Mol. Hum. Reprod. Advance Access originally published online on June 13, 2005
Molecular Human Reproduction 2005 11(6):451-457; doi:10.1093/molehr/gah181
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Divergence of natural killer cell receptor and related molecule in the decidua from sporadic miscarriage with normal chromosome karyotype
1Department of Obstetrics and Gynecology, 3Department of Public Heath, Hokkaido University Graduate School of Medicine, and 2Division of Immunobiology, Research Section of Pathophysiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
4 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine, Kita-ku N15 W7, Sapporo 060-8638, Japan. Email: yhideto{at}med.hokudai.ac.jp
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Abstract |
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The aim of this cohort study was to investigate immunophenotypic characteristics of natural killer (NK) cells by assessing specific molecules expressed in the decidua of sporadic miscarriages and induced abortions. The deciduae were obtained from 29 consecutively seen women whose pregnancies ended in first trimester miscarriages (MS), and the fetal chromosome karyotype of these MS was analysed. Additionally, 13 deciduae were obtained from induced abortion (IA) with informed consent. The expression of perforin, CD94, CD161, CD158a, CD158b, CD244 on CD3–CD56+NK cells, and perforin on CD3+CD8+ T cells was analysed by flow cytometry. The CD158a (mean±SD, 26.2±14.7%) and CD94 (50.2±25.7%) expressions in MS with normal chromosome karyotype (MSNK; n=11) were significantly decreased as compared with those (41.5±19.5%, 71.4±20.4%) in MS with abnormal karyotype (MSAK; n=18) and those (44.3±21.9%, 80.8±17.5%) in IA (n=13). Conversely, the perforin expression on CD3–CD8–CD56+NK cells (76.3±11.0%) and CD3+CD8+T cells (30.6±9.2%) in MSNK was significantly increased as compared with those (66.8±16.6%, 23.6±8.7%) in MSAK and those (62.9±11.6%, 19.7±8.1%) in IA. A positive correlation between CD94 and CD158a expressions on NK cells, negative correlations between CD94 on NK cells and perforin on NK cells/T cells, and between CD158a on NK cells and perforin on T cells were found in the decidua. A divergence of NK cell repertoire in the decidua might be related to aetiology of sporadic MSNK.
Key words: KIR/natural killer cell/pregnancy/recurrent miscarriage/recurrent spontaneous abortion
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Introduction |
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Numerous investigations have been performed focusing on the possible role of immunological abnormalities of natural killer (NK) cells in miscarriage. High preconception peripheral NK cell activity and NK cell number have been found to be associated with subsequent miscarriages in women with recurrent miscarriage (RM) (Aoki et al., 1995
; Emmer et al., 1999; Yamada et al., 2003) as well as in women undergoing IVF treatments (Thum et al., 2004).
NK cells constitutively express neural cell-adhesion molecule (CD56) and are large, granular lymphocytes that mediate lysis of certain viral infected cells or tumour cells. NK cells recognize and lyse target cells by two basic mechanisms: antibody dependent cell cytotoxicity (ADCC) through the Fc
RIIIA molecule, and natural cytotoxicity. NK cell-specific activating receptors are NKp46, NKp44, and NKp30, referred to as natural cytotoxicity receptors (NCR) (Moretta et al., 2000), although their ligands are not known. Another activating NK cell receptor that is expressed mainly by NK cells and activated CD8+ T cells is 2B4 (CD244), whose ligand is CD48 (Nakajima et al., 1999). NKR-P1A (CD161), which is a C-type lectin, has also been shown to participate in triggering cytotoxic activity of certain human NK cell clones (Lanier et al., 1994) and human macrophages (Poggi et al., 1997). Perforin is stored in cytoplasmic granules and, upon activation, NK cells and T cells secrete these cytolytic granules. Perforin monomers are then inserted into the plasma membrane of target cells and polymerize into pore-forming aggregates (Liu et al., 1995), which leads to osmotic lysis, granzyme entry, and killing of the target cells. In addition, NK cells, upon activation, produce large amounts of interferon-(IFN-), which not only displays antiviral activity but also regulates various cells of the immune system; e.g., IFN- induces macrophage activation and T cell polarization towards Th1 effectors.
The activity of NK cells is regulated by the expression of MHC class I molecules on potential target cells (Long et al., 2001). In humans, three distinct families of genes have been defined that encode for receptors of HLA class I molecules. One major group is referred to as killer cell immunoglobulin (Ig)-like receptors (KIR). They possess two or three Ig domains and each member interacts with a different group of closely related HLA class I molecules (Lanier, 1998). A second group of receptors known as immunoglobulin-like transcript (ILT) are also members of the Ig superfamily. The third group of HLA class I receptors are C-type lectin proteins and are composed of heterodimers of CD94 covalently associated with a member of the NKG2 family of molecules. The ligand for most members is the non-classical class I molecule HLA-E (López-Botet and Bellon, 1999).
KIRs with long (L) cytoplasmic tails are inhibitory and contain an immnunoreceptor tyrosine-based inhibition motif (ITIM) sequence, while those with short (S) cytoplasmic tails activate NK cell cytotoxicity through interactions with the adapter molecule, DAP12 (Lanier et al., 1998). NK cells expressing KIRs with ITIM sequences, such as KIR2DL1 (CD158a) and KIR2DL2/L3 (CD158b), are inhibited from lysing target cells that express HLA class I molecules reactive with the expressed KIR (Moretta and Moretta, 1997). In contrast, the expression of KIRs without an ITIM (e.g., KIR2DS) by NK cells appears to promote cytolysis against target cells expressing an appropriate HLA class I ligand (Moretta et al., 1995).
Recently, it has been demonstrated that peripheral NK cell activities and percentages prior to conception (Yamada et al., 2003) and early gestation (Yamada et al., 2001) in RM women whose pregnancies are destined to end in miscarriage with normal fetal chromosome karyotype (MSNK) are higher than those in RM women with subsequent live birth and in RM women with subsequent miscarriage with abnormal chromosome karyotype (MSAK). These findings suggest that elevated NK cell activities in the peripheral blood are causally associated with MSNK in RM women.
However, there have been no studies on immunophenotypic changes of decidual NK cells in sporadic cases of miscarriage. In the present cohort study, therefore, we prospectively investigated the immunophenotypic characteristics of decidual NK cells by assessing a variety of NK cell-related molecules and simultaneously performed the fetal chromosome karyotyping in sporadic miscarriages, in order to understand whether any divergence of NK cells is related to MSNK.
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Subjects and methods |
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Patients characteristics
The deciduae were obtained with informed consent from 29 consecutively seen Japanese women (24–42 years old) whose pregnancies ended in first trimester missed miscarriage (MS) at 7–12 weeks of gestation in the Hokkaido University Hospital. Inevitable, complete, or incomplete MS was excluded in this study, so that all 29 patients had no symptom of bleeding or lower abdominal pain when diagnosed. The fetal chromosome karyotype was simultaneously analysed by G-banding techniques. Eleven of 29 MS were found to be MSNK, and the remaining 18 had MSAK. MSAK included 17 with numerical aberration (12 trisomies, 4 monosomy-X, and 1 triploidy) and 1 with structural aberration. Thirteen deciduae were obtained with informed consent from Japanese women (19–36 years old) whose pregnancies resulted in induced abortions (IA) at 6–11 weeks of gestation in an affiliated clinic. The fetal karyotyping in IA was not performed.
The ages (mean±SD) of women with MSNK, MSAK, and IA were 29.9±5.3, 34.3±5.3, and 27.5±6.4 years old, respectively. The gestational ages at evacuation of MSNK and MSAK were 9.0±1.1 and 9.7±1.3 weeks of gestation calculated by last menstrual periods; 7.7±0.9 and 7.8±1.2 weeks of gestation calculated by the size of gestational sac and crown-rump length, respectively. The gestational age at evacuation of IA was 8.0±1.3 weeks of gestation calculated by crown-rump lengths. Fetal heart movement was once detected in 6 of 11 MSNK, 13 of 18 MSAK, and all cases of IA. Previous miscarriage numbers in women with MSNK, MSAK, and IA were 0.9±1.6, 1.2±1.8, 0±0, respectively.
Flow cytometric analysis
Deciduae were obtained from dilatation and curettage operations and suspended in phosphate buffered saline (PBS) containing 0.2% bovine serum albumin (BSA)and 0.1% sodium azide, were then minced by surgical scissors and strained through nylon mesh (59 µm). A lysing solution containing NH4Cl and EDTA was added for 10 min at room temperature to lyse the erythrocytes. Decidual cells were washed twice with PBS and resuspended with 1 ml of PBS before flow cytometric analyses.
For the NK cell analyses, the cells were stained with fluorescein isothiocyanate (FITC)-conjugated anti-CD3 (SK7) mAb (Becton Dickinson, San Jose CA, USA), phycoerythin (PE)-conjugated anti-CD56 (NKH-1) (Beckman Coulter, Inc., Fullerton, CA, USA). Other mAb combinations were as follows: anti-CD3 (S4.1)-allophycocyanin (APC) (CALTAG Laboratories, Burlingame CA, USA), anti-CD56 (NKH-1)-phycoerythin-cyanine 5 (PC5) (Immunotech, Marseille Cedex, France), anti-CD94 (HP-3B1)-PE (Immunotech), and anti-CD161 (DX12)-FITC (Becton Dickinson); anti-CD3 (SK7)-FITC (Becton Dickinson), anti-CD56 (NKH-1)-PC5 (Immunotech), and anti-CD158a (EB6)-PE (Immunotech) or anti-CD158b (GL183)-PE (Immunotech) or anti-CD244 (C1.7.1)-PE (Immunotech).
For the staining of intracellular perforin, the cells were washed and fixed with fixation buffer (CALTAG), and then washed with permeabilization buffer (CALTAG). These fixed and permeabilized cells were stained with mouse anti-human perforin (
G9) (Becton Dickinson) with RPE-Cy5-conjugated F(ab')2 fragment of rabbit anti-mouse immunoglobulins (DAKO Cytomation, Glostrup, Denmark), and then stained with anti-CD3 (SK7)-FITC (Becton Dickinson), anti-CD56 (NKH-1)-PE (Beckman Coulter) and anti-CD8 (B9.11)-APC (Immunotech).
Three and four colour flow cytometric analyses were carried out using a FACS Calibur flow cytometer (Becton Dickinson) and CellQuest Software. The gating and frequencies of CD158a+, CD94+, CD244+ cells in decidual CD3–CD56+ NK cells, and perforin+ cells in decidual CD3+ CD8+ T cells are shown in Figures 1 and 2.
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Statistical analysis
Statistical analysis of the data was performed using a parametric analysis of variance (ANOVA) followed by post-hoc analysis (Bonferroni/Dunn test). In addition, the Mann–Whitney U-test was used for comparisons between 2 groups. Correlations were tested by single regression analyses. Values of P<0.05 were considered statistically significant using Statview.
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Results |
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Table I shows percentages of cell subpopulation with expression of a variety of NK cell-related molecules.
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Numbers of decidual CD3–CD56+NK cells were not different among MSNK, MSAK, and IA. Using a parametric ANOVA followed by the Bonferroni/Dunn test, however, CD158a (mean±SD, 26.2±14.7%), CD94 (50.2±25.7%) and CD244 (81.3±24.6%) expressions in MSNK were significantly decreased as compared with those (41.5±19.5%, 71.4±20.4% and 93.5±4.0%) in MSAK and those (44.3±21.9%, 80.8±17.5% and 92.2±4.5%) in IA. Conversely, the perforin expression on CD3–CD8–CD56+ NK cells (76.3±11.0%) and CD3+CD8+T cells (30.6±9.2%) in MSNK was significantly increased as compared with those (66.8±16.6%, 23.6±8.7%) in MSAK and those (62.9±11.6%, 19.7±8.1%) in IA. When the Mann–Whitney U-test was used, the P values were the same as those of ANOVA, as shown in Table I for CD158a, CD94, and CD8– perforin. There was a trend towards altered perforin expression in CD8+ cells between MSNK and MSAK (P=0.09), and significant difference between MSNK and IA (P<0.01). However, there were no significant differences in CD244 expression when data was analysed by Mann–Whitney U-test.
Figure 3 shows individual distribution of perforin+ cell percentages in the decidual NK cells (Figure 3A) and T cells (Figure 3B), and distribution of CD94+ cell (Figure 3C) and CD158a+ cell (Figure 3D) percentages in the decidual NK cells.
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: women with miscarriage with abnormal fetal chromosome karyotype (n=18). 
: women with induced abortion (n=13).By regression analyses we found that CD94 expression was positively correlated (r2=0.17, P<0.01; r2=0.47, P<0.001) with CD158a expression on decidual NK cells (Figure 4A), whereas, the CD94 expression was negatively correlated (r2=0.20, P<0.01; r2=0.22, P<0.05) with perforin expression on NK cells (Figure 4B). Additionally, we found that both the CD94 expression (r2=0.15, P<0.05; r2=0.34, P<0.01) and the CD158a expression (r2=0.12, P<0.05; r2=0.24, P<0.05) on NK cells were negatively correlated with perforin expressions on T cells as shown in Figure 4C and 4D. The former r2 and P values were calculated from all 42 subjects and the latter values from MSNK plus IA (n=24) excluding MSAK.
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Discussion |
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There is a growing body of evidence that innate immunity plays an important role in the immune response to disease as well as pregnancy maintenance. It has been demonstrated that peripheral NK cell activities and percentages are abnormally elevated prior to conception in RM women whose subsequent pregnancies are destined to end in MSNK, but this NK cell accentuation are not detected in RM women with subsequent MSAK (Yamada et al., 2003
). It is widely acknowledged that MSAK were caused by lethality of chromosomally abnormal embryos, and there is no necessity that MSAK accompanies immunological abnormality except effects of fetal demise. Recently, we have found a decrease in expression of inhibitory CD158a (KIR2DL1) on peripheral NK cells in RM women, suggesting attenuation of inhibitory mechanisms in NK cells might be related to recurrence of miscarriages (Yamada et al., 2004).
Since no immunological causes of sporadic cases of MSNK have been understood and why MSNK happens are still largely unknown, we postulated that attenuation of inhibitory mechanisms on NK cells are causally related to sporadic cases of MSNK as well. Then, we planned and commenced this prospective cohort study. Although a previous study found increased CD56+ cell number in MSNK as compared with MSAK (Arck et al., 2001), NK cell percentages at maternofetal interface in MSNK did not differ from those in MSAK or IA in the present study. However, in the decidua of MSNK, expressions of inhibitory CD158a and CD94 receptors on NK cells were found to be decreased, and conversely expressions of cytolytic perforin on NK cells and cytotoxic T cells were found to be increased. These changes were not likely to originate from effects of fetal demise, because no or minimal differences in expressions of these molecules were detected between MSAK and IA. In the present cohort study we for the first time demonstrated that immunological abnormalities including increased cytotoxicity of NK cells and T cells might be one of the many causes of sporadic MSNK.
Additionally, we found that expression of CD94 was positively correlated with inhibitory CD158a and was negatively correlated with perforin in decidual NK cells; and that expressions of CD94 and CD158a on decidual NK cells were negatively correlated with perforin in decidual T cells. These findings suggest that the immunophenotype of decidual NK cells deviate by changing expression of CD94, CD158a, and perforin coordinately, and that NK cells and cytotoxic T cells in the decidua cooperate from inhibition to activation in MSNK. These immunophenotypic changes of NK cells and cytotoxic T cells associated with deteriorated embryo development might originate from common activation stimuli and cross-talk of these cells in the decidua causing the immunodystrophiosm (Shimada et al., 2003; Shimada et al., 2004) at the maternofetal interface.
The CD158a is the HLA-Cw supertype-specific KIR expressed on NK cells in peripheral blood as well as in the decidua (Verma et al., 1997). The invading fetal trophoblast cells that express HLA-C (King et al., 1996) might normally be protected from cytotoxicity by maternal NK cells expressing inhibitory CD158a. The decreased expression of inhibitory CD158a on NK cells might cause over-cytotoxicity to invading trophoblast cells and developing embryos, and thereby be causally related to MSNK. A 4-fold increase in CD56+CD158a+/CD158b+ cell percentages in the first trimester decidua as compared with the peripheral blood has been demonstrated during normal pregnancy (Lewis et al., 2002). One study found that that the proportions of decidual CD158a+/CD158b+ NK cells in anembryonic pregnancy were markedly decreased as compared with normal pregnancy (Chao et al., 1999). Other investigators demonstrated that expression of CD158a, but not CD158b, on NK cells in peripheral blood mononuclear cells and peritoneal fluid was increased in women with endometriosis as compared with controls (Maeda et al., 2002a; Maeda et al., 2002b). Analogically, these authors suggested that an increase in CD158a expression was a pathologic factor promoting immunotolerance status to implanted tissues in endometriosis. Thus, a divergence of CD158a (KIR2DL1) expression might be pathologically involved in particular reproductive diseases such as endometriosis (Maeda et al., 2002a; Maeda et al., 2002b), RM (Yamada et al., 2004), and miscarriage (Chao et al., 1999) as well as sporadic MSNK.
It has been noted that EB6 mAb, which was used in the present study as well as in the aforementioned studies directed to the CD158a ‘inhibitory’ receptor (KIR2DL1) also may recognize the ‘activating’ p50 form of the receptor (KIR2DS1) (Lewis et al., 2002). For this reason, phenotypic analyses using this mAb might not precisely distinguish between the two forms. However, affinity of HLA-C ligand to KIR2DS1 receptor was known to be extremely low as compared with to KIR2DL1 receptor. NK cell function is governed by a balance between inhibitory and activating receptors, where the inhibitory signal generally dominates the activating signal (Lanier, 1997). A recent genetic study found that women with RM of alloimmune etiologies carried less genotypes of inhibitory KIRs (2DL1, L2, L3) than controls, suggesting that a limited inhibitory KIR repertoire was involved in etiologies of RM (Varla-Leftherioti et al., 2003). The Japanese were found to be less heterogeneous in KIR genohaplotypes than other ethnicity; almost 100% of Japanese carry the 2DL1 gene, but 35% or less carry the 2DS1 gene (Yawata et al., 2002). Therefore, the majority of CD158a molecules detected by EB6 mAb in the present study could be inhibitory KIR2DL1 molecules.
One previous study reported decreased expression of inhibitory CD94 and increased expression of CD69—the latter of which is usually expressed on many activated cells of haematopoietic origin—in peripheral CD56+ NK cells in RM women (Ntrivalas et al., 2001). It has been found that NK cytotoxicity can be blocked by inhibitory CD94 receptor (Borrego et al., 1999) and correlate inversely with expression of inhibitory CD94 on NK cells in the peripheral blood (Coulam and Roussev, 2003). Inhibitory receptor complexes (CD94-NKG2A) belong to the C-type lectin superfamily and contain ITIM sequences in their cytoplasmic tails. CD94-NKG2A receptors interact with complexes consisting of the non-classical HLA-E molecule bound to a peptide derived from the leader sequence of a classical HLA class I protein (McQueen and Parham, 2002). Human inhibitory CD94-NKG2A receptor has a high affinity for its ligand HLA-E/peptide than the activating CD94-NKG2C receptor, where there seems to be a direct correlation between the binding affinity of the HLA-E/peptide for CD94-NKG2 receptors and triggering of a response by NK cells (Vales-Gomez et al., 1999). Therefore, the decreased expression of CD94 on NK cells might cause impaired inhibition and over-cytotoxicity to invading trophoblast cells that expressed HLA-E, and thereby be causally related to MSNK.
CD244 (2B4) that contains ITAM motifs is expressed mainly by NK cells and activated CD8+ T cells (Nakajima et al., 1999). Engagement of 2B4 by antibodies or its ligand CD48 induces natural cytotoxicity and IFN- production (Valiante and Trinchieri, 1993; Nakajima et al., 1999; Tangye et al., 1999), while inhibitory function of CD244 receptor has recently been demonstrated (Mooney et al., 2004). In the present study, CD244 expression was found to be statistically different by the Bonferroni/Dunn test, but not when the Mann–Whitney U-test was used. Perforin is stored in cytoplasma of NK cells and T cells, and directly relate to cytotoxicity of these cells. In the present study, accumulation of these cytolytic granules in decidual NK cells and T cells, being inversely correlated with CD94 and CD158a expression on NK cells, was found in MSNK. To the best of our knowledge, this is the first report demonstrating that perforin accumulation in NK cells and T cells was related to reproductive failures.
Recent studies have demonstrated that combinations of KIR and HLA-C genotypes influence a risk of pre-eclampsia (Hiby et al., 2004) and antiviral immunity to hepatitis C virus (Khakoo et al., 2004). It has also been reported that the maternal KIR genotypes are not associated with RM (Witt et al., 2004), which arouses a new controversy with a previous result from Varla-Leftherioti et al. (2003). All human NK cells express at least one KIR gene and all of the KIR genes in a person's KIR genotype are expressed by some of that person's NK cells. Within a person's NK cell population the expression of KIR is very heterogeneous due to the expression of different number of KIR genes and different combination of KIR genes (Valiante et al., 1997). Therefore, in future studies it is necessary to analyse the maternal KIR genotypes and KIR expressions in the decidual NK cells together with the fetal HLA-C genotypes in order to further assess whether, KIR receptor-HLA ligand interactions are really one of causal etiologies of RM and MSNK. In this view, to study KIR phenotypes in Japanese women seems to have a good merit because Japanese populations are less heterogeneous in KIR genohaplotypes and have very high frequency of the KIR-AA genotype as compared with Caucasians (Hiby et al., 2004).
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Acknowledgements |
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This work was supported in part by a Grant-in-Aid (No. 14370521) and a Grant-in-Aid for the 21st Century COE program on ‘Topological Science and Technology’ from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by a Grant-in-Aid from the Ministry of Health, Labor and Welfare of Japan.
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Submitted on December 27, 2004; resubmitted on February 13, 2005; accepted on April 18, 2005.
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