# The Fetal Allograft Revisited: Does the Study of an Ancient Invertebrate Species Shed Light on the Role of Natural Killer Cells at the Maternal-Fetal Interface?

Authors: Amy Lightner; Danny J. Schust; Yi-Bin A. Chen; Breton F. Barrier
Journal: Clinical and Developmental Immunology
 (2008)

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## Abstract

Human pregnancy poses a fundamental immunological problem because the placenta and fetus are genetically different from the host mother. Classical transplantation theory has not provided a plausible solution to this problem. Study of naturally occurring allogeneic chimeras in the colonial marine invertebrate, Botryllus schlosseri, has yielded fresh insight into the primitive development of allorecognition, especially regarding the role of natural killer (NK) cells. Uterine NK cells have a unique phenotype that appears to parallel aspects of the NK-like cells in the allorecognition system of B. schlosseri.  Most notably, both cell types recognize and reject “missing self” and both are involved in the generation of a common vascular system between two individuals. Chimeric combination in B. schlosseri results in vascular fusion between two individual colonies; uterine NK cells appear essential to the establishment of adequate maternal-fetal circulation. Since human uterine NK cells appear to de-emphasize primary immunological function, it is proposed that they may share the same evolutionary roots as the B. schlosseri allorecognition system rather than a primary origin in immunity.


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## Body

## 1. The Human Maternal-Fetal Relationship

Human pregnancy poses a fundamental
immunological problem because the placenta and fetus are genetically different
than the host mother. In 1953, Sir Peter Medawar posited the fetus as a
successful solid organ transplant, initiating a wave of research that attempted
to explain fetal implantation in terms of classical transplantation immunology
[1]. The mediators of the adaptive immune system are thought to be responsible
for transplant rejection. High intrinsic allogeneic interactions of CD8+ T
cells with foreign major histocompatibility complex (MHC) class I molecules are
considered to be the major mediator, but minor histocompatibility antigens, CD4
T cells, and specific antibodies also play a significant role. Accordingly, many have studied fetal survival
in the context of escape from the maternal adaptive immune system via
anatomical separation, antigenic immaturity of the fetus, and/or immunological
inertness of the mother. However, mother and fetus are not truly anatomically
separate because placental tissue, derived from fetal trophoblasts, invades
deep into maternal uterine myometrium along spiral arteries, replacing maternal
arterial endothelium. This allows for the exchange of cellular and noncellular
material between mother and fetus. The presence of fetal blood cells,
leukocytes, and trophoblast cells in the maternal circulation contradicts a
role for the placenta as an effective immunologic barrier [2]. In addition, mothers do mount an
immune response to paternal antigens and, not infrequently, possess specific
antibodies or cytotoxic T cells against paternal MHC molecules. The presence of
this response has been shown to have no effect on pregnancy outcome [2–4],
an observation hypothesized in the past to be related to the presence of paternal-antigen
specific maternal regulatory T-cells, of blocking antibodies that protect the
fetus, and/or of immunosuppressive plasma proteins [2–6]. It is also
doubtful that the uterus is an immunologically privileged site, because, unlike
the brain or testes, it is endowed with a well-developed lymph drainage system [3].
Finally, while patients with autoimmune diseases provide ample evidence that
there are maternal immunomodulatory changes during gestation, maternal immunity
can certainly still mount a successful adaptive response against nonself.Colonial ascidians, a class of marine
invertebrates commonly known as sea squirts or tunicates, may offer a unique
perspective on the maternal-fetal relationship. Like mother and fetus, colonial
ascidians experience a natural exchange of allogeneic tissue. Colonies that are
successful in this exchange somehow avoid mutual rejection and reap the benefits
of chimeric life. This phylogenetically ancient species manages this balancing
act without benefit of an adaptive immune system (which first evolved in
cartilaginous fish) [4]. Study of the immunological mediators for this system
of natural allorecognition may reveal the evolutionary precursor to modern
mechanisms for the human parallel of colonial life: the maternal-fetal
relationship. The colonial ascidian, B. schlosseri, is interesting for three
reasons: (1) its colonial chimerism has been extensively studied, (2) it appears
not to possess an adaptive immune system, and (3) it is of the urochordate subphylum,
a group of chordates thought to lie on the evolutionary line leading directly
to vertebrates.


## 2. Botryllus Schlosseri

Recent reviews have summarized the life
cycle and allorecognition of B. schlosseri in detail, but a brief summary is
presented here [5, 6]. B. schlosseri,
commonly called the star ascidian or golden star tunicate, is native to Europe,
but has spread to coastlines around North America, Asia, and Australasia.
Each individual colony member (zooid) has its ventral side attached to a
substrate, upon which the colony grows laterally, while the free dorsal end has
two openings, the buccal and atrial siphons (Figure 1). Zooids measure 1–1.5 millimeters
in length. They are usually grouped together into star-shaped clusters or
systems of 3–12 members, with
the atrial siphons of all individuals opening into a common chamber in the
cluster’s center. Colonies consist of a number of clusters embedded in a common
gelatinous matrix, the tunic. The Botryllus colony has the potential to grow
quite large and may be comprised of up to a thousand individuals [7]. Zooid propagation occurs through asexual
reproduction, so all zooids within an individual colony are genetically
identical. A common vascular system
connects each zooid cluster and terminates in peripheral sacs called ampullae
that are not only important for colony adhesion to substrate, but also allow
for intercellular contact and exchange among zooids. When the peripheral
ampullae of different colonies come into contact, they either anastomose and
remodel their vessels to form a shared vasculature under a common tunic [8], or
develop inflammatory lesions, indicating a site of rejection (Figure 2) [9, 10].Figure 1
Botryllus schlosseri colony formation. The B. schlosseri individual is
called a zooid. It attaches to the substrate that it will grow on by one end.
Its free end has two openings or siphons. The zooid reproduces asexually and
groups of 3–12 zooids will group together to form a cluster or system, with the
free end of each zooid dumping into a central chamber. Clusters, in turn, join to form the B.
schlosseri colony. All clusters in a colony are housed in a common tunic and
share a common vasculature. Vessels in a colony terminate in peripheral
ampullae that, while covered in the tunic, present sites of colony-to-colony
interactions.Figure 2
Botryllus schlosseri colony interactions. In the wild, colonies of B.
schlosseri can become quite large, and genetic analyses reveal these colonies
to be multichimeric. Interactions between genetically distinct colonies are
governed by an allorecognition system controlled by the
fusibility/histocompatibility locus (Fu/HC). When genetically distinct colonies
contact one another, they will anastamose if one or both Fu/HC loci are
recognized as self. Fusion involves the creation of a shared vasculature and
common tunic. If neither Fu/HC loci are shared, rejection will occur and
inflammatory lesions will develop at sites of contact. One colony will be
largely resorbed after acceptable recognition and successful colony fusion, although
some germ and somatic cells of the resorbed individual will persist in the
survivor, creating a parasitic relationship.This natural chimerism is mediated by an
allorecognition system, primarily controlled by a single, highly polymorphic
locus, the fusibility/histocompatibility locus (Fu/HC) that contains up to
several hundred codominantly expressed alleles
[11, 12]. B. schlosseri allograft reactions differ from
MHC-dependent vertebrate graft rejection. Whereas mammalian solid organ
transplant rejection is thought to rely on host T-cell engagement with foreign
MHC molecules (nonself), B. schlosseri rejection is based on failure to
recognize self as encoded by the Fu/HC locus. Rejection occurs only when no
Fu/HC allele is shared between the two individual colonies. Fusion via a shared
vasculature is permitted when at least one Fu/HC allele is shared. In contrast,
vertebrate graft rejection occurs if either MHC haplotype differs. Lastly, and
unlike vertebrate MHC molecules, there is no evidence that the Fu/HC system
functions in antigen presentation, although it may encode genes involved in
innate immunity, such as complement and pattern recognition
receptors [13, 14].B. schlosseri colony fusion in the presence of acceptable allorecognition may have
several advantages. Larger size may aid in the control of a long-term feeding
substrate and may limit inter-specific competition. In fact, the respiration
rate of individual zooids decreases as colony size increases [15]. It has been
proposed that environmental conditions (primarily water flow and food supply)
dictate the number of zooids per generation, the number of coexisting
generations in a colony [16], and the rate of colony resorption (see below).
While it is still unclear if colony forming is a true survival technique, it
stands to reason that colony fusion shifts the unit upon which natural
selection acts from the individual’s genotype to that of the fused colony. The
high degree of somatic “heterozygosity” in a multichimera may protect it from
hierarchal somatic resorption and thereby create the best somatic “container”
for the reproduction of its gametes.Whereas the formation of multichimeras
seems to be preferred in nature, as evidenced by the preference of larvae to
settle in aggregates of kin colonies [13] and to co-settle with parental
colonies [14], phenotypic resorption of
individual colonies occurs in the majority of typically bichimeric animals that
thrive in the laboratory setting. In most of these bichimeric colonies, this
resorption after initial fusion follows a strict genetic hierarchy. (if colony
A resorbs colony B and colony B resorbs colony C, then colony A will always
resorb colony C.) Heterozygotes at the Fu/HC locus are always dominant in that
they always resorb homozygotes [17]. Two additional genes, referred to as the
resorption/histocompatibility (Re/HC) loci, also determine the hierarchy of the
resorption reaction [18]. These genes are not linked to the Fu/HC locus and
appear to sort independently.To understand the molecular basis of
allorecognition, chimeras were designed from two colonies, each heterozygous at
the Fu/HC locus, and sharing one allele [19]. These investigations demonstrated
that the mediators and effectors of histoincompatibility circulate throughout
the common vascular system of fused colonies and that blood components of even
the resorbed genotype remain following colony resorption. In B. schlosseri,
hemocytes differentiate along two defined pathways, becoming either (1)
phagocytes that are macrophage—like in their
immunostaining characteristics or (2) cytotoxic cells, including hyaline
amebocytes [20] and morula cells [21, 22]. Of these cell types, the morula
cells appear to be the major immunomodulatory hemocytes in ascidians as they
alone display significant changes in cytokine (IL-1α and TNF-α) secretion upon immunostimulation [23].
Morula cells are also the most viable candidate mediators of the
alloimmune-mediated resorption [22, 24]. These hemocyte-derived ascidian blood
cells are capable of cytotoxic activity, they proliferate in response to T-cell
and B-cell mitogens, and they accumulate at the ampullae during rejection
reactions [25]. Ascidian blood cells and human lymphocytes share common
immunoglobulin superfamily proteins and a highly polymorphic disulfide linked,
membrane bound heterodimer that may be a precursor to the MHC
products [26, 27].


## 3. Cellular Parasitism

Several studies have demonstrated that
after allogenic fusion and subsequent colony resorption, germ and somatic stem
cells of the resorbed partner can survive and replicate within the other
partner's soma and/or gonads (Figure2) [28]. Thus, the initial fusion/resorption
reaction may actually result in somatic or germ cell parasitism at the cellular
level [29]. However, if all individuals could fuse, one supercompetitor
genotype could dominate and homogenize the genome of the entire species [30].
Therefore, while the initial fusion/rejection self-recognition reaction likely
evolved to facilitate competition among closely related kin, the rejection
prevents one dominant genotype from homogenizing the genotype of the entire
species through germ-cell parasitism, with the benefit of preserving genetic
diversity.In addition, it appears that somatic and germ cell resorption events are
independent of one another [31]. The genotype selected somatically may not be
the one selected gametically. The apparent somatic “winner” by gross resorption
could turn out to be the gametic “loser” if all of its germ cells are colonized
and parasitized by the resorbed individual. In fact, both types of cellular
parasitism seem to represent independent stem cell lineages existing
simultaneously [14]. The retention of stem cells from seemingly resorbed
individuals allows the colony to be phenotypically plastic in response to its
environment. Indeed, evidence has shown that environmental changes can alter
the colony phenotype [9].


## 4. B. Schlosseri—the Evolutionary Link

Based on the chordate characteristics of
its larva, the ascidians appear to be among our closest invertebrate
relatives [32]. If B.
schlosseri shares a common invertebrate ancestor with humans, it must sit at a
critical point in vertebrate evolution, just before the development of the
adaptive immune system. There are, in fact, examples of invertebrate species,
such as the marine organism Hydractinia, that predate B. schlosseri by several
hundred million years, but exhibit a highly specific allorecognition system
[33]. Recognition in these organisms, however, appears to occur via
interactions in ectodermal- and/or endodermally-derived cells [33–35].Natural chimeric relationships, which are integral
to the B. schlosseri life cycle, exist rarely among eutherians—organisms
utilizing a placenta to allowin corpus fetal development. Examples include spontaneous early fusion of dyzygotic
twins, rare cases of germ cell chimerism, and proliferation of fetal cells in
the maternal blood system after parturition
[36, 37]. One instance
of natural chimerism, however, is remarkably common—the maternal-fetal
allograft itself. Evolutionary remnants of an allorecognition system found in
the common ancestor shared by B. schlosseri and modern eutherians may govern maternal-fetal
allogeneic interactions. For B. schlosseri, a single self-identification system
appears to govern its initial allogeneic interactions. In higher vertebrates,
inhibition of NK cell cytolysis by self-MHC class I molecules resembles the
Fu/HC system of B. schlosseri in that it is based on the suppression of
cytolytic activity via recognition of self.


## 5. NK Cells

It is commonly accepted that NK cells share
a developmental precursor with T lymphocytes [38]. In fact, some believe that  the NK cells,
found in all invertebrates, are the evolutionary precursor to lymphocytes [38, 39]. NK cells are a component of the innate immune system, thought to be
important in the immune response against viruses and tumors that may
downregulate expression of classical MHC molecules [38–40]. They are
non-T, non-B lymphocytes which do not require prior exposure to act and do not
act by recognition of nonself. NK cell activation is regulated by a complex
interplay between multiple activating and inhibiting signals [41]. Inhibitory
signals are mainly delivered by the self MHC class I products normally present
on the surface of nucleated cells. The activating signals may be delivered by
several recognized cell surface receptors present on NK cells, including CD16,
the killer inhibitory receptor (KIR)2DS, and NKp46 [42, 43]. NK cells kill
target cells via discharge of cytoplasmic granules or by cytokine signaling to
nearby macrophages.Seventy percent of human endometrial
leukocytes during early pregnancy are large granulated lymphocytes, while 20%
are macrophages, and 10% are T cells. B cells and peripheral CD16+CD56+NK cells
are nearly absent [44]. CD16 is a transmembrane receptor for immunoglobulin
(Ig)G and CD56 is an Ig family glycoprotein expressed on the surface of all NK
cells. Granulated lymphocytes had been identified in the endometrium of many
species, but they were not identified as NK cells until intense expression of
CD56 was demonstrated. Note that the CD56 marker is only found in higher order
primates and not found in the species that had been studied prior to its
discovery (e.g., rodent, porcine, and bovine) [45].


## 6. Uterine NK Cells

In humans, uterine granulated lymphocytes
differ immunophenotypically from peripheral blood NK cells in that they are
CD56bright and CD16−, whereas peripheral blood NK cells are CD56dim and CD16+ [39, 46]. In addition, although reverse transcriptase polymerase
chain reaction (RT-PCR) has confirmed that uNK cells express the same families
of inhibitory and activating receptors as peripheral NK cells, they do so in
different proportions, and with variability among individual
women [39, 46, 47].Uterine NK cells are only found in the
human endometrium during the menstrual years, implying an active role in
reproduction. Their population peaks during the progesterone-dependent
secretory phase of the menstrual cycle. After implantation, they persist in the uterine mucosa, gathering in
high concentrations at the site of placental invasion. Although substantial
numbers of CD56+ cells remain in placental tissue during the third trimester of
pregnancy [48], their number gradually decreases over pregnancy and they are
usually absent in term decidua [39, 49].The uterine mucosa is the only tissue in
the human body where NK cells of any kind are known to proliferate and survive
in large numbers. In the late secretory phase and early pregnancy, decidual uNK
cells appear localized to the stratum functionalis, forming aggregates around
spiral arteries and glands [44, 46]. Initially, it was speculated that this
localization was due to the effect of the diffusion of progesterone from blood
into the perivascular tissues, since large numbers of uNK cells are seen after
progesterone treatment. However, more recent evidence suggests the perivascular
distribution reflects the trafficking of uNK precursors from the circulation
[46, 50].


## 7. Trophoblast MHC Molecules

Placenta and uterine mucosa are the primary
tissues of the maternal/fetal interface. Placental villous syncytiotrophoblast
and extravillous cytotrophoblast cells are the fetal cells most intimately
contacted by maternal cells (Figure3). According to mRNA analysis, these cells
do not express normal levels of classical MHC I or MHC II molecules [51, 52].
Instead, the extravillous cytotrophoblast cells express two nonclassical MHC I
molecules, human leukocyte antigen (HLA)-G and HLA-E, and low levels of the
classical MHC I molecule, HLA-C [53, 54]. When compared to HLA-A and HLA-B, HLA-C, -E, and -G exhibit
much lower surface expression, fewer alleles, reduced polymorphism at peptide
binding sites, and lower intrinsic reactivity with CD8+ T-cells [53, 55]. This
suggests that the primary function of trophoblast HLA molecules is something
other than the presentation of foreign peptide to CD8+ T-cells. In addition,
trophoblast MHC products are uniquely resistant to the strategies that multiple
viral pathogens employ to evade immune detection [53, 56–58], suggesting that
these class I products do not have a primary role in pathogen defense.Figure 3
The human maternal-fetal interface. Fetal blood enters and exits the
placenta via the umbilical cord. Fetal vessels lie at the core of each
placental villae and all villae are lined externally by trophoblast cells. The
cells of the inner layer (green) are called villous cytotrophoblast cells.
Those of the outer layer develop from the villous cytotrophoblast through syncytialization
and are called syncytiotrophoblast (orange). Floating villae are completely
bathed in maternal blood; anchoring villae traverse the intervening
blood-filled space to attach to the maternal decidua. At the tips of the
anchoring villae, a subpopulation of cytotrophoblast cells leaves the villae to
invade the maternal endometrial decidua. Here, these extravillous cytotrophoblast (blue) cells encounter
populating maternal immune cells. Some extravillous cytotrophoblast cells will
invade the maternal uterine arteries and become endovascular trophoblast cells
(blue). Appropriate vascular invasion by
endovascular trophoblast cells results in remodeling of the uterine vasculature
(inset, right) and adequate placental perfusion. Poor vascular invasion by
endovascular trophoblast cells results in limited remodeling of the uterine
vasculature (inset, left), a condition associated with adverse pregnancy
outcomes.Substantial evidence demonstrates that MHC
molecules, including trophoblast MHC products, play a role in the inhibition of
NK cell mediated target lysis. Inhibitory receptors on NK cells include members
with immunoglobulin-like characteristics [leukocyte Ig-like receptors (LIRs)
and killer Ig-like receptors (KIRs)] and heterodimers with characteristics of
C-type lectins (CD94/NKGs) [59]. It is now known that the KIRs recognize the
classical MHC products (HLA-A,-B and -C), and CD94/NKG2
recognizes HLA-E molecules [46, 60, 61]. The recent discovery of the crystal structure of HLA-G [62] supports
tight binding to LIR1 and LIR2 and poses a plausible ligand-receptor
interaction.  Others have demonstrated interactions between HLA-G and
KIR2DL4 as well [63]. Furthermore, treatment of fetal cells with monoclonal
antibodies directed against HLA-G and HLA-C abolishes their resistance to NK
cell mediated lysis [64], while transfection of HLA-G into NK susceptible cell
lines prevents NK cytolysis [65]. Although HLA-G expression has been recently
described in multiple malignancies and chronic inflammatory conditions, it is
never expressed in significant amounts in normal tissues other than fetal
trophoblasts [66].


## 8. uNk Cell Function

The most important role of uNK cells may be
the regulation of fetal implantation and initial establishment of the placenta
through vascular remodeling. During implantation, fetal trophoblast tissue
invades muscular uterine tissues and spiral arteries, converting the latter
into enlarged structures with limited vascular resistence, poor responsivity to
vasoactive signals, and the capability for high conductance (Figure3). These
changes are necessary to supply sufficient blood volume to the fetus. When
trophoblast invasion is not sufficient, fetal circulation is compromised
resulting in miscarriage, idiopathic uterine growth retardation (IUGR),
stillbirth, and pre-eclampsia [55, 66]. In fact, decreased expression of HLA-G
on human extravillous trophoblast is associated with reductions in placental
invasion, shallow placentation, and development of pre-eclampsia, a maternal
disease associated with impaired placental vascularization and development [67]. Recognition of
trophoblast MHC products by uNK cells could serve as one trigger for cytokine
release to induce and modulate this vascular remodeling. The repertoire of
cytokines secreted by uNK cells includes VEGF-C, PIGF, Ang-2, TNF-alpha, IL-10,
GM-CSF, IL-1Beta, TGF-Beta1, CSF-1, LIF, and IFN-gamma [68–71], any or
all of which may help to establish a functionally healthy maternal-fetal
circulation [39, 47]. One cytokine, IFN-gamma, seems to be particularly
involved in the control of trophoblast invasion and the remodeling of uterine
spiral arteries during the first half of pregnancy. Indeed mice deficient in
either uNK cells or IFN-gamma have implantation site abnormalities and failure
of decidual artery remodeling. They exhibit fetal loss in the second half of
gestation, an overall smaller placental size, and progressive lesions
suggestive of hypertension-mediated arteriosclerosis in the uterine vessels
[72]. These defects can be reversed by grafting bone marrow from NK cell
competent, but T and B cell immunodeficient, severe combined immunodeficiency
(SCID) mouse donors [73] or RAG-2-/-IFNgamma-/-mice treated
with murine IFN-gamma [74]A more precise understanding of the roles
of uNK cells in human pregnancy awaits future study of uNK cell receptor
expression and cytokine release. Studies such as in vitro trophoblast invasion assays in the presence of Ang-2
[75], TNF-alpha [76, 77], IFN-gamma [77], and TGF-beta1 [78, 79] have
provided insight into the role of cytokine production in the control of
extravillous trophoblast invasion. Similar in vivo study of cytokine production
and effects at the maternal-fetal interface is highly complicated due to the
short half life of cytokines, difficulty in staining for endogenous versus
exogenous cytokines, considerable variation in the microenvironment of the uNK
cell, and obvious ethical considerations.


## 9. Evolutionary Considerations

We have presented evidence that mammalian
uNK cells are important for the development of the placenta’s vascular supply:
immunotropism appears to both promote trophoblast invasion and the remodeling
of spiral arteries. Vascular fusion among terminal ampulla after acceptable
Fu/HC-mediated recognition in B. schlosseri chimerae leads to allogenic
interactions reminiscent of those established at the maternal/fetal interface. Although
the morula cells that mediate the recognition/rejection response of B.
schlosseri can help in the foreign cell recognition that determines the
activity of phagocytic cells [80, 81], they are one of only 3 types of
hematocyte-derived cells in ascidians. The latter, recently-described function is
partially redundant to the role of primary phagocytic cells and may have been
secondarily gained through adaptation. Like human uNK cells, morula cells are
thought to rely largely on the recognition of self rather than the engagement
of nonself ligands. It is from this comparison that we hypothesize that
allorecognition and innate immunity are largely distinct entities with separate
evolutionary origins.Evolutionary precursors of fetal
trophoblasts may have expressed trophoblast MHC products to engage uNK cells,
and only later evolved the classical MHC molecules that participate in immune
defense. It is not difficult to imagine that peripheral NK cells evolved from
uNK or a common precursor cell, possibly in response to viral pathogens not
effectively curtailed by MHC-T-cell-based immunity. One might then speculate
that the intrinsic reactivity existing between T cells and foreign MHC has its
origin in NK cell-trophoblast MHC allorecognition.Can a system of allorecognition used in
modern sessile marine invertebrates for promoting survival and reproduction
have given rise to the vertebrate adaptive immune system? Clearly, given the
survival of invertebrates, all of whom possess only innate immunity, adaptive
immunity is not essential to survival and proliferation of some species.
Intrinsic allorecognition, while present in both colonial ascidians and
mammals, serves different, but vital, functions in each case. To further
unravel the mystery of the fetal-maternal relationship, the uNK cell lineage
needs to be traced back in evolution. Much more information will become available once the genetic analyses of
human uNK cells and the B. schlosseri NK-like cells are performed. Thus far, multiple
analogs and several true homologues linked to MHC genes, cytokines, signaling
proteins, and adhesion molecules have been found in the genome of B.
schlosseri. Recently, it was shown that monoclonal antibodies directed against
human IL-1 and TNF-alpha could stain a subpopulation of stimulated B.
schlosseri blood cells [23]. However, no classic MHC molecule or HLA-G homolog
has yet been found in the B. schlosseri genome [14], and few Fu/HC gene
products have been identified [82].HLA-G-like genes are present in lower
primates [83–85]. In fact, an HLA-G-like product is the only class I
molecule expressed in certain New World Monkeys. This demonstrates that this
molecule can function effectively in innate and adaptive immunity. Further,
significant polymorphism is detectable in the NK receptor-, T cell receptor-,
and peptide-binding regions of the HLA-G-like molecules of New World Primates,
but not of Old World Monkeys, suggesting divergent evolution and divergent
functions [84]. The former certainly has primary immune function and a role in
pathogen defense; this is unlikely to be true for the latter. The presence of
trophoblast MHC homologues should be further investigated in lower mammals and
genetic linkage studies should be performed with the Fu/HC locus to determine a
possible relationship. The most obvious obstacle to finding a true evolutionary
relationship is that homologous molecules operating in nonidentical systems may
have different constraints on structural conservation and, thus, may display
distinct patterns of change [30]. Still, whether B. schlosseri allorecognition
eventually proves to be truly homologous or merely analogous, its use for
comparison has resulted in fresh insight into the governing mechanisms and the
evolutionary origins of the human maternal-fetal relationship.



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