Placenta (2004), 25, 1–8

doi:10.1016/S0143-4004(03)00167-X

CURRENT TOPIC

The Immunological Paradox of Pregnancy: A Reappraisal

A. Moffett a and Y. W. Loke

Research Group in Human Reproductive Immunobiology, Department of Pathology, University of Cambridge,
Tennis Court Road, Cambridge CB2 1QP, UK
Paper accepted 17 June 2003

The survival of the allogeneic conceptus has long been an immunological paradox. Medawar was the first to propose an evasive
mechanism based on the concept of self/non-self recognition described in classical transplantation immunology. Since then,
several newer models of self/non-self recognition have been proposed, such as the PAMP/PRR system, the Missing Self and the
Danger Hypothesis. The present paper considers the fetal-maternal relationship in the context of all these models. The conclusion
reached is that none of them is really appropriate because the interface between trophoblast cells of the fetal placenta and the
leukocytes of the maternal decidua is unique. Pregnancy is not simply a case of acceptance or rejection like a transplant. The
immunological mechanism must provide a balanced environment whereby the conceptus is nurtured by the mother and yet
prevented from excessive invasion. Future identification of trophoblast ligands and their respective receptors on uterine Natural
Killer cells and other leukocytes is likely to offer the best insight as to how this symbiotic state is achieved.
Placenta (2004), 25, 1–8  2003 Elsevier Ltd. All rights reserved.

INTRODUCTION
In the light of the discovery of the Major Histocompatibility
Complex (MHC) and its role in transplantation, the seminal
essay written by Medawar in 1953 drew a logical comparison
between an allograft and a fetus (Medawar, 1953). Despite
both being non-self, the fetus grows and yet the transplant
is rejected. Medawar himself performed no experiments to
address this conundrum but suggested that the placenta must
play a central role in fetal acceptance as it is the trophoblast
cells which interface with the mother. However, his other
proposals—maternal immunosuppression and immaturity of
fetal antigens—together with subsequent diverse hypotheses
by others have not withstood the test of time. Why is
the solution to this problem so elusive? We believe that the
analogy using self/non-self discrimination to compare the
graft/host and placental/maternal relationship has become a
misleading framework in which to conduct experiments.
Recently, alternative concepts have been proposed for how
the immune system operates to maintain the integrity of the
host (Figure 1). In this essay we consider whether these
newer models are more appropriate to explain the success of
the maternal-fetal interaction. We conclude that although
many of these do offer valuable insights none of them,
as they stand, explain Medawar’s immunological paradox
a
To whom correspondence should be addressed. Tel.: +44-1223-
333727; Fax: +44-1223-765065; E-mail: am485@cam.ac.uk
0143-4004/04/$–see front matter
because there are many features about pregnancy which are
unique and which are not found in any other immunological
situation.
IMMUNOLOGICAL MODELS
The classical self/non-self model formulated by Burnet and
Medawar proposed that each lymphocyte expresses a single
receptor for a foreign antigen and signalling through this
triggers an immune response (Burnet, 1959) (Figure 1a).
Lymphocytes with receptors for non-self in the form of
pathogens and allogeneic cells will be present and, if these are
encountered, elimination of the infectious agent or rejection of
the allograft results (Billingham, Brent and Medawar, 1953).
The random generation of these clonally distributed receptors
by gene rearrangement during fetal development means that
the T and B lymphocytes which acquire receptors reactive to
antigens present in the fetus need to be deleted. In this way
tolerance to self and infectious or other stimuli encountered
before birth is acquired.
The revelation that it is not only T and B cells which have
receptors for non-self has now changed our views of self/non-
self recognition. Medzhitov and Janeway have shown that
microbes can be detected by the conserved molecular patterns
that are essential to their physiology but not a part of their
vertebrate hosts (Figure 1b). These are known as pathogen
associated molecular patterns (PAMPs) (Janeway, 1992;
 2003 Elsevier Ltd. All rights reserved.
2 Placenta (2004), Vol. 25

Figure 1. Models of immunological recognition shown in a simplified schematic form.

Medzhitov and Janeway, 2002). This system permits the microbes. Importantly, the receptors for PAMPs, known as
host to distinguish between microbial non-self and normal pattern recognition receptors (PRR), are germ line encoded
self but as all microbes posses PAMPs it will not allow and are mainly found on antigen presenting cells
discrimination between pathogenic and non-pathogenic (APC)—dendritic cells and macrophages. Once a PRR is
Moffett and Loke: Reproductive Immunology Revisited
engaged by a PAMP, the APC is induced to mature, process
the microbial antigen and up-regulate co-stimulatory ligands
for presentation to T cells. It is, thus, the APC and not a
lymphocyte that initially detects the microbial non-self. This
model does not consider the nature of the immune response
to allografts, auto-antigens or to transformed cells and so
its applicability to the maternal-fetal interaction is not
immediately apparent.
Another way of detecting self depends on self receptors
which, on binding to normal host cells, will provide an
inhibitory signal preventing leukocyte activation. If self mol-
ecules are missing the lack of inhibition allows dominance
of activating receptors which can drive leukocytes to kill,
phagocytose etc. This Missing Self hypothesis was proposed
by Karre in relation to Natural Killer (NK cells) which are
prevented from cytotoxicity by binding to self MHC class I
molecules on target cells (Karre et al., 1986) (Figure 1c). NK
cells survey the levels of class I molecules on a host’s cell and
down regulation of these class I molecules (e.g. by viral
infection) will lead to killing. In this way the host can therefore
perceive something as foreign by both the presence of
difference (T cells) as well as the absence of similarity
(NK cells).
Other examples of self-recognition systems relating to other
leukocytes are Siglecs (sialic acid-binding Ig-like lectins) and
CD47. Siglecs are found on myeloid cells and NK cells and
are inhibited by binding sialylated glycoproteins (Crocker
and Varki, 2001). CD47, which is expressed on all cells
including RBC, binds to another inhibitory receptor, SIRP
,
preventing phagocytosis by macrophages (Oldenburg et al.,
2000). As these markers of self are found on normal healthy
cells they can, therefore, prevent killing by NK cells and
phagocytosis by macrophages but their absence on microbes
and infected, transformed or senescent cells will make the
latter susceptible to attack. Following the discovery of
HLA-G, a monomorphic, trophoblast-specific HLA class I
molecule, we used this model to try and explain why tropho-
blast survives despite the presence of abundant decidual NK
cells (King and Loke, 1991). The idea was that the HLA-G
molecule acted as a surrogate ‘self’ class I molecule preventing
NK cell killing. Subsequent experiments by us and others have
not supported this hypothesis (Avril et al., 1999; King et al.,
2000).
Matzinger has introduced a broader model to understand
how the immune system discerns any unhealthy cell and this
has moved away from the concept of entities such as self/non-
self, foreign or microbial. The Danger Model proposes that the
host is alerted by the presence of alarm signals released by
damaged cells and tissues (Matzinger, 1994) (Figure 1d). The
insult may be exogenous (e.g. microbial, poison) or endogen-
ous (e.g. viral, necrosis) but will not emanate from healthy
tissue. This proposal is attractive in its simplicity as it turns
around the problem of defining all the agents and situations to
which the immune system will react towards the concept that
normal healthy cells and tissues will not stimulate leukocyte
activation. Perhaps this is a tautology and the theory certainly
3
Figure 2. The nature of trophoblast.
still does lack details of how each damaging scenario might be
explained in molecular terms.
It is worth reflecting that the proponents of these models
came from the field of classical immunology where response
to pathogens and transplants is a dominant preoccupation.
Reproductive immunologists have always followed mainstream
immunology and tried to fit the immunology of the maternal-
fetal relationship into the paradigms of the day. Can this be
done with any of these models? Although it is to be expected
that the same general principles will apply to all placental
mammals there is, in fact, considerable species diversity. Much
is known about the human situation, however, and this will
form the basis of the present discussion.
THE NATURE OF TROPHOBLAST
In pregnancy, the tissue contact where the maternal immune
system primarily encounters the fetus is in the form of the
placental extravillous trophoblast (EVT) cells which, in
humans, invade deep into the maternal uterine wall (Moffett-
King, 2002). The essential questions that arise are whether the
above models can explain how the maternal leukocytes present
in the uterus are alerted to the presence of these semi-
allogeneic trophoblast cells and then how do they subsequently
respond?
The trophoblast cell has many characteristics which are not
considered by classical immunologists (Figure 2). It is not a
somatic cell but is extraembryonic, derived from trophecto-
derm which is the first lineage to differentiate in the embryo
(Rossant and Cross, 2001). Therefore, an important distinction
is that it is not a normal healthy somatic cell but a normal
extraembryonic cell. Peculiar features of extraembryonic tro-
phoblast cells include the presence of unmethylated DNA
(Rossant et al., 1986; Ohgane et al., 2002), the frequent
presence of giant cells formed from either fusion, endo-
reduplication, polyploidy or polyteny (Potgens et al., 2002;
Cross et al., 2003) and the expression of imprinted genes
4 Placenta (2004), Vol. 25
(Georgiades et al., 2001), endogenous retroviral products
(Mi et al., 2000) and oncofetal proteins (Hammarstrom, 1999).
The EVT has a genetic contribution from the father and is
thus an allogeneic normal cell in the mother, but unlike other
situations where allogeneic cells come into contact, such as
transplantation, there are important differences. The highly
polymorphic HLA class I (HLA-A and HLA-B) and class II
molecules displayed by somatic cells which initiate recognition
of the allograft and its subsequent rejection are not displayed
by trophoblast cells, although the less polymorphic HLA-C is
present (Moffett-King, 2002). It is therefore, not a transplant
in terms of Burnet and Medawar’s original concept of self/
non-self because MHC non-self is not present. Furthermore, it
cannot be considered ‘missing self’ because it does have a
genetic contribution from the mother. EVT expresses an
unusual combination of three HLA class I molecules two of
which (HLA-E and HLA-C) are known to be dominant
ligands for NK cells. Indeed HLA-E is virtually monomorphic
and would be perceived as ‘self’ by maternal NK cells
expressing the inhibitory receptor CD94/NKG2A thus
preventing cytotoxicity (King et al., 2000).
Matzinger has considered the problem of the fetal allograft
in terms of the Danger Model and has suggested that the
difference in outcome is because the surgical trauma and
hypoxia of the iatrogenic transplant situation results in tissue
damage and necrosis, whereas as pregnancy is a natural
phenomenon, with intermingling of normal healthy cells,
alarm signals are not sent (Matzinger, 2002). However, at a
cellular level the placental bed is not a harmonious site, indeed
it has been described as a ‘battle-ground’ (Robertson, 1987).
There is necrosis at the uterine surface where the anchoring
villi attach (Nitabuch’s layer) as well as the characteristic
‘fibrinoid’ necrosis of the spiral arterial media (Kaufmann and
Burton, 1994). The trophoblast cells around these arteries have
a spidery appearance when stained for cytokeratin suggesting
cell damage (Loke and King, 1995). Thus, both fetal and
maternal cells are damaged although it is remarkable how the
invasion through the decidua basalis between the spiral arteries
is accompanied by relatively little damage compared to that
seen with tumour invasion. It is only at specific anatomical
sites in the placental bed that necrosis is seen. This battle-
ground cannot be considered ‘danger’ free and from the
viewpoint of the Danger Model leukocytes should be alerted.
It would appear that viewing the fetus as an allograft in the
terms of the Self/non-self, Danger or Missing Self hypotheses
is not illuminating and may even be distracting.
At first sight it would seem non-self PAMP recognition by
APC is also not relevant to pregnancy since this was proposed
as a mechanism to distinguish between non-infected self and
microbial non-self. Clearly trophoblast is not microbial. How-
ever, PRR may have evolved initially to bind ligands present
in the host and have then been subsequently co-opted by
microbes to gain entry into target cells. Precedents for this are
well known and include HIV binding to CD4 and EBV to
CR2. Indeed, several PRR have been shown to bind to
endogenous ligands such as Hsp and DNA CpG sequences
(Krieg, 2000; Ohashi et al., 2000). Although bacteria lack CpG
methylation enzymes most mammalian DNA is methylated.
Perhaps, the unmethylated DNA characteristic of extraembry-
onic trophoblast could act as a PRR ligand mimicking
bacteria.
Furthermore, there is the intriguing finding that human
endogenous retroviral (HERV) products are expressed by
trophoblast (Taruscio and Mantovani, 1988; Harris, 1998) so
in some respects it could be considered an ‘infected’ cell and
might be discerned by PRR such as Toll-like receptor (TLR)
3 which binds double-stranded (ds) RNA (Akira and Hemmi,
2003). The HERV could act in other ways to influence the
maternal immune system. For example, they might provide
trophoblast specific peptides for HLA class I molecules or
encode MHC-like molecules that bind NK receptors. These
are speculative ideas but there is support from a protein,
EBI-3, whose expression is induced in EBV-transformed B
cells (Devergne et al., 2001). This protein is normally
expressed at high levels in the placenta and interestingly, the
dominant peptide eluted from trophoblast HLA-G is derived
from this molecule (Lee et al., 1995). Other peptides predomi-
nate if HLA-G is expressed in cell lines and thus the cell
expressing HLA-G may alter binding to its receptor. EBI-3
can also form heterodimers with members of the IL-12 family
(Devergne, Birkenbach and Kieff, 1997; van Seventer, Nagai
and van Seventer, 2002). This trophoblast derived IL-12-like
cytokine might direct the nature of the maternal immune
response by acting on uterine DC, T or NK cells.
THE MATERNAL UTERINE IMMUNE SYSTEM
The maternal uterine immune system is thus meeting an
apparently ‘normal’ but invading and selectively destructive
extraembryonic cell with unmethylated DNA. It has
distinctive expression of MHC molecules, endogenous retro-
viral products and other placental-specific molecules and
hormones. It will not readily fit into any category of
non-self, allogeneic, foreign or infected. However, it may be
‘alarming’ to the mother by the damage wrought in the decidua
and spiral arteries. How does the mother discern the presence
of these trophoblast cells in the uterus and what is the
response?
The absence of B cells and paucity of T cells in the uterine
mucosa suggests that the adaptive immune system is not as
important as the innate system. Indeed, NK cells and macro-
phages are the main types of maternal leukocyte present and
NKT cells have also been described (King, 2000; Boyson et al.,
2002). Do any of these leukocytes have receptors which could
perceive trophoblast? Despite the emphasis placed in the
literature on the necessity for the avoidance of maternal T cell
reactivity during pregnancy it has always been hard to define
how T cells might directly react to human trophoblast given
the absence of HLA class II and HLA-A and HLA-B
molecules. Although HLA-C is polymorphic, it has low levels
of surface expression and HLA-C-reactive T cells are rare in
Moffett and Loke: Reproductive Immunology Revisited
transplant recipients. Indirect recognition by uptake of other
trophoblast molecules by decidual APC would appear more
likely and in this case the ability of the decidual DC to tolerize
or stimulate will be crucial. Characterization of decidual DC
reveals they are an immature myeloid type similar to those
found at other body surfaces such as the dermis, lung or gut
but their functional capabilities are still unknown (Gardner
and Moffett, 2003).
Decidual NKT cells have also been identified at appreciably
higher numbers than in the peripheral blood. These cells
express an invariant TCR capable of binding to an MHC-like
molecule, CD1D. Definitive confirmation that CD1D is
expressed by trophoblast is still lacking but other ligands could
be present that are capable of binding to these cells (Boyson
et al., 2002). As yet there is virtually no information on the
possible expression of PRR such as Toll-like receptors (TLR)
on DC, macrophages and other leukocytes in the decidua
nor is it known whether stress molecules are induced on
maternal and trophoblast cells by the placental invasion and
destruction.
NK cells are heterogenous due to differential expression of
various inhibitory and activating receptors. Decidual NK cells
express a wide array of receptors but the ligands for only a few
of these are known. However, a mechanism by which maternal
leukocytes could directly recognize trophoblast has now been
identified. This has been demonstrated for the receptor for
HLA-E, CD94/NKG2A, by using HLA-E tetramers which
bind decidual NK cells (King et al., 2000). How HLA-G, the
only trophoblast-specific HLA class I molecule, is discerned
is still controversial. Besides members of the ILT family
expressed by decidual macrophages there are likely to be
receptors for HLA-G on NK cells such as KIR2DL4, a
member of the Killer-cell immunoglobulin-like receptor (KIR)
family (Allan et al., 1999; Rajagopalan and Long, 1999).
Trophoblast ligands for another KIR, KIR3DL3, the mRNA
of which is detectable in uterine but not blood CD56dim NK
cells (unpublished), and for activating NK receptors such as
NKG2D, NKp30 and NKp46 await identification.
NK CELL ALLORECOGNITION
In many respects unravelling the interaction between HLA-C
and the KIR2D receptors present on decidual NK cells is
likely to be particularly rewarding because unlike HLA-E
and HLA-G, HLA-C is polymorphic and the father will
therefore assert his genetic difference in the trophoblast of his
fetus by donating one of his HLA-C allotypes. In terms of
allorecognition in the context of reproduction, trophoblast
non-self HLA-C is likely to be of particular importance
(Figure 3).
The KIR gene family is also polymorphic with variation in
the number of KIR genes present in different individuals at the
KIR locus on chromosome 19. The combination of genes on
one chromosome is the KIR haplotype. There is also allelic
polymorphism of individual genes and this diversity, created
5
by both gene content and polymorphism, means unrelated
individuals rarely have the same KIR genotype (Vilches and
Parham, 2002). The KIR gene family includes inhibitory
receptors (KIR2DL1, KIR2DL2, KIR2DL3) that have
specificities for polymorphic determinants of all HLA-C allo-
types; the latter are known as the KIR epitopes of HLA-C. All
HLA-C allotypes have either asparagine or lysine at position
80 of the
1 domain and this dimorphism distinguishes the two
KIR epitopes. Potential NK cell alloreactions can occur if a
NK cell from one individual has a receptor for an HLA-C KIR
epitope that is lacking on cells from another individual (miss-
ing self). This is a quite different form of non-self recognition
based on NK cell KIR and not TCR or PRR expressed by T
cell and APC respectively.
The importance of NK cell allorecognition is seen in bone
marrow transplantation where the dominant pattern of NK cell
alloreactivity has been shown to be due to the two HLA-C
epitopes (Parham and McQueen, 2003). Indeed, NK cell
alloreactions are beneficial in patients with acute myeloid
leukaemia (AML) when HLA-mismatched haploidentical
transplants are performed. The donor is a family member who
is identical for one HLA haplotype and mismatched for the
other, a situation with obvious resonance to pregnancy. Some
of the donor NK cells may possess a KIR receptor for an
HLA-C epitope lacking in the recipient but present in donor.
These NK cells are not inhibited by ‘self’ MHC and kill the
leukaemic cells of the recipient (Ruggeri et al., 2002). In
this scenario, therefore, NK cell allorecognition is actually
beneficial. Could the same be true in pregnancy?
Not all KIR with specificities for HLA-C KIR epitopes are
inhibitory. For example, KIR2DS1 is an activating receptor
that binds all the HLA-C allotypes which have lysine at
position 80 (HLA-Clys80). A possible situation that could arise
is the presence of both KIR2DS1 in the recipient (mother) and
its ligand, the HLA-Clys80 KIR epitope, in the donor (father).
This KIR epitope would be absent in the mother. Maternal
NK cell activation could then occur but only in this particular
maternal KIR paternal HLA-C combination.
The potential for NK cell alloreactions to occur during
pregnancy is, therefore, present and this has not been consid-
ered by any of the four models described earlier in this essay.
Maternal NK cell allorecognition of the fetus may not only be
important at the implantation site, but could also influence the
engraftment or clearance of fetal leukocytes which may occur
when fetal cells are spilt into the maternal circulation at
delivery. Persistence of fetal cells can be associated with later
onset of diseases in the mother such as scleroderma (Nelson,
2002).
MATERNAL IMMUNE EFFECTOR
MECHANISMS
A separate consideration from the question of how the
maternal immune system detects the presence of trophoblast is
the type of immune response that is generated. The CD56bright
6 Placenta (2004), Vol. 25

Figure 3. NK allorecognition.

NK cells produce an array of cytokines but little is known
about how the profile alters in the shift from the non-pregnant
to pregnant state and after interaction with trophoblast. Atten-
tion needs to be directed to the distinctive nature of the
decidual tissue which must guide both innate and adaptive
effector immune responses. Apart from the unique compos-
ition of leukocytes, decidua is characterized by the presence of
plump stromal cells secreting copious amounts of proteins (e.g.
renin, IGFBP-1, prolactin) and extracellular matrix proteins
(King, 2000). How will this decidual microenvironment drive
the immune responses initiated there?
DC will either stimulate or tolerize T cells after migration
from the periphery to the lymph nodes depending on the
signals received at their original surface location. Stimulation of
maternal T cells would not be expected without signals to the
DC inducing costimulatory molecules. Interestingly, many of
the factors known to induce tolerogenic DC are also integral to
the decidualizing process and include Vitamin D3, and PGE-2
(Harizi et al., 2002; Griffin and Kumar, 2003). With regard to
NK cells the unique microenvironment will be important in the
proliferation and differentiation of these cells in utero. The
difference in phenotype of decidual NK cells compared with
Moffett and Loke: Reproductive Immunology Revisited
their peripheral blood counterparts, particularly with regard to
the difference in KIR repertoire, is likely to be induced by the
tissue they inhabit (King 2000; King et al., 2000).
CONCLUSION
The local decidual immune system must contribute to the
nurturing environment of the uterus which functions to mould
the placental cells as they migrate, allowing the optimum
delivery of nutrients to the fetus without endangering the
mother. The idea that immune responses can be nurturing and
beneficial has come from another tissue, the skin, where epi-
dermal T cells with an invariant receptor, bind a self mol-
ecule induced by the damage from wounding. The response is
to generate cytokines (e.g. KGF) that stimulate epidermal
growth and healing. It appears in this situation that these tissue
ACKNOWLEDGEMENTS
This paper was based on a lecture given by Professor Y.W. (Charlie) Loke at the IFPA meeting held in Melbourne, Australia 2002.
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