Molecular Human Reproduction, Vol. 5, No. 11, 1083-1088,
November 1999
© 1999 European Society of Human Reproduction and Embryology
Molecular aspects of pregnancy |
Leukocyte function-associated antigen-1 expression on decidual natural killer cells in patients with early pregnancy loss
Department of Obstetrics and Gynecology, Ehime University, School of Medicine, Shitukawa, Shigenobu-cho, Onsen-gun, Ehime 791-0295, Japan
Abstract
A large number of CD56bright natural killer (NK) cells, which comprise a very small fraction of peripheral blood lymphocytes, appear in the endometrium during the late secretory phase and early pregnancy. These cells are thought to immunologically maintain or inhibit pregnancy. However, the details regarding their contribution to the immuno-elimination systems of embryonic cells or decidual stromal cells remain unclear. Recently, leukocyte function-associated antigen-1 (LFA-1) was shown to play a critical role in the regulation of NK cytolysis in peripheral blood lymphocytes. We speculated that LFA-1 on the decidual CD56bright NK may be involved in the regulation of pregnancy. The expression of LFA-1 on the decidual CD56bright NK cells was analysed using flow cytometry with fluorescent monoclonal antibodies; CD56 (NKH1), CD16 (Fcg-R3) and CD11a (LFA-1 
-chain). In comparison with non-pregnant endometrium during the late secretory phase, the subpopulation of CD56brightCD16– cells in decidual lymphocytes was significantly increased during normal pregnancy, but was less than that in early pregnancy loss (P < 0.05). Furthermore, the number of CD56bright NK cells expressing LFA-1 was significantly higher in early pregnancy loss, and the late secretory phase, than during normal pregnancy (P < 0.05). Our results indicate that up-regulation of LFA-1 on CD56bright NK cells is related to spontaneous abortion or the onset of menstruation.
decidua/early pregnancy loss/LFA-1/NK cells
Introduction
A large number of CD56brightCD16– natural killer (NK) cells, which comprise a very small fraction of peripheral blood lymphocytes (<1%), appear in the endometrium and decidua during the late secretory phase and early pregnancy (Starkey et al., 1988
; Ritson and Bulmer, 1989; King et al., 1989b, 1991). Recent studies have shown that decidual CD56bright NK produce various cytokines such as granulocyte-colony stimulating factor (G-CSF), granulocyte–macrophage CSF (GM-CSF), macrophage CSF (M-CSF), tumour necrosis factor (TNF)-, interferon (IFN)-
and leukaemia inhibitory factor (LIF), which were thought to play important roles in regulation of the proliferation and differentiation of trophoblastic cells (Saito et al., 1993; Jokhi et al., 1994, 1995; King et al., 1996). Furthermore, decidual CD56bright NK cells contain perforin/cytolysine that has been suggested to directly lyse embryonic or decidual cells (Lin et al., 1991; King et al., 1993; Rukavina et al., 1995; Gudelj et al., 1997).
Several studies have suggested that peripheral NK cells have deleterious effects on fetal development, resulting in spontaneous abortion in humans (Yokoyama et al., 1994; Aoki et al., 1995; Beer et al., 1996; Katano et al., 1997; Vassiliadou and Bulmer, 1998). However, peripheral NK cells differ from decidual NK cells in their point of surface markers (Starkey et al., 1988; King et al., 1989b, 1991; Ritson and Bulmer, 1989) and native NK cytotoxicity (King and Loke, 1991). Therefore, the details of the contribution of decidual NK cell-mediated cytolysis, which is thought to occur within the endometrial stroma, to the immune mechanisms involved in onset of menstruation or pregnancy loss remain unclear.
Leukocyte function-associated antigen-1 (LFA-1), which is a member of the ß-2 integrin family, is a surface membrane gycoprotein composed of two non-covalently linked chains, (CD11a, 180 kDa) and ß (CD18, 95 kDa) (Keizer et al., 1985), and is expressed on most leukocytes (Krensky et al., 1983; Martz, 1987). In peripheral blood, most NK cells strongly express LFA-1, compared with B lymphocytes, helper/inducer T cells, and precursor–suppressor T cells (Desroches et al., 1990). LFA-1 has been shown to play a critical role in the regulation of peripheral NK cell-mediated cytotoxicity (Krensky et al., 1983; Hall et al., 1985; Schmidt et al., 1985; Mentzer et al., 1986). However, LFA-1 expression on decidual NK cells has not been investigated in detail. In the present study, we examined the expression of LFA-1 on endometrial and decidual CD56bright NK cells in the late secretory phase, early normal pregnancy, and early pregnancy loss and investigated the role of LFA-1 expression on CD56bright NK cells in the immune reactions responsible for spontaneous abortion or onset of menstruation.
Materials and methods
Sample collection
Endometrial or decidual samples and peripheral blood samples were obtained with informed consent from 30 women who had requested elective abortion (normal pregnancy), 40 women with primary early pregnancy loss (pregnancy loss) who underwent dilation and curettage, and 12 women who underwent endometrial dating or total hysterectomy during the late secretory phase in Ehime University Hospital, Japan, from June 1997 to October 1998 (Table I).
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Decidual tissues of normal pregnancy and early pregnancy loss
In all cases of elective abortion, the fetal heartbeat was detected by transvaginal ultrasonography. Women with early pregnancy loss were diagnosed by transvaginal ultrasonography as having experienced fetal heartbeat arrest or missed abortion, and dilation and curettage was performed within 3 days after diagnosis. Genital bleeding did not occur in any of the pregnancy loss patients.
All viable pregnancy patients had no history of previous miscarriage and no patients of early pregnancy loss were recurrent or habitual aborters. None of the early pregnancy loss patients had auto-immune diseases, thyroid-dysfunction, toxoplasm infection, syphilis, rubella, cytomegalovirus infection, herpes virus infection, lupus anti- coagulant, or hereditary diseases before the operation. Chorionic tissue was collected from 20 of the 40 early pregnancy loss patients with their informed consent for embryonic chromosomal analysis by the G-banding method. Serum progesterone concentrations in pregnancy loss were measured by enzyme immunoassay.
Endometrial tissues in the late luteal phase
Of 12 women who underwent endometrial dating, nine were infertile due to presence of the male factor, and female infertility factors such as endometriosis, endocrinological disorders, immunological disease, or inflammatory disease were not detected. Endometrial dating was performed using a small dull curette for routine analysis before intracytoplasmic sperm injection (ICSI) or in-vitro fertilization (IVF)/embryo transfer treatment. Three women who underwent total hysterectomy for myoma uteri had no menstrual problems. These samples were collected by curettage before the operation under anaesthesia as in endometrial dating. The endometrium was dated according to previous criteria (Noyes et al., 1950) and was confirmed as being in the late secretory phase of the menstrual cycle.
After the curettage, all decidual and endometrial samples were immediately put into a sterile plastic tube with transport medium at 4°C.
Preparation of endometrial, decidual and peripheral blood lymphocytes
Endometrial and decidual samples in -minimal essential medium (MEM; Gibco BRL products, Rockville, MD, USA) supplemented with 10% fetal calf serum were washed gently and adhering blood clots were removed with microscissors to prevent contamination with peripheral blood at 4°C. Then decidual tissue was mechanically disrupted and filtered through sterile stainless steel (pore size: 250 µm) and nylon mesh (pore size: 50 µm) according to the previous report (Lachapelle et al., 1996). Finally, mononuclear cells were isolated by Ficoll–Paque (Pharmacia Inc, Uppsala, Sweden) centrifugation at 4°C. These cells were washed twice with phosphate-buffered saline (PBS), and resuspended in PBS with 3% bovine serum albumin (BSA) at 4°C. Peripheral blood (2 ml) was collected in plastic tubes containing 10 mmol/l EDTA. Peripheral lymphocytes were separated by Ficoll–Paque gradient at 4°C and the mononuclear fraction was aspirated off and then washed twice with PBS. These cells were resuspended in PBS with 3% BSA (final concentration 0.5x106/ml) at 4°C.
Immunofluorescence staining and flow cytometry
Cell suspensions were stained for 30 min at 4°C with the following monoclonal antibodies labelled with fluorescein isothiocyanate (FITC) or phycoerythrin (PE) to analyse the surface antigens of decidual lymphocytes: anti-CD56 (NKH1-PE; Coulter Co, Miami, FL, USA), anti-CD16 (Fcg-R3-FITC; Pharmingen, San Diego, CA, USA), and anti-CD11a (LFA-1-FITC; Pharmingen). The labelled samples were washed twice with PBS at 4°C and analysed using single or two-colour flow cytometry (FACS; Becton-Dickinson, San Jose, CA, USA). Prior to analysis, 1 µg/ml of propidium iodide (PI; Sigma, St. Louis, MO, USA) was added to the suspensions to distinguish dead cells and debris from the electrically-gated lymphocyte cluster. The fluorescent background was detected using an isotype-matched non-reactive fluorescence conjugated monoclonal antibodies (IgG1–FITC and PE). Fluorescent signals were detected though a 530 nm filter for FITC, a 580 nm filter for PE and a 610 nm filter for PI. Immunofluorescence reactivity was analysed in 1x104 cells from the gated cell cluster in each sample.
Flow cytometric characterization was performed with Cell Quest version 3.0.1f (Becton-Dickinson, San Jose, CA, USA) on a Power Macintosh 8600/250 (Apple Computer Inc, Cupertino, CA, USA). Results are shown as mean ± SD, and statistical comparisons were carried out using unpaired Student's t-test.
Results
The subpopulation of endometrial and decidual leukocytes; CD4, CD8, CD14, CD56dim, and CD56bright were shown in Table II. The frequency of CD8 T cells in early pregnancy and pregnancy loss decreased significantly (P < 0.05) compared with that in the late secretory phase. There was no change in the frequency of CD4 T cells. Earlier reports (Komada et al., 1998) showed that the frequency of CD3 T cells was significantly lower in early pregnancy than in the menstrual cycle. Our findings were in agreement with this report and showed that a decrease in CD3 T cells was associated with a decrease in CD8 T cells. The frequency of CD4/CD8 T cells (CD3 T cells) was higher, and that of CD14 monocyte/macrophages or CD56bright NK cells was lower in the present study than those in previous reports (Starkey et al., 1988; King et al., 1991). This discrepancy may be due to the difference of cell isolation methods. We did not use enzyme digestion, but mechanically disrupted decidual tissue. In addition, disrupted tissue was filtered through a nylon mesh. Therefore, monocytes/macrophages may have adhered to the mesh.
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Flow cytometric characterization using CD56–PE and CD16–FITC monoclonal antibodies (mAb) demonstrated that the predominant population of NK cells in endometrial and decidual lymphocytes in the late secretory phase, normal pregnancy, and pregnancy loss was CD56brightCD16–, with a few CD56dimCD16+ or CD56brightCD16+. In contrast, NK cells of peripheral blood lymphocytes were mostly CD56dimCD16+ with a few CD56brightCD16– NK cells. These findings were in agreement with those of previous studies (Starkey et al., 1988
; Ritson et al., 1989; King et al., 1989b, 1991; Lachapelle et al., 1996).
Figure 1 shows flow cytometric characterization using CD56–PE and CD11a–FITC mAb against decidual or peripheral lympocytes. In the normal pregnant decidua, ~60% of CD56bright NK cells expressed CD11a, whereas almost all CD56dim NK cells expressed CD11a. Also, almost all CD56dim NK cells in peripheral lymphocytes expressed CD11a. Furthermore, in pregnancy loss and the late secretory phase, the expression of LFA-1 on CD56bright NK cells was significantly increased, compared with that in normal pregnancy.
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Compared with the non-pregnant endometrium in the late secretory phase, the subpopulation of CD56brightCD16– cells was significantly increased in normal pregnancy (43.8 ± 16.8 versus 24.3 ± 15.0%, P < 0.05), but was less than that in early pregnancy loss (59.2 ± 16.7%). Furthermore, the mean LFA-1 expression rate on decidual/endometrial CD56bright NK cells was significantly higher in pregnancy loss (83.8 ± 13.2%, P < 0.05) and the late secretory phase (88.0 ± 9.2%, P < 0.05) than in normal pregnancy (62.4 ± 18.4%) (Figure 2
). However, the frequency of CD56brightCD16– NK cells in the late secretory phase was lower in the present study than those in previous reports (Starkey et al., 1988; King et al., 1989b). This discrepancy may have been due to the difference of cell isolation methods (mechanical disruption versus enzyme digestion, density of Ficoll versus Lymphoprep, and thermal condition; 4°C versus 37°C during enzyme treatment).
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Chromosomal analysis of chorionic villi was performed in pregnancy loss patients (trisomy:9, triploidy:1, 45XO:3, 46XX or 46XY:7). The population of CD56brightCD16– NK cells in the decidual lymphocytes or the percentage of CD11a-positive cells in the CD56bright cell population were not different between normal and aberrant karyotype groups (66.9 ± 14.4% versus 59.0 ± 18.4%, 80.8 ± 13.2% versus 88.8 ± 13.2% respectively).
In pregnancy loss, the relationship between serum progesterone concentration and the population of CD56brightCD16– cells in decidual lymphocytes and the percentage of CD11a-positive cells in the CD56bright cell population were analysed. However, no significant correlations were detected (r = 0.54, P = 0.20, and r = 0.14, P = 0.75 respectively).
Discussion
Earlier reports (Starkey et al., 1988, Ritson et al., 1989, King et al., 1989b, 1991; Lachapelle et al., 1996) showed that the predominant phenotype of NK cells in the endometrium and decidua during the late secretory phase and early pregnancy was CD56brightCD16– and that in peripheral blood was CD56dimCD16+. Our observations were consistent with these findings.
This study demonstrated that these CD56bright NK cell cluster showed a very low expression of CD11a, compared with that of CD56dim NK cells of the endometrium or peripheral blood. LFA-1 was demonstrated to play a critical role in NK cell-mediated cytotoxicity by experiments involving blocking of killer activity with anti-LFA-1 monoclonal antibody (Krensky et al., 1983; Schmidt et al., 1985; Hall et al., 1985; Mentzer et al., 1986). In decidual predominant CD56bright NK cells, the inhibition of this adhesion molecule was consistent with a previous study in which decidual NK cell-mediated cytotoxicity against the trophblastic cells or the K562 cells was shown to be weak compared with peripheral NK activity (King et al., 1989a, 1990).
Another surprising result was that numbers of LFA-1 expressing CD56brightCD16– NK cells in the endometrium/decidua in either the late secretory phase or early pregnancy loss were significantly increased compared with that in the normal pregnancy. Recently, it was reported that intercellular adhesion molecule-1 (ICAM-1), which is a ligand of LFA-1, was expressed on the surface of the decidual stromal cells (Tabibzadeh and Poubouridis, 1990; Tawia et al., 1993; Ruck et al., 1994) or trophoblastic cells (Xiao et al., 1997). Therefore, our results suggested that LFA-1 expressed on CD56brightCD16– NK cells could be strongly related to the immunological interaction between endometrial/decidual NK cells and the stromal or trophoblastic cells via LFA-1/ICAM-1 adhesion, and the activation of this pathway may play a very important role in onset of menstruation or pregnancy loss. Recently, it was reported that the LFA-1 expression on decidual NK cells in spontaneous abortion specimens was higher than that in normal pregnancy (Komada et al., 1998). Our observations were consistent with these findings. However, they reported scanty data on nine spontaneous abortion samples, five of which were aberrant karyotype embryos. No data were demonstrated with respect to normal versus abnormal karyotype. Our results, in which decidual NK activity was not influenced by trophoblastic cellular karyotype, is new important information for the elucidation of mechanisms in early pregnancy loss. Furthermore, in our study, the frequency of CD56bright CD11a+ NK cells during the late luteal phase was higher than that in Komada's report. This discrepancy may have been due to the difference of cell isolation methods and/or sampling. In cell isolation, we used nylon mesh and Ficoll–Paque centrifugation, but they did not use nylon mesh and centrifuged samples by a two-step density Percoll gradient. In addition, we obtained almost all of the specimens from women with male or tubal factor infertility during day 24 onwards of the menstrual cycle (average: day 25). They used hysterectomy specimens during day 22 onwards of the menstrual cycle (average: unknown).
Details of the mechanisms involved in the regulation of LFA-1 expression and proliferation of decidual CD56brightCD16– NK cells remain unclear. Recent studies demonstrated that decidual CD56brightCD16– NK cells expressed interleukin-2 receptors (IL-2Rb) and small low amounts of IL-2 induced killer activity of decidual CD56brightCD16– NK cells (Ferry et al., 1990, 1991; Nishikawa et al., 1991; King et al., 1992). Therefore, the IL-2 released by the other decidual lymphocytes, e.g. Th1 cells, was probably related to LFA-1 expression and/or proliferation of decidual CD56brightCD16– NK cells. A recent study indicated that IL-2 modulates the expression of the LFA-1 adhesion molecule in peripheral CD56dim NK cells (Robertson et al., 1990). Further studies of the altered cytokine production from Th1 and Th2-like cells in the human decidual stroma are necessary.
In addition, recent studies showed that, in vitro, progesterone promotes the preferential development of Th2-like cells and induces transient IL-4 production by established Th1 cells (Piccinni et al., 1995) or induces T-cells to produce NK inhibitory protein (PIBF) (Szekeres et al., 1995; Check et al., 1996; Kelemen et al., 1996). Therefore, withdrawal of serum progesterone in the late secretory phase is thought to stimulate endometrial NK cell activity through T-cell modulation, and this NK cytolysis induces breakdown of the endometrium. However, this hypothesis cannot clearly explain all cases of immune-mediated pregnancy loss, because progesterone inadequacy is not recognized in all such cases. Our results indicate no correlation between serum progesterone concentrations and changes in the subpopulation or LFA-1 expression of decidual NK in pregnancy loss are consistent with this consideration.
According to the `missing self' hypothesis, NK cells recognize and eliminate cells that fail to express self major histocompatibility complex (MHC) class I molecules (Ljunggren and Karre, 1990). In addition, a recent study showed that trophoblast cells directly in contact with the maternal tissues express the class I molecule HLA-G, which may be involved in protecting the trophoblast from recognition by NK cells. Furthermore, the receptors on NK cells that recognize HLA-G were also identified (Pazmany et al., 1996). Therefore, decidual NK cells could recognize and reject trophoblast cells with aberrant HLA-G, irrespective of the reduction of progesterone or increases in the amounts of Th1-type cytokine. A recent report (King et al., 1998) demonstrated that uterine NK cells have killer inhibitory receptors (KIR) and that the CD94/NKG2 family can recognize class I molecule HLA. The population of KIR expressing uterine NK cells and the antigenic density are not the same in peripheral blood NK cells and uterine NK cells from the same pregnant individual. In addition, the expression of these NK receptors varies between different women. Therefore, these authors suggested that this heterogeneity in expression of NK receptors means that NK cell effector functions may vary, depending on both the maternal NK receptor repertoire and on the HLA class I antigen profile of the placental trophoblastic cells. Further detailed studies of the interaction between these receptors of uterine NK cells and HLA class I antigen expressed on trophoblastic cells in decidua of early pregnancy loss are necessary.
We also investigated whether chromosomal abnormalities in the trophoblast affected the LFA-1 expression rate of CD56bright NK cells in the decidua in pregnancy loss. However, no clear differences were observed between normal and aberrant chromosomes. Our observations indicated that decidual NK activity was not influenced by trophoblastic cellular karyotype.
In conclusion, increases in the amounts of LFA-1 expressed on decidual CD56brightCD16– NK cell could be related to early pregnancy loss or onset of menstruation through the LFA-1/ICAM-1 adhesion pathway. Further investigations may elucidate the mechanism of recurrent abortion and implantation failure in IVF.
Notes
1 To whom correspondence should be addressed 
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Submitted on March 31, 1999; accepted on August 16, 1999.
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