Volume 53(11): 1413–1420, 2005

Journal of Histochemistry & Cytochemistry

http://www.jhc.org

ARTICLE

Immunohistochemistry in Human Placental Tissue—Pitfalls

of Antigen Detection

Arnd Honig, Lorenz Rieger, Michaela Kapp, Johannes Dietl, and Ulrike Kämmerer
Department of Obstetrics and Gynecology, University of Wuerzburg, Germany
The Journal of Histochemistry & Cytochemistry

SUMMARY Because incongruous controversial staining results are a common phenome-

non in the placenta, methodical investigations are important to prevent researchers from
obtaining misleading results. While investigating dendritic cells (DC) at the human fetoma-
ternal interface, we observed staining of endothelial cells (EC) in chorionic villi for CD83.
Given the high specificity of this antigen for DC, this did not seem credible. Previous studies
had revealed the same surprising staining pattern with human leukocyte antigen (HLA)-G
antibodies. We therefore analyzed human placental EC staining more closely. Both CD83
and HLA-G antibodies were of the same mouse IgG2b isotype. We also observed EC stain-
ing with a panel of control antibodies of the IgG2b isotype. This suggests a high affinity of
human placental capillaries for mouse IgG2b. Several commonly used techniques for block- KEY WORDS
ing nonspecific binding of antibodies could not prevent this nonspecific EC staining. A new human placenta
preincubation step with purified human IgG was introduced. This abolished any placental IgG2b isotype
EC staining with CD83, HLA-G, and IgG2b isotype control antibodies, presumably by block- nonspecific binding
ing Fc receptors, whereas specific staining patterns remained unchanged. Mouse antibody HLA-G
of the IgG2b isotype are bound nonspecifically by vascular endothelial cells in human pla- human IgG
centa and this can be overcome by blocking with purified human IgG. This blocking proce- Fc receptor
dure could also be appropriate for frozen tissues other than placenta in which Fc receptors endothelial cells
are expressed. (J Histochem Cytochem 53:1413–1420, 2005) immunohistochemistry

Immunohistochemistry is a technique that not
only allows the detection of antigens, but also enables
determination of their morphological localization and
the spatial relationships of different antigens to each
other. It is a valuable tool for research in the field of
implantation and placentation, in which interrelation-
ships between antigens and their coexpression are
more important than their mere sensitive detection.
We investigated frozen samples of human first tri-
mester placenta with a mouse monoclonal antibody
against CD83 (clone HB15a), which is specific for a sub-
set of the dendritic cell (DC) lineage. As anticipated,
decidual DC showed a clear and reproducible staining
pattern. However, to our surprise, vessels in the pla-
cental villi were also stained. Because CD83 is a highly
Correspondence to: Ulrike Kämmerer, PhD, Department of Obstet-
rics and Gynecology, Josef-Schneider-Strasse 4, D-97080 Würzburg,
Germany. E-mail: frak057@mail.uni-wuerzburg.de
Received for publication February 25, 2005; accepted June 21,
2005 [DOI: 10.1369/jhc.5A6664.2005].
specific surface marker for DCs at a certain stage of
their maturation, its expression on endothelial cells
(EC) did not seem plausible (Zhou and Tedder 1995;
Banchereau and Steinman 1998).
We obtained similar unexpected staining results
with the anti–human leukocyte antigen (HLA)-G anti-
body clone BFL-1 (Bensussan et al. 1995). HLA-G is
an atypical major histocompatibility complex class 1
antigen with limited polymorphism. It has been de-
scribed to be specifically expressed by extravillous cy-
totrophoblast (Kovats et al. 1990; McMaster et al.
1995; Hiby et al. 1999), although staining of EC of
villous vessels for this antigen has also been described
(Blaschitz et al. 1997). Because of the similarity of
the two unexpected results, we hypothesized that
the staining pattern observed with the two antibody
clones on frozen sections of placental tissue was unre-
lated to CD83 and HLA-G antigen expression. Both
the antibody clones were of the IgG2b isotype. Be-
cause staining of placental EC was not observed with
numerous antibodies of the IgG1 and IgG2a isotypes,

© The Histochemical Society, Inc. 0022-1554/05/$3.30 1413

 1414 Honig, Rieger, Kapp, Dietl, Kämmerer

the aberrant staining pattern observed seemed to be
restricted to IgG2b antibodies. To confirm this hy-
pothesis, we investigated the “specificity” of this bind-
ing of antibodies to placental villous EC with several
different antibodies. In addition, various established
blocking procedures known to prevent nonspecific bind-
ing of antibodies in immunohistochemistry and the ap-
plication of purified human immunoglobulin were tested
in an attempt to overcome the problem of nonspecific
binding in placental sections.
Materials and Methods
Tissue Specimens
The investigations were approved by the institutional Ethics
The Journal of Histochemistry & Cytochemistry
ature. The detection reaction was developed with 3,3-diami-
nobenzidine (Sigma; Deisenhofen, Germany). Sections were
counterstained with Meyer’s hematoxylin (Sigma), dehydrated
through graded ethanols and xylene, and embedded in Vitro-
Clud (Langenbrink; Emmendingen, Germany). The sections
were examined and photographed with a Leika Othoplan
microscope (Leica Microsystems; Bensheim, Germany).
Additional Blocking Procedures and Solutions
Several different blocking procedures were applied to pre-
vent the postulated nonspecific binding: before the applica-
tion of the primary antibodies, the sections were incubated
for 30 min at room temperature in one of the following block-
ing solutions: (a) 5% bovine serum albumin (Sigma), (b) 1%
heat-inactivated (30 min 56C) fetal calf serum (PAA Labora-
tories; Cölbe, Germany), (c) 2.5% human AB serum (PAA

Committee. Tissue was obtained from 10 healthy women
undergoing legal therapeutic abortion of an intact pregnancy
at 7–12 weeks of gestation via suction curettage. Chorionic
villi and fragments of decidual tissue were identified macro-
scopically and taken from each specimen to be snap-frozen
in liquid nitrogen. Samples were stored at
80C until histo-
logical examination and immunohistochemical investiga-
tions were performed
Immunohistochemistry
The antibodies applied in the study are listed in Table 1. The
specificity of the primary antibodies was confirmed by stain-
ing of frozen sections of human lymph nodes and skin. Serial
frozen sections were cut at 4 m and placed onto APES
(3-amino-propyltriethoxy-silane; Roth, Karlsruhe, Germany)-
coated slides. They were air-dried overnight to destroy en-
dogenous peroxidases, then fixed in acetone and rehydrated
in TBS (25 mM TRIS/HCl, pH 7.4, 137 mM NaCl, 2.7 mM
KCl) for 10 min each.
For standard immunohistochemical staining, the sections
were exposed to the primary antibodies at appropriate dilu-
tions in antibody diluent with background-reducing compo-
nents (Dako; Hamburg, Germany) for 30 min at room tem-
perature. For negative controls, sections were incubated in
parallel with the antibody diluent alone. After being rinsed
in TBS five times, all sections were incubated with a horse-
radish peroxidase–labeled goat anti-mouse specific secondary
antibody (dilution 1:100; Dako) for 30 min at room temper-
Laboratories), and (d) 20% normal goat serum (Dako). All
four blocking reagents were diluted in Dulbecco’s PBS (with-
out Ca2 and Mg2; PAA Laboratories).
Preincubation with purified IgG was performed with a
mixture of human IgG immunoglobulins (stock solution: 30
mg/ml; Beriglobin; Behringwerke, Marburg, Germany) diluted
in PBS, with which the sections were incubated for 30 min at
room temperature. A series of dilutions (1:10, 1:50, 1:100,
1:500) was tested. After the blocking procedure, excess liq-
uid was removed and the standard immunohistochemical
procedure was performed immediately as described previ-
ously.
Results
Standard Immunohistochemistry
All the antibodies listed in Table 1 were applied to
each of the 10 different tissue samples. When the stan-
dard immunohistochemical procedure was applied,
antibodies against CD83 and HLA-G and two differ-
ent IgG2b isotype control antibodies produced the stain-
ing of EC in chorionic villi under investigation anti-
body (Figures 1A, 1C, 1E, and 1G). Negative control
sections incubated with the substrate solution only
showed no background staining, confirming satisfac-
tory elimination of endogenous peroxidases by the air-
dry step. Control samples stained with the horseradish

Table 1 Primary monoclonal antibodies used throughout the study

Antigen Antibody Isotype Dilution Concentration Specificity
ICA DAK-GO1 IgG1 1:100 1 g/ml Aspergillus niger glucose oxidase
ICA DAK-GO5 IgG2a 1:100 1 g/ml Aspergillus niger glucose oxidase
ICA DAK-GO9 IgG2b D 1:20 4.3 g/ml Aspergillus niger glucose oxidase
ICA 49.2 IgG2b P 1:500 0.1 g/ml Trinitrophenol
CD9 MM2/57 IgG2b 1:100 1 g/ml Monocytes, granulocytes, endothelial smooth muscle, platelets, stromal cells
CD64 10.1 IgG1 1:200 0.5 g/ml FcR I
CDw32 FLI8.26 IgG2b 1:200 0.5 g/ml FcR II
CD16 3G8 IgG1 1:200 0.5 g/ml FcR III
CD34 QBEND/10 IgG1 1:100 1 g/ml Endothelial vesicles
CD83 HB15A IgG2b 1:100 2 g/ml Langerhans cells, activated DC
HLA-G BFL 1.1.2 IgG2b 1:50 4 g/ml Extravillous trophoblast cells

ICA, isotype control antibody; D, Dako; P, Pharmingen; HLA, human leukocyte antigen; DC, dendritic cell.
 Pitfalls of Immunohistochemistry in Placental Tissue 1415
The Journal of Histochemistry & Cytochemistry

Figure 1 Immunohistochemical staining of human early pregnancy placenta with (right) and without (left) blocking with human IgG. The
staining results are compared in corresponding sections. Magnification 250. (A,B) CD83. (A) Clear immunostaining of placental vessels for
CD83 (IgG2b) is seen with the standard IHC procedure. (B) No immunoreactivity for CD83 is observed in the adjacent section when the
blocking protocol is employed. (C,D) Human leukocyte antigen (HLA)-G. (C) Immunostaining by the standard protocol with the HLA-G spe-
cific clone BFL 1.1.2 (IgG2b) results in strong staining of endothelial cells. (D) Inclusion of the blocking step eliminates this staining. (E,F)
IgG2b isotype control (d). (E) There is weak but clearly visible immunoreactivity of endothelial cells with IgG2b isotype (d) antibody. (F) Pre-
incubation with human IgG demonstrates that binding of IgG2b isotype (d) can be suppressed. (G,H) IgG2b isotype (p). (G) Strong staining
of fetal capillaries with IgG2b isotype (p) antibody is seen. (H) This staining of IgG2b isotype antibody can be suppressed by blocking with
nonspecific human IgG.
 1416 Honig, Rieger, Kapp, Dietl, Kämmerer

peroxidase–labeled secondary antibody alone did not
exhibit any nonspecific staining. As shown in Figures
1E and 1G, placental villous EC were clearly stained
by both IgG2b isotype control antibodies, whereas the
IgG1 and IgG2a antibodies did not produce any stain-
ing with the standard protocol, even when used at
higher concentrations than recommended by the sup-
plier (not shown). One of the two IgG2b isotype con-
trol antibodies (Dako) also produced weak staining of
Hofbauer cells (Figure 1E). These cells were not stained
by the other IgG2b isotype antibodies or the antibod-
ies against HLA-G and CD83. The staining results are
summarized in Table 2.
Blocking Procedures
The Journal of Histochemistry & Cytochemistry
1:50 totally disappeared (Figures 1B, 1D, 1F, and 1H).
There was still nonspecific background staining at a
dilution of 1:50, and no blocking effect was seen at a
dilution of 1:100 (not shown). To optimize the cost:ef-
fect ratio, a dilution of 1:50 (corresponding to 0.6 mg/
ml human immunoglobulin) was selected as standard
for our blocking protocol. This blocking step did not
interfere with the specific detection of CD83-positive
dendritic cells with the HB15a clone (Figures 3E and
3F) or HLA-G–positive extravillous trophoblast cells
(Figures 3G and 3H) in the decidua basalis.
Expression of Fc Receptors
To identify the receptors or antigens responsible for the
nonspecific binding, we analyzed Fc receptor expression

Several different procedures were applied in an attempt
to block possible nonspecific binding of IgG2b anti-
bodies to the placental tissue. Incubation of the sec-
tions in BSA (5%), fetal calf serum (1%), human AB
serum (2.5%), and goat serum (20%), respectively, did
not prevent nonspecific binding to villous EC and Hof-
bauer cells (not shown). Blocking with antibody dilu-
ent with background reducing component also failed
to prevent nonspecific binding of IgG2b isotype con-
trol antibodies. Unfortunately, even when two of these
blocking procedures were performed consecutively on
one section, the IgG2b isotype control antibodies still
bound to villous EC (data not shown).
We hypothesized that one or more Fc receptors
could be responsible for the nonspecific binding and
applied purified and concentrated human IgG immu-
noglobins diluted in PBS (at 1:10, 1:50, 1:100, 1:500)
before the sections were incubated with the primary
antibody. After this preincubation step, the nonspe-
cific binding of all antibodies (both isotype control an-
tibodies, anti-CD83 clone HB15a, and anti-HLA-G
clone BFL-1) to villous vessels at dilutions of 1:10 and
in human placenta specimens by staining tissue sec-
tions with antibodies against CD64 (FcRI), CDw32
(FcRII), and CD16 (FcRIII; Table 1).
No staining for FcRIII was observed in fetal endo-
thelial cells or placental Hofbauer cells (Figures 2A
and 2B). Figures 2C and 2D demonstrate that placen-
tal vessel EC are clearly positive for FcRII (CDw32),
even if incubation with the primary antibody is pre-
ceded by incubation with human IgG immunoglobulin
(Figure 2D). Decidual macrophages showed moderate
staining for FcRII. The antibody against CD64, stained
only Hofbauer cells in the placental villous stroma (Fig-
ures 2E and 2F).
Does Preincubation with IgG Interfere
with Specific Detection?
To determine whether the “preincubation” step with
human IgG interferes with specific antibody binding
to the endothelial cells of placental vessels, we used
anti-CD34 (IgG1). This antibody is directed against en-
dothelial cells and CD34 is also expressed on he-

Table 2 Cell type–dependent results of immunohistochemistry with and without blocking by human IgG1
Placental endothelial cells Hofbauer cells Specific stained cells in placenta/decidua
Staining procedure Staining procedure Staining procedure
Antigen Isotype Standard Pre-IgG Standard Pre-IgG Cell type Standard Pre-IgG
ICA IgG1



None


ICA IgG2a



None


ICA IgG2b D 


None


ICA3 IgG2b P 

None


CD9 IgG2b     Endothelial cells  
CD16 IgG1



Macrophages  
CDw3 IgG2b  /   Macrophages  
CD34 IgG1  /

Endothelial cells  
CD64 IgG1     Monocytic lineage  
CD83 IgG2b 


Dendritic cells  
HLA-G IgG2b 


EVT  

Grades of staining intensity:
, negative; , weak; , moderate; , strong. Pre-IgG  Preincubation with human IgG (0.6 mg/ml) as blocking procedure.
ICA, isotype control antibody; D, Dako; P, Pharmingen; EVT, extravillous trophoblast; HLA, human leukocyte antigen.
 Pitfalls of Immunohistochemistry in Placental Tissue 1417
The Journal of Histochemistry & Cytochemistry

Figure 2 Analysis of placental Fc receptors in early pregnancy placenta. Immunohistochemical detection with (right) and without (left) the
blocking procedure. (A–E) Magnification: 250; (F) 300. A,B: FcRIII. Specific staining for FcRIII (CD16; IgG1) before (A) and after (B) inclu-
sion of the preincubation step. Neither the endothelial cells of fetal capillaries nor Hofbauer cells are reactive antibody for FcRIII. Blocking
with IgG does not affect the staining intensity (B). (C,D) FcRII. Staining for FcRII with anti-CDw32 (IgG2b) reveals strong immunoreactivity
of villous endothelial cells and faint staining of Hofbauer cells. Preincubation with human IgG does not influence this staining pattern (D).
(E,F) FcRI. Monocytes were specifically stained with anti-CD64 (IgG1) before (E) and after (F) inclusion of the preincubation step. Hofbauer
cells show strong expression and vessels weak expression of CD64. Blocking with IgG does not affect the staining intensity or pattern (F).

matopoietic progenitor cells (Table 2). In addition, we
applied a anti-CD9 (IgG2b) antibody clone to specifi-
cally stain endothelial cells (Table 1). Preincubation
with human IgG did not interfere with specific stain-
ing of villous endothelial cells by either antibody, al-
though the staining intensity for CD34 was slightly
decreased (Figures 3C and 3D). Fetal endothelial cells
stained for CD9 and this was not influenced by the
preincubation procedure with human IgG (Figures 3A
and 3B).
The antibodies directed against FcRI (CD64) (Fig-
ures 2E and 2F), FcRIII (CD16) (data not shown),
and CD9 are known to detect antigens that are expressed
on monocytes. Macrophage staining with these anti-
bodies in decidual areas attached to the placenta was
not altered by preincubation with purified IgG (data
not shown). Likewise, specific staining of endothelial
cells for CD9 was not affected and for CD34 staining
intensity decreased only slightly by the IgG-blocking
procedure (Figures 3B and 3D). In summary, the spe-
cific staining of endothelial cells, macrophages, mature
dendritic cells (Figure 3F), and extravillous cytotro-
 1418 Honig, Rieger, Kapp, Dietl, Kämmerer
The Journal of Histochemistry & Cytochemistry

Figure 3 The blocking procedure does not interfere with specific antigen detection. Left: conventional immunostaining; right: immuno-
staining after preincubation with human IgG at a dilution of 0.6 mg/ml. (A,B) CD9. The staining of endothelial cells of villous vessels for CD9
(IgG2b) (A) is not altered by inclusion of the blocking procedure (B); magnification 250. (C,D) CD34. Specific staining of vascular endothe-
lium for CD34 (IgG1) without (C) and with the preincubation step (D). Staining intensity is slightly decreased after inclusion of the preincu-
bation step (magnification 250). (E,F) CD83. Detection of mature dendritic cells in human decidua with anti-CD83 (IgG2b) is not impaired
by preincubation with IgG (F) as compared with a standard staining protocol (E) (magnification 400). (G,H) Human leukocyte antigen
(HLA)-G. Detection of invasive extravillous trophoblast with the antibody clone BFL 1.1.2 directed against HLA-G (IgG2b) before (G) and af-
ter (H) inclusion of the IgG preincubation step. Blocking influences neither the pattern nor the intensity of staining (H; magnification 250).
 Pitfalls of Immunohistochemistry in Placental Tissue
phoblast (Figure 3H) in the decidua was not affected
by preincubation with IgG, but nonspecific binding of
IgG2b isotype antibodies disappeared.
Discussion
In the course of investigations into immunological in-
teractions between trophoblasts and immune cells in
early pregnancy placenta and decidua, we observed
staining of endothelial cells in placental villi with clone
HB15a (anti-CD83) and clone BFL-1 (anti-HLA-G)
antibodies. Although this staining seemed to be spe-
cific, the expression of CD83 and HLA-G on the same
structure did not seem plausible. HLA-G is a fre-
quently investigated antigen in placenta, and there
The Journal of Histochemistry & Cytochemistry
was only one study describing HLA-G expression by
endothelial cells in placental chorionic villi (Blaschitz
et al. 1997). A search for features common to the two
unexpected immunohistochemical reactions revealed
that both primary antibodies were mouse monoclonal
antibodies of the IgG2b isotype. We formulated the
hypothesis that placental villous endothelial cells might
possess a specific affinity for mouse monoclonal anti-
bodies of the IgG2b subtype. A finding reported by
Johnson et al. (1975) also pointed to the nonspecific
nature of the observed staining: they found nonspe-
cific binding of aggregated IgG to fetal villous endo-
thelial structures.
To test this hypothesis in experiments, we applied
mouse monoclonal IgG2b isotype control antibodies and
found that this indeed led to endothelial cell staining
in chorionic villi. That all these staining reactions van-
ished after purified human IgG was applied as a prein-
cubation step suggested that they were nonspecific.
We used antibodies against CD34 (IgG1) and CD9
(IgG2b), which belong to different IgG subtypes, to in-
vestigate whether this preincubation would interfere with
specific endothelial staining. In these experiments, spe-
cific detection of EC was found to be largely unaf-
fected by preincubation. Further experiments revealed
that preincubation with IgG does not interfere with
other specific IHC reactions.
We can only speculate as to which structure in hu-
man placenta is responsible for the nonspecific bind-
ing of mouse IgG2b isotype antibodies observed. The
obvious candidates are Fc receptors, which are known
to mediate maternofetal IgG transport. Because of the
known homology of mouse and human placental trans-
port mechanisms, it is possible that human Fc recep-
tors might have an affinity for mouse antibody (Lyden
et al. 2001; Simister 2003). Both species have a hemo-
chorial placenta and exhibit parallels in terms of IgG
transport from mother to fetus. It is therefore conceiv-
able that mouse IgG2b could bind to human placental
Fc receptors that normally bind human IgG in the
course of maternofetal immunoglobulin transport. Such
1419
crossreactivity could result in stable Fc binding of
these antibodies, which would explain the immunohis-
tochemical results we obtained.
In keeping with the results of Kameda et al. (1991)
and Lyden et al. (2001), we found the human placenta
to be negative for FcRIII (CD16). Our findings were
also consistent with those of Wainwright and Holmes
(1993) and Bright et al. (1994) in that FcRII (CDw32)
was clearly detectable on vascular endothelium in the
villi. After the preincubation step, the intensity of stain-
ing with anti-CDw32 (IgG2b) decreased. The more in-
tense staining of this antibody without preincubation
is most probably the result of additional binding of
antibodies via this Fc receptor in the human placenta.
Our results with FcRI (CD64) confirmed the findings
of Lyden et al. (2001) with regard to vascular endo-
thelium, which was negative for this receptor.
Conflicting research findings concerning the pres-
ence of Fc receptors in the placenta have been pub-
lished (Simister and Story 1997; Saji et al. 1999;
Gafencu et al. 2003). FcRII detection nicely exempli-
fies how challenging the immunohistochemical inves-
tigation of the placenta can be. Five different investi-
gators used clone IV3, a mouse monoclonal antibody,
of the IgG2b subclass to detect FcRII expression by
fetal EC in term placenta. Three studies found expres-
sion of FcRII (Kristoffersen et al. 1990; Micklem et
al. 1990; Sedmak et al. 1991), whereas two did not
(Stuart et al. 1989; Kameda et al. 1991), which under-
lies the necessity for improvements in immunohis-
tochemistry techniques in human placenta.
Hofbauer cells are fetal macrophages that are known
to express multiple Fc receptors (Saji et al. 1999; Ly-
den et al. 2001). Although one of the IgG2b isoform
control antibodies stained these cells, nonspecific IgG
preincubation prevented this staining, suggesting that
receptors responsible for nonspecific binding could be
expressed on these macrophages.
Whether one of the fetal Fc receptors known to be
expressed on placental vessels or other, still to be iden-
tified receptors mediate crossreactivity with mouse
IgG2b has not yet been fully elucidated. One potential
candidate is FcRIIb2, which was found by Lyden et
al. (2001) to be expressed on fetal EC.
In conclusion, our study has shown that the inter-
pretation of immunohistochemical studies performed
on frozen sections of human placental tissue is a de-
manding task. The difficulties arise from one of the
organ’s functions, maternofetal IgG transport. There
is an obvious tendency of this tissue to absorb anti-
bodies in an antigen-independent manner. This non-
specific binding of antibodies is not seen in formalin-
fixed placental tissue. However, numerous primary
antibodies fail to stain fixed (and paraffin-embedded)
tissue, so the problem of nonspecific binding associ-
ated with the use of frozen tissue needs to be solved.
 1420
As demonstrated in the present study, this nonspecific
staining can be eradicated by the application of puri-
fied human IgG before the primary antibody. The block-
ing procedure with immunoglobulin could also be ap-
propriate for frozen tissues other than placenta, such
as the tissue of the immune system and certain epithelia,
in which Fc receptors are expressed (Stuart et al. 1989).
However, even when this reliable tool is employed to
improve the specificity of immunohistochemical stain-
ing, suitable controls on serial sections should still
always be included. These controls should involve
staining with antibodies of the same IgG isotype but
irrelevant specificity, which are applied at the same
concentrations as the original primary antibodies.
The Journal of Histochemistry & Cytochemistry
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