Immunology of Eclampsia

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Immunology of Pre-EclampsiaChristopher W. G. Redman, Ian L. Sargent

Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford, UK

Introduction

Pre-eclampsia is relatively common, affecting about

3% of pregnancies. It originates in the placenta and

causes variable maternal and fetal problems. At its

worst, it may threaten maternal and perinatal

survival. It is defined as a syndrome (a pattern of

clinical features) and is probably heterogeneous in

origin as it is in presentation.

Placentation, the Uteroplacental Circulation and

Staging of Pre-Eclampsia

Pre-eclampsia results from imbalance between

factors produced by the placenta and maternal

adaptation to them. There are two broad classes of

pre-eclampsia: maternal and placental, although

many cases are a mix of the two.1 Placental

pre-eclampsia is the outcome of poor placentation in

early pregnancy (weeks 818). It comprises failure to

remodel spiral arteries supplying the uteroplacental

circulation. Normal placentation requires that cyto-

trophoblast invade the placental bed where they

come into contact with maternal tissues. The distal

ends of the spiral arteries are then transformed into

widely dilated, structureless conduits. Spontaneous

miscarriage, especially if recurrent, is also associated

with poor placentation2 and is the extreme end of a

spectrum of compromise (Fig. 1).

Pre-eclampsia has pre-clinical (symptomless) and

clinical stages;1 until recently, only the final phase

could be detected by clinical screening. The latter is

the outcome of placental dysfunction secondary to

oxidative stress and a maternal inflammatory reac-

tion to its presence.3 Poor placentation is probably

not the primary cause of pre-eclampsia. Changes in

circulating trophoblastderived factors associated

with an increased risk of pre-eclampsia can be

Keywords

HLA-C, immunoregulation, indoleamine 2,3-

dioxygenase, NK cells, placentation, regulatory

T cells, systemic inflammatory response

Correspondence

CWG Redman, Nuffield Department of

Obstetrics and Gynaecology, University of

Oxford, John Radcliffe Hospital, Oxford OX39DU, UK.

E-mail: [email protected]

Submitted February 1, 2010;

accepted February 1, 2010.

Citation

Redman CWG, Sargent IL. Immunology of

Pre-eclampsia. Am J Reprod Immunol 2010;

63: 534543

doi:10.1111/j.1600-0897.2010.00831.x

Pre-eclampsia develops in stages, only the last being the clinical illness.

This is generated by a non-specific, systemic (vascular), inflammatory

response, secondary to placental oxidative stress and not by reactivity

to fetal alloantigens. However, maternal adaptation to fetal (paternal

alloantigens) is crucial in the earlier stages. A pre-conceptual phase

involves maternal tolerization to paternal antigens by seminal plasma.

After conception, regulatory T cells, interacting with indoleamine 2,3-di-

oxygenase, together with decidual NK cell recognition of fetal HLA-C onextravillous trophoblast may facilitate placental growth by immunoregu-

lation. Complete failure of this mechanism would cause miscarriage,

while partial failure would cause poor placentation and dysfunctional

uteroplacental perfusion. The first pregnancy preponderance and partner

specificity of pre-eclampsia can be explained by this model. For the first

time, the pathogenesis of pre-eclampsia can be related to defined

immune mechanisms that are appropriate to the fetomaternal frontier.

Now, the challenge is to prove the detail.

REVIEW ARTICLE

American Journal of Reproductive Immunology 63 (2010) 534543

534 2010 John Wiley & Sons A/S


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detected before placentation is completed.4 It is

probable that pre-eclampsia results from abnormal

trophoblast growth and differentiation, at any time

after the earliest stages of implantation.4 The pri-

mary dysfunction may be immunologic leading to

the concept of a three-stage disease.5

This review is mainly focused on placental pre-

eclampsia. The central issue is whether maternal

immune responses to trophoblast generate normal or

abnormal placentation?

Throughout, we emphasize that, in overt pre-

eclampsia, non-specific inflammatory responses

contribute to pathogenesis. Placentation in early

pregnancy appears to involve specific maternal

immune responses to fetal alloantigens, which

generate partner specificity.

Clinical and Epidemiological considerations

Pre-eclampsia occurs mainly in first pregnancies.

This has been explained by invoking immune mech-

anisms linked to the belief that a genetically foreign

fetus challenges the maternal immune system.6 Thehypothesis is that the maternal immune system

learns to accommodate the fetus. Such adaptation

may be relatively defective in a first pregnancy but

less so in subsequent pregnancies. Furthermore,

there may be partner specificity,7 which strengthens

the argument that pre-eclampsia results from a rela-

tive failure to induce maternal tolerance of paternal

alloantigens.8

Partners, Coitus, Sperm, and Semen

A change of partner seems to restore the risk of pre-

eclampsia to that of primiparity in multigravid

women, for example Zhang and Patel 2007.9 But, a

change of partner is also associated with a long

inter-pregnancy interval.9,10 After correction for the

latter, the association with the former disappears.11

However, a short interval between first coitus and

conception (coital interval) with the same partner

also increases the risk of pre-eclampsia.12,13 In this

context, there is clear evidence for partner specific-

ity. These features suggest that exposure to paternal

sperm or seminal plasma or both tolerizes the

mother to fetopaternal alloantigens and failure of

this immunoregulation increases the risk of pre-

eclampsia (Stage 0 of pre-eclampsia).

Immune priming, by coitus, has been demon-strated in mice.14 Seminal plasma appears to be

more important than sperm. It contains paternal

type I and type II MHC antigens and high concentra-

tions of transforming growth factor-b (TGFb). TGFb

induces regulatory T cells (T(reg)) or, in a more pro-

inflammatory environment, Th17 cells.15 In mice,

exposure to seminal fluid at mating induces toler-

ance to paternal alloantigens and an accumulation

of T(reg) in the uterine draining lymph nodes, which

may facilitate implantation.16

Pregnancy itself confers further protection to pre-

eclampsia in later pregnancies by the same partner.

This is probably true even after an abortion,

although the evidence is inconsistent.17 Both forms

of protection (before or after conception) appear to

be relatively short lived, explaining the increased

risk of pre-eclampsia after a long inter-pregnancy

interval.

The importance of pre-conceptual exposure to

semen can explain why artificial insemination with

donor sperm, intracytoplasmic sperm injection, or

barrier methods of contraception, summarized by

Dekker (2002),18 are all associated with increased

risks of pre-eclampsia (Fig. 2).

Natures Transplant and MaternalPlacental

Interfaces

Reproductive immunology has focused on the con-

cept of the semi-allogeneic fetus and its possible

rejection by classical T-cell responses to alloantigens.

But, the placenta not the fetus comprises the trans-

plant. The placental cell of interest is trophoblast.

Fig. 1 Establishing the intervillous circulation. Before 8 weeks, the

spiral arteries are plugged by cytotrophoblast and there is no inter-

villous perfusion. During the next 4 weeks, the arteries progressively

unplug. With inadequate trophoblast invasion of the placenta bed, this

happens prematurely. Then either miscarriage ensues or pregnancy

continues with dysfunctional placental perfusion which leads on topre-eclampsia. Adapted from Burton and Jauniaux (2004).2

IMMUNOLOGY OF PRE-ECLAMPSIA


2010 John Wiley & Sons A/S 535


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Maternal immune cells are confronted by different

trophoblast subtypes at multiple maternalplacental

interfaces depending on gestational age and ana-

tomic location (Table I). The interfaces may be in

maternal tissues (decidua) or maternal blood (inter-villous space). The earliest comprises syncytiotropho-

blast of the implanting embryo (Interface I), the

only time that syncytiotrophoblast lies at a tissue

interface. The intervillous circulation is established

after 8 weeks. Before then, chorionic villi are bathed

in uterine gland secretions histiotrophic nutrition

to the first-trimester fetus.19 By the end of the first

trimester, Interface I is replaced by three others:

formed by invasive cytotrophoblast in the placentalbed (Interface II), with the chorion leave (Interface

III), and by syncytiotrophoblast bathed by maternal

blood in the intervillous space (Interface IV). These

concepts extend our earlier proposals.20 In the first

half of pregnancy, Interfaces I and II dominate.

Interface II diminishes after 16 weeks,21 while Inter-

face IV is activated with onset of the uteroplacental

circulation at 89 weeks5 and enlarges with placental

growth to become the dominant interface after

20 weeks. The early interfaces are concerned with

implantation, placentation, and stages 1 and 2 of

placental pre-eclampsia. Interface IV is largest and,

at the end of pregnancy, generates the final stage 3

of the disorder.

Immune Mechanisms and Causes of Pre-eclampsia:

Where, When, and How?

If immune mechanisms are relevant, there must be

maternal immune recognition of trophoblast, which

regulates implantation, placental growth, and

placentation. It needs to be partner specific and to

generate immune memory. It should be consistent

with the structure of the immune maternalfetal

interfaces, with the types of maternal immune cellspositioned at the interfaces and the antigens

expressed by trophoblast. Partner specificity requires

trophoblast expression of paternal alloantigens and

their recognition by maternal immune cells.

Fig. 2 Maternal tolerance to fetal alloantigens. A longer pre-concep-

tion duration of coitus reduces the risk of pre-eclampsia by promotingmaternal tolerance to paternal antigens. The tolerizing mechanism is

not activated with some forms of assisted conception. Pregnancy itself

enhances this tolerance which is slowly lost after delivery. Whether a

change of partner increases the risk of pre-eclampsia depends on the

coital interval with the new partner, not the duration of time since the

last pregnancy. *IVF: in-vitro fertilisation; ICSI: intracytoplasmic sperm

injection.

Table I The four maternal-fetal immune interfaces and preeclampsia

Alloantigen specific recognition of paternal antigens.

Increasing maternal systemic inflammatory response secondary to placental factors.aWeeks are calculated from last normal menstruation. Conception is assumed at the start of week 3.

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Immunoregulation implies a mechanism, which

may partially fail to cause deficient placentation or,

by extension, fail completely to cause spontaneous

abortion. Memory points to T-cell involvement.

HLA (Human Leukocyte Antigen) Expression by

Human Trophoblast

Human trophoblast has limited expression of strong

transplantation antigens (Fig. 3). These include non-

polymorphic HLA-E, F, and G which cannot signal

paternal specificity whereas HLA-C, on extravillous

(invasive) cytotrophoblast in Interface II, can. But

this interface regresses in the second half of preg-

nancy.22 Stage 3, the clinical stage of pre-eclampsia,

occurs when interface IV, the villous syncytium, is

dominant. This is devoid of HLA expression.

Immune mechanisms are of interest in the first and

second stages of pre-eclampsia. The clinical third

phase is generated by a maternal systemic inflamma-

tory response, which is unlikely to be alloantigen

driven.

Stage 1 Pre-Eclampsia: Peri-implantation and the

Histiotrophic Placenta

At this stage, specific immune mechanisms in the

placental bed are almost inaccessible to study. If

immunoregulatory mechanisms fail completely,

spontaneous abortion would ensue whereas partialfailure might lead to continuing pregnancy with a

small placenta. This creates a continuum between

abortion and pre-eclampsia.2,23

Indoleamine dioxygenase 2,3-dioxygenase (IDO),

an enzyme involved in the catabolism of tryptophan,

is an important immune regulator. It is activated inantigen-presenting cells by various inflammatory

stimuli including interferon-c. Tryptophan is an

essential amino acid. Its depletion by catabolism

starves T cells in the tissue micro-environment.

This promotes their differentiation into regulatory T

cells [T(reg)].24 IDO acts as a switch: in its presence,

T(reg) are promoted; in its absence, T(reg) are repro-

grammed to acquire a Th17 phenotype, with more

pro-inflammatory activity.25 T(reg) modulate

immune responses in an antigen-specific way, hence

their importance for allogeneic pregnancy, for which

they are essential (see elsewhere in this issue). Preg-

nant mice treated with IDO inhibitor (4.5 days post

conception) reject allogeneic but tolerate syngeneic

fetuses.26 If the inhibitor is given later (6.5 days post

conception), allogeneic pregnancies continue but sig-

nificant systolic hypertension develops compared to

mice with syngeneic pregnancies.27 Proteinuria is

inconsistently present but, in this report, the mice

were killed relatively early (16.5 days) and the full

evolution of the pregnancies was not defined. Hence

in a mouse model, antigen- and stage-specific

immune mechanisms are highly important. Early

dysfunction leads to pregnancy loss; but dysfunction

at a slightly later stage is associated with one featureof pre-eclampsia (hypertension) toward the end of a

continuing pregnancy.

Expression of IDO in human endometrium begins

in the luteal phase in the glandular epithelium and

stromal leukocytes. This pattern regresses during the

second trimester when expression begins in tropho-

blast,28 particularly strongly in invasive cytotropho-

blast,29 where it might be expected to modulate

interactions with decidual immune cells. In short, its

position at Interfaces I and II is highly relevant to

potential immune mechanisms in stages 1 and 2 of

pre-eclampsia.

In summary, together with TGF-b, the compo-

nents of an alloantigen-specific immunoregulatory

mechanism [IDO and T(reg)] are located at interface

I, are primed by pre-conceptual exposure to part-

ners semen and, if dysregulated, could explain why

primiparity and primipaternity are risk features for

pre-eclampsia.

However, there is little evidence available at the

moment for two reasons. Interface I can only beFig. 3 HLA expression by subsets of human trophoblast. Adapted

from van Maurik et al. (2009).21





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studied before the outcome of pregnancy can be

known. If the pregnancy is continuing, then the inter-

face is accessible only to indirect measurements. Sec-

ondly, there is doubt about how best to identify and

measure T(reg) during human pregnancy.30

No mea-surements have been reported in stages 1 and 2 of

pre-eclampsia where they would be most likely to

influence allogeneic responses at interface II. Whether

measures in peripheral blood are a good indicator of

decidual activity is not known. Many authors look for

concurrent expression of CD4 and CD25 or CD25bright

to identify T(reg) and most find that their proportions

are increased in normal pregnancy, for example Som-

erset et al. (2004).31 However, the data are inconsis-

tent, as are the methods used. T(reg) themselves are

phenotypically and functionally heterogeneous32 so

the relevant subset to study is not known.

Recognition of HLA-C in the Early Human Decidua

HLA-C is a key trophoblast molecule in relation to

pre-eclampsia in stages 1 and 2. Both decidual T cells

and the more abundant decidual NK cells can recog-

nize paternal HLA-C. The importance of decidual NK

cells is described elsewhere in this issue. They

express killer immunoglobulin-like receptors (KIR)

for which HLA-C is the dominant ligand. HLA-C has

more than 100 alleles. Its KIR receptors are them-

selves extremely polymorphic. There are up to 17

different human KIR genes each with its own poly-morphisms, some that activate, others that inhibit.

The number of KIR genes in different genotypes var-

ies. One genotype may itself be variably expressed

by differential expression of KIR genes, fixed by

methylation with the phenotype passed to daughter

cells.33 In other words, maternalfetal immune rec-

ognition at the site of placentation appears to be

highly individualized by two polymorphic gene sys-

tems, maternal KIRs and fetal HLA-C molecules.

KIR haplotypes fall into two groups, A and B, the

latter distinguished by additional activating recep-

tors. Uterine NK cells make chemokines and angio-

genic cytokines, which promote trophoblast

invasion. Their secretion is enhanced by ligation of a

stimulatory KIR receptor (haplotype B) and reduced

by ligation of haplotype A receptor as is summarized

by Moffett and Hiby (2007).34 The former combina-

tion, in vivo, would be predicted to protect from pre-

eclampsia. Possible maternal KIR genotypes could be

AA (no activating KIR) or ABBB (presence of one

or more activating KIRs).

HLA-C haplotypes can also be grouped as C1 and

C2, depending on a single amino acid dimorphism in

the alpha-1 domain. HLA-C2 interacts with KIRs

more strongly than HLA-C135 so that maternal HLA-

C2 with fetal KIR BB could be the best combinationfor promoting adequate placentation and avoiding

pre-eclampsia. This is what is observed. In a con-

verse manner, Kir AA mothers confronted with

HLA-C2 fetuses are the most susceptible to pre-

eclampsia.36 Similar patterns occur in recurrent mis-

carriages which, as already mentioned, may share

the same causation with pre-eclampsia, at the most

extreme end of the spectrum.37

Although this form of maternalfetal immune

recognition can explain the partner specificity for pre-

eclampsia, it does not readily explain protection con-

ferred by a previous pregnancy by the same partner.

Pre-eclampsia and Immunologic Memory

Protection from pre-eclampsia has relatively short-

term partner specificity. This could imply involve-

ment of T cells and T-cell memory. The evidence is

that paternal HLA-C is recognized by decidual

T(reg), which can down regulate anti-paternal

responses.38,39 The stability of T(reg) memory is still

being determined. Natural T(reg) seem to be stable

whereas those that are inducible probably are not.40

It is therefore likely that decidual T(reg) bestow, at

least, short-term memory which could protect frompre-eclampsia in a second pregnancy with a short

inter-pregnancy interval but this needs further

investigation. The specific involvement of T(reg) in

the genesis of pre-eclampsia is difficult to investigate;

there are no data at the moment.

Recently, it has become evident that NK cells them-

selves can sustain memory and mount the equivalent

of a secondary immune response.41 Indeed, macro-

phages can generate a form of memory by epigenetic

modification of specific TLR genes.42 Thus, an

immune explanation for the primiparity and primipa-

ternity effects of pre-eclampsia has become more

plausible but awaits further investigation.

The Third Stage of Pre-eclampsia and Maternal

Systemic Inflammation

Poor placentation leads to small muscular spiral

arteries which supply high pressure pulsatile flow to

the intervillous space. Damage from rapid changes in

oxygenation and hydrostatic stress ensues.43 The

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arteries retain responsiveness to vasoconstrictors,

which can exacerbate oxidative stress further.

Oxidative and ER stress are both features of the

pre-eclampsia placenta.44 They are also powerfully

pro-inflammatory. We propose that the inflamma-tory drive of pre-eclampsia results from the three-

way interactions between these two stresses and

inflammatory responses3,45,46 in the placenta

(Fig. 4). We further suggest that the third stage of

pre-eclampsia is not caused by rejection of an allo-

geneic placenta but by a global maternal inflamma-

tory response to a damaged placenta.

This is superimposed on a background of systemic

inflammatory response common to all normal preg-

nancies, which starts in the luteal phase of the men-

strual cycle,47 when an allogeneic fetus cannot be

implicated. The normal response intensifies with

advancing gestational maturity.48 We have empha-

sized the diverse and widespread nature of this sort

of response (Fig. 5), which can explain the complex

clinical presentations of severe pre-eclampsia, includ-

ing endothelial, metabolic, coagulation, and comple-

ment abnormalities.49 We previously highlighted

that pre-eclampsia is not an intrinsically different

state from normal pregnancy but the extreme end of

a continuous spectrum of responses that are a fea-

ture of pregnancy itself. Many physiological

changes of normal pregnancy itself are simply less

severe manifestations of the same changes in pre-

eclampsia.

Trophoblast Derived Factors and Pre-eclampsia

Elsewhere we summarize the several possible tro-

phoblast-derived factors that potentially contribute

to maternal systemic inflammation.3 These include

growth factors, activin-A, corticotrophin-releasing

hormone, and leptin, all of which have documented

pro-inflammatory actions. Another pro-inflamma-

tory placental factor has been recently described,namely free heme, which is strongly pro-oxidant

and pro-inflammatory.50 It is ectopically synthesised

in the placenta and placental bed in pre-eclampsia.

A final candidate factor comprises placental micro-

vesicles.

Activated cells release microvesicles (200500 nm)

by blebbing of the cell membrane. Apoptotic cells

release larger microvesicles or apoptotic bodies.

Cells can also secrete nanovesicles or exosomes

(40100 nm). Microvesicles are shed from cell sur-

faces after activation, while nanovesicles are stored

in multivesicular bodies and secreted constitutively.

Microvesicles are normally detectable in blood from

healthy individuals and are increased where there

is vascular or inflammatory stress. They are derived

from various intravascular sources (platelets, leuko-

cytes, endothelial cells, and so on) and can be

identified by the specific markers they express.

There is increasing awareness of their potential as

markers for arterial, inflammatory, and malignant

diseases.51

Fig. 4 Three stages of pre-eclampsia. Stages 1 and 2 lead to dysfunc-

tional uteroplacental perfusion and placental oxidative stress. This and

the associated inflammatory and endoplasmic reticulum stresses lead

to abnormal placentalmaternal signalling and overt pre-eclampsia.

Fig. 5 The systemic inflammatory network has metabolic components

as well as involving the intravascular coagulation and complement

systems. The main players are inflammatory leukocytes and endothe-lium. All are activated in pregnancy relative to non-pregnancy and

further activated in pre-eclampsia relative to normal pregnancy.3





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Micro- and nanovesicles are of interest in

pre-eclampsia because they can be markers of

inflammatory and endothelial dysfunction, are

immunoregulatory, and because there is a preg-

nancy-specific component derived from trophoblast.Syncytiotrophoblast microvesicles and nanovesicles

are shed in normal pregnancy and in significantly

increased amounts in pre-eclampsia.5254 They have

an anti-endothelial effect52 and are also pro-inflam-

matory in vitro.53

Microvesicular shedding from the syncytial surface

would be expected to increase in two situations. The

first is with increased placental size. Pre-eclampsia is

predominantly a disorder of the third trimester when

the placenta reaches its greatest size. Multiple

pregnancies are associated with a higher risk of pre-

eclampsia and also larger placentas. The second

situation would be associated with placental oxida-

tive stress in the most severe pre-eclampsia, typically

of early onset. The placentas are usually abnormally

small but may generate microvesicles with a more

intense inflammatory stimulus, for example, by an

increased content of peroxidized lipids.55 Whether

these microvesicles are a cause or consequence of

systemic vascular stress is not known.

Immunoregulation in Stage 3 Pre-eclampsia

Only two aspects will be covered in detail: T(reg)

and the role of IDO.Elsewhere in this issue, the concept of the Th2

bias of normal pregnancy and the need to update

the Th1Th2 paradigm in terms of Th17 and regula-

tory T cells [T(reg)] is discussed. Pre-eclampsia is

associated with a Th1 bias; but this extends beyond

Th cells to a type I bias of NK cells.56 However, in

normal pregnancy, there may also be a bias away

from IL-17 producing cells, which is not found in

pre-eclampsia.57 Th17 stimulates autoimmunity and

coordinates the inflammatory response to infection.

Its potential to harm pregnancy is not yet defined.

The increase in circulating T(reg) found by some

authors in normal pregnancy appears to be lost in

pre-eclampsia (several authors, for example Sasaki

et al. (2007).58 However, the available data are

inconsistent. T(reg) are heterogeneous without spe-

cific markers59 so that their identification, for exam-

ple by flow cytometry, is problematic. In addition,

they function in tissues so that measures in periph-

eral blood are not easy to interpret. That Stage 3

pre-eclampsia is caused by loss of immune regulation

to an allogeneic fetus owing to T(reg) dysfunction is

inconsistent with the evidence that the end-stage of

the disease is a non-specific inflammatory response

to a damaged placenta. A simpler interpretation is

that a Th1 environment tends to suppress the gener-ation of T(reg).60 The interactions between IDO and

T(reg) have already been mentioned, T(reg) differen-

tiation being stimulated by IDO. Indirect measures

suggest that IDO is less active in stage 3 pre-eclamp-

sia.61 Given that 3rd stage pre-eclampsia involves

maternal systemic inflammation, it would be pre-

dicted that IDO would be activated. So this observa-

tion is unexplained. However, there is two way

interaction between T(reg)62 and IDO such that

underactive T(reg) responses could cause less IDO

activity. The full detail awaits further analysis.

Pre-eclampsia and Autoantibodies

Certain function perturbing autoantibodies can

increase the risk of pre-eclampsia most notably anti-

phospholipid and anti-angiotensin II type I receptor

antibodies.63,64 It is difficult to argue that these are

the specific cause of the syndrome even though the

latter autoantibodies can generate a pre-eclampsia-

like disorder after administration to pregnant mice.65

In a casecontrol study, we found that such antibod-

ies were relatively common in normal pregnancy

controls and not present in a substantial minority of

cases.66

Cross-reactivity with parvovirus B19 VP2protein was demonstrated although serological evi-

dence of previous parvovirus infection was not more

common in pre-eclampsia cases. Th17 activity pre-

disposes to autoimmunity.67 If the possible Th17 bias

of pre-eclampsia is confirmed, this might amplify the

induction of these antibodies in at least some cases,

which might contribute to the pathology.

Conclusion

Different immune mechanisms operate at different

interfaces during the three stages of pre-eclampsia.

The diversity of the changes in the final stage is well

explained by a maternal systemic inflammatory

response secondary to oxidative placental damage.

Now, for the first time, there is the potential to

explain the early phases of pre-eclampsia in terms of

immune mechanisms that are appropriate and

located at Interfaces I and II and account for the first

pregnancy preponderance of pre-eclampsia. The

challenge is to turn potential into reality. A

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provisional scheme of the immune mechanisms of

pre-eclampsia is in Fig. 6.

Acknowledgments

We acknowledge support from the Wellcome Trust

Grant Ref GR079862MA. Our work is also supported

by the Oxford Partnership Comprehensive Biomedi-

cal Research Centre with funding from the Depart-

ment of Healths NIHR Biomedical Research Centres

funding scheme. The views expressed in this publica-

tion are those of the authors and not necessarily

those of the Department of Health.

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Fig. 6 Summary of immune events in pathogenesis of pre-eclampsia.

The mechanisms of Stage 0 and Stage 1 have yet to be proved; the

involvement of T(reg), dendritic cells, and Indoleamine dioxygenase

2,3-dioxygenase (IDO) is speculative but supported by experiments inmice. Stage 02 mechanisms largely concern uterine mechanisms.

Stage 3 disease is a systemic inflammatory disorder.





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Immunology of Eclampsia

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