【参考文献】American Journal of Reproductive
Immunology (AJRI)に掲載予定
Antiphospholipid Antibodies in Recurrent
Early Pregnancy Loss and Mid to Late Fetal
Loss*
Toshitaka Sugi, M.D., Ph.D., Hidehiko Matsubayashi,
M.D., Ph.D.,
Tsunehisa Makino, M.D., Ph.D..
From the Department of Obstetrics and Gynecology,
Tokai University School of Medicine, Isehara,
Japan.
*Report of the Japan Antiphospholipid Project
Group
注)青字の部分は特に目を通して欲しいところです。
ABSTRACT
PROBLEM: Associations have been reported
between antiphospholipid antibodies (aPL),
mainly anticardiolipin antibodies (aCL) and/or
the lupus anticoagulant, and recurrent pregnancy
losses (RPL). However, relatively few studies
describing antiphosphatidylethanolamine antibodies
(aPE) have been reported.
METHODS: Patients with recurrent early pregnancy
losses (n=145) and mid to late pregnancy
loss(es) (n=26) were screened for aPE and
aCL.
RESULTS: In patients with recurrent early
pregnancy losses, prevalence of IgG aPE (17.9%,
p=0.001) and IgM aPE (12.4%, p=0.01) was
significantly higher than in the control
group. In patients with mid to late pregnancy
loss(es), prevalence of IgM aPE (19.2%, p=0.008)
and IgG aCL (23.1%, p=0.02) was significantly
higher than in the control group.
CONCLUSIONS: Our data suggest that aPE may be a risk
factor in patients with mid to late fetal
loss(es) as well as recurrent early pregnancy
losses.
Key words:
Antiphosphatidylethanolamine antibodies,
anticardiolipin antibodies, kininogen, antiphospholipid
syndrome
INTRODUCTION
Antiphospholipid syndrome has been described
as the association of thromboembolic events
and/or pregnancy loss with presence of lupus
anticoagulant and antiphospholipid antibodies
(aPL) to anionic phospholipids (PL) such
as cardiolipin.1,2 Besides cardiolipin, other
PL have been used in ELISA plates, both anionic
and neutral, or even zwitterionic as phosphatidylethanolamine
(PE).
Recent evidence shows that many aPL to negatively
charged PL do not target anionic PL per se,
but are specific for anionic PL-binding plasma
proteins. At present, the most common and
best characterized plasma protein aPL antigenic
targets are b2-glycoprotein I (b2GPI) and
prothrombin.3 We also reported that certain
antiphosphatidylethanolamine antibodies (aPE)
are not specific for PE per se, but are directed
to PE-binding plasma proteins; for example,
high molecular weight kininogen (HK), low
molecular weight kininogen (LK) and proteins
in complex with HK, factor XI or prekallikrein.4,5
The female reproductive tract is the second
richest site for kininogen and its metabolic
products in the body.6-9 The kininogen concentration
in reproductive tissues and plasma was reported
to fluctuate during ovulation, pregnancy,
and parturition.6,9 Why the female reproductive
system is so rich in kininogen and what governs
the fluctuation of kininogen concentrations
at the local level remains to be elucidated.
It is noteworthy that aPE have been described
as the sole aPL in patient with thrombotic
diseases.10-16 Recently, we reported a stronger
association between recurrent pregnancy losses
(RPL) and aPE than between RPL and antibodies
to anionic PL for early gestational losses.17
A positive test result for aPE was more frequent
in the patients with recurrent early pregnancy
losses than in the members of the control
group (p=0.0002). In contrast, there was
no statistically significant difference in
the incidence of positive test results for
antibodies to anionic PL between the recurrent
early pregnancy loss group and the control
group. In this study, 21 patients were positive
for plasma protein-dependent IgG aPE. Nineteen
(90.5%) of these 21 patients were kininogen-dependent.
Gris et al. also reported that aPE were found
to be independent risk factor for unexplained
early fetal loss.18 Since PE is a major component
of both the outer and inner leaflets of cell
plasma membranes, autoantibodies to PE and/or
PE binding proteins might exert an effect
on both resting and activated cells or cell
fragments.
Fetal loss, occurring mostly in the second
and third trimesters of pregnancy in aCL
and/or lupus anticoagulant positive mothers,
is one of the hallmark clinical manifestations
of the antiphospholipid syndrome.19-21 There
is however no available data concerning the
prevalence of aPE in patients with mid to
late pregnancy loss. In this study, we showed
data on patients with recurrent early pregnancy
losses and mid to late fetal loss.
MATERIALS AND METHODS
Patients and Controls
From January 2001 to December 2001, serum
samples were obtained from 171 nonpregnant
patients with a history of pregnancy loss(es) who
referred to the SRL laboratory (Tokyo, Japan)
for detection of aPL. All patients were referred
by obstetricians of the 9 hospitals, who
were involved in our abnormal pregnancy program.
Among the patients, 2 groups were defined
according to clinical data. The main biological
and clinical characteristics of these groups
of patients are given in Table I.
Early pregnancy loss group consisted of 145
patients with at least 2 episodes of unexplained
early pregnancy loss defined as pregnancy
loss before the 10th week of pregnancy; exclusive
of ectopic pregnancy and elective abortion.
None of them had any episode of mid to late
fetal loss defined as fetal loss at or beyond
the 10th week of pregnancy.
Mid to late pregnancy loss group consisted
of 26 patients with one or more unexplained
death(s) of a morphologically normal fetus
at or beyond the 10th week of pregnancy.
The exclusion criteria were: any presumptive
cause found for pregnancy loss(es) after
routine evaluation for detection of uterine
factors (i.e., normal hysterosalpingography
and ultrasound examinations); any chromosomal
abnormalities for both partners; any endocrine
factors (normal prolactin and progesterone
levels and normal thyroid function); any
infectious factors (no group B streptococcal
or Chlamydia trachomatis infection); any
diabetes mellitus.
One hundred twenty two age matched, healthy,
nonpregnant female volunteers with no history
of miscarriage were tested as controls.
Sera were collected by clear venipuncture
from the antecubital vein and stored at -80°C
until use.
Methods
The aPE ELISA followed a previously described
procedure.17 Briefly, Immulon 1, microtiter
plates (Dynatech Laboratories, Chantilly,
VA, USA) were coated with 30 ml of 50 mg/ml
PE (Avanti Polar Lipids, Birmingham, AL,
USA) diluted in chloroform : methanol (1:3)
per well and dried under nitrogen. Each well
was blocked for 1h with 10% bovine serum
albumin (BSA; Sigma, St. Louis, MO, USA)
in Tris buffered saline (TBS). To detect
aPE ELISA reactivity, 50 ml of the patient
sera diluted 1/100 in TBS containing 10%
adult bovine plasma (ABP; Sigma Chemical
Co.) was incubated for 1h. aPE was assessed
by using alkaline phosphatase conjugated
monoclonal antibody to human IgG and IgM
(Sigma Chemical Co.). The plates were washed
3 times with TBS after PE coating, blocking,
serum and conjugate incubations. Color development,
produced by paranitrophenyl phosphate substrate,
was measured by optical density at 405nm.
Color development was stopped with 75 ml
of 3N NaOH when the positive controls reached
an optimal density of 1.0 at 405nm. Nonspecific
binding control wells (without phospholipid
coating) were processed in parallel with
the ELISA for aPE, and the background values
were subtracted. Positive values were determined
as previously described.17 Positive samples
were retested to confirm the results.
Serum IgG and IgM aCL were measured by a
commercially available ELISA (Mesacup, MBL,
Nagoya, Japan). This kit contains 10% adult
bovine serum in its dilution buffer. Calibration
was performed using a dilution curve prepared
with the provided commercial calibrator which
had been previously evaluated against standards
from the Antiphospholipid Standardisation
Laboratory, University of Louisville, Kentucky,
USA. A normal range was established using
the control individual sera with the cut-off
corresponding to the 95th percentile of the
obtained control values. Thus, IgG-aCL<10
GPL units/ml and IgM-aCL <8 MPL units/ml
were considered negative.
Serum IgG to b2GPI-cardiolipin complex (aCL-b2GPI,
IgG) was measured by a commercially available
ELISA (Yamasa Corporation, Tokyo, Japan)
according to the manufacturer's recommendations.
This kit contains purified human b 2GPI (1.51
mg/well) in the dilution buffer. Positive
values were determined by previously described
methods.17
Statistical analysis
Differences between the two groups were analyzed
for statistical significance (p<0.05)
with the c2test.
Table I. Characteristics of the 3 groups
of women in the study
Early
pregnancy loss group Mid to late pregnancy
loss group Control women
N 145 26 122
Age (mean+SD) [range]
31.9+4.4 [21-43] 32.4+3.9
[25-39] 32.5+4.4 [26-41]
Number of pregnancy losses (mean+SD) [range]
Before the 10th week of pregnancy 2.8+1.2
[2-10] 1.7+1.3
[0-7] 0
At or beyond the 10th week of pregnancy 0 1.5+1.6
[1-3] 0
RESULTS
Prevalence of aPL in the early pregnancy
loss group
Patients with recurrent early pregnancy losses
(n=145) were screened for aPE. The prevalence
of aPL in the early pregnancy loss group
is reported in Table II and compared to that
of normal controls. Twenty six (17.9%) and
18 (12.4%) patients of these 145 patients
were positive for IgG and IgM aPE, respectively.
Positive test results for IgG aPE [odds ratio:
4.22, 95% confidence interval (1.68-10.64),
p=0.001] and IgM aPE [odds ratio: 4.18, 95%
confidence interval (1.38-12.71), p=0.01]
were more frequent in the early pregnancy
loss group than in the control group. Four
patients were positive for both IgG and IgM,
aPE. Therefore, 40 (27.6%) patients were
positive for IgG and/or IgM, aPE. The higher retrospective risk for recurrent
early pregnancy loss was associated with
positive IgG aPE.
The same 145 patients with recurrent early
pregnancy losses also were tested for aCL.
IgG and IgM aCL were measured with Mesacup
kit and aCL-b2GPI, IgG was measured with
Yamasa kit. As shown in Table II, 9 patients
(6.2%) and 4 patients (2.8%) were positive
for IgG and IgM aCL, respectively. Five patients
(3.5%) were positive for aCL-b2GPI, IgG.
There was no statistically significant difference
in the incidence of positive test results
for aCL between the early pregnancy loss
group and the control group. Only 4 patients
out of 40 aPE positive patients were also
positive for aCL.
Prevalence of aPL in the mid to late pregnancy
loss group
Patients with mid to late pregnancy loss(es)
(n=26) were screened for aPE. The prevalence
of aPL in the mid to late pregnancy loss
group is reported in Table III and compared
to that of normal controls. Three (11.5%)
and 5 (19.2%) patients of these 26 patients
were positive for IgG and IgM aPE, respectively.
Two patients were positive for both IgG and
IgM aPE. A positive test result for IgM aPE
was more frequent in the mid to late pregnancy
loss group than in the control group [odds
ratio: 7.02, 95% confidence interval (1.74-28.32),
p=0.008]. A positive test result for IgG
aPE was not statistically more frequent in
the patients with mid to late pregnancy loss
than in the members of the control group.
The same 26 patients with mid to late pregnancy
loss(es) also were tested for aCL. IgG and
IgM aCL were measured with Mesacup kit and
aCL-b2GPI, IgG was measured with Yamasa kit.
As shown in Table III, 6 patients (23.1%)
and 3 patients (11.5%) were positive for
IgG and IgM aCL, respectively. Three patients
(11.5%) were positive for aCL-b2GPI, IgG.
A positive test result for IgG aCL was more
frequent in the mid to late pregnancy loss
group than in the control group [odds ratio:
4.28, 95% confidence interval (1.34-13.64),
p=0.02]. There was no statistically significant
difference in the incidence of positive test
results for IgM aCL or aCL-b2GPI, IgG between
the mid to late pregnancy loss group and
the control group. The higher retrospective risk for mid to
late pregnancy loss was associated with positive
IgM aPE. Only one patient out of 6 patients, who
were positive for IgG and/or IgM aPE, was
positive for aCL.
Table II.
Comparison of positive rates for various
antiphospholipid antibodies in the early
pregnancy loss gourp (n=145)
Early pregnancy loss
group (n=145) Control women
(n=122)
n (%) Odds ratio
95%CI p n
(%)
aPE, IgG 26 (17.9) 4.22 1.68-10.64 0.001 6
(4.9)
aPE, IgM 18 (12.4) 4.18 1.38-12.71
0.01 4 (3.3)
aCL, IgG 9 (6.2) 0.94
0.35-2.52 NS 8 (6.6)
aCL, IgM 4 (2.8) 0.83
0.2-3.42 NS 4
(3.3)
aCL-b2GPI, IgG 5 (3.5) 1.42 0.33-6.05
NS 3 (2.5)
NS=not significant
Table III.
Comparison of positive rates for various
antiphospholipid antibodies in the mid to
late pregnancy loss gourp (n=26)
Mid to late pregnancy
loss group (n=26) Control women
(n=122)
n (%) Odds
ratio 95%CI p n
(%)
aPE, IgG 3 (11.5) 2.52
0.59-10.82 NS 6
(4.9)
aPE, IgM 5 (19.2) 7.02 1.74-28.32
0.008 4 (3.3)
aCL, IgG 6 (23.1) 4.28
1.34-13.64 0.02 8
(6.6)
aCL, IgM 3 (11.5) 3.85
0.81-18.35 NS 4
(3.3)
aCL-b2GPI, IgG 3 (11.5) 5.17
0.98-27.3 NS 3
(2.5)
NS=not significant
DISCUSSION
Associations have been reported between aPL,
mainly anticardiolipin antibodies and/or
the lupus anticoagulant, and RPL.1,2 Relatively
few studies describing aPE have been published.10-18
Recently, we reported that certain aPE are
not specific for PE per se, but are directed
to PE-binding plasma proteins, for example,
HK, LK and the HK-binding plasma proteins
factor XI and prekallikrein.4,5 We reported
that 90.5% of PE-binding protein dependent
aPE from RPL patients was kininogen-dependent.17
Since kininogens appear in mammalian reproductive
tissues, we screened pregnancy loss patients
for kininogen dependent aPE by ELISA. We
already reported a stronger association between
RPL and aPE than between RPL and aPL to the
anionic phospholipids during early gestational
losses.17 We now report an association between
mid to late pregnancy loss and IgM aPE as
well as IgG aCL.
Many RPL patients who fit a clinical profile
compatible with antiphospholipid syndrome
are negative for aPL when tested by ELISA.
Explanations for negative findings are manifold,
but often can be attributed to assay variations.
For example, some commercial aCL detection
kits (e.g. Yamasa kit) are designed to use
purified or recombinant b2GPI as the patient
sample diluent. In this situation, patients
with aPL dependent upon the presence of prothrombin
would appear as negative. In this study,
IgG and IgM aCL were measured by Mesacup
kit. This kit contains 10% ABS in its dilution
buffer which should contain CL-binding proteins
other than b2GPI.
Negative results in the aPE ELISA can result
from using a patient sample diluent that
is low or deficient in the kininogens; fetal
calf serum (FCS) and newborn calf serum (NBCS)
contain notably low concentrations of HK
and LK22,23 and should be avoided. Few studies
have appeared implicating aPE in RPL and
thrombosis patients.10-12, 14-16 In these
studies, FCS or NBCS were utilized as the
patient sample diluents. This suggests that
many kininogen dependent aPE may be negative
in these studies. Moreover, prolonged storage
of ABS and ABP at 4°C can result in decreasing
kininogen activity, (T. Sugi, unpublished
observations). We have also found that each
lot of ABS must be screened before use as
an aPE testing reagent because some lots
of ABS contain low concentrations of intact
kininogens. To avoid this problem, ABP has
proven to be a better source of PL-binding
plasma proteins for aPE detection. For optimal
activity the ABS or ABP should be divided
into single-use aliquots, stored frozen and
thawed each day the aPE ELISA is performed.
In this study, we reported the association
between IgM aPE and mid to late pregnancy
loss at or beyond the 10th week of pregnancy.
This is concordant to recent published data
by Gris et al. showing that only IgM aPE,
IgG anti-b2-glycoprotein I antibodies, IgG
anti-annexin V antibodies and lupus anticoagulant
were found to be independent retrospective
risk factors for unexplained early fetal
loss from 10th to 24th week pregnancy.18
The higher retrospective risk for fetal loss
was associated with positive IgM aPE.
Evidence for the presence of a kallikrein-kinin
system in fetoplacental vessels has accumulated
in several studies.24, 25 Mutoh et al.25
indicated that the kinin generating activity
of the kallikrein-kinin system is localized
within the uteroplacental unit. Hermann et
al.7 reported that kininogen and plasma prekallikrein/plasma
kallikrein were present in the endothelial
cells of the placental villous capillaries.
In larger placental blood vessels and the
umbilical cord, neither kininogens nor kallikreins
were detected. The co-localization of kininogen
and plasma prekallikrein/plasma kallikrein
suggests that kinins could be generated locally
in the placental capillaries. The functional
spectrum of biologically active kinins, such
as vasodilation, vasoconstriction, smooth
muscle contraction and relaxation, could
influence placental blood flow regulation.
Moreover, kinins could also have anti-thrombotic/profibrinolytic
activities.26,27 Kinins which are released
within the placenta may play a role in regulating
the placental blood flow and transplacental
transport of substrates and metabolites.7
To effectively influence the placental circulation
and nutrient supply to the fetus, components
of the kallikrein-kinin system should be
situated either within or close to the placental
vasculature.
Both HK and LK bind to platelets.28-30 Domain
3 (D3) of kininogens was found to non-competitively
inhibit thrombin from binding to the platelet
thrombin receptor. By using specific monoclonal
antibodies, Jiang et al.31 showed the D3
region to be responsible for the inhibition
of thrombin binding to platelets. Kunapuli
et al.32 found that recombinant D3 inhibited
thrombin-induced platelet aggregation. We
thus hypothesized that the aPE can bind to
kininogens on the platelet. When bound by
aPE, the platelet-kininogen complex no longer
renders the platelet refractory to thrombin
activation, thus predisposing to aggregation
and thrombosis. Our recent in vitro data
support these observations as we demonstrated
that kininogen-dependent IgG-aPE purified
from several aPE-positive patient plasmas
caused a marked augmentation of thrombin-induced
platelet aggregation, while not affecting
adenosine diphosphate (ADP)-induced platelet
aggregation.33 Moreover, kininogen-independent
IgG-aPE did not affect the thrombin-induced
platelet aggregation. For this to occur,
it is possible that aPE may recognize the
D3 region of kininogens subsequent to their
binding to platelet PE.
Our recent in vitro data suggest that aPE
may recognize the domain 3 (D3) region of
kininogens.34 In this study, we used synthetic
peptides that span the D3 of kininogens in
inhibition and direct binding studies to
identify epitopes that are sites for binding
aPE. Our data demonstrated that among 24
RPL patients who were positive for kininogen-dependent
IgG aPE, 17 patients (70.8%) recognized the
LDC27 peptide. We mapped the aPE binding
region on D3 using plasma from a RPL patient,
who had a high titer of IgG aPE which recognized
LDC27. aPE of this patient recognized a 13-residue
segment in LDC27, named CNA13. Leu331-Met357
(LDC27) and Cys333-Lys345 (CNA13) are located
on the carboxyl-terminal portion of kininogen
D3 which is known as the major kininogen
heavy chain cell attachment site where it
overlaps its cysteine protease inhibitory
region. Because aPE interferes with the balance
of hemostasis in vitro, aPE may therefore
induce a similar condition in patients thereby
causing thrombosis and RPL.
Appendix
In addition to the authors, the Japan Antiphospholipid
Project Group comprised the following individuals:
Mayumi Sugiura Ogasawara (Nagoya City University
Medical School, Nagoya, Japan), Seiichiro
Fujimoto (Hokkaido University, Graduate School
of Medicine, Sapporo, Japan), Fumiki Hirahara
(Yokohama City University, School of Medicine,
Yokohama, Japan), Hitoshi Okamura (Kumamoto
University School of Medicine, Kumamoto,
Japan), Yasunori Yoshimura (Keio University
School of Medicine, Tokyo, Japan), Kunihiro
Okamura (Tohoku University, Graduate School
of Medicine and School of Medicine, Sendai,
Japan), Tatsuo Yamamoto (Nihon University,
School of Medicine, Tokyo, Japan), Yuji Murata
(Faculty of Medicine, Osaka University, Graduate
School of Medicine, Osaska, Japan)
Acknowledgements
We thank the gynecologists and obstetricians
who referred their patients to the SRL laboratory.
We express our thanks to all patients and
control subjects who participated in this
study. We thank Dr. S. Shimano for providing
a part of normal control sera. We thank the
technicians of the SRL laboratory for their
excellent assistance in laboratory analysis.
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