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Immunology and Pregnancy Losses: HLA, Autoantibodies and Cellular Immunity

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Pregnancy loss is the one of the most common obstetrical complications. The majority of pregnancy losses are random or isolated incidences that in many cases are related to genetic abnormalities. However, 2-5 % of reproductive age women experience recurrent miscarriages.1,2 Recurrent pregnancy loss is typically defined as two or three or more consecutive pregnancy losses. Genetic, hormonal, metabolic, uterine anatomical, infectious, environmental, occupational and personal habits, thrombophilia, or immune disorders were reported as possible etiologies.3-6 Despite the many etiologies, a majority of women with recurrent miscarriage have no discernible cause. It has been postulated that immunologic aberrations may be the cause in many of such cases. Immunopathological evaluation of placenta from women with recurrent pregnancy losses of immune etiologies often demonstrate increased inflammatory cell infiltration at the implantation site and increased fibrin deposition on deciduas and/or perivillous placental membrane.7 In addition, thromboembolism has been noticed in 33.9% of the decidual vessels of the placenta from these women.7 These findings and others have suggested that inflammation and coagulation play a role in recurrent pregnancy loss.

Pro-inflammatory cytokines play a central role in the differential effects on the coagulation and fibrinolysis pathways.8,9 Vice-versa, activation of the coagulation system may affect inflammatory responses by direct and indirect mechanisms.10 In animal models, increased levels of Th1 cytokines activate coagulation by up-regulating the novel prothrombinase fgl2 in a mouse model.11 In humans, increased proinflammatory cytokines are reportedly associated with changes in the activated protein C (APC) system with a decrease in the ability to generate APC.12 Pregnant women with increased thrombin reserve and resistance to APC have increased levels of TNF-alpha and this may be important in the risk for adverse pregnancy outcomes.13 Women with recurrent pregnancy losses and/or implantation failures demonstrate significantly increased peripheral blood T helper 1 cells as compared to normal fertile women.14 Increased proinflammatory cytokines and up-regulated thrombophilic tendency seems to play a major role in recurrent pregnancy losses. In a mouse model, a physiological cascade of stress is associated with up-regulation of TNF-alpha, and an IL-12-triggered cascade is characterized by persistent up-regulation of TNF-alpha and IFN-gamma as well as a persistent increase in fgl2.15 In this chapter, possible roles of HLA antigens, autoantibodies, immunocytes and cytokines in inflammatory changes and thrombosis are discussed in relation to recurrent pregnancy losses.

Histocompatibility Gene Products and Their Role in Pregnancy Loss

During a pregnancy the developing fetal placental unit can be considered a semi-allograft, during which allogenic paternal HLA antigens are presented to a mother. Extravillous cytotrophoblasts express nonclassical class I HLA-G and -E molecules,16 with lowered expression of HLA-C antigens even prior to the implantation.17 One of potential roles of these antigens is the protection of trophoblasts from cytotoxicity. In the mouse bc1- or bc2- (which may be homologous to HLA-G1 and HLA-G2 of human) expressing RMA-S cells were protected from NK cell-mediated rejection in vivo. This finding demonstrates a role for blastocyst MHC in protecting transporter associated with antigen-processing (TAP)-deficient trophoblasts from NK cell attack in vivo.18 In humans, natural killer cells are inhibited by HLA-G via NKAT3, which contributes to the survival of the fetal semi-allograft in the mother during pregnancy.19 Despite the experimental data, clinical correlation between HLA-G expression and recurrent pregnancy losses has not been shown.20 In addition to evidence that HLA-G can inhibit NK cells, there is growing evidence that HLA-G can also regulate T cells. The soluble HLA-G1 isoform downregulates both CD8+21 and CD4+ T cell reactivity.22 HLA-G also modulates innate immunity by binding to several NK and/or decidual receptors, inducing secretion of certain cytokines. It is also noteworthy that extraordinary levels of variation in the 5'-upstream regulatory region of HLA-G exist, which may provide evidence for an association between a promoter-region single-nucleotide polymorphism and fetal loss rates. One polymorphism, -725C/G, was associated with fetal loss, with an increased risk for miscarriage in couples in which both partners carried the -725G allele, compared with couples not carrying this allele.23

An excess of human leukocyte antigen sharing in primary and secondary recurrent aborters has been reported. The primary aborters shared human HLA- A and DQ antigens and primary and secondary aborters shared three or more of the human leukocyte A, B, DR, and DQ antigens.24 The role of recessive genes linked to the major histocompatibility complex was speculated on in the pathogenesis of recurrent spontaneous abortions and of gestational trophoblastic tumors. When maternal-fetal histocompatibility for HLA-Class II loci was examined, significantly more couples with RSAs shared 2 HLA DQA1 alleles as compared with fertile control couples. In addition, a significant deficit of HLA DQA1 compatible live born children was observed. It was suggested that HLA-DQA1 compatible fetuses may be aborted early in pregnancy, prior to the time when fetal tissue can be recovered for genetic studies.25 Prospective studies of pregnancy outcome demonstrate increased fetal loss rates among Hutterite couples matching for HLA-B antigens (P = 0.033) or for the entire 16-locus haplotype (P = 0.002). HLA region genes have a role in both pregnancy outcome and mate choice, and selective action of these genes may occur preconceptionally as well as during pregnancy.26

HLA antigens have been associated with the extent of an immune response to specific antigens. Couples with increased HLA sharing and recurrent pregnancy losses often demonstrate lack of anti-paternal cytotoxic antibodies (APCA), anti-idiotypic antibodies (Ab2) and mixed lymphocyte reaction blocking antibodies (MLR-Bf ). Overactivity of T helper-1 (Th-1) cytokines and natural killer (NK) cells have been also reported to be the major alloimmune cause of recurrent spontaneous abortion (RSA).27 These functions may be associated with specific HLA antigens or genes closely linked to them such as certain complement system proteins or TNFα. HLA class II histoincompatibility has been related with amelioration of rheumatoid arthritis during pregnancy.28 This finding suggests a histocompatible pregnancy may evoke maternal autoimmunity and perhaps up-regulate T helper 1 immune responses. The underlying pathology of T helper 1 immune responses in histocompatible pregnancies warrants further studies.

Autoimmune Responses

Early in the investigation of autoimmune correlates and recurrent spontaneous abortions, it was noted that some women without systemic lupus erythematosus have positive lupus anticoagulant and histories of fetal losses. These findings led to the question of whether this correlation was the beginning of systemic lupus erythematosus in these women or a new autoimmune entity with gynecoobstetrical manifestations.29 Autoimmune disorders that affect reproductive processes are often subclinical and most women who present with repeated miscarriage are otherwise well.30 Organ-specific antibodies such as anti-thyroid antibodies, and organ-nonspecific antibodies, including antiphospholipid antibody, lupus anticoagulant, anticardiolipin antibodies, antinuclear antibody, anti-ssDNA, anti-dsDNA, and anti-histone antibody have been reported to be associated with pregnancy losses or obstetrical complications.31-33 Although contradictory results were also reported in regard to the relationship of these antibodies and pregnancy losses, autoantibody associated reproductive failure, characterized by an increased risk of fetal loss and decrease in fecundity appears established. Whether the presence of autoantibodies are direct etiological factors for the pregnancy losses or obstetrical complications, or the epiphenomena, markers of immune activation still need to be explored further.

Antiphospholipid Antibody

The antiphospholipid syndrome (APS) is defined by recurrent pregnancy loss and thrombosis in the presence of antiphospholipid (aPL) antibodies. Experimental data shows that passive transfer of antiphospholipid antibodies result in clinical manifestation of APLS, that is, fetal loss and thrombocytopenia.34 Antiphospholipid antibodies (aPL) are a heterogeneous group of autoantibodies that are detected by both immunoassays and functional coagulation tests. The antigenic targets are negatively charged phospholipids and serum phospholipid-binding proteins. Despite the strong association between aPL and thrombosis, the pathogenic role of aPL in the development of thrombosis has not been fully elucidated. The most frequently utilized serologic markers for APS are lupus anticoagulant, anticardiolipin antibodies (aCL), and recently anti-beta-2-glycoprotein 1 antibodies.35 Interestingly, the trophoblast can be targeted by antiphospholipid antibodies (aPL), especially by anti-phosphatidylserine antibody (aPS).36 Cardiolipin is not present in the trophoblast plasma membrane; nonetheless, anticardiolipin (aCL) has been implicated in trophoblast pathology. Perhaps the crossreactivity between aPS and aCL may have contributed to this pathology.37

Previously we have reported that women with recurrent pregnancy losses demonstrated significantly higher prevalence of aCL, aPS and aPE (anti-phosphatidylethanolamine antibody) than those of normal fertile controls.38 It is noteworthy that the current rheumatological definition of APS does not include aPS or aPE evaluation.39 In addition, current therapy for pregnant women with APS, which is focused on preventing thrombosis by anticoagulation, is only partially successful in averting miscarriage.40 Obstetrical features of aPL needs careful investigation from a different perspective based on possible immunopathological effects of aPL on trophoblasts in addition to thrombogenic effect. Proposed mechanisms include antibody-mediated interference with coagulation homeostasis, activation of platelets and endothelial cells and a T-cell immune response to serum phospholipid-binding proteins.41

Both animal and in vitro experimental models have shown monoclonal and polyclonal aPS and aCL to specifically destroy trophoblast, inhibit syncytium formation, halt human chorionic gonadotropin (hCG) production, and limit trophoblast invasion. Antibodies to PE (aPE) have not been well characterized: however, recent reports document that aPE are associated significantly with very early (embryonic) recurrent pregnancy loss (RPL). During cytokinesis (late telophase) of Chinese hamster ovary (CHO) cells, formation of PE rafts in cleavage furrows is required for completion of cell division and formation of daughter cells. This raises the question whether aPE might interfere with implantation and cell division during embryogenesis.42 Recently, elevated plasma adrenomedullin concentration and uterine arterial pulsatility index (PI) were reported in women with antiphospholipid antibodies and recurrent pregnancy losses.43 Direct effect of the purified IgG positive for anticardiolipin/anti-DNA antibodies from SLE/APS patients with recurrent pregnancy loss (RPL) was reported to reduce rat yolk sac and embryonic growth more than sera negative for these antibodies. These sera reduced cultured human placental trophoblastic cell growth, reduced their proliferation rate and increased their rate of apoptosis.44

Complement activation has been reported to be a central mechanism of pregnancy loss in APS. The fact that F(ab)'2 fragments of aPL antibodies do not mediate fetal injury and that C4-deficient mice are protected from fetal injury suggests that activation of the complement cascade is initiated via the classical pathway.45 When complement activation was blocked, fetal loss was prevented in pregnant mice after injection of antiphospholipid antibodies. Interaction of complement component 5a (C5a) with its receptor is reported to be necessary for thrombosis of placental vasculature.46

Recent data demonstrated that intravenous immunoglobulin G (IVIg) inhibits the thrombogenic effects of antiphospholipid antibodies in vivo and reduces the levels of anti-cardiolipin antibodies in the circulation. Blockade of stimulatory Fc gammaR on inflammatory cells is not necessary for this effect. The mechanism of action on IVIg is more likely saturation of the IgG transport receptor, leading to accelerated catabolism of pathogenic antiphospholipid antibodies. These results have implications in the management of thrombosis in antiphospholipid antibodies and have applications for pregnant patients with a history of antiphospholipid antibody syndrome.47 Each treatment with IVIg resulted in a reduction of anti-cardiolipin antibodies. A partial transient reduction of antiphospholipid antibody levels was observed immediately following each treatment course resulting in an accelerated fetal outcome.48,49

Alterations in cellular immunity have been studied in women with RSA who also have positive aPL. CD56+ NK cell levels are significantly elevated in these women as compared to those of women with negative aPL.50 In addition, lymphocytes from individuals with APS proliferated to ß2GP1 in a serum-free in vitro assay. The response was shown to be Ag-specific, requiring class II molecules, CD4+ T cells, and APCs, and was associated with a selective expansion of CD4+ but not CD8+ T cells. The proliferating T cells produced IFN-gamma but not IL-4, indicating a bias toward a type 1 immune response.51 These findings indicate a bias toward a T helper 1 immune response in individuals with aPL and may be related to ß2GP1 specificity. aPL binds specifically to apoptotic, but not viable, thymocytes, and that binding is dependent upon the presence of beta 2GPI. Moreover, beta 2GPI binds selectively to the surface of apoptotic thymocytes to generate an epitope for antiphospholipid autoantibodies.52 Plasma from APS patients up-regulates surface TF expression on normal human monocytes.53 Moreover, monocytes from patients with primary APS have increased TF Ag and TF-related procoagulant activity that correlates with thrombotic episodes.54

Anti-Thyroid Antibody

Six studies have evaluated the relationship between thyroid antibodies and recurrent abortion, defined as three or more spontaneous miscarriages.33,55-60 The majority of the studies (5/7) reported a statistically significant increase in the incidence of thyroid antibodies in the recurrent abortion group as compared to controls.

The incidence of thyroid antibodies in euthyroid women with recurrent pregnancy loss appears to be significantly increased compared with controls of reproductive age without previous abortions. No correlation between the presence of thyroid autoantibodies and nonorgan-specific autoantibodies could be established.55,56 Organ-specific and nonspecific autoantibodies were speculated to serve independent markers of risk for recurrent pregnancy losses in women with autoimmune abnormalities. The presence of antithyroid antibodies in nonpregnant women with a history of recurrent abortion was reported to identify a subgroup of women at significantly increased risk for yet another pregnancy loss in their next gestation.61 However, a recent study did not confirm this finding.62 It has been reported that euthyroid women with thyroid antibodies developed painless thyroiditis within 1 yr of pregnancy loss. This finding suggests that the immunological changes of a short-term gestation may be sufficient to lead to thyroiditis.63

Several intervention trials have evaluated the impact of immunosuppressive therapy in women with thyroid antibodies.64,65 Although all of the trials revealed a decrease in the incidence of recurrent abortion, each study was limited by methodological concerns.66

Maternal immune response, trophoblast function, and maternal thyroid function are reported to be correlated. The presence of low concentrations of hCG and free T4 and high levels of TSH and gamma globulins in women with threatened abortion suggests a negative outcome for the pregnancy.67 However, direct effect of anti-thyroid antibody on trophoblasts has not been investigated. It is speculated anti-thyroid antibody serves as a marker for autoimmune activation and T cell dysfunction. Further study is needed to investigate a possible direct effect of anti-thyroid antibody on trophoblast and its function.

Cellular Immune Responses in Pregnancy Loss

During the development of the fetal-placental unit, the maternal immune system obviously comes in contact with semi-allogenic antigens and systems must be in place to suppress a possible harmful immune response or to enable the growth of the unit without any pathological harm. The immune system that is exposed to these neoantigens consists of lymphocytes in both the peripheral blood (easily sampled) and the endometrium (obviously more difficult to sample). Peripheral blood reflects the systemic immune responses, whereas lymphocytes in the endometrium reflect the local environment. Studies concerning the lymphocyte populations in these two types of compartments have been reported for both normal pregnancies and pregnancy losses.

T Cells in Peripheral Blood

T cells can be characterized by their expression of surface molecules (phenotype) and by their capacity to produce various cytokines. Studies done in women with unexplained pregnancy losses suggest T cell alterations that may be involved in the pathogenesis of recurrent pregnancy loss. In peripheral blood, CD3 positive T cell levels are not different in nonpregnant women with a history of recurrent pregnancy losses as compared to those of normal fertile women.14,50,68 However, when CD3+ T cell levels are measured during the first trimester of women who miscarried a recent index pregnancy, the levels were significantly lower than those of women who successfully delivered a live infant.50 Although the exact mechanism has not been studied, it has been suggested that the proportional decrease of CD3+ T cell population in women who miscarried a pregnancy may result from a proportional increase of CD19+ B cells and/or CD56+ NK cells. An increase in either of these cell populations has been associated with pregnancy loss as described below.

It has been suggested that a successful pregnancy is a Th2 cytokine related phenomenon and that Th1 cytokines can be detrimental to a pregnancy.69 While there is a scarcity of data from human pregnancy indicating that Th1-type immune effectors actually lead to pregnancy loss, there is some compelling evidence linking inappropriate Th1-type immunity to pregnancy loss. The percentages of T helper cell (CD3+/CD4+) levels in women with RSA were not different from those of normal fertile women in our studies.14,50 Another study demonstrated elevated CD4+ cells in women with RSA.68 However, CD3+/CD4+ T helper cells can be further characterized by their patterns of cytokine production into T helper 1 and 2 cells. Percentages of peripheral blood Th1 (CD3+/CD4+/TNF-alpha+, CD3+/CD4+/IFN-gamma+) and Th2 cells (CD3+/CD4+/IL-10+, CD3+/CD4+/IL-4+) were determined by flow cytometric analysis in women with histories of recurrent pregnancy losses and normal fertile women. No statistical differences were found between these two groups. However, when the ratios of these cells (Th1/Th2) were determined and compared in these two groups, women with recurrent pregnancy losses had significantly elevated Th1:Th2 ratios compared to that of normal fertile controls.14 The underlying etiology of a shift in Th1/Th2 polarization needs further investigation.

T suppressor cell (CD3+/CD8+) levels were not different in women with recurrent pregnancy losses compared to controls.14 The cytokine production pattern of CD3+/CD8+ cells was parallel to that of CD3+/CD4+ cells. The same trend was noticed in CD3+/CD8+ cells in regards to cytokine production. The ratio of CD3+/CD8+/TNF-α to CD3+/CD8+/IL-10 cells was significantly elevated as compared to those of normal controls. CD8(+)11b(-) cells was significantly higher in patients with recurrent pregnancy loss in comparison with healthy women and T suppressor CD8(+)11b(+) lymphocytes were lower in women with pregnancy failures in comparison with the control group.68 This compelling study demonstrated significantly elevated Th1 immune responses in peripheral blood lymphocytes of women with recurrent pregnancy losses or multiple implantation failures, which may reflect the systemic contribution of Th1 cytokines. The percentage of CD56+ regulatory T-cells (CD3+/CD56+) in the peripheral blood of patients with a history of recurrent abortion was less than that in the nonpregnant or pregnant women. These results suggest that CD56+ T-cells with extrathymic properties may be associated with the maintenance of normal pregnancy in humans.70

In peripheral blood of healthy pregnant women the percentage of T cells with γδ TCR+ was significantly higher (P < 0.001) than in that of recurrent aborters or of nonpregnant individuals. These gamma/delta TCR-bearing lymphocytes may have a role in progesterone-dependent immunomodulation.71 In peripheral blood of healthy pregnant women, the most frequently occurring chain combination was gamma1.4/delta1, whereas in recurrent aborters, the gamma9/delta2 combination was predominant.72 Thus these two functionally distinct subpopulations are present in the peripheral blood of pregnant women and may also be related to pregnancy outcome.

Endometrial T Cells

The leukocytes that are found in the endometrium or decidua during pregnancy obviously play a role in maintaining a pregnancy. During the menstrual cycle leukocytes progressively infiltrate the endometrium and they may constitute as many as 30% of decidual cells in early pregnancy.73 CD3+, CD8+, CD4+, TcR αβ+, and TcR γδ+ cells are present in all phases of the menstrual cycle and in early pregnancy in the endometrium. The proportion of these subsets in relationship to total CD3+ T cells is not different between pregnant and nonpregnant human endometrium. However, significantly fewer T cells were detected in endometrium from early pregnancy compared to nonpregnancy tissues.74 These findings led to the suggestion that endometrial T cells are unlikely to play a significant role in implantation and the maintenance of human pregnancy since they decrease in number considerably in the first trimester of gestation.74

A decreased percentage of endometrial CD8+ T lymphocytes and an increased CD4: CD8 ratio has been reported in recurrent aborters. Conversely, recurrent aborters who had normal CD8+ and CD20+ cell numbers and a normal CD4:CD8 ratio subsequently underwent successful pregnancies, while patients with continuing abortions had lymphoid populations similar to those observed in group of habitual aborters group.75 Elevated CD4+, CD14+, CD16+, CD56+ and MHC class II+ cells are also reported in women with recurrent miscarriage compared to controls but contradictory to the other report no differences were seen in CD3+ and CD8+ cells.76 Patients who had miscarriages following endometrial biopsy had significantly more CD4+, CD8+, CD14+, CD16+, and CD56+ leukocytes in their endometrium than either those who had live births or women with proven fertility.76 It seems that endometrial lymphocytes of recurrent aborters display a distinct immunophenotypic profile and recurrent aborters have altered endometrial immunologic conditions.

Pregnancy is apparently associated with a TH2 environment. CRTH2 is a chemo-attractant receptor for PGD2 and mediates PGD2-dependent migration of blood Th2 cells. In a normal pregnancy, CRTH2+ Th2 cells and CRTH2+ Tc2 (cytotoxic) cells are significantly increased at the materno—fetal interface (implantation site) in the decidua. It has been suggested that Th2 and Tc2 cells may be recruited to the materno—fetal interface, at least in part, in a PGD2-mediated manner.77 In contrast, in the decidua basalis accumulation of Tc2 cells decreased in recurrent spontaneous aborters with abnormal chromosomes and both Th2 and Tc2 cells decreased in recurrent spontaneous aborters with normal chromosomes. In the decidua parietalis, the number and percentage of Th2 and Tc2 cells are similar in normal pregnancy, RSA with normal or abnormal chromosome.78

Natural Killer Cells

Very early in the study of reproductive immunology, the role of peripheral blood NK cells (CD16+/56+) in the failure of an early pregnancy was suggested. NK cells were shown to recognize trophoblast cells.79 Although NK cells cannot kill trophoblastic cells in vitro, NK cells activated by cytokines (TNF-alpha, Interferon gamma or IL-2) may kill trophoblast cells in vitro.80 Indeed a recent study showed that women with recurrent pregnancy losses, infertility and assisted reproductive failures have significantly increased activated peripheral blood NK cell levels (CD56+/69+) compared to normal fertile controls.81 In addition, activated NK cells can produce cytokines that are abortogenic.75 Endometrial bed biopsies from women experiencing recurrent pregnancy losses and infertility of unknown etiology reveal an increase in conventional NK cells (CD56+/16+, CD57+ cells).7,82 Peripheral blood NK cells (CD56+, CD56+/16+) are significantly elevated in women with recurrent pregnancy losses, infertility and assisted reproductive failures as compared with normal control women.83,84 Quantitation of peripheral blood NK cells in women with recurrent pregnancy losses and infertility of assisted reproductive failures have shown a significant elevation associated with spontaneous abortion of a conceptus of normal karyotype, and abnormal level associated with loss of embryos that are karyotypically abnormal.50,85,86 Furthermore, increased peripheral blood NK cell cytotoxicity has predictive value for pregnancy losses.84,87 Thus, conventional NK cells and failure to suppress NK cell activation plays an important role in immunologically preventable spontaneous abortions. Intravenous immunoglobulin G infusion treatment has been shown to downregulate NK cell killing capacity.83,88 and enhances CD8+ cell activity.82 Both of these events may be necessary for a successful pregnancy to occur.

Activated NK cells may play a role in implantation failure. Infertile women had a significantly higher expression of the NK cell activation markers CD69+ and CD161+ compared to fertile women.89 NK cytotoxicity correlated inversely with expression of NK cells bearing the inhibition marker of CD94+. None of the successfully pregnant women of that cycle had elevated levels of NK cytotoxicity whereas 50% of those experiencing a chemical pregnancy loss and those not becoming pregnant had elevated levels of NK cytotoxicity. Thus, immunologic markers can identify mechanisms involved in implantation failure. Activation markers of CD69+ and CD161+ expressed on NK cells as well as NK cytotoxicity can be added to the previously reported risk factors for immunologic implantation failure.90 A recent report documented an association between increased numbers of circulating NK cells and heavy metal excretion, which may be a causative factor in some cases of subfertility and recurrent miscarriage.91

Endometrial NK Cells

Natural killer cells are the most abundant cell population in endometrium and constitute 50-90% of lymphocytes in human uterine decidua in early pregnancy. These cells have a different phenotypic expression (CD16-/CD56bright) than peripheral blood NK cells (CD16+/CD56dim). In term placentas higher percentages of CD56dimCD16+ NK cells and CD56-CD16+ cells were found in decidua basalis whereas the percentage of CD56brightCD16-uterine NK cells was significantly higher in decidua parietalis.92 These findings suggest functional differences may occur even in different tissues during implantation and growth of the maternal fetal unit.

Recently, a microassay analysis comparing the expression of approximately 10,000 genes in decidual NK cells and peripheral NK cells revealed three-fold changes in 278 of the genes. The greatest number of these genes encoded surface proteins, including the unusual lectin-like receptors, NKG2E and Ly-49L, several killer cell Ig-like receptors, the integrin subunits alpha(D), alpha(X), beta1, and beta5, and multiple tetraspanins (CD9, CD151, CD53, CD63, and TSPAN-5). Interestingly, two secreted immunomodulatory proteins, galectin-1 and progestagen-associated protein 14, were selectively expressed in decidual NK cells.93 These findings suggest that decidual NK cells probably have an immunoregulatory role during development of the fetus and genes are activated in that environment during a normal pregnancy.

Infertile women have fewer CD56+ cells than normal fertile controls throughout the luteal phase.94 In women with recurrent abortions, higher numbers of endometrial CD56+ NK cells were found compared to normal endometrial tissue suggesting a role for CD56+ NK cells in recurrent early pregnancy loss.95 In a similar study, however, no significant difference in the overall number of endometrial NK cells was reported, although in the same report a higher ratio of CD56bright : CD56dim cells was detected in women with recurrent miscarriages as compared to normal controls, suggesting that NK subsets may be important.75 When ‘classic’ CD57+ NK cells were investigated, significantly increased numbers of CD57+ NK cells were found in spontaneous abortion cases when compared with normal human pregnancy.96 CD57+ NK cells at the placental implantation site was significantly increased in 29.6% of women with recurrent pregnancy losses as compared to placental implantation site of elective abortion.7

Flow cytometric analysis of decidual lymphocytes from normal pregnancy demonstrated that the relative proportion of decidual NK cells was increased to approximately the same extent in normal, anembryonic pregnancies and recurrent pregnancy losses. Nonetheless, higher decidual NK activity was found in tissue from women with anembryonic pregnancy and recurrent spontaneous abortion than in normal pregnancies.97 These studies support the notion that increased decidual NK cell activity or numbers is related with pregnancy losses. Interestingly, a decrease of CD56+ cells, was noticed in choriocarcinoma and hydatidiform mole, compared with normal pregnancy, suggesting the necessity of a balance between NK and T cells in controlling trophoblast invasion.98 Although a direct correlation between the number of CD57+ decidual NK cells and trophoblast invasion has not been studied, 54% of women with recurrent pregnancy losses demonstrated inadequate trophoblast invasion in placental tissue using immunohistochemical techniques that measured depth and the number of cytotrophoblasts.7

CD16-CD56bright NK cells that are isolated from total decidual mononuclear cells at the early stage of pregnancy produce many different cytokines such as G-CSF, GM-CSF, M-CSF, TNF-alpha, IFN-gamma, LIF and IL-8. These cytokines may play an important role in a successful pregnancy.99,100 In addition to these cytokines, HLA-G present on transfected cell lines (mHLA-G) can stimulate vascular endothelial growth factor production by uterine NK cells. These cells also can stimulate proliferation and cytokine production by NK cells, while down-modulating the response of unfractionated uterine mononuclear cells.101 This finding suggests that the interaction of HLA molecules on trophoblast cells can induce uterine NK cells to produce growth promoting factors or other similar molecules.

The NK cell activity and DNA synthesis of decidual CD16-CD56bright cells was reported to be markedly elevated after IL-2 but not IL-4 treatment.102 IL-2 stimulation of decidual NK cells was reported to be induced by stem cell factor (SCF). Decidual CD16-CD56bright NK cells express SCF receptor, c-kit but not CD16+ NK cells. Although SCF does not directly influence DNA synthesis in decidual NK cells, it increases the IL-2R alpha expression on CD16-CD56bright NK cells, resulting promotion of NK cell proliferation in response to IL-2.103 IL-4 inhibits the expression of the IL-2 receptors (IL-2R alpha, IL-2R beta, and IL-2R gamma) on decidual CD16-CD56bright NK cells.102 This suggests that IL-4 blocks the IL-2-induced NK activity and DNA synthesis of decidual CD16-CD56bright NK cells by inhibiting the expression of IL-2R alpha, beta, and gamma. Thus a TH2 cytokine can affect a TH1 mediated function. TGF-beta 2 hardly affected IL-2-induced NK activation and proliferation.104

The importance of regulatory T cells in pregnancy is just being studied in humans. The percentages of NKT cells during pregnancy were significantly increased in the decidua compared with peripheral blood. The percentages of IL-4 and IFN-γ producing NKT cells were significantly higher in the decidua compared with the peripheral blood. These findings suggest that NKT cells might control the Th1/Th2 balance by producing IL-4 and IFN-γ at the feto-maternal interface.105


As new technologies emerge and a better understanding of how the many components of the immune system interact to aid in the growth of the fetus, new treatments will be available to help women with recurrent spontaneous abortions or multiple implantation failures with or without any history of pregnancy loss. Meanwhile, it is clear that local and systemic immunological differences can be found in these women compared to women with normal pregnancies. Some of the data may appear contradictory due to the difficulty in stratifying women with different causes of pregnancy losses. It is important to obtain clinical samples at the optimum time of pregnancy to perform the immunological tests or immunopathological techniques that will benefit these patients. Also, comparisons of the differences in normal pregnancy and pregnancy loss between cytokines, chemokines, homing receptors, hormones, and other molecules that modulate the immune response can only add more information and result in better treatment. However, there is ample evidence that shifts in levels of subsets of peripheral and endometrial NK cells, changes in functional NK cytotoxicity, alterations in cytokine ratios of T helper 1 cells, and the presence of autoimmunity to both organ specific or nonspecific antigens, occur both systematically and locally in recurrent pregnancy losses.


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