THYROID

Volume 9, Number 7, 1999

Mary Ann Liebert, Inc.

The Immunology of Pregnancy

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ANTHONY P. WEETMAN

ABSTRACT

Pregnancy is an immunological balancing act in which the mother's immune system has to remain tolerant of pa-
ternal major histocompatibility (MHC) antigens and yet maintain normal immune competence for defense against
microorganisms. The placenta separates fetal and maternal blood and lymphatic systems and it is fetal trophoblast
that plays the major role in evading recognition by the maternal immune system. Trophoblast cells fail to express
MHC class I or class II molecules and the extravillous cytotrophoblast cells strongly express the nonclassic MHC
gene encoding HLA-G, which may downregulate natural killer (NK) cell function. In addition, the trophoblast
expresses Fas ligand, thereby conferring immune privilege: maternal immune cells expressing Fas will undergo
apoptosis at the placenta/decidua interface. A third protective mechanism exploited by the trophoblast is the ex-
pression of the complement regulatory proteins CD46, CD55, and CD59. Uterine decidual and placental cells
produce a huge array of cytokines which, in part, contribute to the deviation of the immune response from Thl
to Th2. This may leave the mother more open to infection whose control is Thl-dependent, but increased pro-
duction of Thl cytokines has been linked to spontaneous abortion and small-for-dates babies. This bias in cy-
tokines and hormonally mediated effects on the thymus and on B cells may also contribute to the suppression of
autoimmune responses and changes in circulating and local T-cell subsets in pregnancy.

INTRODUCTION (3), and it is very likely that it is a multiplicity of mecha-

nisms, rather than any one factor, which maintains preg-
is
immunological balancing The act. fe- nancy. This review briefly describes the local and systemic
Pregnancy
an

expresses both maternal and paternal major histo-

tus
and because the cellular im-
compatibility (MHC) antigens,
mune response involved in transplantation rejection is
directed against these antigens, the mother must avoid such
a fate for the fetus. At the same time, generalized im-
munosuppression, for instance of the kind used to main-
tain graft survival, is too high a price to pay because of
the consequences with regard to infection and loss of tu-
mor surveillance.
The potential immunological mechanisms involved in
maintaining pregnancy were originally described by
Medawar (1): (1) the fetus does not engender an immune
response; (2) the maternal immune response is suppressed;
(3) the uterus is an immunologically privileged site; and (5)
the placenta is a barrier between mother and fetus. We
now know that allografts placed in an intrauterine site can
be rejected, albeit slowly, and that the maternal immune
system is not generally suppressed (2). On the other hand,
deviation of the maternal immune system, from a Thl to
a Th2 response, may be necessary for successful pregnancy
effects and interactions of pregnancy and the immune sys-
tem.
CONCEPTION
Spermatozoa are HLA class I- and Il-negative that helps
them evade recognition by the immune system. In addi-
tion, they express the complement regulatory protein CD46
on the inner acrosomal membrane (2). However, other
antigen molecules foreign to the mother are present on
spermatozoa and there are many class I- and Il-positive
cells in the ejaculate. Maternal responses to these may be
suppressed by immunomodulators in seminal plasma, and
these may contribute indirectly to the success of pregnancy.
Lack of adequate exposure to seminal plasma increases the
risk of implantation failure, spontaneous abortion, and
preeclampsia. Recent work suggests that a key molecule
involved in this effect of seminal plasma, at least in mice,
is transforming growth factor-i (TGFi) that induces an

Section of Medicine, Clinical Sciences Centre, University of Sheffield, Northern General Hospital, Sheffield, United Kingdom.
643
 644
endometrial inflammatory infiltrate and stimulates epithe-
lial expression of a number of proinflammatory and
chemoattractant molecules (colony-stimulating factors,
regulated on activation, normal T-cell expressed and se-
creted (RANTES), macrophage inflammatory proteins, in-
terleukin-6 [IL-6]) (4). In turn, this response causes local
activation of macrophages which may serve to clear de-
bris, or, more contentiously, initiate a Th2 (protective) re-
sponse and/or induce tolerance to paternal MHC. Such tol-
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erance is demonstrated by crossing 2 histoincompatible
strains of mice and then transplanting paternal strain tu-
mor cells: all virgin females reject the cells but none of the
pregnant or pseudopregnant (uterine ligated) females do so
(4). Thus exposure to ejaculate induces hyporesponsiveness
to paternal MHC antigens.
THE TROPHOBLAST
The placenta separates fetal and maternal blood and
lymphatic systems. The chorionic villi are composed of fe-
tal stem vessels and mesenchyme surrounded by villous cy-
totrophoblast and syncytiotrophoblast, the latter forming
a continuous multinuclear cell layer without intercellular
junctions. This layer is essentially endothelial with regard
to the maternal circulation. Extravillous cytotrophoblasts
proliferate from chorionic villi, forming a shell, and invade
the maternal decidua.
Clearly it is the trophoblast that must play the major
role in evading recognition by the maternal immune sys-
tem. The simplest of the strategies used by the trophoblast
is the failure of these cells to express either MHC class I
or class II molecules and this ensures that maternal T cells
bearing the a T-cell receptor cannot mount a classic cy-
totoxic attack against fetal paternal alloantigens (5). In ad-
dition, the placental extravillous cytotrophoblast cells
strongly express the nonclassic (MHC class lb) gene en-
coding HLA-G (6). This is tissue-specific, as no other adult
tissue expresses HLA-G, which has only limited polymor-
phism. Expression of HLA-G may serve at least 2 im-
munological functions. First, it may be important in down-
regulation of natural killer (NK) cell function; trophoblast
cells are not killed by NK cells unless HLA-G is blocked.
Secondly, HLA-G may be recognized by certain T cells. For
instance, it may serve as an activator of CD8+ T cells as
CD 8 can bind to HLA-G and these cells may have a sup-
pressor function.
The trophoblast also protects itself through expression
of Fas ligand (FasL), thereby conferring immune privilege
in the same way as for cornea and Sertoli cells of the testis
(7). Fas (CD95) and FasL are members of the tumor necro-
sis factor-receptor/nerve growth factor-receptor superfam-
ily and their interaction leads to programmed cell death or
apoptosis (8). Fas is expressed on many cells, whereas FasL
is restricted to sites of privilege and to the immune system,
where interaction between Fas and FasL is important in
eliminating self-reactive T cells (most clearly demonstrated
by the generalized autoimmunity seen in mice with defec-
tive Fas or FasL expression). In mice, FasL is expressed on
uterine glandular epithelial cells and decidual cells and on
placental trophoblast cells, predominant expression shift-
ing through pregnancy from uterus to placenta (9). The
WEETMAN
importance of this is obvious, as FasL will be positioned
to induce apoptosis in maternal Fas+ T cells. The conse-
quences are shown in gld mice, with a genetic defect re-
sulting in a lack of functional FasL; these animals have ex-
tensive leucocytic infiltrates at the placenta-decidua
interface, frequent rsorption sites, and small litter sizes
(9).
At least in part through such Fas/FasL interactions, the
maternal T cells acquire a transient state of tolerance spe-
cific for paternal alloantigens. This has been clearly shown
in experiments using H-2k female mice transgenic for T-
cell receptor recognizing H-2b; when mated with H-2b
males, there was a reduction in H-2b-specific T cells at
midgestation (10). This recognition and tolerance of ma-
ternal T cells occurs outside the thymus and reverses after
delivery. If fetal components are so recognized, then ma-
ternal MHC-peptide complexes expressed by the fetus
could also tolerize the maternal immune system and this
could account for remission of autoimmunity, including
thyroid autoimmune disease, during pregnancy, without
the occurrence of generalized immunosuppression.
A third protective mechanism exploited by the tro-
phoblast is expression of complement regulatory proteins,
which inhibit the activation of complement by classic or
alternative pathways. From at least 6 weeks of gestation,
the trophoblast expresses CD46 (membrane cofactor pro-
tein), CD55 (decay accelerating factor) and CD59: the first
2 essentially inhibit C3 convertase activity while CD59 pre-
vents membrane attack complex formation at the terminal
stage of complement activation (11). Relative differences
in expression of the 3 molecules exist at different tro-
phoblast sites. The most important roles of these proteins
are to prevent activation of maternal C3 via the alterna-
tive pathway and to counter any tendency to complement-
mediated injury via maternal immunoglobulins with fetal
specificities: maternal immunoglobulin G (IgG) is obvi-
ously transported across the placenta (Table 1) and this
could otherwise pose a considerable threat to the fetus.
CYTOKINES AND OTHER SOLUBLE FACTORS
A huge arrange of cytokines are produced by uterine and
decidual cells and by the placenta (12): these include
colony-stimulating factors, interleukin (IL) IL-1, IL-2, IL-
4, IL-5, IL-6, IL-10, type 1 interferon, interferon-y, tumor
necrosis factor-a, and TGF/3. Th2 cytokines tend to pre-
dominate locally at the maternal-fetal interface in preg-
Table 1. Mechanism for Placental
Transfer of IgG after Midgestation
IgG binds to receptor(s) (unknown).
Internalized by endocytosis.
Binds to FcRn at acidic pH in vesicles.
FcRn releases IgG at neutral pH of stroma.
IgG binds to FcyRII on fetal capillary endothelial cells to
be transferred into bloodstream (IgG2 transfer impaired).
Babies have normal immunoglobulin G (IgG) levels (15 g/L)
irrespective of those in mother.
FcR, Fc receptor.
 IMMUNOLOGY OF PREGNANCY 645

nancy, with corresponding bias against a potentially harm- richment of y<5+ T cells, together with a higher than usual
ful (as far the pregnancy is concerned) Thl response (3, proportion of CD8+ a+ T cells, in the decidua in early
as

13). However, this does leave the mother more open to in- pregnancy (25). Both populations could be acting to in-
fection whose control is Thl-dependent, eg, Leishmania hibit maternal responses against fetal antigens, preventing
(14) and Bartonella (15). Studies of cytokines derived from infection or preventing extensive trophoblast invasion of
cultured lymphocytes have shown increased production of the uterus. The y+ T cells respond to trophoblast anti-
Thl cytokines (IL-2 and interferon-y) and reduced pro- gens independent of MHC, suggesting a unique maternal-
duction of IL-10 in women whose pregnancies ended in fetal recognition system (26) compatible with any of these
spontaneous abortion of small-for-dates babies (16,17) possibilities.
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supporting substantial animal evidence that stimulation

and overexpression of Thl cytokines are harmful in preg-
nancy (18). Of course, this is an oversimplification as there MICROCHIMERISM
is a spectrum of cytokine effects in pregnancy, and Thl cy-
tokines are involved in at least 3 aspects of pregnancy: im- Despite the placental barrier, fetal cells commonly ap-
plantation of the very early embryo within the uterus, ini- pear in the maternal circulation early in gestation in nor-
tiation of labor, and in protecting the fetus from viruses mal women; excessive or persistent microchimerism may
and other agents such as Toxoplasma (19). It is, therefore, be implicated in scleroderma and other autoimmune dis-
the time, concentration, and site of appearance of cytokines eases by mechanisms similar to graft-versus-host disease
that determine their effects on pregnancy. (27). As an alternative, the presence of these engrafted cells
A large number of different factors contribute to the bal- or their proteins could break tolerance or could impair the
ance between Thl and Th2 cells in pregnancy. These in- function of host autoantigen-specific immunoregulatory
clude the local productions of cytokines by placenta and cells (28). In either case, such mechanisms could explain
uterus already mentioned, immunoregulatory placental fac- the exacerbation of autoimmune reactivity postpartum, be-
tors such as placental suppressor factor, and trophoblast- cause delivery is a time for major entry of fetal cells into
derived factor, progesterone-induced blocking factor, and the mother's circulation.
presumably exogenous factors such as intercurrent infec-
tion or autoimmune disease in the mother (18). Further in-
vestigations in this area may lead to ways of predicting and SUMMARY
preventing pregnancy loss and to fresh insights into the
changes in thyroid autoimmunity during and after preg- The fetal partial allograft is sustained through pregnancy
nancy. Rather than a generalized immunosuppression, it is by several mechanisms. The most important of these ap-
now clear that there is an immunological bias during preg-
pear to lie at the uterus-placenta interface, particularly with
nancy toward a Th2 response and this does not seem to the placental expression of HLA-G, FasL, and complement
fit with the decline in thyroid antibody levels generally seen
regulatory proteins, and failure to express MHC class I and
during pregnancy (20). If, however, Thl responses are es- II molecules. At least in mice, maternal T cells are partially
sential to maintain autoantibody production, then the and transiently tolerized to paternal alloantigens. The ma-
changes are easier to understand. In addition, the very high ternal helper T-cell response is biased away from a Thl
estrogen levels in pregnancy may act directly to inhibit B- and toward a Th2 response; this protects the fetus but at
cell lymphopoiesis (21). Not all autoimmune disease re- the expense of a risk of infections needing Thl control.
missions during pregnancy may need to invoke complex Excessive Thl
responses in pregnancy appear harmful to
lymphocytic interactions; the reduction in polymorphonu- the pregnancy. The alterations in the maternal immune re-
clear leukocyte function in pregnancy, secondary to the sponse
during pregnancy are associated with remission of
changes in cytokines, may well explain the amelioration of some diseases antepartum and exacerbation postpartum,
rheumatoid arthritis (22). but the exact mechanisms involved remain speculative.

T-CELL SUBSETS
The most detailed, recent survey of circulating T cells in
pregnancy has concluded that there is an early increase of
suppressor-type T cells (CD8+, CDllb+) and NK cells
with strong cytotoxicity (CD16+, CD54"), late decreases
in helper T cells and NK cells and postpartum increases in
helper T cells, cytotoxic T cells (CD8+, CDllb"), yS T-
cell receptor-bearing T cells and CD5+ B cells (23). The
reasons for these changes are unknown but they may well
reflect modulation by the cytokines and other pregnancy-
associated factors just discussed and by hormonal changes:
certainly the thymus undergoes considerable morphologi-
cal alteration during and after pregnancy due to neuroen-
docrine influences (24).
Mention should also be made of the 2- to 4-fold
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Address reprint requests to:
Anthony P. Weetman
Section of Medicine
Clinical Sciences Centre
University of Sheffield
Northern General Hospital
Sheffield S5 7AU
United Kingdom
E-mail: contact@a-weetman.demon.co.uk