Chapter 5, Part 1

   Chapter 5.

Mother-Embryo Immune Conflict as a Reason for Recurrent Spontaneous      Early Abortions

Spontaneous early abortions, i.e., the interruption of a pregnancy without outside intervention before 20 weeks' gestation, refers  to  clinical conditions describing loss of the intrauterine developing product prior to its being considered a viability fetus, the latter conventionally accepted as 500 grams of fetal body weight.   Three or more serially miscarriages is the arbitrarily set point at which a patient is labeled a habitual aborter and her miscarriages as recurrent  (1). The exact frequency of spontaneous abortion in the general population is unknown, and data in the literature are controversial. Although pregnancy loss is common, affecting 10% to as many as 20% of all pregnancies (1), recurrent miscarriage, the occurrence of at least three consecutive first-trimester pregnancy losses, is seen in only 1% of pregnancies  (2). With the availability of sensitive beta-human chorionic gonadotropin serum assays, early pregnancies are now being detected that were formerly written off as simple abnormal prolongations of the menstrual cycle. Delays of 5 to 10 days in the onset of menstrual bleeding are very frequently diagnosed through the beta subunit as spontaneous early abortions. It is therefore estimated that more pregnancies are lost spontaneously than are actually carried to term.

 

                      5.1) Possible reasons for the immune conflict

The causes of recurrent   abortions are classified as anatomical, genetic, endocrinological, immunological, microbiological, and environmental (1). Most recent studies have focused on potential autoimmune and alloimmune causes, and reports have investigated the potential associations between these autoimmune (antithyroid antibodies and antiphospholipid antibodies) and alloimmune (NK cells, cytotoxic T cells, and embryotoxic)  factors and recurrent pregnancy loss.

 

In general, anatomical abnormalities account for less than 1%  of the total number of habitual abortion cases (1). Uterine anomalies cause  spontaneous abortions (3,4). Uterine and cervical factors can lead to habitual abortion due to malformation of the Mullerian duct system. A wide variety of congenital defects exist in which there is abnormal fusion of the two ducts. Cases ranging from simple arcuation of the uterine body to complete duplication of the entire uterus and cervix have been seen. In these cases, the spontaneous abortion usually takes place during the second trimester, when the intrauterine cavity becomes inadequate to support a growing fetus.

 

Morphological changes in the placenta are common reasons for spontaneous recurrent miscarriages. Miscarriage, missed miscarriage, and early- and late-onset pre-eclampsia represent a spectrum of disorders secondary to deficient trophoblast invasion (5). If trophoblast invasion is severely impaired, plugging of the spiral arteries is incomplete, and onset of the maternal intervillous circulation is premature and widespread throughout the placenta. Syncytiotrophoblastic oxidative damage is extensive  and likely a major contributoring factor to miscarriage.

Placental vasculogenesis is a basic feature in all types of pregnancy and a relationship exists between trophoblast cells and vessels in the chorionic villi with the potential to influence each other's functions. Defective chorionic villus vascularization is associated with embryonic death and is considered to induce  miscarriages (6).  Morphological and immunohistochemical markers of cellular stress and damage, such as expression of heat-shock protein 70, formation of N-Tyr residues, and lipid peroxidation, were seen to have increased in tissues obtained from missed miscarriages relative to controls (7). The effect was greatest in those pregnancies of shorter than 77 days' duration and  was associated with increased apoptosis and decreased numbers of mitotic cells, indicating that oxidative stress overwhelms cellular antioxidant defense systems. Placental oxidative stress with resultant damage to the syncytiotrophoblast, secondary to early onset of the maternal circulation, may provide an ultimate common mechanism of embryonic death in spontaneous abortions.

 

Genetic or  chromosomal abnormalities are still believed to be the most common etiological factor underlying spontaneous abortions. Most spontaneous abortions occur before 12 weeks' gestation, and most of these are due to chromosomal errors in the conceptus (8). Indeed, up to 50% of the examined first-trimester losses show some kind of chromosomal abnormality (1). Chromosome abnormality is one of the major causes of early spontaneous abortion after in-vitro fertilization (9). It has been speculated that spontaneous, random errors in meiosis or mitosis occur in sperms or in oocytes or during early embryogenesis, that lead to chromosomal damage. Another possibility relies heavily on defects in parental genes that create chromosomal breaks in the embryo. The dramatic rise in the number of Down syndrome cases associated with advanced parental age suggests that spontaneous chromosomal damage is more common with advancing age.

 

Medical diseases, such as systemic lupus erythematosus, congenital cardiac disease and renal disease, are associated with spontaneous abortions (1). The severity of the underlying disease condition determines the pregnancy outcome. It has been suggested that the high rate of fetal wastage among patients with systemic lupus erythematosus is due to circulating immune complexes. In pregnant patients with congential cardiovascular diseases, the spontaneous fetal wastage is in excess of 50%. With renal disease, especially with coexistent hypertension, the incidence of fetal loss can be extremely high. Individual, uncontrolled studies suggest that diabetes mellitus, especially when there is poor control of the blood glucose level, can lead to increased fetal wastage. 

Syphilis can seriously complicate pregnancy and result in spontaneous abortion, stillbirth, non-immune hydrops, intrauterine growth restriction, and perinatal death, as well as serious sequelae in live-born infected children (10). A literature review   for the period 1983-1996 identified 31 prospective studies with  appropriate control groups, in which   there appeared to be an association, albeit a weak one (odds ratios 4.05), between maternal HIV infection and an adverse perinatal outcome (11). There does, however, appear to be a real and large increase in the risk of infant death  associated with maternal HIV infection, especially when an attempt is made to control for confounding. The presence of the virus in the second trimester of pregnancy is not significantly associated with elevated IL-6 levels or with early postamniocentesis pregnancy loss (12).

Endocrinological abnormalities are present in about a quarter of the women with unexplained recurrent miscarriage (13). Luteal-phase deficiency was found as a reason in approximately 20% to 35% of aborts (1). Thyroid peroxidase antibodies are present in 10% of women at 14 weeks' gestation, and are associated with an increased pregnancy failure (14).

Biochemical abnormalities in the mother's serum have also been found to be a reason for spontaneous abortions. Low plasma folate levels are associated with an increased risk of early spontaneous abortion. Both folate deficiency and folic acid supplements have been reported to increase the risk of spontaneous abortion (15).

Immunological Factors

The immunological relationship between the mother and the fetus is a bi-directional communication that is determined, on the one hand, by fetal antigen presentation and, on the other, by recognition of and reaction to these antigens by the maternal immune system. There is evidence that the immunological recognition of pregnancy is important for the maintenance of gestation, and that inadequate recognition of fetal antigens may result in a failed pregnancy. For example, non-polymorphic class I molecules, particularly  HLA-G class Ib, are expressed in the extravillous cytotrophoblast, in the endothelial cells of the fetal vessels in the chorionic villi, and in amnion cells and the amniotic fluid (16).  These molecules present  antigens for gamma/delta T cells and at the same time defends the trophoblast from cytotoxic effector mechanisms. Following recognition of fetally derived antigens, the immune system reacts with a wide range of protective mechanisms.

The maternal immune response is biased toward humoral immunity and away from cell-mediated immunity that could be harmful to the fetus. Cytokines of maternal origin act on placental development. On the other hand, antigen expression on the placenta determines maternal cytokine pattern (16). Normal human pregnancy is characterized by low peripheral NK activity, and increased NK activity seems to play a role in spontaneous abortions of unknown etiology. In early human pregnancy, most uterine lymphocytes are CD56  granulated NK cells, which do not express CD16 or CD3.  In early pregnancy, they are enriched at sites where the fetal trophoblast infiltrates the decidua. The dynamics of the appearance of uterine NK cells suggests that one of the functions of these cells is control of placentation. 

Endometrial immunological conditions are intrinsically altered in recurrent aborts, and in such cases, endometrial lymphocytes harbor a distinct immunophenotypic profile that precedes implantation (17,18). The prognostic impact of CD8 and CD20 expression supports their predominant role in the development of fetal tolerance, whereas a role for NK cells in the abortion process is suggested by their altered subsets in all repetitive aborts. A higher mean number  of CD56+ cells was documented in the endometrium of women with recurrent early miscarriage  (19). On the other hand, CD56+3+ T cells were found to play a role in the maintenance of pregnancy (20). The phenomenon of a decrease in the proportion of CD56+3+ T cells in decidual lymphocytes, may be due to an immunological  event leading to missed abortion. Despite of these data, it has been noted in recent publications, that immunophenotypic analysis of the endometrium cannot predict pregnancy outcome in women with recurrent abortions (21).

The placenta is the tissue most involved in immune regulation at the maternal-fetal interface. It is comprised of cells of maternal as well as fetal origin, both of which express molecules (HLA-G by the trophoblast and  FasL  by the maternal decidual cells) that play a role in maternal-fetal tolerance (22). Mechanisms which protect the fetus from the maternal immune system include the expression of non-classical MHC molecules by trophoblast cells (23,24), T-cell apoptosis (25), and  complement regulatory proteins expressed on the trophoblast (26)

Most of the polymorphic MHC class Ia and class II antigens are lacking on the surface of human trophoblastic cells, and this is thought to be critical in preventing deleterious maternal immune responses against the fetus (27). However, transgenic expression of paternal class I MHC molecules does not affect pregnancy rates  in animals (28,29), indicating that lack of MHC is not critical in maintaining maternal-fetal   tolerance.

During pregnancy, there is a general downregulation of most of the MHC class Ia and class II molecules just before implantation occurs (22). However, certain class Ib molecules  and minor paternal MHC antigens are expressed. Typically, absence of MHC should lead to the trophoblast's  escape from recognition by cytolytic T lymphocytes (CTL) while rendering them susceptible to NK cells. However, such cytolysis does not take place, and NK cells found in the placenta are of a distinct type and are called uNK cells. These cells are present in the decidua during the first and second trimester, and they modify the uterine arteries to increase blood supply to the fetoplacental unit (30,31). Owing to their increased presence in the decidua and their direct contact with the trophoblast, uNK cells are thought to play a critical role in acceptance/rejection of the fetus.

The extravillous cytotrophoblast expresses the non-classical HLA Ib genes  (HLA-E, HLA-F, and HLA-G. HLA-G), possesses a number of immunomodulatory functions,  and is connected with  immune tolerance in pregnancy (32),   inhibits both CTL responses and NK cell functions (33,34), and   can  induce  CD8+ T-cell apoptosis   through the Fas/FasL pathway (34,35). In humans, HLA-G is thought to facilitate the expression of HLA-E, by forming a complex with it on the trophoblast cell surface and binding to CD94-NKG2. This trimeric complex then binds to NK cells and leads to inhibition of NK cell activity (22).

The establishment of immune privilege at the implantation site is a result, at least in part, of clonal deletion of immune cells that recognize paternal antigens present in the embryo. This is mediated by the expression of FasL on fetal trophoblast or maternal decidual cells (36,37),  where FasL has been shown to promote allograft rejection rather than tolerance (38,39). Fetus-derived FasL has also been shown to be essential for deletion of allospecific maternal T cells during pregnancy (40).  FasL formed in the microvesicles of the trophoblast can compete with the classical surface FasL on these cells, thereby promoting fetal rejection (41,42).

Successful pregnancy is maintained by the expression of complement regulatory proteins expressed on the trophoblast, which prevent damage inflicted by complement activation . Decay-accelerating factor (CD55) and membrane cofactor protein (CD46) are examples of such complement regulatory proteins expressed on the human trophoblast and are crucial for sustaining pregnancy (43).

A clinical association has been established between a history of pregnancy loss in patients with the diagnosis of primary or secondary antiphospholipid syndrome (APS) and the presence of different antiprothrombin antibody subtypes (IgG, IgM and IgA) in patients with APS   (44). Women with antiphospholipid antibodies and a history of pregnancy loss are at high risk during pregnancy for another fetal death (45). In patients with recurrent pregnancy loss, anti-phospholipid, anti-Saccharomycetes cerevisiae, and anti-prothrombin  antibodies were more prevalent than in controls. Anti-prothrombin and anti-phospholipid antibodies were more significantly associated with late vs early pregnancy losses (46).

 

 

5.2)            Humoral and cellular mechanisms of the immune conflict                                                  

 

Protection of the embryo from the adverse maternal environment during early pregnancy is considered to be achieved by the establishment of a transitory permeability barrier created by decidual cells immediately surrounding the implanting embryo (47). The success of normal pregnancy depends upon the protection and growth of the semi-allogenic embryo within the maternal uterine microenvironment. However, a detailed account of the mechanisms by which the genetically incompatible embryo escapes maternal immunological responses during early pregnancy remains unknown (48). Furthermore, the loss of the zona pellucida from the blastocyst prior to implantation, and the loss of the uterine luminal epithelium at the site of the implanting blastocyst make the embryo more vulnerable to maternal insults. Thus, it is speculated that a special barrier mechanism operates at the maternal-conceptus interface to prevent the passage of harmful stimuli to the embryo.

The formation of an anatomical barrier between mother and fetus, the lack of maternal immune responsiveness, and a lack of expression of allogeneic molecules by the fetus have been proposed as mechanisms accounting for the absence of fetal rejection during pregnancy (49). These mechanisms have helped us begin to understand how rejection of the fetus is avoided; however, they do not completely explain how the fetus evades the maternal immune system. Site-specific suppression, in which maternal immune responses are controlled locally at the mather-fetus interface, plays a fundamental role in controlling maternal allogeneic immune responses.

As already noted, the immunological relationship between the mother and the fetus consists of bidirectional communication which relies on fetal antigen presentation and recognition of, and reaction to these antigens by the maternal immune system (16). An interaction is established during pregnancy between the maternal immune system and fetal cells to enable the survival and the normal growth of the fetus. Fetal cells expressing paternal alloantigens are not recognized as foreign by the mother because of an efficient anatomical barrier and local immunosuppression determined by the interplay of locally produced cytokines, biologically active molecules and hormones (50). A special balance between T helper  lymphocytes types Th1 and Th2 has also been observed at the feto-maternal barrier that contributes to controling the immune response at this level (51). 

 

The maternal and fetal immune systems temporarily coexist; both are precisely tuned to detect and reject foreign invasion and yet somehow achieve a symbiotic relationship. This mutual state of tolerance is obviously critical for carrying a pregnancy to term. Two active parts of the immune system maintain protection of the mother: (i) a humoral immune system in which foreign tissue invokes an antibody response via B-cell recognition of antigenic surfaces, and (ii) cell-mediated immunity in which T-cells and NK  cells seek out and destroy foreign tissue (52). Several mechanisms are thought to invoke immune tolerance of the fetus. These include: absence of MHC-I antigens, presence of unique HLA surface molecules, nonspecific reduction of systemic immunoreactivity, a possible role  for blocking antibodies, expression of complement regulatory proteins, and factors of locally reduced immunoreactivity.

It has been well documented that the potential immunological mechanism  involved in the maintenance of pregnancy contains several components: (i) the embryo does not engender an immune response, (ii) the maternal immune response is suppressed, (iii) the uterus is an immunologically privileged site, and (iv) the placenta constitutes a barrier between the mother and the fetus. The most important factors for the maintenance of pregnancy appear to lie at the uterus–placenta interface. In particular, expression of FasL and complement regulatory proteins, and failure to express MHC class I and II molecules in the placenta are thought to be crucial factors for maintaining a pregnancy (25,53,54).

Trophoblast cells fail to express MHC class I or class II molecules, except HLA-C and HLA-G (55,56). In addition, the trophoblast also protects itself by expressing  FasL  (25,54), thereby conferring immune privilege. Fas is expressed on many cells, whereas FasL expression is restricted to sites of immune privilege and activated CTL and CD4+ Th1 cells.   FasL expression has been  reported in first-trimester and term human placental villi (57), and expression sites of FasL are obviously positioned to induce apoptosis in maternal Fas-positive immune cells, such as NK and T cells (25). Fetal responses are clearly sensitive to the ambient cytokine environment of pregnancy (58), and the capacity of the fetus to produce IL-13 and IL-10 is directly related to the level of these cytokines produced by the mother in response to fetal alloantigens (59).

Responsiveness to paternal HLA antigens is a key factor controlling the activity of the maternal immune system in pregnancy. HLA-G,   selectively expressed on the cytotrophoblast, plays the role of protector   as opposed to the lysis carried out by the decidual uterine NK cells (60). HLA mismatching between maternal and paternal (fetal) antigens may be a source of the immune stimulation during pregnancy, altering the cytokine balance in the placenta  (61). Placental HLA-G proteins facilitate semi-allogeneic pregnancy by inhibiting maternal immune responses to foreign (paternal) antigens which action on the immune cells   and   may serve as powerful tools in the prevention of immune rejection of the embryo (32). While profound cytokine shifts threaten pregnancy, it has been speculated that mild reactivity between maternal and paternal (fetal) antigens may activate antigen-presenting cells to provide an important stimulus for fetal immune maturation (particularly Th1 responses) (59).

Several mechanisms have been reported to participate in the maternal-fetal interface. These mechanisms include fetal factors such as trophoblast cell properties and altered MHC class I expression as well as local maternal factors such as specialized uterine NK cells and a shift in the T-helper cell cytokine profile from a type 1 to a type II array (62). Novel immunomodulators are found to be expressed in the local uterine environment to aid in fetal survival. Furthermore, the fetal cells persist in the maternal circulation long after pregnancy is over   and may have implications for autoimmune diseases.  CD95-L (Fas-L) presenting on trophoblastic cells plays a part in establishing foeto-placental tolerance by inducing apoptosis of immune-defense cells (63).  Expression of   FasL  by the human trophoblast has been   accepted as a mechanism providing protection against the lytic action of activated decidual immune cells expressing Fas receptor (64).

Immunologic investigations proved the presence of specific systems which block the function of antipaternal maternal antibodies, as well as the formation of cytotoxic maternal T cells to paternal antigens (65). The system preventing rejection of an embryo as a graft during pregnancy   functions at the level of the maternal and fetal tissues and is coded by HLA-G, HLA-E and HLA-C molecules (66). A high level of complement-regulatory proteins (CD46, CD55 and CD59), in response to the synthesis of complement-fixing maternal antibodies to paternal antigens and regulation of the placental HLA expression as a preventive reaction of the feto-placental unit to the influence of maternal CTL, are the most important protective mechanisms of the placenta (67).

The following protective mechanisms are common for both the placenta and uterus: expression  of FasL, prevention of infiltration of activated immune cells, and regulation of immunosuppression, which prevents proliferation of immune cells and high natural immunity (NK cells and macrophages) of the deciduas (67). The maternal-fetal interface represents an immunologically unique site that must promote tolerance of the semi-allogenic fetus, whilst maintaining host defense against a diverse array of possible pathogens. Pregnancy is therefore an immunological balancing act. Trophoblasts do not express MHC class I or II, except HLA-C and G, but express FasL, which confers immune privilege (68). Expression of receptor-binding cancer antigen   and FasL in the   cytotrophoblast  may play a role in the downregulation of the maternal immune response, thereby maintaining pregnancy in its early stage.

 

There appears to be variability in the capacity of women to develop tolerance to paternal antigens with successive pregnancies. Pregnancy may in turn modify maternal immune responses, reducing, for example, maternal allergy (69). In some situations, successive pregnancies have 'more successful Th2 skewing' and lower incidence of Th1-mediated complications (70). However, in other situations, where Th1 responses are adaptive (i.e., in the protection from placental malaria), higher Th1 responses are seen with successive pregnancies, and these protect the fetus  (71). Thus, it appears that while all pregnancies have to cope with a degree of maternal/fetal incompatibility, immune responses in pregnancy vary as a result of a complex interplay between maternal immune programming and adaptation to environmental factors. 

 

Maternal patterns of immune  response can directly influence immune development in offspring. For example, women prone to allergic immune responses to allergens may  also have altered immune responses to other antigens including fetal antigens (59). Altered cytokine responses at birth have significant implications for subsequent immunological development and allergic disease (72,73). There is evidence indicating a direct influence of maternal atopy on Th1 dysfunction at birth (74). The recognized predisposition for allergic Th2 responses in atopic women may modify immune responses in pregnancy and directly alter fetal immune responses. There is also growing evidence that altered T-cell cytokine responses in fetal and early postnatal life are associated with allergic disease in pre-schoolchildren (72).

 

There are no apparent relationships between maternal allergy and cytokine responses to fetal alloantigens (59).  In contrast, neonates born to allergic mothers show  stronger lymphoproliferative responses to maternal alloantigens.  While genetic factors also have a strong influence on fetal immune responsiveness, it has been suggested that the placental microenvironment could be an equally (if not more) important determinant of immune reactivity in the early postnatal period    (59).   The development of allergic disease at 6 years was significantly associated with stronger maternal responses to fetal alloantigens. These data may explain the suggestion that maternal influences during gestation have a stronger influence than those of the father on the development of allergic disease in offspring (75). Specifically, maternal lymph proliferation, IL-13 and IFNγ responses were higher in response to fetal alloantigens if children subsequently developed allergic disease. Thus, allergic outcomes appear to be more strongly associated with direct maternal–fetal immune interactions than 'genetic risk'. 

 

The newborn's immune system grows rapidly from its small size at birth primarily by exposure to the intestinal microflora normally obtained from the mother at and after birth. While building up its immune system, the infant is supported by the transplacental IgG antibodies, which also contain anti-idiotypic antibodies, possibly also actively priming the offspring  (76). The immune system develops in fetal life and is qualitatively quite complete at delivery, although certain cytokines are produced only at low levels. Also, many cells such as phagocytes and dendritic cells are not yet adequate in number and function  (77). The lymphocyte population is very limited, and the immune system of new-born mice, for example, is reported to be only a few percent of that of an adult (78). The major impetus for the expansion of the lymphoid population is exposure to the microbial flora colonizing the gut from birth on.  The neonate clearly needs help from the mother for immediate protection, for colonization with the mother's gut flora, and for the long-term buildup of its own immune system. This immunological support arrives via the placenta and the milk.

 

 

 

 

 

 

            5.3) Pathological changes in  the placental barrier as a reason for                                            spontaneous early abortions

 

The mother establishes a special interaction with the fetus in pregnancy, allowing its normal survival despite the different   antigens. The main factors contributing to these favorable conditions for the fetus are efficient local immunosuppression and the formation of a protective anatomic barrier between the mother and the fetus (79,80). The placental barrier is   responsible for the normal functioning and development of these two immunologically different organisms (81,82), as it allows them to tolerate one another  and escape from the immune  allogeneic  mother-fetus conflict  (64,83).

An example  of such a conflict can be seen in the hemolytic disease of fetuses and newborns caused by maternal anti-rhesus antibodies  to erythrocyte   antigens inherited from the father (84). Early pregnancy loss, the reasons for which in 50% of the cases remain unknown, has also been proposed to be due to maternal-embryonic conflict (85).  Different maternal cells   cross the maternal-fetal barrier and participate in spontaneous abortions (CD45RO/UCHL1+ cells)  or cause growth delay and recurrent reproductive failure (CD5+ cells)    (86).  A high rate of apoptosis in cells of the chorionic villi, especially of the syncytiotrophoblast, has been described in spontaneous early aborts and  was explained as an increase in the activity of immune processes in the placenta (68,87).

We have described orphological changes in the placental barrier in spontaneous early abortions under the maternal-embryonic immune conflict, and the role of maternal IgG, IgA and IgM as well as of some immunocompetent cells and apoptosis-related components in these changes (88). We expected this approach to provide a better understanding of the etiology and pathogenesis of early allogeneic maternal-fetal immune conflict as a possible reason for spontaneous early abortions. Using immuno- histochemical methods, we examined   the chorionic villi and other tissues  obtained from 54 aborts between weeks 3.5 and 8 of pregnancy (89). The material was divided into two groups (Table VII). Group I (control) contained 15 medically recommended and spontaneous early aborts  with no signs of inflammations or pathological immune processes.  Group II contained 39 spontaneous early aborts with acute chorionic villitis. Table VIII  shows the  relationship between the characteristics of the mothers with fetal disorders and the distribution of cases with recurrent early pregnancy loss among the studied population of patients.

 

 

 

 

 

 

 

 

 

 

 

Table VII. The number and pregnancy age of aborts 

 

 

In parenthesis, number of aborts in %.

Group I (control), medical and early spontaneous aborts  without signs of inflammations or pathological immune processes.  Group II, early spontaneous aborts with acute villitis.  Note high similarity in the age of aborts in both studied groups. After week 8, cases of the group II have not been found.

 

 

 

 

 

 

 

 

 

 

 

 

Table VIII. Relative distribution of cases with recurrent early pregnancy loss among the studying population of patients (% to total number of patients).

 

 

Age of patients varied between weeks 3.5 and 8. 

 

 

 

 

In the chorionic villi from group II,  changes were related to all structures and were manifested as acute villitis. Disorders of the villous capillaries (thrombovasculitis)  were manifested in apoptosis, disruption of the endothelium  and of erythroblasts, in mucous swelling of the capillary basal membrane and in coagulation of blood proteins. Igs were found in some of the endothelial cells and in erythroblasts. Apoptotic cells were TUNEL-positive. p53 was present in the damaged capillaries but was not seen in the destroyed capillaries.

 

A basic feature of pregnancy is placental vasculogenesis, and a relationship exists between trophoblast cells and vessels in the chorionic villi. Defective chorionic-villus vascularization is associated with embryonic death and is considered to induce  miscarriages (6).  The number of villi with vessel destruction in aborts with acute villitis (group II) varied from 3% to 33%, averaging 12.5±1.3% (89). As a final result of capillary destruction and their disappearance, the average number of normal capillaries per villus was twofold lower in group II than in group I (2.04±0.6 and 4.53±0.3, respectively, p<0.001),  whereas the number of avascular villi   was threefold higher in cases from   group II compared to those from   group I  (Fig. 5).  

 

Considerable changes were seen in the monocytes (Kaschenko-Hofbauer cells) and promonocytes in the chorionic villi (89). Many of them were in different phases of apoptosis, and they contained p53, but not Fas or FasL. The number of promonocytes increased sharply in   group II relative to   group I (Table IX). In some cases, the  number of promonocytes reached 92% and even 100% of all mononuclear phagocytes. A high number of phagolysosomes per cell section was seen in monocytes and promonocytes in group II (Table IX). Many of phagolysosomes contained IgG and IgA (up to 50 and even  100 per cell section).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Fig.5. The number of  morphologically damaged chorionic villi (% to the total number of villi). 1, Villi with normal capillaries; 2, Villi with spasmodic capillaries; 3, Villi with villitis and thrombovasculitis; 4, Avascular villi; 5, Edemic villi; 6,   Intravillous hemorrhages. Values in the groups II were significantly different from the group I (p<0.05-0.001).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table IX.

The number of monocytes and  promonocytes in the chorionic villi and of macrophages in the maternal decidua

(After ref. 89)

 

 

 

^a See footnotes to Table VII.

^b Significantly different from the number of  mononuclear phagocytes in chorionic villi, p<0.001.

^c Significantly different from the values in the group I, p<0.01-0.001.