Soluble HLA-DR levels in the maternal circulation of

normal and pathologic pregnancy

Andrea Steinborn, PhD,a Vera Rebmann, PhD,b Alexander Scharf, MD,a Christof Sohn, MD,a and
Hans Grosse-Wilde, MDb
Frankfurt/Main and Essen, Germany

OBJECTIVE: The purpose of this study was to determine that circulating HLA-DR molecules are important
candidates for the monitoring of maternal immunostimulation and immunosuppression.
STUDY DESIGN: Concentrations of soluble HLA-DR molecules were estimated in EDTA plasma samples of
61 nonpregnant women, 123 healthy pregnant women in the second trimester, 66 healthy women who were
delivered at term, and 136 women who were delivered because of complications such as uncontrollable pre-
term intrauterine activation, abruptio placentae, intrauterine growth retardation, preeclampsia, and HELLP
(hemolysis, elevated liver enzymes, low platelet count) syndrome.
RESULTS: In comparison to nonpregnant women, the normal course of pregnancy was associated with
strongly increasing levels of soluble HLA-DR from second trimester on until term. In comparison to women
who were delivered preterm because of uncontrollable intrauterine activation, increased soluble HLA-DR con-
centrations were detected in case of HELLP syndrome (P < .05), although decreased levels were detected in
the case of intrauterine growth retardation, preeclampsia (P < .01), and abruptio placentae (P < .01).
CONCLUSION: Dysregulation of the maternal immune response to pregnancy may play an important role in
the cause of complicated pregnancies. (Am J Obstet Gynecol 2003;188:473-9.)

Key words: Soluble HLA-DR molecules, HELLP (hemolysis, elevated liver enzymes, low platelet
count) syndrome, intrauterine growth retardation, preeclampsia, abruptio placentae

During pregnancy the fetus represents a semiallograft.
The mechanisms by which the maternal immune system
does not reject the fetus, despite the presence of paternal
alloantigens, still remain incompletely understood. Al-
though the placenta acts as a barrier between the maternal
and the fetal circulation, a two-way cell traffic exists across
this barrier.1,2 Therefore, regulation of maternal immune
responses to the fetus seems to be essential for fetal sur-
vival. It has been hypothesized that the fetus must be pro-
tected against destructive maternal immune defense
reactions,3 but it also was proposed that maternal immune
recognition of pregnancy is necessary for its success.4
A striking feature of immune regulation in pregnancy is
the suppression of cell-mediated immunity and the up-reg-
ulation of humoral immune functions. TH2 cytokines (in-
terleukin-4, interleukin-5, interleukin-10) were identified
From the Department of Obstetrics and Gynecology, University of Frank-
furt/Main,a and the Institute for Immunology, University of Essen.b
Supported by a grant from the Held/Hecker Research Foundation at the
University of Frankfurt/Main.
Received for publication April 24, 2002; revised August 29, 2002; ac-
cepted September 20, 2002.
Reprint requests: A. Steinborn, PhD, Department of Obstetrics and Gy-
necology, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frank-
furt/Main, Germany. E-mail: Steinborn@em.uni-frankfurt.de
© 2003, Mosby, Inc. All rights reserved.
0002-9378/2003 $30.00 + 0
doi:10.1067/mob.2003.55
as the predominating mediators at the fetomaternal inter-
face, and systemic immune responses to antigens were
shown to be biased towards TH2 reaction profiles.5 Further
mechanisms of tolerance induction obviously occur at the
fetomaternal interface. Fetal villous cytotrophoblasts and
syncytiotrophoblasts, which are in direct contact with the
maternal circulation, do not express the classic highly poly-
morphic HLA class I or class II molecules, except for low
levels of HLA-C on the extravillous cytotrophoblastic cells.
Alternatively, these cells express the nonclassic HLA-G and
HLA-E antigens, which both can block the cytotoxicity of
maternal natural killer cells.6-8
Loss of these tolerogenic mechanisms may be involved
in the cause of pregnancy-associated diseases such as pre-
eclampsia, intrauterine growth retardation (IUGR),
abruptio placentae, and HELLP (hemolysis, elevated
liver enzymes, low platelet count) syndrome. A common
event of all these disorders is an inadequate trophoblast
invasion of the maternal spiral arteries and poor placen-
tal perfusion in early pregnancy. Insufficiencies of the
uteroplacental circulation can be detected noninvasively
by the use of Doppler ultrasonography. Abnormal
Doppler findings (such as persistent notching of the uter-
ine artery wave forms) are able to predict the occurrence
of these disorders during the further course of the preg-
nancy.9 Recently, it was demonstrated that an increased
number of fetal cells can be detected in the maternal cir-

473
474 Steinborn et al
Table I. Clinical characteristics of patients with complicated pregnancies
3 (preterm intrauterine 4 (abruptio placentae,
Characteristic activation, n = 29) n = 17)
Labor 29 0 0
Rupture of membranes 12 0 0
Cervical insufficiency 5 0
Fetal growth retardation 0 1
Hypertension 0 3
Proteinuria 0 0
Elevated liver enzymes 0 2
Low platelet count 0 1
Preterm delivery <37 wk 29 16
Term delivery >37 wk 0 1
culation in the case of preeclampsia.10 Moreover, it was
shown that there is a TH1/TH2 imbalance in patients with
preeclampsia with predominant TH1-type immunity.11
Further findings suggest that Fas antigen expression on
cytotoxic T lymphocytes is higher in patients with severe
preeclampsia12 and that preeclampsia is associated with
increased placental apoptosis.13
All these findings propose that cell-mediated immunity
may play a role in the cause of preeclampsia and probably
in the cause of other complications, especially of compli-
cations that are associated with poor invasion of the spiral
arteries in early pregnancy. Induction of cell-mediated
immune responses of the mother to fetal antigens may
cause the activation of maternal antigen-presenting cells,
TH1 lymphocytes, and cytotoxic T cells. Such activated
cells express high amounts of HLA-DR antigens on the
cell surface, and increased amounts of these molecules
may be shed into the maternal circulation. Therefore,
soluble HLA-DR (sHLA-DR) serum level may appear as a
useful parameter with which to monitor the maternal im-
mune response during pregnancy. The aim of this study
was to investigate the levels of sHLA-DR under physio-
logic and pathologic conditions in the blood of nonpreg-
nant and pregnant women. The results that were
obtained may contribute to our understanding of the
role of the maternal immune response in normal and
pathologic pregnancies.
Material and methods
Human subjects. Soluble HLA-DR levels were deter-
mined in the EDTA plasma that was obtained from
pregnant women (n = 325) and a control panel of non-
pregnant women (n = 61). Blood samples from women in
the second trimester were taken at hospital admission,
and blood samples from women in the third trimester
were taken within 24 hours before delivery. Samples were
collected into tubes that contained EDTA and were cen-
trifuged at 1500g for 10 minutes at 4°C. The plasma was
removed and stored in aliquots at –80°C until they were
assayed. The study was approved by the Regional Ethics
February 2003
Am J Obstet Gynecol
Patient group (No.)
5 (IUGR, 6 (preeclampsia, 7 (HELLP syndrome,
n = 18) n = 55) n = 17)
0 0
3 0
0 0 0
18 14 2
7 55 4
0 55 17
0 2 17
0 3 17
11 45 16
7 10 1
Committee. All women were fully informed of the aim of
the study, and informed consent was obtained from all
participants. The pregnant women were stratified into
seven different groups, according to pregnancy compli-
cations and outcome (Table I).
Group 1 consisted of 123 healthy women (19-24 weeks
of gestation) who had attended our ultrasonographic
unit for the detection of fetal malformations. Uterine
artery Doppler velocimetry was applied for the identifica-
tion of pregnancies with probable adverse perinatal out-
come but were not taken into consideration for the
obstetric treatment. At the time of blood sampling, the
risk factors that may affect uteroplacental circulation
(such as hypertension, oligohydramnion, or IUGR) were
not present in these women. Pregnancy outcomes of all
these women were evaluated by a review of the maternal
and neonatal hospital records after the delivery (Table
II).
Group 2 consisted of 66 healthy women who were de-
livered of term neonates (38-42 weeks of gestation) with
normal birth weight after the onset of spontaneous term
labor or elective cesarean delivery because of
cephalopelvic disproportion, breech presentation, or
fear of vaginal birth. None of these patients showed any
clinical signs of preeclampsia or HELLP syndrome.
Group 3 consisted of 29 women who were delivered
preterm (25-37 weeks of gestation) because of uncontrol-
lable intrauterine activation. This diagnosis was made in
the case of uncontrollable labor, rupture of fetal mem-
branes, or cervical insufficiency. Intra-amniotic infection,
which was confirmed by histologic examination of the
fetal membranes, umbilical cord, and chorionic plate was
not diagnosed for these patients.
Group 4 consisted of 17 women (25-38 weeks of gesta-
tion) with diagnosis of abruptio placentae, which was de-
fined as the complete or partial separation of the
placenta before delivery. The diagnosis was based on the
clinical presentation and examination of the delivered
placenta by the attendant at delivery. Other pregnancy
complications (such as IUGR, preeclampsia, or intrauter-
Volume 188, Number 2
Am J Obstet Gynecol
Table II. Pregnancy outcome of 123 patients with and without persistent notching of the uterine arteries after 19 to 24
weeks of gestation and sHLA-DR levels
Abnormal Doppler findings
(bilateral uterine notching)
Pregnancy outcome No. Median sHLA-DR level (range)
Normal pregnancy 30
Affected pregnancies 43
Preeclampsia 14
IUGR 25
Abruptio placentae 4 623 (233-1199)
Totals 73
Levels are given in nanograms per milliliter.
ine infection) that increased the risk for placental abrup-
tion were not diagnosed for these patients.
Group 5 consisted of 18 patients (25-38 weeks of gesta-
tion) who were delivered by cesarean delivery or vaginally
after the induction of labor because of a growth-restricted
fetus. Labor was induced in the case of ultrasonographic
detection of fetal growth arrest and advanced gestational
age. Cesarean delivery was performed in the case of
pathologic fetal Doppler findings or fetal heart rate pat-
terns that necessitated cesarean delivery. After delivery,
IUGR was diagnosed in the case of a birth weight of <10th
percentile for gestational age. None of the fetal growth-
restricted cases was complicated by preeclampsia.
Group 6 consisted of 55 patients (25-41 weeks of gesta-
tion) with clinical symptoms of preeclampsia. The disease
was diagnosed in the presence of a blood pressure of
>140/90 mm Hg on two separate occasions, 6 hours
apart, along with significant proteinuria (>300 mg/L in a
24-hour collection period or a dipstick reading of >2+ on
a voided random urine sample in the absence of urinary
tract infection) in previously normotensive women.
Group 7 consisted of 17 women (25-39 weeks of gesta-
tion) with HELLP syndrome. The diagnosis of HELLP
syndrome was made if hemolysis, elevated liver enzyme
levels, and thrombocytopenia were present. The labora-
tory parameters of these patients were serum haptoglo-
bin concentrations of <0.3 g/L, a thrombocyte count of
<150,000 cell/µL, and aspartate aminotransferase and
alanine aminotransferase levels of >30 U/L. All patients
in this group had significant proteinuria and showed
characteristic clinical symptoms (such as left-sided epi-
gastric pain, flickering in front of one’s eyes and exagger-
ated reflexes).
Determination of sHLA-DR molecules. sHLA-DR levels
were measured by enzyme-linked immunosorbent assay
technique, as described previously.14 For the capture of
sHLA-DR molecules, microtiter plates were coated
overnight at 4°C with monoclonal antibody (mAb) L243
(immunoglobulin G2a; Becton Dickinson, Heidelberg,
Germany) that was specific for the HLA-DR α/β het-
erodimer plus peptide at a final concentration of 0.04
Steinborn et al 475
Normal
Doppler findings
No. Median sHLA-DR level (range)
492 (140-4023) 37 520 (196-4976)
480 (147-4634) 13 574 (189-3160)
444 (147-3022) 3 381 (211-1049)
502 (160-4634) 10 624 (189-3160)
0 —
494 (140-4634) 50 574 (189-4976)
µg/mL. After free binding sites were blocked with 1%
bovine serum albumin in phosphate-buffered saline solu-
tion, undiluted serum samples were incubated for 1.5
hours at 37°C, and bound sHLA-DR molecules were de-
tected by mAb CR3/43 (immunoglobulin G1; Dakopatts,
Hamburg, Germany), which recognized a monomorphic
determinant on HLA class II β chains. Bound mAb
CR3/43 was detected by an alkaline phosphatase conju-
gated anti-murine immunoglobulin G1 (Serva, Heidel-
berg, Germany). 4-Methylumbelliferylphosphate (1
nmol/L) in diethanolamine (1 mol/L) and magnesium
chloride (0.5 mol/L) served as substrate solution. After
substrate turnover, the fluorescence intensities were mea-
sured at an excitation wavelength of 355 nm and an emis-
sion wavelength of 460 nm with the use of a fluorescence
reader (Fluoroskan II; Labsystems, Helsinki, Finland) for
microtiter plates. To calculate the protein concentration
of sHLA-DR molecules, a standard curve was performed
by serial dilutions of affinity purified HLA-DR1 (provided
by Dr S. Jurcevic, Harefield Hospital, UK). The minimum
detectable sHLA-DR concentration was 100 ng/mL. The
intra-assay and interassay variations were <5% and <10%,
respectively.
Statistical analysis. After distribution, the analysis data
were presented as median value and the respective range.
The statistical significance of the differences between the
patient groups was evaluated after the gaussian distribu-
tion was tested by the nonparametric H test of Kruskal
and Wallis, which is used for simultaneous comparison of
>2 study populations. Each H test was followed by a Dunn
test. A probability value of <.05 was considered to be sta-
tistically significant. Further, Spearman correlation and
regression analysis were used to relate sHLA-DR values
with the gestational week.
Results
sHLA-DR levels in healthy nonpregnant and pregnant
women. EDTA plasma samples from 61 female blood
donors were studied for the content of sHLA-DR plasma
levels to establish reference values for nonpregnant
women. The median sHLA-DR value for these women was
476 Steinborn et al
Fig 1. Detection of soluble HLA-DR molecules in circulation of
pregnant women during normal course of pregnancy (A) and
women who were delivered preterm because of complicated
pregnancy (B). None of the women who were delivered at term
had any clinical signs of disease, and normal term delivery of all
women tested in the second trimester was confirmed by review of
maternal and neonatal hospital records after delivery. sHLA-DR
levels were significantly different between nonpregnant women
and pregnant women in second trimester and increased to 10-
fold until term. In case of preterm delivery because of compli-
cated pregnancy, striking differences of sHLA-DR plasma levels
were measured. In comparison to women who were delivered
preterm because of uncontrollable intrauterine activation (PIA;
labor, advanced cervical dialtation, rupture of fetal membranes),
significantly increased sHLA-DR plasma levels were found in cir-
culation of women with HELLP syndrome; significantly de-
creased sHLA-DR levels were found in circulation of women with
preeclampsia or abruptio placentae.
324 ng/mL (Fig 1, A), with a range of 21-1496 ng/mL. To
establish sHLA-DR levels for pregnant women at different
trimesters, samples of 123 healthy women of group 1 and
66 healthy women of group 2 were tested. In group 1, an
early diastolic notch was diagnosed for 73 patients, and
50 patients did not have an early diastolic notch on either
side of the uterine arteries. Pregnancy outcomes and
sHLA-DR levels of these patients are summarized in Table
II. From the 123 patients, 67 patients had uncomplicated
pregnancies and were delivered of normal healthy
neonates at term (38-42 weeks of gestation). The median
sHLA-DR value of these patients was 497 ng/mL (range,
140-4976 ng/mL). No significant differences of sHLA-DR
levels were found between these patients and patients
February 2003
Am J Obstet Gynecol
with pregnancy-related complications (such as pre-
eclampsia, IUGR, or abruptio placentae). Further, there
was no significant difference of HLA-DR levels between
patients with detectable bilateral notching of the uterine
arteries (median value, 494 ng/mL; range, 140-4634
ng/mL) and those patients without (median value, 574
ng/mL; range, 189-4976 ng/mL). In the healthy women
of group 2, a median sHLA-DR value of 3511 ng/mL
(range, 1395-6010 ng/mL) was found. Fig 1, A, presents
the sHLA-DR levels that were obtained from plasma sam-
ples of healthy nonpregnant and pregnant women in the
second trimester and at term delivery. Compared with
nonpregnant women, sHLA-DR level was increased sig-
nificantly (P < .01) in the case of the successful establish-
ment of pregnancy in the second trimester and steadily
increased to a 10-fold level until term.
sHLA-DR levels in pregnant women with pathologic
pregnancies. Further estimations of sHLA-DR levels were
done in plasma samples of women with pathologic preg-
nancies. Because sHLA-DR increases during the course of
pregnancy, only sHLA-DR levels that were obtained from
women who were delivered preterm (25-37 weeks of ges-
tation) were included in the comparison for the different
pregnancy complications. A median sHLA-DR value of
1488 ng/mL (range, 344-4420 ng/mL) was found in 29
women who were delivered preterm because of uncon-
trollable intrauterine activation (group 3). Soluble HLA-
DR plasma levels of these women were between the levels
of healthy pregnant women in the second trimester and
women at term. Therefore, sHLA-DR values of this pa-
tient group seem to be within the normal range with re-
gard to the fact that sHLA-DR increases during
pregnancy. In contrast, striking differences of HLA-DR
levels were detected in the circulation of patients who
were delivered preterm because of pregnancy complica-
tions that were associated with inadequate trophoblast in-
vasion of the spiral arteries in early pregnancy (such as
placental abruption [group 4], IUGR [group 5], pre-
eclampsia [group 6], and HELLP syndrome [group 7]).
In comparison with patient group 3 (Fig 1, B), signifi-
cantly decreased concentrations of sHLA-DR were mea-
sured in the circulation of 16 patients who were delivered
preterm because of placental abruption (median value,
389 ng/mL; range, 183-1462 ng/mL; P < .01) and of 45
patients who were delivered preterm because of pre-
eclampsia (median value, 523 ng/mL; range, 35-3655
ng/mL; P < .01). Decreased levels of sHLA-DR were also
detected in the circulation of 11 patients who were deliv-
ering preterm because of IUGR (median value, 676
ng/mL; range, 194-3372 ng/mL), but the differences
were not significant. For women with HELLP syndrome
(n = 16), however, increased sHLA-DR levels (median
level, 5046 ng/mL; range, 804-11391 ng/mL; P < .05)
were detected. Within group 6 (n = 55) no significant dif-
ference was found between sHLA-DR levels that were ob-
Volume 188, Number 2 Steinborn et al 477
Am J Obstet Gynecol

tained at preterm (n = 45) and at term delivery (n = 10;

data not shown).
The relationship of sHLA-DR levels to the gestational
week in healthy and pathologic pregnancies is shown in
Fig 2. A positive linear correlation (r = 0.821, P < .0001) of
sHLA-DR levels and gestational week was found for
healthy pregnant women. Most sHLA-DR levels from
women with uncontrollable intrauterine activation were
very close to the 95% CI of the regression line that was
obtained from healthy pregnant women, which indicates
that these sHLA-DR values were normal for the respective
gestational week. Contrary to this observation, most
sHLA-DR levels from patient group 4 through 6 fell below
the regression line, which included the 95% CI obtained
in healthy pregnant women. This substantiates that the
differences of sHLA-DR levels that were found in these
groups are due to pregnancy pathologic condition rather
than gestational week. The sHLA-DR values of patients
with HELLP syndrome revealed the characteristic distrib-
ution above the regression line, which indicated the dras-
tic sHLA-DR increase.

Comment
During early pregnancy, the fetal tissues invade the ma-
ternal decidua. A successful course of pregnancy depends
on adequate placentation and requires sufficient blood
supply to the intervillous space of the growing placenta.
Therefore, remodeling of the uterine arteries is neces-
sary, and reduced invasiveness of the cytotrophoblastic
cells is associated with the development of diseases (such
as preeclampsia, HELLP syndrome, IUGR, and abruptio
placentae).9 Because ongoing invasion invariably brings
the conceptus into contact with maternal immunocom-
petent cells, fetomaternal interactions during the embry-
onic and fetal development are of decisive importance,
concerning success of pregnancy and fetal outcome.
Our results clearly demonstrate that sHLA-DR mole-
cules are increased significantly in the blood of healthy
pregnant women in the second trimester in comparison
with nonpregnant women and further increase approxi-
mately 10-fold at term. The increase of sHLA-DR that is
Fig 2. Detection of sHLA-DR molecules in circulation of patients
observed during the course of pregnancy appears to be
with (A) preterm intrauterine activation (open squares) and
specific because, in healthy control subjects and in healthy patients who were delivered at term (n = 132, closed dia-
healthy nonpregnant women, sHLA-DR plasma levels are monds), (B) IUGR (n = 18, open squares), preeclampsia (n = 55,
found to be stable.15,16 Because remarkable activation of open triangles), and abruptio placentae (n = 17, asterisks), or (C)
maternal peripheral blood leucocytes is reported in the HELLP syndrome (n = 17, open squares) during the course of
pregnancy in comparison with patients in second trimester (19-
third trimester17 and HLA-DR molecules are normally
24 weeks of gestation, normal Doppler findings, normal preg-
shed from activated immunocompetent cells, it seems nancy outcome), patients who were delivered preterm because
likely that the increasing sHLA-DR concentrations in the of intrauterine activation (25-37 weeks of gestation), and healthy
circulation of pregnant women are attributed to an in- patients who were delivered at term (38-42 weeks of gestation).
tensified maternal immune response towards the fetus. In Obviously, uncontrollable intrauterine activation is not associ-
ated with abnormal concentrations of sHLA-DR concentrations
contrast, the maternal immune system should not be
in maternal blood. In contrast, strong deviations of sHLA-DR lev-
stimulated to a great extent in early pregnancy because els were found in cases of pregnancy complications that were as-
the extravillous trophoblasts are negative for classic HLA sociated with insufficient trophoblast invasion, such as abruptio
molecules but positive for nonclassic HLA-G and HLA-E. placentae, IUGR, preeclampsia, and HELLP syndrome.
478 Steinborn et al
These molecules protect the fetal cells from maternal
T- and natural killer–cell activities and facilitate the inva-
sion of trophoblast cells into the maternal tissues during
early gestation.7,8 Moreover fetal trophoblast cells protect
themself by the expression of Fas ligand, thereby confers
immune privilege in a similar manner as the cornea and
Sertoli cells of the testis. Synthesis of Fas ligand enables
these cells to induce apoptosis of cells that express Fas
(CD95), such as natural killer cells, TH1 cells, and acti-
vated cytotoxic T cells.18
Our interpretation of increasing amounts of sHLA-DR
in the second and third trimester as a maternal immune
reaction against the fetus implicates circulating fetal cells,
which express paternal alloantigens and an increasing
cell traffic during the course of pregnancy. This already is
reported for fetal erythroblasts but may not be restricted
to that cell type.10,19 On the other hand, sHLA-DR mole-
cules in the blood of pregnant women may not originate
exclusively from activated immunocompetent cells of the
mother but also from the fetus. Recent reports clearly
demonstrated the presence of fetal-derived soluble HLA
antigens in the maternal blood.20 Therefore, the increase
of sHLA-DR molecules in the maternal blood during the
course of pregnancy may be attributed partly to increas-
ing amounts of fetal-derived sHLA-DR molecules. Be-
cause sHLA-DR molecules are able to induce apoptosis in
a T-cell–restricted manner,21 even low amounts of fetal-
derived sHLA-DR can be important for the regulation of
the maternal immune system or for the maintenance of
the fetomaternal immune balance during pregnancy.
The observed deviation of sHLA-DR levels in patho-
logic pregnancies may mirror abnormalities in the trans-
fer of fetal-derived cells or soluble antigens. Therefore,
decreased or increased sHLA-DR levels may reflect dis-
turbed blood supply to the placenta, which leads to a di-
minished or enhanced exchange of fetal-derived cells
and antigens. Uncontrollable preterm labor, advancing
cervical dilatation, or rupture of fetal membranes are not
characterized by an anomalous fetomaternal cell or anti-
gen traffic. In case of these pregnancy disorders, we
found normal sHLA-DR levels that seem to correspond
with the gestational week. In women with IUGR, placen-
tal abruption and preeclampsia, however, we found re-
duced sHLA-DR levels. Interestingly, these three
pregnancy pathologic conditions were characterized by
insufficient trophoblast invasion in early pregnancy. In a
previous study, increasing sHLA-DR levels were found
after in vitro fertilization to be associated with intact preg-
nancy and decreasing sHLA-DR levels in early fetal loss.15
For preeclampsia, several reports demonstrated an exces-
sive maternal inflammatory response that seems to be me-
diated by granulocytes and monocytes.17,22,23 For
preeclampsia, it is further documented that both TH1 and
TH2 responses are up-regulated and that HLA-DR, as a
marker for activation, was shown to be expressed stronger
February 2003
Am J Obstet Gynecol
on T cells in patients with preeclampsia than in normal
subjects.24 In addition to these reports, other studies
demonstrated an increased number of fetal cells and fetal
DNA in the periphery of women with preeclamp-
sia.10,25,26 Based on this, one may expect increased sHLA-
DR levels in preeclampsia. Surprisingly, we found
decreased sHLA-DR plasma levels in women with pre-
eclampsia and increased sHLA-DR plasma levels in cases
of HELLP syndrome. Our findings could support the as-
sumption that the pathogenesis of these two pregnancy
complications are different, although most investigators
share the opinion that the HELLP syndrome represents
an advanced stage of preeclampsia. Our opinion is that
the strong divergent sHLA-DR plasma levels in pre-
eclampsia and HELLP syndrome do not rule out the pos-
sibility that disturbances of the maternal immune
response against the fetal antigens could be involved.
Chronic rejection of the fetal allograft may cause increas-
ing infiltration of HLA-DR expressing cells (ie, activated
immune cells into the lymphatic organs). Thus, reduced
numbers of activated immune cells may circulate in the
maternal blood. It seems likely that decreased amounts of
sHLA-DR molecules, which to all probability are derived
by shedding from activated immune cells, are due to re-
duced numbers of activated immune cells in the maternal
circulation. On the other hand, we observed drastically
elevated levels of sHLA-DR molecules in almost all pa-
tients with HELLP syndrome. It is interesting to note that
acute rejection after organ transplantation or severe graft
versus host disease after bone marrow transplantation is
associated with increased plasma levels of sHLA-DR.27
Therefore, our observations propose that HELLP syn-
drome in contrast with preeclampsia reflects acute rejec-
tion of the fetal allograft. Moreover, measurement of
sHLA-DR levels may be helpful for the identification of
women with preeclampsia who are at increased risk for
HELLP syndrome during the further course of the preg-
nancy. Further evidence for disturbed immune responses
are provided by the fact that both HELLP syndrome and
preeclampsia are found to be associated with the occur-
rence of autoantibodies in the maternal circulation.28,29
In conclusion, the results of this study clearly demon-
strate substantial similarities between pregnancy disor-
ders that are associated with insufficient trophoblast
invasion and propose that the regulation of maternal im-
mune functions may play a decisive role in the pathogen-
esis of these diseases.
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