Immunology of Pre-Eclampsia

Christopher W. G. Redman, Ian L. Sargent

Nufeld Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford, UK
Introduction
Pre-eclampsia is relatively common, affecting about
3% of pregnancies. It originates in the placenta and
causes variable maternal and fetal problems. At its
worst, it may threaten maternal and perinatal
survival. It is dened as a syndrome (a pattern of
clinical features) and is probably heterogeneous in
origin as it is in presentation.
Placentation, the Uteroplacental Circulation and
Staging of Pre-Eclampsia
Pre-eclampsia results from imbalance between
factors produced by the placenta and maternal
adaptation to them. There are two broad classes of
pre-eclampsia: maternal and placental, although
many cases are a mix of the two.
1
Placental
pre-eclampsia is the outcome of poor placentation in
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 placentation
2
and is the extreme end of a
spectrum of compromise (Fig. 1).
Pre-eclampsia has pre-clinical (symptomless) and
clinical stages;
1
until recently, only the nal phase
could be detected by clinical screening. The latter is
the outcome of placental dysfunction secondary to
oxidative stress and a maternal inammatory 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 inammatory response
Correspondence
CWG Redman, Nufeld Department of
Obstetrics and Gynaecology, University of
Oxford, John Radcliffe Hospital, Oxford OX3
9DU, UK.
E-mail: christopher.redman@obs-gyn.ox.ac.uk
Submitted February 1, 2010;
accepted February 1, 2010.
Citation
Redman CWG, Sargent IL. Immunology of
Pre-eclampsia. Am J Reprod Immunol 2010;
63: 534543
doi:10.1111/j.1600-0897.2010.00831.x
Pre-eclampsia develops in stages, only the last being the clinical illness.
This is generated by a non-specic, systemic (vascular), inammatory
response, secondary to placental oxidative stress and not by reactivity
to fetal alloantigens. However, maternal adaptation to fetal (paternal
alloantigens) is crucial in the earlier stages. A pre-conceptual phase
involves maternal tolerization to paternal antigens by seminal plasma.
After conception, regulatory T cells, interacting with indoleamine 2,3-di-
oxygenase, together with decidual NK cell recognition of fetal HLA-C on
extravillous 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 rst pregnancy preponderance and partner
specicity of pre-eclampsia can be explained by this model. For the rst
time, the pathogenesis of pre-eclampsia can be related to dened
immune mechanisms that are appropriate to the fetomaternal frontier.
Now, the challenge is to prove the detail.
REVIEW ARTICLE
American Journal of Reproductive Immunology 63 (2010) 534543
534 2010 John Wiley & Sons A/S
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-specic inammatory responses
contribute to pathogenesis. Placentation in early
pregnancy appears to involve specic maternal
immune responses to fetal alloantigens, which
generate partner specicity.
Clinical and Epidemiological considerations
Pre-eclampsia occurs mainly in rst pregnancies.
This has been explained by invoking immune mech-
anisms linked to the belief that a genetically foreign
fetus challenges the maternal immune system.
6
The
hypothesis is that the maternal immune system
learns to accommodate the fetus. Such adaptation
may be relatively defective in a rst pregnancy but
less so in subsequent pregnancies. Furthermore,
there may be partner specicity,
7
which strengthens
the argument that pre-eclampsia results from a 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 rst coitus and
conception (coital interval) with the same partner
also increases the risk of pre-eclampsia.
12,13
In this
context, there is clear evidence for partner specic-
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-
inammatory environment, Th17 cells.
15
In mice,
exposure to seminal uid 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 articial insemination with
donor sperm, intracytoplasmic sperm injection, or
barrier methods of contraception, summarized by
Dekker (2002),
18
are all associated with increased
risks of pre-eclampsia (Fig. 2).
Natures Transplant and MaternalPlacental
Interfaces
Reproductive immunology has focused on the 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 to
pre-eclampsia. Adapted from Burton and Jauniaux (2004).
2
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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 rst-trimester fetus.
19
By the end of the rst
trimester, Interface I is replaced by three others:
formed by invasive cytotrophoblast in the placental
bed (Interface II), with the chorion leave (Interface
III), and by syncytiotrophoblast bathed by maternal
blood in the intervillous space (Interface IV). These
concepts extend our earlier proposals.
20
In the rst
half of pregnancy, Interfaces I and II dominate.
Interface II diminishes after 16 weeks,
21
while Inter-
face IV is activated with onset of the uteroplacental
circulation at 89 weeks
5
and enlarges with placental
growth to become the dominant interface after
20 weeks. The early interfaces are concerned with
implantation, placentation, and stages 1 and 2 of
placental pre-eclampsia. Interface IV is largest and,
at the end of pregnancy, generates the nal stage 3
of the disorder.
Immune Mechanisms and Causes of Pre-eclampsia:
Where, When, and How?
If immune mechanisms are relevant, there must be
maternal immune recognition of trophoblast, which
regulates implantation, placental growth, and
placentation. It needs to be partner specic and to
generate immune memory. It should be consistent
with the structure of the immune maternalfetal
interfaces, with the types of maternal immune cells
positioned at the interfaces and the antigens
expressed by trophoblast. Partner specicity requires
trophoblast expression of paternal alloantigens and
their recognition by maternal immune cells.
Fig. 2 Maternal tolerance to fetal alloantigens. A longer pre-concep-
tion duration of coitus reduces the risk of pre-eclampsia by promoting
maternal tolerance to paternal antigens. The tolerizing mechanism is
not activated with some forms of assisted conception. Pregnancy itself
enhances this tolerance which is slowly lost after delivery. Whether a
change of partner increases the risk of pre-eclampsia depends on the
coital interval with the new partner, not the duration of time since the
last pregnancy. *IVF: in-vitro fertilisation; ICSI: intracytoplasmic sperm
injection.
Table I The four maternal-fetal immune interfaces and preeclampsia
Alloantigen specic recognition of paternal antigens.
Increasing maternal systemic inammatory response secondary to placental factors.
a
Weeks are calculated from last normal menstruation. Conception is assumed at the start of week 3.
REDMAN AND SARGENT
American Journal of Reproductive Immunology 63 (2010) 534543
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Immunoregulation implies a mechanism, which
may partially fail to cause decient placentation or,
by extension, fail completely to cause spontaneous
abortion. Memory points to T-cell involvement.
HLA (Human Leukocyte Antigen) Expression by
Human Trophoblast
Human trophoblast has limited expression of strong
transplantation antigens (Fig. 3). These include non-
polymorphic HLA-E, F, and G which cannot signal
paternal specicity whereas HLA-C, on extravillous
(invasive) cytotrophoblast in Interface II, can. But
this interface regresses in the second half of 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 rst and
second stages of pre-eclampsia. The clinical third
phase is generated by a maternal systemic inamma-
tory response, which is unlikely to be alloantigen
driven.
Stage 1 Pre-Eclampsia: Peri-implantation and the
Histiotrophic Placenta
At this stage, specic immune mechanisms in the
placental bed are almost inaccessible to study. If
immunoregulatory mechanisms fail completely,
spontaneous abortion would ensue whereas partial
failure might lead to continuing pregnancy with a
small placenta. This creates a continuum between
abortion and pre-eclampsia.
2,23
Indoleamine dioxygenase 2,3-dioxygenase (IDO),
an enzyme involved in the catabolism of tryptophan,
is an important immune regulator. It is activated in
antigen-presenting cells by various inammatory
stimuli including interferon-c. Tryptophan is an
essential amino acid. Its depletion by catabolism
starves T cells in the tissue micro-environment.
This promotes their differentiation into regulatory T
cells [T(reg)].
24
IDO acts as a switch: in its presence,
T(reg) are promoted; in its absence, T(reg) are repro-
grammed to acquire a Th17 phenotype, with more
pro-inammatory activity.
25
T(reg) modulate
immune responses in an antigen-specic 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-
nicant systolic hypertension develops compared to
mice with syngeneic pregnancies.
27
Proteinuria is
inconsistently present but, in this report, the mice
were killed relatively early (16.5 days) and the full
evolution of the pregnancies was not dened. Hence
in a mouse model, antigen- and stage-specic
immune mechanisms are highly important. Early
dysfunction leads to pregnancy loss; but dysfunction
at a slightly later stage is associated with one feature
of pre-eclampsia (hypertension) toward the end of a
continuing pregnancy.
Expression of IDO in human endometrium begins
in the luteal phase in the glandular epithelium and
stromal leukocytes. This pattern regresses during the
second trimester when expression begins in 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-specic 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 be
Fig. 3 HLA expression by subsets of human trophoblast. Adapted
from van Maurik et al. (2009).
21
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American Journal of Reproductive Immunology 63 (2010) 534543
2010 John Wiley & Sons A/S 537
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
inuence allogeneic responses at interface II. Whether
measures in peripheral blood are a good indicator of
decidual activity is not known. Many authors look for
concurrent expression of CD4 and CD25 or CD25
bright
to identify T(reg) and most nd 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 heterogeneous
32
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, xed 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 AB BB (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-C1
35
so that maternal HLA-
C2 with fetal KIR B B could be the best combination
for promoting adequate placentation and avoiding
pre-eclampsia. This is what is observed. In a 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 specicity 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 specicity. 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 from
pre-eclampsia in a second pregnancy with a short
inter-pregnancy interval but this needs further
investigation. The specic involvement of T(reg) in
the genesis of pre-eclampsia is difcult to investigate;
there are no data at the moment.
Recently, it has become evident that NK cells 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
modication of specic 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 Inammation
Poor placentation leads to small muscular spiral
arteries which supply high pressure pulsatile ow to
the intervillous space. Damage from rapid changes in
oxygenation and hydrostatic stress ensues.
43
The
REDMAN AND SARGENT
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538 2010 John Wiley & Sons A/S
arteries retain responsiveness to vasoconstrictors,
which can exacerbate oxidative stress further.
Oxidative and ER stress are both features of the
pre-eclampsia placenta.
44
They are also powerfully
pro-inammatory. We propose that the inamma-
tory drive of pre-eclampsia results from the three-
way interactions between these two stresses and
inammatory responses
3,45,46
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 inamma-
tory response to a damaged placenta.
This is superimposed on a background of systemic
inammatory 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 intensies 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 inammation.
3
These include
growth factors, activin-A, corticotrophin-releasing
hormone, and leptin, all of which have documented
pro-inammatory actions. Another pro-inamma-
tory placental factor has been recently described,
namely free heme, which is strongly pro-oxidant
and pro-inammatory.
50
It is ectopically synthesised
in the placenta and placental bed in pre-eclampsia.
A nal candidate factor comprises placental 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 inammatory stress. They are derived
from various intravascular sources (platelets, leuko-
cytes, endothelial cells, and so on) and can be
identied by the specic markers they express.
There is increasing awareness of their potential as
markers for arterial, inammatory, and malignant
diseases.
51
Fig. 4 Three stages of pre-eclampsia. Stages 1 and 2 lead to dysfunc-
tional uteroplacental perfusion and placental oxidative stress. This and
the associated inammatory and endoplasmic reticulum stresses lead
to abnormal placentalmaternal signalling and overt pre-eclampsia.
Fig. 5 The systemic inammatory network has metabolic components
as well as involving the intravascular coagulation and complement
systems. The main players are inammatory leukocytes and 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
inammatory and endothelial dysfunction, are
immunoregulatory, and because there is a preg-
nancy-specic component derived from trophoblast.
Syncytiotrophoblast microvesicles and nanovesicles
are shed in normal pregnancy and in signicantly
increased amounts in pre-eclampsia.
5254
They have
an anti-endothelial effect
52
and are also pro-inam-
matory in vitro.
53
Microvesicular shedding from the syncytial surface
would be expected to increase in two situations. The
rst is with increased placental size. Pre-eclampsia is
predominantly a disorder of the third trimester when
the placenta reaches its greatest size. Multiple
pregnancies are associated with a higher risk of 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 inammatory stimulus, for example, by an
increased content of peroxidized lipids.
55
Whether
these microvesicles are a cause or consequence of
systemic vascular stress is not known.
Immunoregulation in Stage 3 Pre-eclampsia
Only two aspects will be covered in detail: T(reg)
and the role of IDO.
Elsewhere in this issue, the concept of the Th2
bias of normal pregnancy and the need to update
the Th1 Th2 paradigm in terms of Th17 and 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 inammatory response to infection.
Its potential to harm pregnancy is not yet dened.
The increase in circulating T(reg) found by some
authors in normal pregnancy appears to be lost in
pre-eclampsia (several authors, for example Sasaki
et al. (2007).
58
However, the available data are
inconsistent. T(reg) are heterogeneous without spe-
cic markers
59
so that their identication, for exam-
ple by ow 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-specic inammatory 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 inammation, 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 difcult to argue that these are
the specic 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 VP2
protein 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 conrmed, this might amplify the
induction of these antibodies in at least some cases,
which might contribute to the pathology.
Conclusion
Different immune mechanisms operate at different
interfaces during the three stages of pre-eclampsia.
The diversity of the changes in the nal stage is well
explained by a maternal systemic inammatory
response secondary to oxidative placental damage.
Now, for the rst time, there is the potential to
explain the early phases of pre-eclampsia in terms of
immune mechanisms that are appropriate and
located at Interfaces I and II and account for the rst
pregnancy preponderance of pre-eclampsia. The
challenge is to turn potential into reality. A
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American Journal of Reproductive Immunology 63 (2010) 534543
540 2010 John Wiley & Sons A/S
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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