Immunologic characteristics of repeated spontaneous abortions

In 28 couples with spontaneous abortions, data of immunological investigations revealed an elevated frequency of HLA DR compatibility and immunological characteristics defining distinct patterns of immune responsiveness. In the half of women with recurrent spontaneous abortion (RSA) we observed a failure to develop a recognition response to paternal inherited fetal antigens expressed by the lack of classical evidence of in vivo allo-immunization such as antipaternal antibodies, and the absence of the inhibitors of cell-mediated immunity found in maternal blood during pregnancy. In few cases, the paternal cells are inefficient to elicit in vitro maternal cell-mediated lympholysis. In most women with a normal pregnancy occurring after spontaneous abortions or prior to RSA, an immune recognition response was evidenced by the presence of antipaternal antibodies and/or blocking factor acting on in vitro cell-mediated lympholysis. These observations support the hypothesis that immunological process could be the cause of some fetal losses of unknown etiology, through a defective or unsuitable maternal immune response.     

The maternal-fetal relationship in human pregnancy: an immunogenetic perspective.

Although the mechanisms by which the fetal allograft escapes rejection are still poorly understood, abundant evidence has accumulated suggesting multiple roles for major histocompatibility complex (MHC) genes in pregnancy. Specific maternal MHC genotypes and maternal-fetal histocompatibility have been associated with recurrent spontaneous abortion, decreased fecundity, segregation distortions, altered sex ratios, fetal growth rates, and maternal autoimmune disease progression. In this review, the evidence for a variety of MHC gene effects in human pregnancy is considered.     

Regulation of costimulatory signal in maternal-fetal immune tolerance

Citation
Jin L‐P, Fan D‐X, Li D‐J. Regulation of costimulatory signal in maternal‐fetal immune tolerance. Am J Reprod Immunol 2011; 66: 76–83 A pregnancy is associated with modifications in the immune status of the mother, but the mechanisms are not well understood. Several observations have indicated that CD28/CTLA‐4 and B7‐1/B7‐2 are involved in the maternal–fetal immune regulation. This review aims to recapitulate our current knowledge concerning the role of CD28/CTLA‐4 and B7‐1/B7‐2 in maternal–fetal immune regulation. Several studies suggest that up‐regulation of B7‐2 and/or CD28 and/or down‐regulation of CTLA‐4 are correlated with the occurrence of pregnancy loss. Therefore, an accurate expression of costimulatory molecules at the maternal–fetal interface may ensure that the decidual cells do not elicit a ‘danger’ signal to the maternal immune system, perhaps instead contributing to the establishment of immune tolerance in vivo. It is showed that costimulation blockade with anti‐B7 mAbs results in altered allogeneic T‐cell response and overcomes increased maternal rejection to the fetus, which improves fetus growth in the abortion‐prone system. These findings suggest that the anti‐B7‐treated T cells not only function as potent suppresser cells but also exert immunoregulatory effect on the maternal T cells. This procedure might be potentially useful to immunotherapy for human recurrent spontaneous abortion.     

Controversies in reproductive immunology.

Nine areas of current controversy in the field of immunology of reproduction have been selected for discussion: (1) do antisperm antibodies cause infertility; (2) does cell mediated immunity cause infertility; (3) do antibodies cause spontaneous abortion; (4) is abortion due to rejection of the "fetal allograft"; (5) is altered antigen expression crucial for survival of the "fetal allograft"; (6) is abortion mediated by graft rejection mechanisms; (7) does locoregional suppression prevent abortion; (8) does immunization to prevent abortion and promote pregnancy act via immunotropism and cytokine cross-talk; (9) do immune responses prevent spontaneous abortion in humans? The reasons for debate and uncertainty are reviewed and current data considered in an attempt to arrive at the most likely answer to each question. Directions for future research are proposed where appropriate.     

Treatment of recurrent spontaneous abortion by immunization with paternal lymphocytes: correlates with outcome

Previous observations have suggested that defective recognition of fetal alloantigens by the maternal immune system is associated with recurrent pregnancy failure and that this may be prevented by boosting the maternal immune system with paternal or pooled third-party leukocytes. The mechanism whereby this process achieves success is not clear, and accordingly to explore this we immunized 28 couples with recurrent fetal loss with 80 x 10(6) paternal peripheral blood mononuclear leukocytes (PBML) and followed various immunological parameters. The couples studied, in whom 55% achieved a successful pregnancy, showed no increase in sharing of human lymphocyte antigen (HLA)-A, -B, or -DR antigens and no consistent evidence of a decreased mixed leukocyte reaction (MLR) or MLR plasma-blocking factors compared with control couples. Immunization did not alter these parameters but did induce antipaternal lymphocytotoxins, although the presence of the latter did not correlate with pregnancy outcome. There was a correlation between rapid conception after immunization and a subsequent successful pregnancy. A successful pregnancy also correlated with sustained postimmunization, postconception maternal antipaternal allospecific CD-8+ suppressor T cells. Although these findings provide overall evidence that immunization produces changes in the way in which the maternal immune system interacts with the fetus, larger numbers of couples and a higher dose of paternal lymphocytes will be needed to establish clearly whether this therapy works and its mechanism of action.     

Prevention of T cell-driven complement activation and inflammation by tryptophan catabolism during pregnancy

Indoleamine 2,3 dioxygenase (IDO) activity during pregnancy protects developing fetuses from maternal immune responses in CBA mice. We show here that fetal allografts were rejected only in mating combinations where paternally inherited tissue antigens elicited potent maternal T cell responses after exposure to IDO inhibitor. IDO inhibitor treatment triggered extensive inflammation at the maternal-fetal interface in susceptible mating combinations, which was characterized by complement deposition and hemorrhagic necrosis. Identical inflammatory responses occurred in B cell-deficient (RAG-I-/-) mothers that carried a monoclonal cohort of CD8+ T cells specific for a single paternally inherited fetal major histocompatibility complex antigen. Thus, fetal allograft rejection was accompanied by a unique form of inflammation that was characterized by T cell-dependent, antibody-independent activation of complement. In contrast, no inflammation, complement deposition or T cell infiltration was elicited when mice carrying syngeneic fetuses were exposed to IDO inhibitor. These data show that IDO activity protects the fetus by suppressing T cell-driven local inflammatory responses to fetal alloantigens.     

早期不明原因反复自然流产发生与蜕膜中免疫细胞的研究进展

人类妊娠被认为是一种半同种异体抗原移植，母胎间存在着某种免疫耐受机制来维持妊娠的进行，但目前为止这种免疫耐受机制尚不明确。大量的研究发现不明原因反复自然流产患者蜕膜中调节性T细胞的数量和功能均显著降低，表明调节性T细胞在避免胎儿免疫排斥中发挥着重要的作用。同时NK细胞作为早期妊娠蜕膜中的优势淋巴细胞亦对妊娠的维持起着重要的作用，不明原因反复自然流产患者蜕膜NK细胞数量和活性比正常妊娠妇女明显升高，同时CD56^＋CD16^＋／CD56^＋CD16^-NK细胞比例失衡。由此可见，妊娠早期不明原因反复自然流产的发生与蜕膜中淋巴细胞的异常表达相关，通过对这种复杂机制的研究可以为不明原因反复自然流产的预防和治疗提供依据。     

The role of indoleamine‐2,3‐dioxygenase in normal and pathological pregnancies

The survival of allogeneic fetus during pregnancy contradicts the laws of immune responses. Behind this paradoxical phenomenon, the mechanism is quite complex. Indoleamine‐2,3‐dioxygenase (IDO) is the first and rate‐limiting enzyme of tryptophan catabolism. Emerging evidence shows that IDO is expressed at the maternal‐fetal interface, including trophoblast cells, decidual stroma cells, decidual immune cells (eg, natural killer cells, T cells, and macrophages), and vascular endothelial cells of decidua and chorion. Moreover, the expression and activity of IDO are different among non‐pregnant, normal pregnant, and pathological pregnant conditions. IDO plays important roles in normal pregnancy through immune suppression and regulation of fetal invasion and circulation. However, the abnormal expression and dysfunction of IDO are associated with some pathological pregnancies (including recurrent spontaneous abortion, preeclampsia, preterm labor, and fetal growth restriction).     

Decidual and peripheral blood CD4+CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases

Human pregnancy represents a situation of semiallograft to maternal host. Therefore, it has been reported that tolerance to the fetal allograft represents a mechanism for maintaining a pregnancy. CD4(+)CD25(bright) regulatory T cells are known to play an important role in the development and maintenance of tolerance in peripheral tissues. However, the potential role of CD4(+)CD25(bright) T cells in maintaining human pregnancy has not been reported. In this study, we show that early human pregnancy decidua contains an abundance of CD4(+)CD25(bright) T cells, which express CD152(CTLA-4) at a high level. CD4(+)CD25(bright) T cells mediate potent inhibition of autologous T-cell proliferation by anti-CD3 stimulation. Furthermore, these cells inhibit the proliferation of autologous CD4(+)CD25(-) T cells in a dose-dependent fashion. This suppressive function of decidual CD4(+)CD25(+) T cells required cell-to-cell contact. The proportion of decidual CD4(+)CD25(bright) T cells was significantly lower in specimens from spontaneous abortion compared to those from specimens from induced abortions. These results suggest that decidual CD4(+)CD25(bright) T cells contribute to the mechanisms mediating maternal immune tolerance of conceptus antigens and therefore might contribute to the maintenance of pregnancy.     

REVIEW ARTICLE: Toll‐Like Receptors at the Maternal–Fetal Interface in Normal Pregnancy and Pregnancy Disorders

Citation Koga K, Mor G. Toll‐like receptors at the maternal–fetal interface in normal pregnancy and pregnancy disorders. Am J Reprod Immunol 2010 Toll‐like receptors (TLR) form the major family of pattern recognition receptors (PRR) that are involved in innate immunity. Innate immune responses against microorganisms at the maternal–fetal interface may have a significant impact on the success of pregnancy, as intrauterine infections have been shown to be strongly associated with certain disorders of pregnancy. At the maternal–fetal interface, TLRs are expressed not only in the immune cells but also in non‐immune cells such as trophoblasts and decidual cells; moreover, their expression patterns vary according to the stage of pregnancy. Here, we will describe potential functions of TLRs in these cells, their recognition and response to microorganisms, and their involvement in the innate immunity. The impact of TLR‐mediated innate immune response will be discussed via animal model studies, as well as clinical observations.     

Regulatory T Cells: Regulators of Life

Pregnancy still represents one of the most fascinating paradoxical phenomena in science. Immediately after conception, the maternal immune system is challenged by the presence of foreign paternal antigens in the semen. This triggers mechanisms of recognition and tolerance that all together allow the embryo to implant and later the fetus to develop. Tolerance mechanisms to maintain pregnancy are of special interest as they defy the classical immunology rules. Several cell types, soluble factors, and immune regulatory molecules have been proposed to contribute to fetal tolerance. Within these, regulatory T cells (Treg) are one of the most studied immune cell populations lately. They are reportedly involved in fetal acceptance. Here, we summarize several aspects of Treg biology in normal and pathologic pregnancies focusing on Treg frequencies, subtypes, antigen specificity, and activity as well as on factors influencing Treg generation, recruitment, and function. This review also highlights the contribution of fetal Treg in tolerance induction and addresses the role of Treg in autoimmune diseases and infections during gestation. Finally, the potential of Treg as a predictive marker for the success of assisted reproductive techniques and for therapeutic interventions is discussed.     

Role of immune cells in pregnancy

The human uterus is generally considered to be an immunologically privilege site that isolates the implanted allogeneic embryo from an aggressive maternal immune response. Maternal tolerance of the fetal allograft could be the result of the integration of numerous mechanisms promoted by decidual natural killer (NK) cells, macrophages and T cells. In this review, we outline the possible role of all these immune cells on the maintenance of pregnancy, focusing on the role of the T cells.     

Immune regulation during pregnancy and host-pathogen interactions in infectious abortion

The immunological mechanisms that govern the success of pregnancy in outbred mammals are complex. During placental formation the invasion of fetal cells into maternal tissue must be controlled to prevent damage to the mother. Equally, maternal recognition of pregnancy must be such that allorejection of the fetus does not occur. Despite the complexity of this phenomenon, it is clear that cytokines play a crucial role at the maternofetal interface and in the periphery to ensure that pregnancy proceeds successfully. Inflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) can exert detrimental effects in the placenta and tend to be present at low concentrations, whereas the regulatory cytokines interleukin (IL)-10 and tranforming growth factor-beta (TGF-beta) are beneficial and tend to predominate. This means that infection with pathogens that target the placenta and that elicit inflammatory responses may cause abortion by giving rise to a detrimental combination of cytokines that causes damage but does not control the disease. Infectious abortion is discussed in the context of the modulation of host immune responses during pregnancy, taking into account the different placental structures present in human beings, rodents and ruminants.     

Immune cells and molecules in pregnancy: friends or foes to the fetus?

Considering allograft rejection as a basic feature of the immune system, the mammalian pregnancy is an immunological paradox where the semi-allogeneic fetus is not rejected. How are the demands of pregnancy solved in the context of maternal immunity? Medawar’s original proposal of maternal immune inertness during pregnancy should be revised to active materno-placental tolerance. Multiple mechanisms are involved in peripheral and local tolerance induction that prevents fetal rejection while maintaining competent immune surveillance and protection. The goal of this review is to discuss the major cellular and molecular components of the immune system that control and promote fetal survival.     

Regulatory T cells in pregnancy

Tolerance mechanisms are responsible for the survival of the fetus within the maternal uterus without being attacked by the cells of the maternal immune system despite their direct contact. Regulatory T cells (Treg) were claimed to be important players in the tolerance towards the fetus bearing alloantigens. Recent evidence confirmed an augmentation in the number of Treg during pregnancy and, most importantly, diminished numbers of Treg were associated with immunological rejection of the fetus. This could be prevented by adoptively transferring CD4⁺/CD25⁺ Treg cells from normal pregnant mice into abortion-prone animals. Treg prevented abortion while creating a transient tolerant microenvironment characterized by high levels of TGF-β, LIF, and HO-1. Downregulated levels of Treg were accordingly also reported during human miscarriage. Furthermore, we have evidence suggesting that, to be protective, Treg need to be activated by male antigens during pregnancy.     

REVIEW ARTICLE: Immunology of Pre‐Eclampsia

Citation Redman CWG, Sargent IL. Immunology of Pre‐eclampsia. Am J Reprod Immunol 2010 Pre‐eclampsia develops in stages, only the last being the clinical illness. This is generated by a non‐specific, systemic (vascular), inflammatory response, secondary to placental oxidative stress and not by reactivity to fetal alloantigens. However, maternal adaptation to fetal (paternal alloantigens) is crucial in the earlier stages. A pre‐conceptual phase involves maternal tolerization to paternal antigens by seminal plasma. After conception, regulatory T cells, interacting with indoleamine 2,3‐dioxygenase, together with decidual NK cell recognition of fetal HLA‐C on extravillous trophoblast may facilitate placental growth by immunoregulation. Complete failure of this mechanism would cause miscarriage, while partial failure would cause poor placentation and dysfunctional uteroplacental perfusion. The first pregnancy preponderance and partner specificity of pre‐eclampsia can be explained by this model. For the first time, the pathogenesis of pre‐eclampsia can be related to defined immune mechanisms that are appropriate to the fetomaternal frontier. Now, the challenge is to prove the detail.     

Apoptosis of T Cells in the First Trimester Human Decidua

PROBLEM: Apoptosis has been accepted as a mechanism for maintaining tolerance in the immune system. The induction of apoptotic cell death can also be a possible outcome of the lymphocyte activation. Expression of Fas ligand (FasL) by the human trophoblast has been proposed as a mechanism providing protection against the lytic action of decidual immune cells. The aim of this study was to determine whether decidual T cells undergo apoptosis during abortion. METHOD OF STUDY: We studied apoptosis of T cells isolated from the first-trimester decidua in 12 women after spontaneous or elective abortion. We used gel electrophoresis to detect DNA fragmentation. Cells undergoing DNA fragmentation also were identified by DNA analysis using flow cytometry. This method was based on the accumulation of ethanol-fixed apoptotic cells in the sub-GO/G1 peak of the DNA content as a result of the loss of DNA fragments from the cells and because of a reduced DNA ability to be stained by propidium iodide. In addition, the expression of Fas antigen on the surface of decidual T cells (CD3⁺) also was determined. RESULTS: We did not detect apoptosis by the “ladder” technique. However, the apoptotic index (the percentage of positive cells per total number of cells) ranged from 2% to 24% using flow cytometry. CONCLUSIONS: Trophoblast cells usually fail to stimulate alloantigen-specific T cells, but they may express nonclassical major histocompatibility complex alloantigens to which mothers can produce immunoglobulin G alloantibody, which requires T helper cell activation. The apoptosis of T cells in the human decidua, probably through Fas-FasL signaling, may be a defense mechanism against rejection of the fetal allograft by the maternal immune system.     

HLA-G--母胎界面的一个免疫耐受分子

正常妊娠显示母体对同种异体胎儿的一种免疫耐受,HLA-G蛋白作为HLA移植抗原的代表限制性表达在母胎界面上,不仅不引起母体对胎儿的免疫排斥反应,相反被认为在母胎免疫耐受中起积极作用.     

Modulatory effect of intravenous immunoglobulin on Th17/Treg cell balance in women with unexplained recurrent spontaneous abortion

Recurrent spontaneous abortion (RSA) is a growing problem worldwide. In a majority of cases, the cause remains unknown but there is increasing evidence that immunologic factors play an important role. Intravenous immunoglobulin (IVIg) therapy has been proposed to have immune modulatory effects and therefore been applicable for the treatment of patients with RSA. Although its efficacy is still controversial, several recent studies suggest that IVIg treatment may improve pregnancy outcomes. CD4⁺ T cells and their related cytokines play an important role in maternal‐fetal immune regulation, and an imbalance of Th17/Treg cell ratio has been proposed as a cause for RSA. We review the scientific evidence supporting a modulatory effect of IVIg on Th17/Treg cell balance and discuss the potential mechanisms how IVIg might enhance Treg cells function. We propose that correction of Th17/Treg cell dysregulation could be one of the mechanisms that can explain the positive therapeutic effects of IVIg therapy. Consequently, selecting patients with abnormal Th17/Treg cell ratios could increase the success of IVIg therapy.     

Specific maternal anti-fetal lymphoproliferative responses and their regulation by natural immunosuppressive factors.

Maternal immune responses to autologous and/or oncodevelopmental antigenic determinants expressed on fetal tissues may constitute a potential hazard to fetal survival distinct from the well-studied maternal immune reactivity directed against paternally-derived fetal alloantigens. Splenic T cells with a helper phenotype (Lyt 1+2-) obtained from primiparous CBA/J mice pregnant by syngeneic matings were found to proliferate in response to co-culture with syngeneic Lyt 1-2- fetal thymus cells. In contrast, splenic T cells from virgin animals failed to react against fetal stimulator cells, suggesting that autosensitization to fetal gene products is a pregnancy-associated phenomena. Addition of anti-Ia alloantiserum at initiation of culture virtually abrogated the blastogenic response by maternal T cells, indicating that this is an Ia-dependent reaction. The addition of natural suppressor (NS) cells or alpha-fetoprotein (AFP), both of which are naturally occurring pregnancy-associated immunoregulatory factors, was found to markedly inhibit in-vitro maternal anti-fetal autoreactivity. NS cells and AFP may play an important role in maintaining homeostasis in the fetal-placental environment during murine pregnancy.