REVIEW ARTICLE

Toll-Like Receptor Signaling and Pre-Eclampsia

Fang Xie1, Stuart E. Turvey2, Michelle A. Williams3, Gil Mor4, Peter von Dadelszen1
1
Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada;
2
Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada;
3
Department of Epidemiology, University of Washington, School of Public Health and Community Medicine, Seattle, WA, USA;
4
Department of Obstetrics, Gynecology and Reproductive Sciences, Reproductive Immunology Unit, Yale University School of Medicine, New
Haven, CT, USA

Keywords Systemic inflammation and abnormal ⁄ poor placentation represent hall-

Pre-eclampsia, Toll-like receptors signaling
Correspondence
Fang Xie, Department of Obstetrics and
Gynecology, University of British Columbia,
2H30-4500 Oak Street, Vancouver, BC V6H
3N1, Canada.
E-mail: fang.cindy.xie@gmail.com
Submitted June 24, 2009;
accepted August 17, 2009.
Citation
Xie F, Turvey SE, Williams MA, Mor G, von
Dadelszen P. Toll-like receptor signaling and
pre-eclampsia. Am J Reprod Immunol 2010;
63: 7–16
marks of pre-eclampsia. Accumulating evidence suggests that infectious
agents might increase the risk of pre-eclampsia; the innate immune
defense mechanisms may interact with pro-inflammatory pathways, and
contribute to the development of pre-eclampsia. The evidence for this
has been supported by indirect epidemiologic and clinical studies, as
well as by some direct support from experimental studies. Recent data
directly implicate signaling by Toll-like receptors in the pathogenesis of
pre-eclampsia, and establish a crucial link between pre-eclampsia and
defense against both foreign pathogens and endogenously generated
inflammatory ligands. Here, we review the rapid progress in this field,
which has improved our understanding of the interplay between patho-
gen invasion, innate immune defense mechanisms, and pre-eclampsia.

doi:10.1111/j.1600-0897.2009.00745.x

investigations have increasingly suggested that inflam-

Introduction
Pre-eclampsia, complicating at least 5–8% of all preg-
nancies, is not only a major cause of obstetric mortality
and morbidity but also increased the risk for later car-
diovascular disease.1 The clinical findings of pre-
eclampsia can manifest as either a maternal syndrome
(hypertension, proteinuria, or various symptoms), or a
fetal syndrome (growth restriction), or both.2 Despite
recent progress toward understanding the cause of pre-
eclampsia, the etiology of this serious disorder remains
elusive. Current theories include abnormal placenta-
tion, cardiovascular maladaptation to pregnancy,
genetic, and immune mechanisms, an enhanced sys-
temic inflammatory response, and angiogenic factors.3
It seems probable that multiple factors are involved.4
Although the placenta has been shown to play a cru-
cial role in the development of pre-eclampsia, recent
American Journal of Reproductive Immunology 63 (2010) 7–16
ª 2009 John Wiley & Sons A/S
matory and immune mechanisms, activated by infec-
tious or non-infectious agents, and even host-derived
molecules, might be important in the pathogenesis of
pre-eclampsia. Now, exciting discoveries related to sig-
naling via Toll-like receptors (TLRs) have rekindled
intense interest in the relationship between immune
defense mechanisms and the established maternal sys-
temic inflammatory response seen in pre-eclampsia. In
this review, we discuss the background leading to these
discoveries, highlight emerging evidence, and present
the outlook for new interventions for pre-eclampsia.
Toll-like receptor signaling and the innate immune
response
In 1997, vertebrate homologs of the Drosophila spp.
transmembrane ‘pattern recognition receptors’ (PRR)
7
 XIE ET AL.

‘Toll’ were identified and termed as ‘Toll-like recep-
tors’.5 To date, 10 TLRs have been identified.6 They
are a family of pattern-recognition receptors and
have been shown to be central to the innate
immune response.7
TLRs Associated Pathogen Molecular Patterns
Toll-like receptors recognize conserved pathogen-
associated molecular patterns (PAMPs) on microor-
ganisms. Different TLRs recognize different classes of
PAMPs.8 TLR1, 2, 4, and 6 recognize lipopetides. The
major ligands for TLR2 include the following: specific
cell-wall components of Gram-positive and Gram-
negative bacteria; mycobacteria; fungi; parasites; and
viruses. TLR4 recognizes specific components of
Gram-negative bacterial lipopolysaccharide (LPS). In
contrast to these extracellular-localized TLRs, the so-
called antiviral TLRs (TLR3, 7, 8, 9) have their recog-
nition domains in an endosome within the cell (e.g.
double-stranded viral RNA in the case of TLR3).9
Another class of TLRs binds protein ligands; flagellin,
for example, is detected by TLR5.10 The human TLRs
and their ligands are summarized in Table I.
TLR Activation and the ‘Danger’ Model
It is commonly accepted that TLRs are activated only
by microbial patterns; however, a ‘danger model’ has
been proposed by several studies.11 Matzinger et al.12
reported that the presence of potentially infectious
PAMPs does not necessarily trigger an immune
response unless there is an evidence of host tissue
injury signified by so-called ‘alarm’ signals. In support
of this hypothesis, Matzinger et al. has demonstrated
that, in the absence of any foreign pathogens, resting
dendritic cells can be activated by virally infected or
necrotic cells, but not by healthy cells, or cells under-
going programmed apoptosis.13 Although debate sur-
rounds these studies and theories, there is an
increasing evidence to indicate that TLRs can also
detect host-derived molecules and non-infectious
agents under certain circumstances. For instance,
TLR4, recognized the chemotherapeutic agent paclit-

Table I Human TLRs and Their Ligands

TLR Ligands Origin Reference

TLR 1 Lipoproteins ⁄ triacylated lipopeptides Bacteria, mycobacteria (62)

TLR 2 Bacterial lipoproteins (BLPs) Bacteria (63)
Peptidoglycans Bacteria (64)
Glycosylphosphatidylinositol (GPI) Trypanasoma cruzi (65)
Iipotechoic acid Gram-positive bacteria (66)
Atypical LPS Gram-negative bacteria (67)
TLR 3 Double-stranded RNA (dsRNA) Viruses (68)
TLR 4 R-lipopolysaccharides (LPS) Gram-negative bacteria (69)
Lipid A Gram-negative bacteria (70,71)
Heat shock proteins (HSPs) Host (72,73)
TLR 5 Flagellin Gram-negative bacteria (74)
TLR 6 Diacylated lipopeptides Bacteria (75)
Zymosan Fungi (76)
Soluble tuberculosis factor (STF) Mycobacteria (77)
TLR 7 R-848 (Resiquimod and Imiquimod) Synthetic (22,78)
Loxoribine Synthetic (79)
Single-stranded RNA (ssRNA) Viruses (80)
siRNA Synthetic (81)
TLR 8 R-848 (Resiquimod) Synthetic (78)
Single-stranded RNA (ssRNA) Viruses (79,80)
TLR 9 CpG DNA Bacterial ⁄ Viral (82)
CpG oligodeoxynucleotides (ODNs) Synthetic (83)
Hemozoin Protozoa (Malaria) (84)
TLR 10 Unknown

American Journal of Reproductive Immunology 63 (2010) 7–16

8 ª 2009 John Wiley & Sons A/S

axel.14 In addition, heat shock protein 60, a molecular
chaperone conserved in both invertebrates and verte-
brates, can activate nuclear factor kappaB (NFjB) by
binding to either TLR2 or TLR4.15 Moreover, the
extracellular matrix can stimulate the innate immune
response via TLRs when it is altered after tissue
destruction, even in the absence of pathogens.16
Recognition and activation of host-derived mole-
cules by TLRs may be an important link between pre-
eclampsia and the activation of the maternal immune
system. Indeed, investigations indicate that following
the ligation of TLR-3 by the viral ligand, poly(I:C), or
TLR-4 by bacterial LPS, trophoblast secretion of
chemokines is significantly increased and this in turn
results in elevated monocyte and neutrophil chemo-
taxis.17 Abrahams et al. found that trophoblast cells,
when treated with poly (I:C), produce and secrete
high levels of RANTES (Regulated on Activation Nor-
mal T Expressed and Secreted) and interferon induc-
ible genes.18,19 In addition, Koga et al.20 have shown
that injection of low doses of poly (I:C) induces a
strong pro-inflammatory response by trophoblast
cells leading to changes on the distribution and acti-
vation of immune cells at the implantation site. This
response leads to damage of the placenta and conse-
quent pre-term delivery and fetal death. All these
data suggest that although, TLRs function as impor-
tant sensors for the trophoblast, allowing it to coordi-
nate the local immune response and promote cell
invasion and placental formation.19 TLRs may also
provide the bridge for placental recognition of danger
signals,21 and a subsequent shift in the type of
response generated may have harmful consequences
for the pregnancy, like pre-eclampsia.
TLR Signaling
Activation of TLRs causes an immediate defensive
response, including the production of an array of pro-
inflammatory cytokines and antimicrobial peptides.
Increasing evidence has shown that individual TLRs
can activate overlapping as well as signaling pathways,
ultimately giving rise to distinct biological effects.10
Each TLR activates a number of signaling path-
ways, some of which are common to all TLRs and
some of which are specific to particular TLR types.
Almost all TLRs use a Toll ⁄ Interleukin-1 Receptor
(TIR)-containing adaptor myeloid differentiation pri-
mary response protein (MyD88) to activate a com-
mon signaling pathway that results in the activation
of NF-jB to express cytokine genes relevant to
American Journal of Reproductive Immunology 63 (2010) 7–16
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TLR SIGNALING AND PRE-ECLAMPSIA
inflammation.10 TIR-containing adaptors including
TIRAP (TIR domain-containing adaptor protein),
TRIF (TIR-domain-containing adaptor inducing
interferon b), and TRAM (TRIF-related adaptor mol-
ecule) have been identified and shown to selectively
interact with several TLRs. In particular, activation
of the TRIF-dependent pathway through TLR3 con-
fers antiviral responses by inducing anti-viral genes
including that encoding interferon-b.10
MyD88-Dependent and -Independent Pathways in
TLR Signaling
MyD88 was the first adaptor protein found to be
critical to TLR signaling, and signaling pathways that
act through this adaptor are termed ‘MyD88-depen-
dent pathways’.22 MyD88 can associate with all TLR
types except TLR3. Activation of MyD88-dependent
pathways promotes NFjB translocation to the
nucleus and induces gene transcription of proinflam-
matory cytokines and chemokines.23
The MyD88-independent pathway can involve the
adaptor protein TRIF or TRAM. TLR3 and TLR4 can
activate TRIF-dependent pathways without MyD88
association.10 Studies have revealed that the
MyD88-independent pathway activates the tran-
scription factor interferon regulatory factor 3 (IRF-
3).24 Following virus infection or LPS treatment,
IRF-3 undergoes phosphorylation and translocates
from the cytoplasm to the nucleus, resulting in the
production of interferon and co-stimulatory mole-
cules.6 (See Fig. 1).
Immune mechanisms and pre-eclampsia: evidence
and controversies
Infectious Pathogens in Pre-Eclampsia
Epidemiologic studies have shown that maternal
infection and pre-eclampsia are connected, and have
suggested that the link between these could be
through TLR activation.17,25,26
A recently published systemic review and meta-
analysis has reported that urinary tract infection dur-
ing pregnancy may be associated with an increased
risk of pre-eclampsia.4,27 Epidemiological, pathologi-
cal and animal studies suggest that infectious agents
such as Chlamydia pneumoniae and cytomegalovirus
(CMV) may contribute to clinical cardiovascular dis-
ease and atherosclerosis.28,29 As pre-eclampsia shares
many pathophysiologic features with atherosclerosis,
9
 XIE ET AL.
if there is a link between infection with C. pneumo-
niae and CMV and atherosclerosis, could this associa-
tion also exist in pre-eclampsia? Recently,
researchers have started to examine the role of
C. pneumoniae and CMV infection in pre-eclampsia.30
Several studies detected increased C. pneumoniae anti-
bodies30–33 in pre-eclampsia; evidence came from
enzyme-linked immunosorbent assays and microim-
munofluorescence studies.34,35 Additionally, our
group has detected both elevated CMV antibodies
level30 and gDNA (genomic DNA) loads in women
with early onset pre-eclampsia.36,37 Furthermore, a
genetic study reported that the presence of CMV
increased the risk of developing pre-eclampsia in
women carrying specific HLA-DRB1 alleles.38
In addition, a number of other infectious agents
have been evaluated. These have included Helicobact-
er pylori,39 AAV-2 (Adeno-associated virus-2),40
HIV,41 Malaria,42 Mycoplasma Hominis,43 Epstein–
Barr,44 and HSV-2 (herpes simplex virus 2).44 As
pre-eclampsia is a multi-factorial disorder and not a
singular precipitant of pre-eclampsia maternal syn-
drome, infection may be co-precipitants with other
factors contribute to the pathogenesis of pre-eclamp-
sia. Also, current research findings indicated that
pre-eclampsia is related more closely to total ‘infec-
tious burden’ than to specific pathogens.4
One of the potential importance in activation of the
inflammatory response is LPS. Low doses of LPS
infused into pregnant rats produce pathologic changes
similar to those observed in pre-eclampsia.45 This
10
Fig. 1 Toll-like receptor signaling pathway.
Toll-like receptors (TLR) recognize specific pat-
terns of microbial components that are con-
served among pathogens family. At present,
there are 10 TLR family members that have
been identified in humans. The binding of a
microbial molecule to its TLR, transmits a sig-
nal to the cell’s nucleus through a series of
downstream cascade, ultimately culminate in
the increased expression of immune and
inflammatory response. All TLRs, except for
TLR3, are thought to signal through a MyD88-
IRAK-TRAF6 pathway to induce NF-jB kinases.
suggests that inflammatory cytokines released by
monocytes and macrophages are related to pre-
eclampsia. In addition, following the ligation of TLR-4
by bacterial LPS, trophoblast secretion of chemokines
is significantly increased; this in turn results in
increased monocyte and neutrophil chemotaxis and
activation, changing their supporting role. Indeed, it
has been shown that macrophages in normal preg-
nancy contribute to trophoblast invasion and blood
vessel renewal; however, in pregnancy complications,
the interaction between macrophages and trophoblast
is altered evidenced by their distribution at the
decidua and their response to TLRs stimulation.46,47
A chronic alteration in the balance between
immune cells and trophoblast because microbial fac-
tors may lead to damage of the endothelium from
the spiral arteries, change on the normal blood flow
between the mother and the fetus, which then
might contribute to the pathogenesis of pre-eclamp-
sia.17 These observations suggest that systemic pro-
inflammatory mediators such as LPS through TLR
signaling may be pathogenically linked to the devel-
opment and progression of pre-eclampsia. It is also
possible that the effects are indirectly mediated, for
example, by producing a generalized pro-inflamma-
tory condition in which pre-eclampsia might be facil-
itated. Indeed, recent studies have provided in vivo
evidence for a direct mechanistic link between TLR4
signaling and innate immune system activation and
pre-eclampsia17 (see later ‘Emerging Discoveries:
TLRs and Pre-eclampsia’).
American Journal of Reproductive Immunology 63 (2010) 7–16
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Clinical Trials with Antibiotics
Three clinical trials evaluated the effect of antibiotic
treatment for bacteriuria during pregnancy on the
risk of pre-eclampsia. One randomized controlled
trial noted that treatment with sulphamethoxydi-
azine or sulphadimidine, as compared with placebo,
did not affect the risk of pre-eclampsia.48 Two non-
randomized clinical studies from Germany49 and
Croatia50 reported that, compared with women with
non-treated bacteriuria, antibiotic treatment for bac-
teriuria was associated with a statistically significant
reduction in the incidence of pre-eclampsia. Results
from non-randomized clinical study in Italy,51 indi-
cated that, compared with low risk women who did
not take any antibiotic during pregnancy, pregnant
women treated with spiramycin (because of serocon-
version for Toxoplasma gondii) had a lower incidence
of pre-eclampsia.
However, the difference was not statistically signif-
icant. Recently, Michalowica et al.52 reported the
results of a multi-center trial that periodontal treat-
ment during pregnancy did not significantly alter
the risk of pre-eclampsia. An explanation for these
results may be its association with timing. Once the
damage is made because of the early response to the
infection, the treatment with antibiotics may not
reverse the process. Therefore, the need to develop
therapies is not only that target the bacteria but that
could also regulate the inflammatory process. In the
future, observational studies should be large enough
and adjust for indicators of potential confounding
factors to reconcile these discordant results.
Emerging discoveries: TLRs and pre-eclampsia
Clinical Evidence
The theory that TLRs are linked to pre-eclampsia is
supported by correlations seen in clinical studies.
Mazouni et al. reported that TLRs mediated the
imbalance between an inflammatory and anti-
inflammatory pattern of monocytes in patients with
pre-eclampsia.26 Another study found that TLR4 pro-
tein expression is increased in interstitial trophoblasts
of patients with pre-eclampsia.25 In addition, TLR4
positive trophoblasts from pre-eclampsia patients
were frequently immunoreactive to activated nuclear
factor-kappaB, tumor necrosis factor-alpha, and M30
(a specific apoptosis antigen for trophoblast).25 Kim
et al.25 have suggested that, in pre-eclampsia, ‘danger
American Journal of Reproductive Immunology 63 (2010) 7–16
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TLR SIGNALING AND PRE-ECLAMPSIA
signals’ at the feto-maternal interface, recognized by
trophoblasts through TLR4, may play a key role in
the creation of a local abnormal cytokine milieu. This
indicates a novel mechanism that links pre-eclampsia
to activation of the innate immune system through
TLR4.25
Additionally, pre-eclampsia is engaged with circu-
lating neutrophil activation.53 Our recent data found
that, as compared with normal pregnancy controls,
pre-eclampsia was associated with elevated neutro-
phil TLR2 and 4 mRNA and protein expressions.54
Experimental Evidence
A wealth of evidence suggests that activated TLR sig-
naling could affect pre-eclampsia in multiple ways.
TLRs play a central role in determining the Th1 ⁄ Th2
balance of immune responses. TLR activation pro-
motes the generation of a Th1-dominated immune
response, and inhibits Th2 cytokine production.55
Th1 response up-regulation occurs at the feto-mater-
nal interface in pre-eclampsia, and it is closely
related to poor placentation and endothelial dysfunc-
tion.25
Recent study has shown that TLRs also play a role
in the regulation of immune cell migration by first
trimester trophoblast cells.17 Following the ligation
of TLR3 by the viral ligand, poly(I:C), or TLR4 by
bacterial LPS, trophoblast secretion of chemokines is
significantly increased; this in turn results in ele-
vated monocyte and neutrophil chemotaxis.17 In
addition, TLR3 stimulation induces trophoblast cells
to secrete RANTES.17 These results suggest that a
novel mechanism by which first trimester tropho-
blast cells may differentially modulate the maternal
immune system both during normal pregnancy, and
in the presence of an intrauterine infection.17 Some
studies have indicated that, in first trimester tropho-
blast cells, the apoptotic pathway may be activated
through a heterodimer of either TLR2 ⁄ TLR656 or
TLR2 ⁄ TLR1.17
Genetic Evidence: TLR Polymorphisms and
Susceptibility to Pre-Eclampsia
The genetic variation in the population results some
individuals having a ‘subtle’ but specific immunode-
ficiency. Increasing evidence has demonstrated that
the two common TLR4 polymorphism and TLR2
polymorphism impair TLRs signaling and are associ-
ated with susceptibility to cardiovascular disease57
11
 XIE ET AL.

and pre-term birth58 Recently, several direct studies
of TLR gene polymorphisms in pre-eclampsia have
been described. TLR2 (Arg753Gln) and TLR4
(Asp299Gly ⁄ Thr399Ile) single nucleotide polymor-
phisms (SNPs) appear to alter susceptibility to devel-
oping the maternal syndrome of pre-eclampsia. van
Rijn et al.59 suggested that maternal TLR4 polymor-
phisms alter susceptibility to early-onset pre-eclamp-
sia and elevated liver enzymes and low platelets
(HELLP) syndrome. Additionally, we have found the
presence of TLR2 Arg753Gln and two TLR4 SNPs
(Asp299Gly and Thr399Ile) was associated with
early-onset pre-eclampsia as compared with normal
pregnancy controls.54
We performed a data synthesis of our findings
with those in published reports,59–61 and summa-
rized it in Fig. 2. Through synthesis of these data,
TLR4 and TLR2 polymorphisms appear to lower

SNP WT Risk ratio Risk ratio

Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% Cl M-H, Fixed, 95% Cl
Fraser (UK) 2008 9 14 108 248 56.2% 1.48 [0.97, 2.24]
Xie EOPET (Canada) 6 14 36 204 22.5% 2.43 [1.24, 4.76]
Xie LOPET (Canada) 2 10 50 218 21.3% 0.87 [0.25, 3.08]

Total (95% Cl) 38 670 100.0% 1.56 [1.09, 2.23]

Total events 17 194
Heterogeneity: χ2 = 2.54, df = 2 (P = 0.28); I2 = 21%
0.2 0.5 1 2 5
Test for overall effect: Z = 2.44 (P = 0.01)
Favours experimental Favours control

SNP WT Risk ratio Risk ratio

Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% Cl M-H, Fixed, 95% Cl
5.7.1 EO PET
van Rijn (Holland) 2008 16 36 42 194 19.2% 2.05 [1.31, 3.23]
Xie EOPET (Canada) 11 32 31 186 13.3% 2.06 [1.16, 3.67]
Subtotal (95% Cl) 68 380 32.5% 2.06 [1.44, 2.94]
Total events 27 73
Heterogeneity: χ2 = 0.00, df = 1 (P = 0.99); I2 = 0%
Test for overall effect: Z = 3.96 (P < 0.0001)

5.7.2 LO PET
Molvarec (Hungary) 2008 15 37 165 315 50.7% 0.77 [0.52, 1.16]
Xie LOPET (Canada) 10 31 42 197 16.7% 1.51 [0.85, 2.69]
Subtotal (95% Cl) 68 512 67.5% 0.96 [0.69, 1.33]
Total events 25 207
Heterogeneity: χ2 = 3.49, df = 1 (P = 0.06); I2 = 71%
Test for overall effect: Z = 0.26 (P = 0.79)

Total (95% Cl) 136 892 100.0% 1.31 [1.04, 1.67]

Total events 52 280
Heterogeneity: χ2 = 12.89, df = 3 (P = 0.005); I2 = 77%
0.2 0.5 1 2 5
Test for overall effect: Z = 2.26 (P = 0.02) Favours experimental Favours control
Test for subgroup differences: Not applicable

Fig. 2 The effects of TLR2 (Arg753Gln) (a) and TLR4 (Asp299Gly ⁄ Thr399Ile) (b) single nucleotide polymorphisms on the incidence of pre-eclamp-
sia. EO, early-onset; LO, late-onset; PET, pre-eclampsia; SNP, single nucleotide polymorphism; WT, wild type; Fixed: fixed effects model; CI, confi-
dence interval; M-H, Mantel-Haenszell; The relative contributions of TLR2 and TLR4 genotypes to the development of pre-eclampsia were
estimated and presented as risk ratio (RR) with [95% Confidence Interval (CI)]. The TLR2 and 4 SNP data synthesis was performed by combining our
data with those from Fraser et al.60, Molvarec et al.61, and van Rijn et al.59, respectively. For van Rijn,59 the rates of pre-eclampsia in the TLR-4
SNP (single nucleotide polymorphism) and WT (wild type) groups were calculated by imputation. The exposure (independent) variable was the
presence or absence of any individual SNP. The outcome (dependent) variable was the presence or absence of EOPET (early-onset pre-eclampsia)
or LOPET (late-onset pre-eclampsia). Separate analyses were conducted for TLR-2 and -4 data. The basic data used in the unadjusted analyses con-
sisted of a series of 2 · 2 tables defined by the dichotomous SNP ⁄ WT and early- or late-onset, or mixed, pre-eclampsia ⁄ normal pregnancy con-
trols for each study. The risk ratio was used as the measure of the relation between SNPs and pre-eclampsia. Results from different reports were
combined to produce a pooled risk ratio (95% CI), according to the M–H (Mantel–Haenszel) method. We pooled results from individual studies
using a fixed-effect’s model, and expressed our data as first author (study population’s country), risk ratio, and expressed our data as first author
study (modified from Xie et al.85).

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12 ª 2009 John Wiley & Sons A/S

thresholds for early-onset and severe pre-eclampsia,
in particular (Fig. 2). A concern in all these studies
is the wide range of allele frequencies in control
groups. Inferences from these early studies are lim-
ited in part because of their relatively small sample
size and by the fact that population stratification
(confounding by participants race ⁄ ethnicity) have
not been adequately addressed. Future larger studies
that allow for stratification by race ⁄ ethnicity and
which may also consider gene-gene and gene-envi-
ronment interactions are needed to move this litera-
ture forward. Therefore, more extended studies are
needed to establish whether there is an association
between TLR gene polymorphisms and the risk of
pre-eclampsia, and conclusions must be guarded at
this time. A definitive and fully powered cohort
study is required.
Conclusions and outlook
Recent research in the field of TLR shows that these
receptors play many important roles in pregnancy
complications, especially in pre-eclampsia. Exciting
evidence supporting the theory that TLR activation
contributes to the development and progression of
pre-eclampsia has come from epidemiological, clini-
cal and basic science studies. Previously, most of the
evidence favoring a link between immunity and pre-
eclampsia pathology has been indirect. We now
require more data from experimental animal models,
which might directly implicate the signaling path-
ways associated with innate immunity. Before we
can begin to develop effective therapies, it will be
necessary to expand our understanding of these
links.
Acknowledgments
This study was supported by funding from the Cana-
dian Institutes of Health Research (CIHR) Institute.
FX, SET, and PvD are recipients of BC Michael Smith
Foundation for Health Research. I would like to
acknowledge all the co-authors’ contribution and
thank Dr Perks Anthony for the valuable discussion
on this work.
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