related to the increased II~6 levels. 69 T h e source of these T h l cytokines may be decidual leukocytes. 71 Decidual p r o d u c t i o n of IL-2 is increased in preeclamp-
sia, which may lead to increased proliferative and cytotoxic activities of uterine large granular lymphocytes, and conversion to lymphokine-activated killer cells. 7e It should be noted that the placenta may also p r o d u c e T h l cytokines. Placental cells express erythropoietin, the prototype molecule for transcriptional regulation by hypoxia in mammals. TNF-a and IL-1 have DNA sequences (nearly) homologous to the hypoxiaresponsive e n h a n c e r element of the erythropoietin gene, thus providing a potential, untested, molecular link between placental hypoxia and stimulation of cytokine production. 29 Dysfunctional endothelial cells u n d e r g o activation and produce leukocyte-endothelial adhesion molecules that mediate a d h e r e n c e o f inflammatory cells. This inductive process is mediated by cytokines p r o d u c e d by inflammatory cells and activated endothelial cells. Preeclampsia is associated with increased levels of these adhesion molecules, and this increase may be an early event. 73 Increased IL-6 and IL-1 receptor antagonist levels in preeclampsia correlate with elevated concentrations of these adhesion molecules. Hamai et a174 provided very important evidence that abnormal cytokine production (elevated IL-2 and TNF-a levels) in women destined to have preeclampsia is already present in the first trimester. Therefore, the chronological features of abnormal cytokine production in preeclampsia argue against the placental ischemia hypothesis, but are c o n c o r d a n t with a faulty immunologic maternal-fetal interaction cause of the disease. In preeclampsia, circulating free fatty acids increase 15 to 20 weeks before the onset of clinical disease. TNF-a, IL-1, and IL-6 are known to induce adipocyte lipolysis, p r o m o t e de novo hepatic fatty acid synthesis, and impair hepatic fatty acid oxidation and ketogenesis. Thus, the lipid changes in preeclampsia may reflect cytokine effects. 75 Free fatty acids may impair endothelial prostacyclin and nitric oxide production 76 possibly by reducing toxicity-preventing activity of albumin. 77 Elastase and other neutrophil activation markers.
Activated neutrophils release enzymes such as elastase, which can destroy the integrity o f the endothelium. Plasma elastase levels are elevated in preeclampsia and correlate with markers o f endothelial dysfunction. 78 In normal pregnancy, both serum levels o f TNF-a and IL-6 and levels
The Immunology of Preeclampsia
of their soluble receptors increase with gestational age, 79 and the same holds true for circulating i m m u n e complexes and complement activation. 8~ Neutrophils can be activated by complement factors. Markers for complement activation are increased in preeclampsia and correlate with elastase and neopterin levels and with elevated IL-6 levels. Normal pregnancy is characterized by activated neutrophils, as is evidenced by the increase in intracellular ionized calcium and circulating neopterin, lactoferrin, and defensin levels. Neutrophil activation is increased further in preeclampsia. 81-83 Increased basal neutrophil C D l l b expression in preeclampsia is a strong indication of neutrophil activation in vivo and correlates with plasma uric acid levels, s4 Sacks et al so found that in normal pregnancy both granulocytes and monocytes had significantly raised CD1 lb, CD64, and CD14 levels compared with n o n p r e g n a n t women, whereas in preeclampsia, there is further leukocyte activation characterized by an altered phenotype and increased production of intracellular reactive oxygen species. Therefore, normal pregnancy may represent a "mild" inflammatory state, whereas preeclampsia is characterized by an exaggerated degree of inflammation. Oxygen-free rad/ea/s. Lipid peroxides and oxygen-free radicals are highly reactive and very damaging compounds. In normal pregnancy lipid peroxides increase, but antioxidants also increase to offset their toxic actions. In women with preeclampsia, however, circulating levels of lipid peroxides are increased, but net antioxidant activity is decreased. Activated leukocytes may provide one of the major sources of oxygenfree radicals in preeclampsia. In addition, activated leukocytes may irreversibly convert endothelial xanthine dehydrogenase to xanthine oxidase, thus causing endothelial release of oxygen-free radicals. The placenta is another source of free radical species in preeclampsia. st,s7 Concerning antioxidants, the overall picture in preeclampsia is complex, but it is apparent that the disease can not be characterized as a state of global antioxidant deficiency.88 Watersoluble antioxidant nutrients, such as ascorbic acid, a-tocopherol and/3-carotene initially may be consumed, followed by lipid-soluble antioxidants. 89 Oxidative dysequilibrium in preeclampsia is closely linked with TNF activity. Because they control the oxidation-reduction status of
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mitochondrial glutathione, which is an important endogenous modulator of TNF-a production, antioxidants selectively inhibit TNF-a release. 9o Preeclampsia as a Genetic Disease
Severe preeclampsia and eclampsia have a familial tendency. A complete discussion of the genetics of preeclampsia can be found in a previous article in this issue. The following review will concentrate on the interaction between a genetic predisposition to preeclampsia and the imm u n e system. The development of preeclampsia may be based on a single recessive gene or a dominant gene with incomplete penetrance. Multifactorial inheritance is another possibility.0~,92 The principal reason for doubting the existence of a maternal gene as the sole explanation for preeclampsia is data showing a lack of concordance for susceptibility in a small sample of monozygous twins. 9a Most reports so far are consistent with a relatively c o m m o n allele acting as a "major gene" conferring susceptibility to preeclampsia. Impact of the fetal genotype is demonstrated by the association between preeclampsia and fetal chromosomal abnormalities. 92 The epidemiological link between miscarriages and preeclampsia supports the concept that genetic predisposition to preeclampsia is related to placentation. 94 Assuming that there is autosomal recessive inheritance, no evidence has been found for linkage to the HLA region. 95 An amino substitution in the angiotensinogen gene has been suggested to correlate with the risk of preeclampsia, but not with the risk of hemolysis, elevated liver enzymes, and low platelet count syndrome. Other studies found no association between this allele and preeclampsia, and suggested that it has more to do with a tendency toward hypertension rather than with preeclampsia. 96 An increased incidence of severe preeclampsia or eclampsia has been described in a family with a failure of the nicotinamide adenine dinucleotide (reduced ubiquinone oxidoreductase step in the mitochondrial electron chain), 97 which is of interest considering the possible involvement of a genetic TNF-a-mediated mitochondrial dysfunction in its etiology.9~ Increased expression of TNF-ot in leukocytes may be associated with the increased frequency of a TNF-1
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a l l e l e in p r e e c l a m p s i a t h a t is k n o w n to r e s u l t in h i g h e x p r e s s i o n o f TNF-o~. ~ R e s u l t s o f a r e c e n t genomewide linkage search showed a region on t h e l o n g a r m o f c h r o m o s o m e 4 as a s t r o n g c a n didate region for a preeclampsia susceptibility lOCUS.99 H y p e r t e n s i o n , d y s l i p i d e m i a , a n d i n s u l i n resist a n c e m a y b e p a r t o f s y n d r o m e X (its i n c i d e n c e is m a r k e d l y i n c r e a s e d in p a t i e n t s w h o w e r e g r o w t h r e t a r d e d at b i r t h ) . 1 ~ 1 7T6h u s , a n a l t e r n a t i v e explanation for the apparent "hereditary" characteristics of preeclampsia may be that daught e r s b o r n to w o m e n w i t h s e v e r e p r e e c l a m p s i a can suffer from long-term adverse cardiovascular s e q u e l a e l a t e r i n life, r e s u l t i n g i n a n i n c r e a s e d risk f o r p r e e c l a m p s i a w h e n t h e y a r e p r e g n a n t . T h i s is c o n s i s t e n t w i t h t h e i n c r e a s e d p r e v a l e n c e o f p r e e c l a m p s i a in d a u g h t e r s b o r n to a n e c l a m p tic m o t h e r c o m p a r e d w i t h s i b l i n g s b o r n to t h e s a m e m o t h e r a f t e r a n u n e v e n t f u l p r e g n a n c y . 92 I n s u l i n r e s i s t a n c e is p r e s e n t in m a n y p r e e c l a m p tic w o m e n , w h i c h m a y e x p l a i n s y m p a t h e t i c hyp e r a c t i v i t y i n this c o n d i t i o n . 1~176 Genetic factors in the cause of preeclampsia m a y also b e r e l a t e d to a n u n d e r l y i n g h e r e d i t a r y thrombophilic disorder and hyperhomocyst e i n e m i a , ~~ e s s e n t i a l h y p e r t e n s i o n o r o b e s i t y a n d t h u s i n c r e a s e d s u s c e p t i b i l i t y to p r e e c l a m p sia, o r to t h e c o n t r o l o f t h e T h l - T h 2 b a l a n c e a n d t h u s t h e m a t e r n a l r e s p o n s e a g a i n s t f e t a l antigens. TM
References 1. Working Group on High Blood Pressure in Pregnancy. National High Blood Pressure Education Program Working Group report on high blood pressure in pregnancy: Consensus report. Am J Obstet Gynecol 163: 1689-1712. 1990 2. Duvekot JJ, Peeters LLH: Maternal cardiovascular hemodynamic adaptation to pregnancy. Obstet Gynecol Surv 49:$1-$14, 1994 3. Friedman SA: Preeclampsia: A review of the role of Prostaglandins. Obstet Gynecol 71:122-137. 1988 4. Conrad KP. Colpoys MC: Evidence against the hypothesis that prostaglandins are the vasodepressor agents of pregnancy. J Clin Invest 77:236-245. 1986 5. Sorensen TK. Easterling TR. Carlson RL. et al: The maternal hemodynamic effect of indomethacin in normal pregnancy. Obstet Gynecol 79:661-663, 1992 6. Morris NH, Eaton BM, Dekker GA: Nitric oxide, the endothelium, pregnancy, and pre-eclampsia. Br J Obstet Gynaecol 103:4-15, 1996 7. Molnar M, Suto T, Toth T. et al: Prolonged blockade of nitric oxide synthesis in gravid rats produces sustained
hypertension, proteinuria, thrombocytopenia and intrauterine growth retardation. Am J Obstet Gynecol 170:1458-1466, 1994 8. Pascoal IF, Umans JG: Effect of pregnancy o n mechanisms of relaxation in human omental microvessels. Hypertension 28:183-187, 1996 9. Pijnenborg R: The placental bed. Hypertension in Pregnancy 15:%23, 1996 10. Zhou Y, Damsky CH, Fisher SJ: Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. J Clin Invest 99:21522164, 1997 11. Wheeler T, Elcock CL, Anthony FW: Angiogenesis and the placental environment. Placenta 16:289-296, 1995 12. Loke YWK, King A: Immunology of human placental implantation: Clinical implications of our current understanding. Molecular Medicine Today 3:153-159, 1997 13. Starkey PM: The decidua and factors controlling placentation, in Redman CWG, Sargent LL. Starkey PM (eds): The Human Placenta. Oxford, Blackwell Scientific Publications, 1993, pp 362-413 14. MowbrayJ,Jalali R. Chaouat G, et al: Maternal response to paternal trophoblast antigens. Am J Reprod Biol 37:421-426, 1997 15. Shorter SC. Starkey PM, Ferry BL. et al: Antigenic heterogeneity of human cytotrophoblast and evidence for the transient expression of MHC class I antigens distinct from HLA-G. Placenta 14:571-582, 1993 16. Le Bouteiller P: HLA-G: What's new? AmJ Reprod Biol 38:146-149. 1997 17. King A, Boocock C. Sharkey AM, et al: Evidence for the expression of HLA-C class l mRNA and protein by human first trimester trophoblast.J Immuno1156:20682076. 1996 18. Rouas-Freiss N, Marchal RE. Kirszenbaum M. et al: The O1 domain of HLA-G1 and HLA-G2 inhibits cytotoxicity induced by natural killer cells: Is HLA-G the public ligand for natural killer cell inhibitory receptors. Proc Natl Acad Sci USA 94:5249-5254, 1997 19. Clark DA: Cytokines, decidua, and early pregnancy. Oxf Rev Reprod Biol 15:83-110. 1993 20. Giudice LC: Growth factors and growth modulators in human uterine endometrium: Their potential relevance to reproductive medicine. Fertil Steril 61:1-17. 1994 21. Wegmann TG, Lin H, Guilbert L, et al: Bidirectional cytokine interactions in the maternal-fetal relationship: Is successful pregnancy a Th2 phenomenon? Immunol Today 15:353-356, 1993 22. Mosmann TR. Cherwinski H, Bond MW: Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136:2348-2357. 1986 23. Tafurie A, MferinkJ, Moller P, et al: T cell awareness of paternal alloantigens during pregnancy. Science 270: 630-633. 1995 24. Maejima M. Fujii T. Kozuma S, et al: Presence of HLA-G expressing cells modulates the ability of peripheral blood mononuclear cells to release cytokines. AmJ Reprod Biol 38:79-82, 1997
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25. Clark DA: HLA-G finally does something! AmJ Reprod Biol 38:75-78, 1997 26. Romagnani S: The T h l / T h 2 paradigm. Immunol Today 18:263-266, 1997 27. Cadet P, Rady PL, Tyring SK, et al: Interleukin-10 messenger ribonucleic acid in human placenta: Implications of a role for interleuldn-10 in fetal allograft protection. A m J Obstet Gynecol 173:25-29, 1995 28. Marzi M, Vigano A, Trabattoni D, et al: Characterization of type 1 and type 2 cytokine production in physiologic and pathologic pregnancy. Clin Exp Immunol 106:127-133, 1996 29. Conrad KP, Benyo DF: Placental cytokines and the pathogenesis of preeclampsia. Am J Reprod Biol 37: 240-249, 1997 30. Tranchot-DialloJ, Gras G, Parnet-Mathieu F, et al: Modulations of cytokine expression in pregnant women. A m J Reprod Biol 37:215-226, 1997 31. Gant NF, Daley GI, Chand S, et al: A study of angiotensin-II pressor response throughout primigravid pregnancy. J Clin Invest 52:2682-2689, 1973 32. Jong de CLD, Dekker GA, Sibai BM: The renin-angiotensin-aldosterone system in preeclampsia: A review. Clin Perinatol 18:1-29, 1991 33. Meagher EA, FitzGerald GA: Disordered eicosanoid formation in pregnancy-induced hypertension. Circulation 88:1324-1333, 1993 34. Roberts JM, Redman CWG: Pre-eclampsia: More than pregnancy-induced hypertension. Lancet 341:14471454, 1994 35. McCarthy AL, Taylor P, Graves J, et al: Endotheliumdependent relaxation of human resistance arteries in pregnancy. Am J Obstet Gynecol 171:1309-1315, 1994 36. Davidge ST, Stranko CP, Roberts JM: Urine but not plasma nitric oxide metabolites are decreased in women with preeclampsia. Am J Obstet Gynecol 174: 1008-1013, 1996 37. Begum S, Yamasaki M, Mochizuki M: Urinary levels of nitric oxide metabolites in normal pregnancy and preeclampsia. J Obstet Gynec01 Res 22:551-559, 1996 38. Redman CWG: Platelets and the beginning of preeclampsia. N EnglJ Med 323:478-480, 1991 39. Middelkoop CM, Dekker GA, Kraayenbrink AA, et al: Platelet-poor plasma serotonin in normal and preeclamptic pregnancy. Clin Chem 39:1675-1678, 1993 40. Hunt JS, Chen HL, Miller L: Tumor necrosis factors: Pivotal components of pregnancy. Biol Reprod 54: 4554-4562, 1996 41. Smarason AK, Sargent IL, Starkey PM, et al: The effect of placental syncytiotrophoblast microvillous membranes from normal and pre-eclamptic women on the growth of endothelial cells in vivo. BrJ Obstet Gynaecol 100:943-949, 1993 42. Knight M, Redman CWG, Linton EA, et al: Shedding of syncytiotrophoblast microvilli into the maternal circulation in pre-eclamptic pregnancies. BrJ Obstet Gynaecol 105:632-640, 1998 43. Lockwood CJ, Peters JH: Increased plasma levels of ED1 + cellular fibronectin precede the clinical signs of preeclampsia. Am J Obstet Gynecol 162:358-362, 1990 44. Taylor RN, Heilbron DC, Roberts JM: Growth factor activity in the blood of women in whom preeclampsia
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develops is elevated from early pregnancy. AmJ Obstet Gynecol 163:1839-1844, 1990 Jong de K, Paarlberg M, Geijn van HP, et al: Uric acid production is decreased in future preeclamptic women. J Perinat Med 25:347-352, 1997 Meuris S, Nagy AM, Delogne-DesnoeckJ, et al: Temporal relationship between the human chorionic gonadotrophin peak and the establishment of intervillous blood flow in early pregnancy. Hum Reprod 10:947950, 1995 Cooper JC, Sharkey AM, Charnock-Jones DS, et al: VEGF mRNA levels in placentae from pregnancies complicated by pre-eclampsia. Br J Obstet Gynaecol 103:1191-1196, 1996 Lyall F, Young A, Boswell F, et al: Placental expression of vascular endothelial growth factor in placentae from pregnancies complicated by pre-eclampsia and intrauterine growth restriction does not support placental hypoxia at delivery. Placenta 18:269-276, 1997 Macara L, Kingdom JCP, Kaufman P, et al: Structural analysis of placental terminal villi from growth-restricted pregnancies with abnormal umbilical artery doppler waveforms. Placenta 17:3748, 1996 Strickland DM, Guzick DS, Cox K, et al: The relationship between abortion in the first pregnancy and development of pregnancy-induced hypertension in the subsequent pregnancy. Am J Obstet Gynecol 154:146148, 1986 NeedJA: Pre-eclampsia in pregnancies by different fathers. BMJ ii:548-549, 1975 Trupin LS, Simon LP, Eskenazi B: Change in paternity: A risk factor for preeclampsia in multiparas. Epidemiology 7:240-244, 1996 Robillard PY, Hulsey TC, Alexander GR, et al: Paternity patterns and risk of preeclampsia in the last pregnancy in multiparae.J Reprod Immunol 24:1-12, 1993 Marti JJ, Herrmann U: Immunogestosis: A new etiologic concept of ~essential" EPH gestosis, with special consideration of the primigravid patient. Am J Obstet Gynecol 128:489-493, 1977 Klonoff-Cohen HS, Savitz DA, Cefalo RC, et al: An epidemiologic study of contraception and preeclampsia. JAMA 262:3143-3147, 1989 Robillard PY, Hulsey TC, PerianinJ, et al: Association of pregnancy-induced hypertension with duration of sexual cohabitation before conception. Lancet 344:973975, 1994 NeedJA, Bell B, Meffin E, et al: Pre-eclampsia in pregnancies from donor inseminations. J Reprod Immunol 5:329-338, 1983 Smith GN, Walker M, TessierJL, et al: Increased incidence of preeclampsia in women conceiving by intrauterine insemination with donor versus partner sperm for treatment of primary infertility. Am J Obstet Gynecol 177:455-458, 1997 Weiner HL, Friedman A, Miller A, et al: Oral Tolerance: Immunologic mechanisms and treatment of animal and human-organ specific autoimmune diseases by oral administration of autoantigens. Ann Rev Immunol 12:809-837, 1994 Dekker GA: Oral toleration to paternal antigens and preeclampsia. A m J Obstet Gynecol 174:516, 1996
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61. Clark DA: Does immunological intercourse prevent preeclampsia. Lancet 344:969-970, 1994 62. Robertson SA, Man VJ, Hudson SN, et al: Cytokineleukocyte networks and the establishment of pregnancy. A m J Reprod Biol 37:438-442, 1997 63. Taylor R: Immunobiology of preeclampsia. Am J Reprod Immunol 37:79-86, 1997 64. Colbem GT, Chiang MH, Main EK: Expression of the nonclassic histocompatibility antigen HLA-G by preeclamptic placenta. Am J Obstet Gynecol 170:12441250, 1994 65. Ham N, Fujii T, Yamashita T, et al: Altered expression of human leukocyte antigen G (HLA-G) on extraviUous trophoblasts in preeclampsia: Immunohistological demonstration with anti-HLA-G specific antibody "87G" and anticytokeratin antibody "CAM.2". A m J Reprod Immunol 36:349-358, 1996 66. Lim KH, Zhou Y, Janatpour M, et al: Human cytotrophoblast differentiation/invasion is normal in preeclampsia. A m J Pathol 151:1809-1818, 1997 67. Faas MM, Schuiling GA, BallerJFW, et al: A new animal model for human preeclampsia: Ultra-low-dose endotoxin infusion in pregnant rats. Am J Obstet Gynecol 171:158-164, 1994 68. Kupferminc MJ, Peaceman AM, Aderka D, et al: Soluble tumor necrosis factor receptors in maternal plasma and second-trimester amniotic fluid. Am J Obstet Gynecol 173:900-995, 1995 69. Vince GS, Starkey PM, Austgnlen R, et al: Interleukin-6, tumour necrosis factor and soluble tumour necrosis factor receptors in women with pre-eclampsia. Br J Obstet Gynaecol 102:20-25, 1995 70. Sunder-Plassmann G, Derfler K, Wagner L, et al: Increased serum activity of interleukin-2 in patients with preeclampsia. J Autoimmun 2:203-205, 1989 71. Vince GS, Johnson PM: Immunobiology of human uteroplacental macrophages-Friend and foe? Placenta 17:191-199, 1996 72. Hamai Y, Fujii T, Yamashita T, et al: Pathogenetic implication of interleukin-2 expressed in preeclamptic decidual tissues: A possible mechanism of deranged vasculature of the placenta associated with preeclamps i a . ~ J Reprod Biol 38:83-88, 1997 73. Krauss T, Kuhn W, Lakoma C, et al: Circulating endothelial adhesion molecules as diagnostic markers for the early identification of pregnant women at risk for development of preeclampsia. Am J Obstet Gynecol 177:443-449, 1997 74. Hamai Y, Fujii T, Yamashita T, et al: Evidence for an elevation in serum interleukin-2 and tumor necrosis factor-a levels before the clinical manifestations of preeclampsia. Am J Reprod Biol 38:89-93, 1997 75. Sattar N, Gaw A, Packard cJ, et al: Potential pathogenetic roles of aberrant lipoprotein and fatty acid metabolism in pre-eclampsia. Br J Obstet Gynaecol 103: 614-620, 1996 76. Endresen MJ, Tosti E, Heimli H, et al: Effects of free fatty acids found increased in women who develop pre-eclampsia on the ability of endothelial cells to produce prostacyclin, cGMP and inhibit platelet aggregation. ScandJ Clin Lab Invest 54:549-557, 1994 77. Arbogast BW, Leeper SC, Merrick RD, et al: Hypothe-
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sis: Which plasma factors bring about disturbance of endothelial function in pre-eclampsia? Lancet 343:340341, 1994 Greer IA, Leask R, Hodson BA, et al: Endothelin, elastase, and endothelial dysfunction in pre-eclampsia. Lancet 337:558, 1991 Opsjon SL, Novick D, Wathen NC, et al: Soluble tumor necrosis factor receptors and soluble interleukin-6 receptor in fetal and maternal sera, coelomic and amniotic fluids in normal and pre-eclamptic pregnancies. J Reprod Immunol 29:119-134, 1995 Imrie HJ, McGonigle TP, Liu DTY, et al: Reduction in erythrocyte complement factor 1 (CR 1, CD sS) and decay accelerating factor (DAF, CD ~ ) during normal pregnancy. J Reprod Immunol 31:221-227, 1996 Haeger M, Unander M, Andersson B, et al: Increased release of tumor necrosis factor-alpha and interleukin-6 in women with the syndrome of hemolysis, elevated liver enzymes, and low platelet count. Acta Obstet Gynecol Scand 75:695-701, 1996 Rebelo I, Carvalho-Guerm F, Pereira-Leite L, et al: Comparative study of lactoferrin and other markers of inflammatory stress between preeclamptic and normal pregnancies. EurJ Obstet Gynecol Reprod Biol 64:167173, 1996 Prieto JA, Panyutich AV, Heine RP: Neutrophil activation in preeclampsia. Are defensins and lactoferrin elevated in preeclamptic patients. J Reprod Med 42:2932, 1997 Barden A, Graham D, Beilin LJ, et al: Neutrophil C D l l B expression and neutrophil activation in preeclampsia. Clin Sci 92:37-44, 1997 Sacks GP, Studena K, Sargent IL, et al: Normal pregnancy and preeclampsia both produce inflammatory changes in peripheral blood leukocytes akin to those of sepsis. Am J Obstet Gynecol 179:80-86, 1998 Walsh SW: Lipid peroxidation in pregnancy. Hypertension in Pregnancy 13:1-31, 1994 Hubel CA, Kozlov AV, Kagan VE, et al: Decreased transferrin a n d increased transferrin saturation in sera of women with preeclampsia: Implications for oxidative stress. Am J Obstet Gynecol 175:692-700, 1996 Many A, Hubel CA, Roberts JM: Hyperuricemia and xanthine oxidase in preeclampsia, revisited. Am J Obstet Gynecol 174:288-291, 1996 Mikhail MS, Anyaegbunam A, Garfinkel D, et al: Preeclampsia and antioxidant nutrients: Decreased plasma levels of reduced ascorbic acid, alpha-tocopherol, and beta-carotene in women with preeclampsia. Am J Obstet Gynecol 171:150-157, 1994 StarkJM: Pre-eclampsia and cytokine induced oxidative stress. B r J Obstet Gynaecol 100:105-109, 1993 Chesley LC, Annitto JE, Cosgrove RA: The familial factor in toxaemia of pregnancy. Obstet Gynecol 32: 303-311, 1968 Cooper DW, Brennecke SP, Wilton AN: Genetics of Pre-eclampsia. Hypertension in Pregnancy 12:1-23, 1993 Thornton JG, Onwude JL: Pre-eclampsia: Discordance among identical twins. Br M e d J 303:1241-1242, 1991 Arngrimsson R, Connor JM, Geirsson RT, et al: Is genetic susceptibility for pre-eclampsia and eclampsia as-
The Immunology of Preeclampsia
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sociated with implantation failure and fetal demise? Lancet 343:1643-1644, 1994 Hayward C, Livingstone J, Holloway S, et al: An exclusion map for pre-eclampsia: Assuming autosomal recessive inheritance. A m J Hum Genet 50:749-757, 1992 Wilton AN, KayeJA, Guo G, et al: Is angiotensinogen a good candidate gene for preeclampsia? Hypertension in Pregnancy 14:251-260, 1995 Folgero T, Storbakk N, Torbergsen T, et al: Mutations in mitochondrial transfer ribonucleic acid genes in preeclampsia. Am J Obstet Gynecol 174:1626-1630, 1996 Chen G, Wilson R, Wang SH, et al: Turnout necrosis factor-alpha (TNF-a) gene polymorphism and expression in preeclampsia. Clin Exp Immunol 104:154-159, 1996 Harrison GA, Humphrey KE, Jones N, et al: A genome-
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wide linkage study of preeclampsia/eclampsia reveals evidence for a candidate region on 4q. Am J Hum Genet 60:1158-1167, 1997 Barker DJP, Gluckman PD, Godfrey KM, et al: Fetal nutrition and cardiovascular disease in adult life. Lancet 341:938-941, 1993 Schobel HP, Fischer T, Heuszer K, et al: Preeclampsia--A state of sympathetic overactivity. N Engl J Med 336:1326, 1997 Gans ROB, Dekker GA: Preeclampsia: A state of sympathetic overactivity. N EnglJ Med 335:1480-1485, 1996 Dekker GA, de Vries JIP, Doelitzsch PM, et al: Underlying disorders associated with severe early-onset preeclampsia. Am J Obstet Gynecol 173:1042-1048, 1995 Westendorpp RGJ, LangermansJAM, Huizinga TWJ, et al: Genetic influence on cytokine production and fatal meningococal disease. Lancet 349:170-173, 1997
The immune maladaptation hypothesis of preeclampsia is concordant with cytokine-mediated oxidative stress, chronology of endothelial activation, lipid changes, adverse effect of changing partners, and the protective effect of sperm exposure. Genetic factors may involve underlying hereditary thrombophilic disorders and hyperhomocysteinemia, essential hypertension and/or obesity, or control of the Thl/Th2 balance and thus affect the maternal response against fetal antigens. Placental ischemia and increased syncytiotrophoblast deportation are probably end-stage disease phenomena. Copyright 9 1999 by W.B. Saunders Company p
reeclampsia occurs in 3% to 5% of pregnancies and is a major cause (15% to 20%) of maternal mortality in developed countries and a leading cause of preterm birth and intrauterine growth retardation. 1 In this review, relevant endotheliai and immunologic aspects of normal pregnancy will be discussed and compared with those occurring in preeclampsia. In addition, current hypotheses regarding the etiology of preeclampsia as they relate to the primary hypothesis of immunologic maladaptation will be summarized.
Normal Pregnancy A Vasodilatory State Generalized vasodilatation is the primary hemodynamic change of normal pregnancy and is already present d u r i n g the luteal phase in women who subsequently become pregnant. 2 In the 1980s, pregnancy-associated biological dominance of prostacyclin over thromboxane-A 2 was t h o u g h t to cause vascular refractoriness to vasoconstrictors and thus vasodilation. ~ More recently, it was demonstrated that vasodilator prostaglandins do not mediate the attenuation of systemic and renal pressor responsiveness in pregnancy. 4,5 A n u m b e r of peptide regulatory factors (cytokines, binding proteins, growth factors) released in an appropriate steroid environFrom the Department of Obstetrics and Gynaecology, Free University Hospital, Amsterdam, The Netherlands; and the Department of Obstetrics and Gynecology, University of Tennessee, Memphis, TN. Address reprint requests to Baha M. Sibai, MD, Maternal-Fetal Medicine, University of Tennessee, Memphis, 853 Jefferson Ave, Suite El02, Memphis, TN 38103. Copyright 9 1999 by W.B. Saunders Company O146-0005/99/2301-0004510. 00/0 24
ment appear to play an integral part in this mediation, and nitric oxide may be important as final messenger. 6 In pregnant animals, pharmacological inhibition of nitric oxide synthesis produces a preeclampsia like syndrome. 7 An endothelium-derived hyperpolarizing vasodilatory factor is also involved in pregnancy-associated vasorelaxation, s
The Uteroplacental Circulation in Normal Pregnancy During the initial phases of placental development, cytotrophoblasts stream out of the tips of the anchoring villi, penetrate the overlying syncytiotrophoblast to form cytotrophoblast columns that develop into t h e cytotrophoblast shell. Cytotrophoblasts continue to migrate into the decidua and eventually invade the spiral arterioles. Endovascnlar cytotrophoblasts replace the endothelium of spiral arteries and then invade the media, with resulting destruction of the medial elastic, muscular, and neural tissue. The medial musculoelastic layer is replaced by a fibrinoid matrix in which cytotrophoblasts are embedded. Eventually, cytotrophoblasts become incorporated into the wall of the vessel, and the endothelium appears to be reconstituted. These physiological changes create a low resistance to flow and absence of maternal vasomotor control, which allows an enormous increase in blood supply to the growing fetus. 9 During invasion, cytotrophoblasts are not cytolytic but secrete plasminogen activator and metalloproteinases that effect the extracellular matrix. Activity of these enzymes is influenced by mediators such as beta-human chorionic gonadotropin (/3HCG) and cytokines2 Onset of trophoblast invasive behavior is associated with a shift in ex-
Seminars in Perinatology, Vol 23, No 1 (February), 1999: pp 24-33
The Immunology of Preeclampsia
pression of cell surface adhesion molecules, necessary for adhesion to extracellular matrix proteins for anchorage and traction. Endovascular cytotrophoblasts transform their adhesion receptor phenotype so as to resemble the endothelial cells they replace, t~ Local concentrations of cytokines may be involved in this phenomenon. Vascular endothelial growth factor, an angiogenic growth factor, is among the possible candidates because it is expressed at high levels during placentation. H Vascular endothelial growth factor induces the expression of av/3a integrin on cytotrophoblasts, an adhesion molecule associated with angiogenic invasion, and with the de novo expression of endothelial characteristics by invading cytotrophoblasts. 1~Decidual macrophages are a major source of vascular endothelial growth factor, whereas the receptor for vascular endothelial growth factor has been localized on cytotrophoblasts. Vascular endothelial growth factor is upregulated by hypoxia, which may provide a mechanism through which the placenta develops according to its metabolic requirements, especially in the first 10 weeks of pregnancy when oxygen tension of trophoblast villi is low.11
Immunology of Normal Pregnancy The placenta is essentially an allograph; its implementation involves an allogenetic recognition system based on natural killer cells rather than T cells. 12 About 75% of decidual cells express CD45 reflecting their bone marrow origin. In the late secretory phase of the endometrium, a population also expressing CD56 (a marker of peripheral blood large granular lymphocytes) becomes dominant. As pregnancy progresses, the number of decidual macrophages and T cells remain constant, but the number of large granular lymphocytes declines dramatically, la These lymphocytes resemble natural killer cells. Cells of the natural killer lineage, such as uterine large granular lymphocytes, destroy target cells that are deficient in class I human leukocyte antigens (HLA) expression rather than recognizing the presence of foreign HLA. This is the basis of the "missing self" hypothesis for natural killer cell cytolysisA~ Syncytiotrophoblasts are devoid of classical class I and II HLA. Although this prevents recognition by maternal T lymphocytes, the lack of
25
class I molecules leaves these cells susceptible to attack by natural killer cells. Binding of a maternal IgG antibody to an 80-kDa protein present on syncytiotrophoblast may be important in preventing natural killer cell attack. 14 Invading cytotrophoblasts, which are the cells in direct contact with maternal tissues, express the relatively nonpolymorphic class I molecule HLA-G, which protects them from recognition by natural killer cells. ~,1~ Several HLA-G alleles have been described, but most of these polymorphisms are some distance from the peptide-binding groove, a6 Invasive cytotrophoblasts also express HLA-C. Considering positions important in peptide binding, HLA-C is also less polymorphic when compared with HLA-A and -B. a2,t7 Natural killer cells express killer inhibitory and killer activatory receptors capable of recognizing HLA class I molecules. Interestingly, the repertoire of the above receptors expressed by uterine large granular lymphocytes differs between women. HLA-C appears to be the most pertinent in influencing natural killer cell function. The two killer inhibitory receptors that are specific for all HLA-C alleles also recognize HLA-G, suggesting that HLA-G is the universal inhibitor of cytolysis by natural killer cells. 1~,1s Trophoblast invasion may actually be dependent on appropriate cytokines being produced by uterine large granular lymphocytes and other decidual CD45 cells in response to HLA-G expressed on cytotrophoblasts. This phenomenon is called immunotrophism. Several cytokines, in a close and complex interaction with steroids and prostaglandins, are essential to early pregnancy development. 19 For instance, tumor necrosis factor-a (TNF-~), interferon-~ (IFN-ot), IFN-/3, IFN-T, and transforming growth factor-I/3 (TGF-1/3) inhibit trophoblast growth. Conversely, interleukin-1 (IL-1), vascular endothelial growth factor, granulocyte-macrophage colony-stimulating factor and IL-6 stimulate tro-
phoblast growth. 19,20 Overall natural killer cell and T lymphocyte activity is downregulated in normal pregnancy3 ~ In 1986, two distinct and mutually inhibitory types o f T helper cells were described3 ~ The first type of cell, termed Thl, secretes IL-2, IFN-T, and lymphotoxin. This contrasts with Th2 cells, which secrete IL-4, IL-6, and IL-103 ~ Thl cytokines are associated with cell-mediated immunity and delayed hypersensitivity reactions,
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whereas Th2 cytokines foster antibody responses and allergic reactions. Pregnancy is characterized by Th2 switch. During pregnancy, expression of both CD4 and CD8 is transiently down regulated on 0~/3 TcR+ splenic T cells specific for a paternal major histocompatibility complex class I antigen, which represents a reduced T h l response. 23 HLA-G expressed on cytotrophoblast induces a Th2 response in decidual leukocytes. 24,25 Several substances such as prostaglandin E2, progesterone, TGF-/32, granulocyte-macrophage colony-stimulating factor, and IL-10 ~1,25,26 play a part in the immunoendocrine network in pregnancy maintenance. Placental and decidual cells produce Th2-specific cytokines, including IL-4, IL-5, and ID10. IL-10 acts as a cytokine synthesis inhibitory factor and as an inducer of adrenocorticotropin.1~,21,26,27 The importance of the Th2 switch is supported by the finding that decidual CD4 and CD8 T-cell clones of recurrent abortion patients show reduced IL-4 and IL-10 production. Also, when measured in peripheral leukocytes, normal pregnancy is characterized by a Th2 cytokine profile, whereas spontaneous miscarriages are characterized by a T h l cytokine profile. 2s However, just considering successful pregnancy as a Th2 p h e n o m e n o n is probably an oversimplification, because cytokine expression in pregnancy is very complex and changes t h r o u g h o u t gestation. 29,3~
Preeelampsia A Vasoconstrictory State Development of preeclampsia begins with a loss of vascular refractoriness to vasoactive agents followed by vasoconstriction. Increased vascular sensitivity and subsequent vasoconstriction results in a decrease in intravascular volume. Intravascular volume is shunted, across the "leaky" capillaries, to extravascular spaces. Until recently, absence of normal stimulation of the renin-angiotensin aldosterone system, despite significant hypovolemia and the increased sensitivity to vasoconstrictors, was explained by an impaired endothelial production of prostacyclin and an overproduction of thromboxane-A 2 by platelets. 31-33 Currently, we know that preeclampsia is not simply a state of prostacyclin deficiency. Preeclampsia is characterized by a generalized dysfunction of the maternal endo-
thelium, as is demonstrated by increased levels of factor VIII:R ag, total and cellular fibronectin; thrombomodulin, endothelin, growth factor activity, and a disturbance of the tPA/PAI-1 and prostacyclin/thromboxane-A 2 balance. 34 Preeclampsia is associated with an impairment of endothelium-dependent relaxation in maternal resistance arteriesY Initial studies on actual nitric oxide production in preeclampsia yielded controversial results, 36 mostly because these studies looked at plasma levels of various byproducts. However, two i n d e p e n d e n t studies found a decrease in urinary excretion of nitric oxide metabolites in preeclampsia (which represents a better indicator of overall decreased nitric oxide production) .~6.37 In preeclampsia, platelet activation in the Spiral arteries results in the release of thromboxane-A 2 and serotonin, contributing to platelet aggregation and inducing the formation of fibrin to stabilize the platelet thrombus that may occlude maternal blood flow to a placental cotyledon, thus leading to placental infarction. 3s,39
The Uteroplacental Circulation in Preeclampsia In preeclampsia, physiological changes in the spiral arteries are confined to the decidual portion of the arteries. About one third to one half of spiral arteries escape entirely from endovascular trophoblast invasion. Myometrial segments remain anatomically intact and do not dilate; adrenergic nerve supply to the spiral arteries remains intact. In addition, many vessels are occluded by fibrinoid material and exhibit adjacent foam cell invasion (acute atherosis). 9 Change in expression of adhesion molecules by invasive cytotrophoblasts is abnormal i n preeclampsia and results in decreased trophoblast attachment on extracellular matrix proteins. In preeclampsia, cytotrophoblasts fail to mimic a vascular adhesion phenotype. 9,10This abnormal cytotrophoblast differentiation is not necessarily a primary feature of preeclampsia, but may be a consequence of cytokines produced by activated decidual leukocytes. 1~176
The Origin of Preeclampsia The origin of preeclampsia remains unknown, but three hypotheses are currently the subject of extensive investigation.
The Immunology of Preeclampsia
The Placental Ischemia Hypothesis According to this hypothesis, preeclampsia starts with the process that affects the spiral arteries, which results in a deficient blood supply to the placenta. The ensuing placental ischemia results in increased deportation of syncytiotrophoblast microvillous membrane particles. Such particles from normal and preeclamptic placentae disturb endothelial function, 41 thus, increased deportation of syncytiotrophoblast microvillous membrane particles may cause endothelial dysfunction in preeclampsia. 41,4~ Increased syncytiotrophoblast microvillous membrane particles deportation in established preeclampsia can be explained by the presence of elongated syncytial sprouts 4a representing evidence of placental repair mechanisms. Although placental ischemia is an attractive hypothesis, several concerns dispute its validity. Chronology of the maternal components of preeclampsia do not fit with the placental ischemia hypothesis. Endothelial involvement is present in the first trimester, 43-45 which is difficult to reconcile with the first conceivable stages of placental ischemia. The normal environment for trophoblast in the first trimester is low in oxygen, 1~ and this relative "hypoxia" is likely to be of physiological importance because signs of increased intervillous flow are associated with adverse pregnancy outcome. 46 Decreased placental vascular endothelial growth factor mRNA and maternal plasma vascular endothelial growth factor levels in preeclampsia argue against the placental ischemia concept, 47,48 and structural differences of terminal villi in severe preeclampsia are consistent with an increased oxygen content within terminal villi rather than hypoxia. 49 Thus, increased syncytiotrophoblast microvillous membrane particles deportation as a consequence of placental ischemia is probably a feature of end-stage disease.
Immune Maladaptation Hypothesis Genuine preeclampsia is a disease of first pregnancies. ~ A previous normal pregnancy is associated with a markedly lowered incidence of preeclampsia; even a previous abortion provides some protection in this respect, v~The protective effect of multiparity is, however, lost with change of partner. The adverse impact of having a new partner, first described by Needp 1 has since
27
been found by several investigators. ~,53 Thus, preeclampsia appears to be a problem of primipaternity rather than of primigravidity. 53 Repeated sperm exposure may prevent preeclampsia. 54 Users of barrier contraceptives are at a twofold increased risk of preeclampsia. 55 Robillard et a156 interviewed 1,011 consecutive women about paternity and duration of sexual cohabitation before conception. For both primigravidae and multigravidae, length of sexual cohabitation before conception was inversely related to the incidence of pregnancy-induced hypertension. In concordance with the effects of short sperm exposure and altered paternity, artificial d o n o r insemination results in a substantial increase in the risk of preeclampsia. 57,5s Oral antigens stimulating the gut-associated lymphoid tissue preferentially generate a Th2-type responseP 9 Based on this concept, Dekker 6~ asked 41 primiparous women with a history of proteinuric preeclampsia and a control group of 44 primiparous women if they had oral sex (intraoral ejaculation) with their partner before pregnancy. In the preeclamptic group, significantly less women (44%) had oral sex with their partner before the index pregnancy as compared with the control group (82%). The protective effects of sperm exposure are not fully understood. This may be because of T cells in the genital tract with special receptors that may recognize antigens without the usual requirement for simultaneous binding to class I HLA on the antigen-presenting cell. This could then pave the way to recognition of trophoblast lacking classical HLA. 61 In addition, TGF-~I in seminal plasma initiates endometrial leukocyte infiltration by up-regulating expression of granulocyte-macrophage colony-stimulating factor, but expression of IL-2 is reduced. This results in a transient state of T lymphocyte hyporesponsiveness to paternal class I HLA. 62 In addition to the epidemiological studies, there are numerous reports of immunologic p h e n o m e n a in preeclampsia. These include antibodies against endothelial cells; increased circulating i m m u n e complexes; c o m p l e m e n t activation; complement and i m m u n e complex deposition in spiral arteries, placenta, liver, kidney, and skin; enhanced activity of certain cytokines; and lower proportion of T helper cells in the second trimester of future preeclamptic women. Acute atherosis is histopathologicalty
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Dekker and Sibai
similar to lesions seen in organ i m m u n e rejection. 63 Thus, there is no d o u b t that preeclamptic patients manifest immunopathology, but the question remains as to whether such immunopathology causes (or results from) preeclampsia. I m m u n e complex, complement, and fibrin deposits in decidual vessels may occur in response to rather then be the cause o f vascular occlusion; analogous results described in chorionic villous tissue may have resulted from placental ischemia. C o n c e r n i n g the pivotal role of HLA-G on invasive cytotrophoblasts in escaping maternal imm u n e surveillance, Colbern et a164 were the first to observe a lower level o f mRNA for HLA-G in trophoblasts in preeclampsia as c o m p a r e d with normal pregnancy. But normalization to mRNA for cytokeratin showed that this could be caused by the smaller n u m b e r of trophoblast cells present in preeclamptic placentae. Hara et a165 f o u n d that invading cytotrophoblasts, which were stained for cytokeratin, normally all expressed HLA-G, whereas in preeclampsia, clusters o f cytotrophoblasts were insularly devoid of HLA-G. Similar findings were reported by Lim et al. 66 Attenuated HLA-G expression on invading cytotrophoblasts could be of obvious importance in the pathogenesis of preeclampsia, 67 but whether this p h e n o m e n o n is caused by aberrant trophoblast differentiation or the result of structural gene mutation has not yet been elucidated. If preeclampsia is caused by i m m u n e maladaptation, what are the mediators causing endothelial activation? Decidual leukocytes, when activated, can release a host of mediators that may interact with endothelial cells. Cytokines. Prime candidates for the putative circulating endothelium-activating molecules in preeclampsia are the cytokines. The majority of studies r e p o r t e d so far f o u n d increased TNF-a and IL-1 levels, and increased levels o f soluble TNF-a receptors and IL-1 receptor antagonist. 6s,69 Serum levels of IL-2 (an important cytokine in the T-cell pathway) are also increased in preeclampsia. 7~ Increases in plasma ceruloplasmin, c o m p l e m e n t activity, aa-antitrypsin and haptoglobin, and reduced albumin and transferrin in preeclampsia, are characteristic of an acute phase reaction that may be related to the increased II~6 levels. 69 T h e source of these T h l cytokines may be decidual leukocytes. 71 Decidual p r o d u c t i o n of IL-2 is increased in preeclamp-
sia, which may lead to increased proliferative and cytotoxic activities of uterine large granular lymphocytes, and conversion to lymphokine-activated killer cells. 7e It should be noted that the placenta may also p r o d u c e T h l cytokines. Placental cells express erythropoietin, the prototype molecule for transcriptional regulation by hypoxia in mammals. TNF-a and IL-1 have DNA sequences (nearly) homologous to the hypoxiaresponsive e n h a n c e r element of the erythropoietin gene, thus providing a potential, untested, molecular link between placental hypoxia and stimulation of cytokine production. 29 Dysfunctional endothelial cells u n d e r g o activation and produce leukocyte-endothelial adhesion molecules that mediate a d h e r e n c e o f inflammatory cells. This inductive process is mediated by cytokines p r o d u c e d by inflammatory cells and activated endothelial cells. Preeclampsia is associated with increased levels of these adhesion molecules, and this increase may be an early event. 73 Increased IL-6 and IL-1 receptor antagonist levels in preeclampsia correlate with elevated concentrations of these adhesion molecules. Hamai et a174 provided very important evidence that abnormal cytokine production (elevated IL-2 and TNF-a levels) in women destined to have preeclampsia is already present in the first trimester. Therefore, the chronological features of abnormal cytokine production in preeclampsia argue against the placental ischemia hypothesis, but are c o n c o r d a n t with a faulty immunologic maternal-fetal interaction cause of the disease. In preeclampsia, circulating free fatty acids increase 15 to 20 weeks before the onset of clinical disease. TNF-a, IL-1, and IL-6 are known to induce adipocyte lipolysis, p r o m o t e de novo hepatic fatty acid synthesis, and impair hepatic fatty acid oxidation and ketogenesis. Thus, the lipid changes in preeclampsia may reflect cytokine effects. 75 Free fatty acids may impair endothelial prostacyclin and nitric oxide production 76 possibly by reducing toxicity-preventing activity of albumin. 77 Elastase and other neutrophil activation markers.
Activated neutrophils release enzymes such as elastase, which can destroy the integrity o f the endothelium. Plasma elastase levels are elevated in preeclampsia and correlate with markers o f endothelial dysfunction. 78 In normal pregnancy, both serum levels o f TNF-a and IL-6 and levels
The Immunology of Preeclampsia
of their soluble receptors increase with gestational age, 79 and the same holds true for circulating i m m u n e complexes and complement activation. 8~ Neutrophils can be activated by complement factors. Markers for complement activation are increased in preeclampsia and correlate with elastase and neopterin levels and with elevated IL-6 levels. Normal pregnancy is characterized by activated neutrophils, as is evidenced by the increase in intracellular ionized calcium and circulating neopterin, lactoferrin, and defensin levels. Neutrophil activation is increased further in preeclampsia. 81-83 Increased basal neutrophil C D l l b expression in preeclampsia is a strong indication of neutrophil activation in vivo and correlates with plasma uric acid levels, s4 Sacks et al so found that in normal pregnancy both granulocytes and monocytes had significantly raised CD1 lb, CD64, and CD14 levels compared with n o n p r e g n a n t women, whereas in preeclampsia, there is further leukocyte activation characterized by an altered phenotype and increased production of intracellular reactive oxygen species. Therefore, normal pregnancy may represent a "mild" inflammatory state, whereas preeclampsia is characterized by an exaggerated degree of inflammation. Oxygen-free rad/ea/s. Lipid peroxides and oxygen-free radicals are highly reactive and very damaging compounds. In normal pregnancy lipid peroxides increase, but antioxidants also increase to offset their toxic actions. In women with preeclampsia, however, circulating levels of lipid peroxides are increased, but net antioxidant activity is decreased. Activated leukocytes may provide one of the major sources of oxygenfree radicals in preeclampsia. In addition, activated leukocytes may irreversibly convert endothelial xanthine dehydrogenase to xanthine oxidase, thus causing endothelial release of oxygen-free radicals. The placenta is another source of free radical species in preeclampsia. st,s7 Concerning antioxidants, the overall picture in preeclampsia is complex, but it is apparent that the disease can not be characterized as a state of global antioxidant deficiency.88 Watersoluble antioxidant nutrients, such as ascorbic acid, a-tocopherol and/3-carotene initially may be consumed, followed by lipid-soluble antioxidants. 89 Oxidative dysequilibrium in preeclampsia is closely linked with TNF activity. Because they control the oxidation-reduction status of
29
mitochondrial glutathione, which is an important endogenous modulator of TNF-a production, antioxidants selectively inhibit TNF-a release. 9o Preeclampsia as a Genetic Disease
Severe preeclampsia and eclampsia have a familial tendency. A complete discussion of the genetics of preeclampsia can be found in a previous article in this issue. The following review will concentrate on the interaction between a genetic predisposition to preeclampsia and the imm u n e system. The development of preeclampsia may be based on a single recessive gene or a dominant gene with incomplete penetrance. Multifactorial inheritance is another possibility.0~,92 The principal reason for doubting the existence of a maternal gene as the sole explanation for preeclampsia is data showing a lack of concordance for susceptibility in a small sample of monozygous twins. 9a Most reports so far are consistent with a relatively c o m m o n allele acting as a "major gene" conferring susceptibility to preeclampsia. Impact of the fetal genotype is demonstrated by the association between preeclampsia and fetal chromosomal abnormalities. 92 The epidemiological link between miscarriages and preeclampsia supports the concept that genetic predisposition to preeclampsia is related to placentation. 94 Assuming that there is autosomal recessive inheritance, no evidence has been found for linkage to the HLA region. 95 An amino substitution in the angiotensinogen gene has been suggested to correlate with the risk of preeclampsia, but not with the risk of hemolysis, elevated liver enzymes, and low platelet count syndrome. Other studies found no association between this allele and preeclampsia, and suggested that it has more to do with a tendency toward hypertension rather than with preeclampsia. 96 An increased incidence of severe preeclampsia or eclampsia has been described in a family with a failure of the nicotinamide adenine dinucleotide (reduced ubiquinone oxidoreductase step in the mitochondrial electron chain), 97 which is of interest considering the possible involvement of a genetic TNF-a-mediated mitochondrial dysfunction in its etiology.9~ Increased expression of TNF-ot in leukocytes may be associated with the increased frequency of a TNF-1
30
Dekker and Sibai
a l l e l e in p r e e c l a m p s i a t h a t is k n o w n to r e s u l t in h i g h e x p r e s s i o n o f TNF-o~. ~ R e s u l t s o f a r e c e n t genomewide linkage search showed a region on t h e l o n g a r m o f c h r o m o s o m e 4 as a s t r o n g c a n didate region for a preeclampsia susceptibility lOCUS.99 H y p e r t e n s i o n , d y s l i p i d e m i a , a n d i n s u l i n resist a n c e m a y b e p a r t o f s y n d r o m e X (its i n c i d e n c e is m a r k e d l y i n c r e a s e d in p a t i e n t s w h o w e r e g r o w t h r e t a r d e d at b i r t h ) . 1 ~ 1 7T6h u s , a n a l t e r n a t i v e explanation for the apparent "hereditary" characteristics of preeclampsia may be that daught e r s b o r n to w o m e n w i t h s e v e r e p r e e c l a m p s i a can suffer from long-term adverse cardiovascular s e q u e l a e l a t e r i n life, r e s u l t i n g i n a n i n c r e a s e d risk f o r p r e e c l a m p s i a w h e n t h e y a r e p r e g n a n t . T h i s is c o n s i s t e n t w i t h t h e i n c r e a s e d p r e v a l e n c e o f p r e e c l a m p s i a in d a u g h t e r s b o r n to a n e c l a m p tic m o t h e r c o m p a r e d w i t h s i b l i n g s b o r n to t h e s a m e m o t h e r a f t e r a n u n e v e n t f u l p r e g n a n c y . 92 I n s u l i n r e s i s t a n c e is p r e s e n t in m a n y p r e e c l a m p tic w o m e n , w h i c h m a y e x p l a i n s y m p a t h e t i c hyp e r a c t i v i t y i n this c o n d i t i o n . 1~176 Genetic factors in the cause of preeclampsia m a y also b e r e l a t e d to a n u n d e r l y i n g h e r e d i t a r y thrombophilic disorder and hyperhomocyst e i n e m i a , ~~ e s s e n t i a l h y p e r t e n s i o n o r o b e s i t y a n d t h u s i n c r e a s e d s u s c e p t i b i l i t y to p r e e c l a m p sia, o r to t h e c o n t r o l o f t h e T h l - T h 2 b a l a n c e a n d t h u s t h e m a t e r n a l r e s p o n s e a g a i n s t f e t a l antigens. TM
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