Introduction

In this chapter we describe the role of immune mechanisms in preeclampsia. The issue has always centered on the need to explain why women in their first pregnancies are most susceptible to the condition, which has been combined with the perception that the presence within the mother of a genetically foreign fetus must pose a challenge to the maternal immune system. It has been postulated that immune accommodation to the fetus needs to be “learnt” or immunoregulated. In preeclampsia the adaptation may be relatively defective in a first pregnancy but less so in subsequent pregnancies. There is also the issue of partner specificity and primipaternity.

Maternal Adaptation to a Foreign Fetus

Maternal immune accommodation to paternal antigens expressed by their fetus might be acquired from a previous successful pregnancy or abortion, in the case of the same partner, or exposure to paternal seminal plasma. Partner specificity (primipaternity) was first suggested when a change of partner by parous women seemed to increase the risks of preeclampsia. This study and others were anecdotal or uncontrolled but suggested that the issue was relevant. Subsequent reports seemed to confirm this (for example ref. ) but a systematic review concluded that there are still substantial uncertainties. This was confounded by the finding that longer inter-pregnancy intervals are associated with both a change of partner and preeclampsia Which was the relevant variable: a new partner or delayed conception? One possible modifier is cigarette smoking, which is known to be negatively associated with preeclampsia but positively associated with a change of partner. Statistical adjustment for these associated factors has not been necessarily helpful because of confusion about the causal relationships of associated variables.

The concept that maternal immune adaptation to a partner’s fetus might not be restricted to pregnancy but be learnt before conception by exposures to sperm or seminal fluid (reviewed by Saito et al. 2007 ) was stimulated by a study from Guadeloupe, which showed that a short interval between first coitus and conception significantly increased the risk of preeclampsia regardless of parity but specifically with a new partner ( Table 8.1 ). A more recent investigation confirms the issue of the short interval but only primiparous women were studied.

In summary there is indirect evidence that tolerization to a foreign fetus can occur in prior pregnancies or even before conception, but if tolerance is not achieved, preeclampsia may ensue. Such tolerization would be expected to involve the adaptive immune system. However the more primitive innate immune system, which controls inflammatory responses, is also involved.

Innate and Adaptive Immunity

Innate and adaptive immunity both contribute to the pathogenesis of preeclampsia. Innate immunity is a more primitive, rapid-acting, early-response system for global and relatively nonspecific protection. It evolved to protect single and multicellular organisms from “danger.” Danger takes many forms: physical, for example high temperature, chemical, for example excessive oxidation, trauma, infection, or neoplasia. Of these, oxidative stress is a relevant proinflammatory trigger in both normal pregnancy and preeclampsia.

The innate immune system depends on a network of “danger” receptors, called pattern recognition receptors (PRRs), which are germ-line encoded and recognize many different danger signals. Their ligands may be endogenous, often in the form of modified self-molecules, or exogenous, typically derived from bacteria or viruses ( Table 8.2 ). The same receptor frequently recognizes multiple antigens. Most danger receptors are either soluble or bound to the cell surface but some function intracellularly, for example binding intracellular ligands that are derived from bacteria or viruses. When inflammatory cells are activated they release signals such as cytokines or chemokines that, in turn, attract and “instruct” adaptive immune cells (T or B lymphocytes) to generate antigen-specific responses by means of antibodies or cytotoxic cells. Hence the two systems, innate and adaptive, operate together and in sequence.

Adaptive immunity develops slowly but delivers precise antigen-specific responses with immunological “memory.” It evolved more recently than innate immunity and is present only in vertebrates. The innate and adaptive systems are asymmetrically interdependent; in effect the latter is a functional elaboration of the former. The innate system does not need the adaptive system to function whereas adaptive immunity has an absolute requirement for signals from the innate system. Adaptive immunity is strongly but not exclusively influenced by the so-called “transplantation antigens,” the human leukocyte antigens (HLA), which determine transplant rejection. The distribution of fetal (foreign) HLA on trophoblast is therefore a key issue that has informed much of our insights into pregnancy immunology (see below). The main effectors of adaptive immunity are T cells and B cells. They are triggered by professional antigen-presenting cells expressing class II MHC antigens (HLA-D) that enable them to activate naïve T cells. They comprise dendritic cells, macrophages, and B cells.

In this chapter the inflammatory system is deemed to be the sum of events involving innate rather than adaptive immune changes. It is one component of a much larger system that responds to all cellular stresses, called the integrated stress response.

Innate and Adaptive Immunity

Innate and adaptive immunity both contribute to the pathogenesis of preeclampsia. Innate immunity is a more primitive, rapid-acting, early-response system for global and relatively nonspecific protection. It evolved to protect single and multicellular organisms from “danger.” Danger takes many forms: physical, for example high temperature, chemical, for example excessive oxidation, trauma, infection, or neoplasia. Of these, oxidative stress is a relevant proinflammatory trigger in both normal pregnancy and preeclampsia.

The innate immune system depends on a network of “danger” receptors, called pattern recognition receptors (PRRs), which are germ-line encoded and recognize many different danger signals. Their ligands may be endogenous, often in the form of modified self-molecules, or exogenous, typically derived from bacteria or viruses ( Table 8.2 ). The same receptor frequently recognizes multiple antigens. Most danger receptors are either soluble or bound to the cell surface but some function intracellularly, for example binding intracellular ligands that are derived from bacteria or viruses. When inflammatory cells are activated they release signals such as cytokines or chemokines that, in turn, attract and “instruct” adaptive immune cells (T or B lymphocytes) to generate antigen-specific responses by means of antibodies or cytotoxic cells. Hence the two systems, innate and adaptive, operate together and in sequence.

Adaptive immunity develops slowly but delivers precise antigen-specific responses with immunological “memory.” It evolved more recently than innate immunity and is present only in vertebrates. The innate and adaptive systems are asymmetrically interdependent; in effect the latter is a functional elaboration of the former. The innate system does not need the adaptive system to function whereas adaptive immunity has an absolute requirement for signals from the innate system. Adaptive immunity is strongly but not exclusively influenced by the so-called “transplantation antigens,” the human leukocyte antigens (HLA), which determine transplant rejection. The distribution of fetal (foreign) HLA on trophoblast is therefore a key issue that has informed much of our insights into pregnancy immunology (see below). The main effectors of adaptive immunity are T cells and B cells. They are triggered by professional antigen-presenting cells expressing class II MHC antigens (HLA-D) that enable them to activate naïve T cells. They comprise dendritic cells, macrophages, and B cells.

In this chapter the inflammatory system is deemed to be the sum of events involving innate rather than adaptive immune changes. It is one component of a much larger system that responds to all cellular stresses, called the integrated stress response.

Innate and Adaptive Immunity

Innate and adaptive immunity both contribute to the pathogenesis of preeclampsia. Innate immunity is a more primitive, rapid-acting, early-response system for global and relatively nonspecific protection. It evolved to protect single and multicellular organisms from “danger.” Danger takes many forms: physical, for example high temperature, chemical, for example excessive oxidation, trauma, infection, or neoplasia. Of these, oxidative stress is a relevant proinflammatory trigger in both normal pregnancy and preeclampsia.

The innate immune system depends on a network of “danger” receptors, called pattern recognition receptors (PRRs), which are germ-line encoded and recognize many different danger signals. Their ligands may be endogenous, often in the form of modified self-molecules, or exogenous, typically derived from bacteria or viruses ( Table 8.2 ). The same receptor frequently recognizes multiple antigens. Most danger receptors are either soluble or bound to the cell surface but some function intracellularly, for example binding intracellular ligands that are derived from bacteria or viruses. When inflammatory cells are activated they release signals such as cytokines or chemokines that, in turn, attract and “instruct” adaptive immune cells (T or B lymphocytes) to generate antigen-specific responses by means of antibodies or cytotoxic cells. Hence the two systems, innate and adaptive, operate together and in sequence.

Adaptive immunity develops slowly but delivers precise antigen-specific responses with immunological “memory.” It evolved more recently than innate immunity and is present only in vertebrates. The innate and adaptive systems are asymmetrically interdependent; in effect the latter is a functional elaboration of the former. The innate system does not need the adaptive system to function whereas adaptive immunity has an absolute requirement for signals from the innate system. Adaptive immunity is strongly but not exclusively influenced by the so-called “transplantation antigens,” the human leukocyte antigens (HLA), which determine transplant rejection. The distribution of fetal (foreign) HLA on trophoblast is therefore a key issue that has informed much of our insights into pregnancy immunology (see below). The main effectors of adaptive immunity are T cells and B cells. They are triggered by professional antigen-presenting cells expressing class II MHC antigens (HLA-D) that enable them to activate naïve T cells. They comprise dendritic cells, macrophages, and B cells.

In this chapter the inflammatory system is deemed to be the sum of events involving innate rather than adaptive immune changes. It is one component of a much larger system that responds to all cellular stresses, called the integrated stress response.

Stage 1 Preeclampsia, Interface 1 and Maternal Immune Responses to Trophoblast

The endometrium is an immune tissue. During the luteal phase it differentiates and begins to transform by infiltration of leukocytes. Once early pregnancy is established, decidua leukocytes are mainly (75%) natural killer cells. Macrophages comprise a smaller, but still abundant population. There are also rare dendritic cells and T cells. B cells are conspicuous by their absence. Natural killer cells are part of the innate immune system. Uterine NK (uNK) cells differ in phenotype from most circulating NK cells, are more activated, less cytotoxic and have an enhanced capacity to secrete cytokines and angiogenic factors. The latter promote infiltration of the spiral arteries by invasive trophoblast. uNK cells bear receptors that interact with the unique repertoire of HLA expressed by invasive cytotrophoblast in the placental bed (HLA-C, -E and -G). HLA-C, the only polymorphic HLA expressed by trophoblast, apparently confined to invasive cytotrophoblast, is the ligand for killer immunoglobulin-like receptors (KIR) expressed by uNK cells. The main receptors for HLA-G are the inhibitory leukocyte immunoglobulin-like receptors (LIR -1 and LIR-2) which are expressed by monocytes, NK cells, T cells, and macrophages. It is crucial to the issue of partner specificity of preeclampsia that HLA-C can signal fetal paternity, which can be recognized by the uNK cells.

The KIR receptors that recognize HLA-C on invasive trophoblast are themselves extremely polymorphic such that two individuals are unlikely to have the same genotype. The variability is not simply that of polymorphic genes, but of different patterns of inheritance of up to 17 different genes each with its own polymorphism, some that activate, others that inhibit. The number of KIR genes in different genotypes varies. The expression of the genotype is itself variable through differential expression of KIR genes, which becomes fixed by methylation, with the phenotype passed to daughter cells. HLA-C has more than 1000 haplotypes. In other words, maternal-fetal immune recognition at the site of placentation involves two polymorphic gene systems, maternal KIRs and fetal HLA-C molecules. Hence partner specificity will be high, if not unique (see Chapter 4 ).

KIR haplotypes can be divided into two groups, A and B, the latter being distinguished by additional activating (presumably beneficial) receptors. It is presumed that uNK cells need to be activated to produce cytokines and angiogenic factors to promote placentation. A maternal haplotype B would be predicted to protect from preeclampsia. In any pregnancy, the maternal KIR genotype could be AA (no activating KIR) or AB/BB (presence of one or more activating KIRs).

HLA-C haplotypes can also be grouped as C1 and C2 depending on an amino acid dimorphism at one position in the alpha-1 domain. It is considered that HLA-C2 interacts with KIRs more strongly than HLA-C1 so the combination of maternal HLA-C2 with fetal KIR B/B could be the best for promoting adequate placentation and avoiding preeclampsia. This is what is observed. Kir AA mothers confronted with HLA-C2 fetuses are the most susceptible to preeclampsia, a similar pattern being shown with recurrent spontaneous miscarriages and normotensive fetal growth restriction.

This form of maternal-fetal immune recognition can explain the partner specificity for preeclampsia but not the protection conferred by a previous pregnancy by the same partner, namely the immunological memory. As far as is known, immune memory is provided only by the adaptive immune system.

The issue with respect to trophoblast is one of T-cell recognition of HLA-C. HLA-C has unique features that distinguish if from HLA-A and B. It is less polymorphic for example, and in general its surface expression is lower. However, trophoblast uniquely proves the exception to this rule. Foreign antigens are recognized by T cells when they are bound to HLA-A and -B proteins on the cell surface of antigen-presenting cells – so-called HLA-restriction. HLA-C-restricted presentation of antigens has been less readily demonstrable except in specific viral infections and a few self-peptides. It is important that in the decidua, fetal (paternal) HLA-C, expressed by trophoblast, can bind to both NK and T cells (although not coincidentally). It is also relevant that the KIR receptors that dominate perceptions of interactions between uNK cells and invasive cytotrophoblast are also expressed by T cells where they appear to be able to modulate (inhibit or enhance) T cell responses.

Maternal T cell responsivenes to foreign fetal HLA-C has been detected in the deciduas of normal pregnancies but is thought to be kept in check by T-regulatory cells. Although this is a key issue, T cell reactivity to HLA-C on invasive cytotrophoblast in preeclampsia remains undefined.

Techniques in assisted reproduction create new immune challenges for pregnant women, with hitherto novel immune mating combinations from donated gametes, sperm, oocytes or embryos. Some methods of assisted reproduction increase the risk of preeclampsia. Such modes of conception or a short interval between first coitus and conception may hinder T-cell-dependent tolerance to paternal antigens, which facilitates the establishment of normal pregnancy at Interface 1. Otherwise, abnormal placentation and uteroplacental perfusion can lead to abnormalities at Interface 2 and Stage 2 disease.

Stage 2 Preeclampsia and Interface 2

Normal pregnancy and preeclampsia are both associated with a low-grade systemic (vascular) inflammatory response, which is more intense in preeclampsia. It is believed this is secondary to syncytiotrophoblast stress induced by hypoxia, oxidative stress or both. A generalized response to any form of cellular or tissue damage is inflammation, a hypothesis which has been subsequently validated in many different contexts, not associated with pregnancy. In preeclampsia the maternal response to the oxidatively damaged placenta is what could have been predicted and what has been found. The systemic inflammatory response has massive and wide-ranging consequences, all of which are seen in the second stage of preeclampsia. The nature of the vascular inflammation has unique attributes induced by release of factors from the placenta which are not present in non-pregnant individuals. These include the angiogenic placental growth factor (PlGF) and the antiangiogenic factors, soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and soluble endoglin (sEng) as described in Chapter 6 .

Endothelial Cells are Inflammatory Cells

It has long been known that preeclampsia can be largely explained by diffuse maternal endothelial cell dysfunction (see Chapter 9 ). In the circulation, endothelial cells are key players in systemic inflammatory responses as well as mediating local inflammation by upregulation of adhesion molecules that tether and then anchor marginated leukocytes. In the field of atherosclerosis this is well researched. Atherosclerosis is a focal large-vessel disease; whereas microvascular endothelium promotes diffuse systemic inflammation. Both are examples of vascular inflammation. If preeclampsia is an endothelial disorder then the corollary is that it is also an inflammatory disorder. The latter is a more generalized concept that subsumes the former. Inflammation is one part of a more generalized and integrated stress response, hence other systems are inevitably involved and the stresses distributed between different cellular systems. Cellular oxidative stress will for example induce endoplasmic reticulum (ER) stress, the unfolded protein response and an inflammatory response (reviewed in ).

Inflammation and the Integrated Stress Response

The integrated stress response (ISR) is evolutionarily ancient. Central to the response is ER stress and the unfolded protein response, which enhances removal of unfolded proteins and re-programs protein translation in the ER. While most protein synthesis is reduced, that of specific transcription factors, promoting production of stress response proteins that restore homeostasis, is augmented via numerous sensors of cell damage or dysfunction. Among the stress response proteins are molecular chaperones, antioxidants, transcription factors and so on. Inflammation is part of the ISR; it activates and is activated by oxidative stress and ER stress.

Protein folding consumes energy. Not surprisingly ER stress is precipitated by energy deficiency, for example from hypoxia or glucose deprivation. The ISR has profound effects on metabolism that help cells survive under stress and return to homeostasis. ER stress in the liver is particularly sensitive to inflammatory stimuli and underlies the acute-phase response.

Widespread Implications of Vascular Inflammation

It is self-evident that vascular inflammation involves endothelium as well as inflammatory leukocytes (granulocytes, macrophages, and natural killer lymphocytes). However, the coagulation system, liver and adipose tissue also directly contribute soluble factors to the inflammatory response ( Table 8.3 ). The full extent of vascular inflammation on diverse systems may not be appreciated, nor the two-way interactions between its components. For example, blood coagulation is not only activated by inflammatory processes but thrombin, the final trigger to coagulation, also stimulates inflammation via specific receptors. Angiogenesis, oxidative stress, and obesity are all tightly linked to inflammatory responses and all highly relevant to preeclampsia, as is described subsequently. The acute-phase response is a complex inflammatory stress response originating from the liver.

Nuclear factor-κB (NF-κB) is a transcription factor expressed by nearly all cells, which is central to many inflammatory responses. It is activated by numerous stressors, including inflammatory and oxidative stresses, and suppressed by hCG, estrogen, IL-4, and IL-10. It is also activated by oxidative and endoplasmic reticulum (ER) stress. These stresses also are prominent features of the syncytium in the preeclampsia placenta. The interaction between NF-κB and hypoxia inducible factor (HIF)-1α, the transcription factor that controls cellular responses to low oxygen tension, is particularly close. HIF-1α activates transcription of over 400 genes involved in the regulation of immune and inflammatory responses and related functions. The acute-phase response is a complex inflammatory stress response originating from the liver.

Vascular inflammation brings in its trail the secretion of many factors that orchestrate its expression. Many of these are altered in preeclampsia.

The origins of preeclampsia lie in the placenta, specifically the syncytium, which demonstrates all the indicators of an ISR. Three major stresses – ER, inflammatory and oxidative – are particularly relevant to preeclampsia and tightly interlinked. A number of trophoblast-derived mediators, discussed below and in Chapter 6 (sVEGR-1, PlGF), disseminate the placental problem by causing vascular inflammation, which provokes widespread dysfunction in many maternal systems. Ultimately, the dysfunction is more than simply vascular and has major metabolic effects.

Cytokines, Chemokines, Growth Factors, Adipokines and Angiogenic Factors

A diverse group of secreted proteins and glycoproteins coordinate the inflammatory response. The term cytokine originally referred to peptides that are produced by and act on immune and hematopoietic cells. Although they are critical for both innate and adaptive immune function, they can also be secreted by non-immune cells and have non-immune functions that are relevant to the pathophysiology of preeclampsia. Some are chemokines, for example interleukin-8 (IL-8), that stimulate the migration of inflammatory cells. Adipokines include proteins that are secreted from (and synthesized by) adipocytes but exclude products of other cell types in adipose tissue, such as macrophages. They include cytokines such as IL-6, classical adipokines (leptin, resistin, adiponectin) and even acute-phase proteins (PAI-1, angiotensinogen). The classical adipokines all have actions on immune cells, that is they have cytokine-like activity, as well as angiogenic activity, as reviewed by Ribatti et al. Angiogenic factors (see Chapter 6 ) include VEGF, which is also a growth factor for endothelium. Other biologically active proteins or peptides can have cytokine-like activity, such as angiotensin II (Ang II); which is directly proinflammatory. By its induction of VEGF, Ang II is also indirectly angiogenic. Insulin on the other hand, while it is a mitogen, is antiinflammatory, as reviewed by Dandona et al. Despite these cytokine-like actions, Ang II and insulin are not considered to be cytokines. In summary, the nomenclature surrounding these factors can be confusing and limit an understanding of their wider actions and their involvement with inflammatory responses in particular.

Metabolism and Vascular Inflammation

Circulating proinflammatory factors such as endotoxin or tumor necrosis factor (TNF)-α cause insulin resistance and hence hyperlipidemia. The hyperlipemia of sepsis has been known for many years (see review by Harris et al.). Lipolysis releases free fatty acids, which contribute to the insulin resistance peripherally.

Obesity, which is a risk factor for preeclampsia ( Chapter 7 ), is characterized by a vascular inflammatory response. It arises because adipose tissue is not simply an energy store but a source of proinflammatory cytokines and other metabolic mediators (adipokines) as mentioned in the preceding section and is the principal source of leptin. Leptin is secreted during acute inflammation and has an important action on immune cells, all of which express the leptin receptor. Leptin thereby causes or enhances proinflammatory responses, as reviewed by Matarese et al. It can be classified as a cytokine as well as an adipokine. The net effect is that obesity is a state of chronic systemic inflammation.

The importance of obesity in generating the inflammatory response is demonstrated by its reversal after weight loss. Visceral rather than subcutaneous fat is more important in this context. Obesity is a key part of the metabolic syndrome, which also includes insulin resistance with impaired glucose tolerance or overt diabetes, dyslipidemia, and hypertension. Obesity-associated IL-6 can induce the acute-phase response including production of circulating C-reactive protein (CRP). Elevated CRP is a typical feature of the metabolic syndrome but other plasma acute-phase reactants, such as fibrinogen, are similarly increased. Some acute-phase proteins are listed in Table 8.4 . In the mouse liver the acute-phase response involves nearly 10% of the genome, indicating the complexity and magnitude of the response.

Vascular inflammation is accompanied by an increase in triglyceride-rich lipoproteins, a reduction in high-density lipoprotein cholesterol, and impairment of cholesterol transport. These metabolic alterations, which promote atherosclerosis, may explain an epidemiological link between chronic inflammation and cardiovascular disease.

The term metaflammation has been applied to the combination of low-grade chronic vascular inflammation and metabolic changes. It underlies chronic conditions such as obesity, atherosclerosis and type 2 diabetes, and, as discussed above, shares many features with preeclampsia.

Acute-Phase Response

The acute-phase response may also be a chronic response to local or systemic inflammation. It comprises variable changes in circulating plasma protein concentrations and other phenomena such as fever, anemia, leukocytosis and metabolic adaptations especially involving the liver and adipose tissue. Proteins linked to this response, acute-phase proteins, are synthesized in the liver. They are classified as positive if they increase with systemic inflammation (e.g., C-reactive protein, CRP) or negative if they decrease (e.g., albumin) ( Table 8.4 ).

The concentrations of CRP increase rapidly in response to inflammatory stimuli. Human CRP binds with high affinity to phosphocholine residues and other intrinsic and extrinsic ligands, including native and modified plasma lipoproteins, damaged cell membranes and various phospholipids and constituents of microorganisms and plant products. CRP is therefore a pattern-recognition receptor for a range of “danger” molecules.

Vascular Inflammation in Normal Pregnancy and Preeclampsia

A subtle systemic inflammatory response precedes conception in the luteal phase of the menstrual cycle but becomes overt in the first trimester of pregnancy. Features of the response are wide-ranging. Some that are deemed to be physiological adaptations of pregnancy are in fact components of the acute-phase response such as reduced plasma albumin and increased fibrinogen concentrations. Many such examples have been summarized by Redman and Sargent. CRP is modestly elevated in pregnancy, starting in the first trimester, when the long-recognized leukocytosis of pregnancy, another sign of systemic maternal inflammation, is established.

As pregnancy advances the vascular inflammation strengthens to peak during the third trimester. The concept was consolidated by flow cytometric analyses of circulating inflammatory leukocytes. The changes are associated with increases in circulating inflammatory cytokines in the second half of pregnancy (several reports, cited in ; Table 8.5 ).

The inflammatory changes are associated with evidence of increasing systemic oxidative stress, in terms of several circulating markers particularly oxidized lipids. In this regard, it is key that oxidative stress and chronic inflammation are related processes in ISR. The inflammatory response generates oxidative stress (reviewed in ) and, in a converse fashion, oxidative stress can stimulate an inflammatory response.

Measurements of circulating inflammatory cytokines during pregnancy can give complex results, owing in part to circulating binding proteins. Direct measurement of plasma concentrations of the proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) show increased levels relative to non-pregnancy towards the end of gestation. Another method is to measure their production within peripheral blood mononuclear cells ex vivo, before or after stimulation. Intracellular cytokines can be measured flow cytometrically, but the intense stimulation required can introduce artifacts. Studies of peripheral blood cells exclude the possible contributions of endothelial cells which secrete IL-6, TNF-α and several other cytokines, as well as chemokines.

Stage 2 preeclampsia, which appears to originate from the syncytial surface (Interface 2) of the placenta, is characterized by an exaggerated maternal vascular inflammatory response involving the inflammatory biomarkers of normal pregnancy, which are more severely affected in preeclampsia ( Table 8.6 ).

Table 8.6

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