Human Reproduction Update Advance Access originally published online on August 19, 2004
Human Reproduction Update 2004 10(6):497-502; doi:10.1093/humupd/dmh040
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Fetal cells in maternal tissue following pregnancy: what are the consequences?
Division of Genetics, Department of Pediatrics, Tufts–New England Medical Center, Box 394, 750 Washington Street Boston, MA 02111, USA
1 To whom correspondence should be addressed. Email: kjohnson{at}tufts-nemc.org
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Abstract |
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Abstract
IntroductionThe presence and persistence of fetal cells in murine maternal tissue was first reported over 20 years ago, although it is only more recently that the occurrence and potential consequences of fetomaternal cell trafficking in humans have been fully appreciated. Fetal cell microchimerism is a growing field of investigation, although the data are contradictory relative to the health consequences of persistent fetal cells in maternal tissues. Understanding of the types of cells being transferred from fetus to mother, the location of these fetal cells within the various maternal tissue types, and the functionality of these cells may ultimately lead to measures to minimize or eliminate the deleterious effects of the cells, or to efforts to take advantage of the presence of these cells for therapeutic purposes. This review focuses on the origins of fetal cell microchimerism research and the different hypotheses regarding the consequences of persistent fetal cells in the mother, the various diseases that have been evaluated with respect to fetomaternal cell trafficking, the potential variables associated with the frequency, persistence and tissue distribution of fetal cells in maternal tissue, and an assessment of future direction in this innovative field of inquiry.
Key words: fetal cell microchimerism / fetomaternal trafficking / pregnancy / review
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Introduction |
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The term ‘microchimerism’ first appeared in a peer-reviewed paper when Liégeois et al. (1977)
reported on the steady state, low-level proliferation of allogeneic bone marrow cells in the laboratory mouse. The term was proposed to describe long-term donor cell survival in a small proportion relative to the host cell numbers, and 4 years later this same research group demonstrated the presence of allogeneic fetal cells in maternal tissue during and long after pregnancy (Liégeois et al., 1981). In the quarter century that has passed since these papers, microchimerism has been shown to develop as a result of blood transfusion, twinning, organ transplant and bidirectional trafficking during pregnancy. This has resulted in dozens of publications that report on the presence (or absence), persistence, and maternal tissue distribution of fetal cells, as well as on potential mechanisms and health implications of fetal cell microchimerism. This review will focus first on the origins of this research and the different hypotheses regarding the consequences of persistent fetal cells in the mother. Next, the various diseases that have been evaluated with respect to fetal cell microchimerism, often with conflicting results being obtained by different laboratories, will be reviewed. The potential variables associated with the frequency, persistence and tissue distribution of fetal cells in maternal tissue will then be discussed, followed by an assessment of future research direction in this field, including the development of animal models for investigations into the mechanisms of fetomaternal cell trafficking.
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Origins and hypotheses |
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Although the presence and persistence of fetal cells in murine maternal tissue was first reported over 20 years ago, it was not until more recently that the occurrence and potential consequences of fetomaternal cell trafficking in humans was fully appreciated. In 1996, while investigating prenatal diagnosis using fetal cells present in the blood of pregnant women, Bianchi et al. (1996)
reported on the long-term persistence of fetal progenitor (CD34+ and CD34+/38+) cells in maternal blood for decades following pregnancy and speculated on the consequences of fetal cell microchimerism. The implications of persistent fetal cells in maternal tissue led to the generation of the ‘bad microchimerism’ hypothesis, which was first proposed in the rheumatology research community (Nelson, 1996). This hypothesis suggested that the persistence of fetal cells following pregnancy led to a graft-versus-host-like response in parous women, and that the resultant maternal immune response to these ‘foreign’ cells may contribute to postpartum autoimmune disease pathogenesis. The higher frequency of certain autoimmune diseases in women than men and the age-specific incidence patterns of some disorders, among other observations, were considered as evidence in support of this hypothesis.
Subsequently, research reports began to appear in the literature that conflicted with this hypothesis. These included reports on the absence of fetal cell microchimerism in autoimmune disorders that follow the pattern of female predilection, such as Sjogren's syndrome (Toda et al., 2001) and primary biliary cirrhosis (Rubbia-Brandt et al., 1999), as well as the presence of microchimerism in non-autoimmune diseases, including infectious hepatitis (Johnson et al., 2002), thyroid disease (Srivatsa et al., 2001) and cervical cancer (Cha et al., 2003). These varied and sometimes conflicting data led to two other hypotheses regarding fetal cell microchimerism. One is that the observed fetal cells are merely innocent bystanders and have no impact on maternal health. The other, the ‘good microchimerism’ hypothesis, suggests that persistent fetal cells, instead of inducing a maternal immune response, provide a rejuvenating source of fetal progenitor cells that may have the capacity to participate in maternal tissue repair processes.
While there is no agreement within the microchimerism research field as to which hypothesis (or perhaps more than one) is correct, the publications that are now regularly appearing in the literature (20–25 papers per year) are providing further insights into the mechanism(s) of fetomaternal cell trafficking. Understanding of the types of cells being transferred from fetus to mother, the location of these fetal cells within the various maternal tissue types, and the functionality of these cells may ultimately lead to measures to minimize or eliminate the deleterious effects of the cells, or to efforts to take advantage of the presence of these cells for therapeutic purposes.
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Disease associations: systemic sclerosis/scleroderma |
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Most of the research reports on fetal cell microchimerism in humans that first appeared in the literature were related to autoimmune disease. One of the associations that has been extensively investigated is between microchimerism and systemic sclerosis (SSc). Some reports demonstrated the presence of fetal cells in skin lesions from women with SSc (Artlett et al., 1998
) and in multiple tissue sites in SSc patients but not controls (Johnson et al., 2001a). Others showed a quantitatively greater number of fetal cells in skin tissue from SSc patients (Ohtsuka et al., 2001) and in peripheral blood of women with scleroderma than controls (Nelson et al., 1998; Lambert et al., 2002). Ichikawa et al. (2001) demonstrated that while the presence of microchimerism was not specific for SSc, there were more fetal cells present in SSc patients compared to controls. The results of these studies led the investigators to suggest that microchimerism may be involved in the pathogenesis of SSc and/or scleroderma.
Other studies addressed the relationship of HLA compatibility and microchimerism in SSc/scleroderma. These reports suggested that HLA class II compatibility may allow fetal cells to cross the placenta and remain unrecognized until subsequent activation of these cells (Artlett et al., 1997), or that HLA class II compatibility between scleroderma patients and their children was more common than for controls (Nelson et al., 1998), but not necessarily a requirement for persistence of fetal cells postpartum (Evans et al., 1999). Different research groups subsequently made conflicting suggestions, either that the HLA class II allele DQA1*501 is associated with persistent fetal cell microchimerism in scleroderma (Lambert et al., 2000), or that this allele does not appear to play a role in the development of microchimerism and SSc (Artlett et al., 2003). Conflicting immunological data are also reflected elsewhere in the literature; Selva-O'Callaghan et al. (2003) reported that fetal cell microchimerism (as measured in peripheral blood) does not seem to play a major role in most cases of SSc in Spanish patients and Murata et al. (1999) concluded that microchimerism alone may not be the pathogenic mechanism in Japanese women with SSc. Although the involvement of fetal CD4+ T lymphocytes (Artlett et al., 2002a), and perhaps those fetal CD4+ T helper cells with a type 2-oriented profile (Scaletti et al., 2002), in the pathogenesis of SSc has been reported, taken together, these data illustrate the unknown nature of the role that persistent fetal cells may play in this autoimmune disease.
The potential role of microchimerism in autoimmune disease pathogenesis led Gannage et al. (2002) to study a variety of connective tissue diseases, including SSc, in a case–control study. These investigators found that microchimerism was common among all individuals analysed, and that both the proportion of cases and controls as well as the quantitative level of microchimerism in SSc patients, those with other connective tissue disorders, and controls were similar. They concluded that while microchimerism is likely not to be a risk factor for the development of connective tissue disease, it may be linked to other variables, such as early miscarriages.
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Disease associations: other autoimmune disorders |
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In addition to SSc and scleroderma, other autoimmune diseases have been studied to examine the relationship between autoimmunity and microchimerism. These reports are similarly contradictory. For example, Tanaka et al. (1999)
, Rubbia-Brandt et al. (1999), Corpechot et al. (2000), Invernizzi et al. (2000) and Schoniger-Hekele et al. (2002) all concluded from their studies that fetal cell microchimerism alone does not play a significant role in the pathogenesis of primary biliary cirrhosis (PBC). These investigators demonstrated detectable fetal cell microchimerism in the livers of control women. However, Fanning et al. (2000) found that male cells, presumably fetal in origin, were present in eight out of 19 patients with PBC but in none of the patients with either chronic hepatitis C or alcoholic liver disease (n=20), (patients not separated into groups) and concluded that microchimerism may be involved in the pathogenesis of this disease. Male cells of presumed fetal origin have also been observed in the affected liver tissue of a woman with autoimmune hepatitis (unpublished data; see Figure 1).
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Kuroki et al. (2002)
demonstrated the presence of non-host cells in inflammatory lesions of patients with Sjogren's syndrome (SS), suggestive of a possible role of microchimerism in the pathogenesis of this disease, while Toda et al. (2001) found no evidence of microchimerism in the peripheral blood of SS patients. Johnson et al. (2001b) reported extensive microchimerism in a patient with systemic lupus erythematosus (SLE), predominantly in the areas of intestinal tissue that were severely affected by disease. However, Mosca et al. (2003) showed that the proportion of patients and controls with peripheral blood microchimerism as well as the absolute numbers of these cells in both groups were equivalent, suggesting that microchimerism does not interfere with disease course in SLE. Subsequently, Khosrotehrani et al. (2004) reported on the absence of fetal cell microchimerism in cutaneous lesions of lupus. These investigators suggested that disease severity might play a role in the recruitment of microchimeric cells to areas of tissue damage, in that extensive maternal tissue damage may be required for the development of microchimerism in cases of SLE.
Studies of autoimmune thyroid disorders have provided additional evidence of the association between fetal cell microchimerism and autoimmunity, although these studies have also led to additional speculation that fetal cells may not be involved in disease induction. For example, Srivatsa et al. (2001) and Ando et al. (2002) demonstrated the presence of microchimeric cells in tissue from postpartum women with various thyroid disorders and Graves' disease respectively. However, these authors found that fetal microchimeric cells are common in thyroid tissue affected with non-autoimmune disease, and thus concluded that there is a relationship between microchimerism and thyroid disease, or that there is a modulating effect of microchimerism on thyroid disease respectively. The study of Hashimoto's thyroiditis by Klintschar et al. (2001) led to the conclusion that although microchimerism may play a role in the development of this autoimmune disorder, they could not rule out the hypothesis that fetal cells are ‘innocent bystanders’ in a process triggered by other mechanisms.
Although the results of these reports appear contradictory, it is possible that study design played a role in the discordant findings. For example, data suggestive of a role of microchimerism in SS and SLE resulted from analyses of disease-affected tissue, such as the inflammatory lesions in the study of Kuroki et al. (2002), whereas data showing a lack of an association resulted from analyses of peripheral blood. This suggests that the tissue type(s) and the areas within these tissues that are analysed as well as disease type and status, pregnancy history and immunological competence are important variables for the accurate assessment of fetal cell microchimerism and autoimmunity, and for evaluation of the different hypotheses regarding microchimerism.
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Disease associations: non-autoimmune diseases |
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While the majority of research efforts to date investigating microchimerism and disease in postpartum women have addressed autoimmune disorders, the results of other studies suggest that fetal cell microchimerism may occur in a much wider disease spectrum. Srivatsa et al. (2001)
showed that microchimerism occurs in both autoimmune and non-autoimmune forms of thyroid disease. In this study, the authors described one patient with a progressively enlarging goitre in which apparently fully differentiated male thyroid follicles were present. These authors concluded that this observation may be due to the acquisition, migration, and differentiation of fetal stem cells. The observation of extensive microchimerism in liver tissue from a woman who developed chronic hepatitis C following intravenous drug use (Johnson et al., 2002) led these authors to conclude that fetal cells may be present in disease-affected tissue as participants in tissue repair processes. Cha et al. (2003) demonstrated the presence of male cells, presumably fetal in origin, in affected tissue from women with cervical cancer. These authors suggested that fetal cell microchimerism may be associated with this type of cancer, as the male cells appeared to be diploid and therefore not likely to be persistent spermatocytes, and that these data expand the potential relationship between microchimerism and disease in women. These studies, taken together, suggest that fetal cell microchimerism may be a relatively common occurrence in women with both autoimmune and non-autoimmune diseases. |
Potential confounding variables |
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Conclusions from studies of microchimerism have led to speculation about the involvement of a number of variables involved in fetomaternal cell trafficking. Holzgreve et al. (1998)
demonstrated a higher number of fetal cells in the circulation of women with pre-eclampsia than controls and suggested that fetal cell trafficking is disturbed in women with this disease. The role of fetal loss or termination of pregnancy has also been implicated in the subsequent development of microchimerism. Bianchi et al. (2001) found that a large fetomaternal transfusion occurs after elective termination of pregnancy. A subsequent meta-analysis of all published research reports that included complete pregnancy history information found that fetal loss was significantly associated with the development of microchimerism (Khosrotehrani et al., 2003a). In the case of autoimmune disease development, Artlett et al. (2002b) showed that those patients with a history of prior pregnancies had a later onset of disease, less severe lung involvement, and a lower rate of death than women who had never been pregnant. Indeed, these results suggest that the effect of pregnancy is a positive one, and may be due to the acquisition of fetal cells with therapeutic potential. Women who have never been pregnant lack this source of cells and therefore have to rely on endogenous cells for tissue repair, which leads to more severe disease consequences.
In addition to pregnancy history, the effect of procreation with multiple partners has also been implicated as an influence in the development of microchimerism. Olsen et al. (2003) studied two groups of women: those whose children shared a biological father and those who had multiple partners but the same number of pregnancies and live births. These investigators found that women who had children with more than one partner had higher mortality rates than those who had had only a single partner. This difference was even greater when women had more than two partners. While the authors did not suggest that these differences were exclusively associated with microchimerism, they did conclude that caution is needed when studying the health effects of pregnancy, and that the number of biological fathers, as well as the number of sexual partners, must be considered when studying the effects of microchimerism. Complete pregnancy histories of the women involved in studies of fetomaternal cell trafficking are paramount, as a full-term pregnancy is not necessary for the establishment of microchimerism. Indeed, fetal loss may be a major contributor of fetal cells that have the potential to establish residency in maternal tissue, and pregnancy as brief as a few months may have important long-term health consequences for women (Bianchi et al., 2001).
Sources of foreign cells in maternal tissue other than pregnancy may also be involved in the apparent development of fetal cell microchimerism. The majority of studies presented here rely exclusively on the detection of Y chromosome DNA either by fluorescence in situ hybridization (FISH) analysis or PCR amplification, and are therefore actually assessing male cell microchimerism. The unequivocal identification of microchimeric cells as fetal in origin would require, for example, the analysis of paternally inherited DNA polymorphisms. As this type of DNA analysis of microchimeric cells is not routinely performed due to technical challenges, reliable studies of fetomaternal cell trafficking require the elimination of these other potential sources of microchimerism by accurate clinical histories. Therefore, potential female subjects must be excluded if they have had blood transfusions or organ transplants, or if they have a male twin. For example, Lee et al. (1999) showed that long-term microchimerism occurs following transfusion in severe trauma patients, as donor leukocytes were shown to survive in immunocompetent recipients up to 1.5 years after transfusion (the longest time-point analysed). Khosrotehrani et al. (2003a) suggested that a major hindrance to the study of fetal cell microchimerism is the lack of pertinent pregnancy histories as well as the consideration of other sources of foreign cells.
Most of the studies cited in this review have been analyses of ‘putative’ fetal cell microchimerism. Although many investigators have taken great care to ensure that patients with sources of microchimerism other than pregnancy (such as transfusion and transplantation) have not been analysed, definitive identification of these cells as fetal remains elusive. Indeed, only Johnson et al. (2002), in their case report of microchimerism in a woman with infectious hepatitis, have reported results of DNA polymorphism analysis in an attempt to definitively identify persistent microchimeric cells as fetal in origin. In this case, the PCR results showed that the male cells were haplo-identical with the woman at each locus tested, but the polymorphisms did not match her son's DNA. They may have originated from an elective termination of pregnancy that occurred nearly two decades before her disease diagnosis. Human tissue specimens are typically prepared as formalin-fixed, paraffin-embedded blocks, and this fixation process cross-links DNA, which inhibits the effective PCR amplification of target DNA polymorphisms within the microchimeric cells. Until genotypic analyses of microchimeric cells can be routinely and reliably performed, all studies of human microchimerism based on the presence or absence of the Y chromosome should be referred to as studies of ‘putative’ fetal cell microchimerism. The alternative to developing PCR methods for the unequivocal identification of human microchimeric cells as fetal in origin is the development of animal models of fetal cell microchimerism.
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Animal models |
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Laboratory animals such as mice and rats have placentation different from that of humans and therefore the resultant fetal cell microchimerism may also differ. However, the use of these animals has many advantages over the use of archived human tissue specimens for the assessment of fetomaternal cell trafficking. For example, pregnancy histories can be controlled and monitored through breeding, and breeding pairs can be selected based on genetic background. All tissue specimens can be prepared to allow for a wide range of analytical tests to be performed. For example, tissue can be analysed freshly or after appropriate fixation that allows for robust PCR amplification of fetal-specific DNA sequences. In addition, tissue can be prepared as frozen or paraffin-embedded sections to allow for the appropriate immunohistochemical approach to be followed.
Some investigators have already reported on the use of animal models for the study of fetal cell microchimerism. In addition to the work by Liégeois et al. (1981), Bonney and Matzinger (1997) used quantitative PCR to assess the number of male cells in multiple tissues from normal mice undergoing their first pregnancy. The results of this study showed that fetal cell migration occurs in only a fraction of pregnancies, and the authors suggested that mothers are not continuously exposed to circulating fetal cells and that the maternal immune system has the capacity to eliminate these cells without eliminating the fetus.
The murine model used by Christner et al. (2000) to study fetomaternal cell trafficking provided evidence that microchimerism may be a result of disease, particularly dermal inflammation and fibrosis. For this study, Christner et al. induced the mouse equivalent of systemic sclerosis by injection with vinyl chloride. Their results showed a 48-fold increase of microchimeric cells in peripheral blood after treatment with vinyl chloride, as well as skin inflammation and splenomegaly accompanied by cellular infiltration and fibrosis. While these authors concluded that microchimeric cells may be a necessary factor in the pathogenesis of autoimmunity, it is possible that these cells were recruited as a response to tissue damage caused by an exogenous source. Additional models of injury in mice and any associated fetal cell microchimerism in the affected tissue will undoubtedly contribute to the understanding of the mechanisms involved with these cells in maternal tissue repair.
In addition to studies using mouse models of fetal cell microchimerism, Jimenez and Tarantal (2003) demonstrated the presence of male fetal DNA in the circulation of rhesus monkeys during pregnancy. The results of this study were similar to findings in humans, in that fetal DNA concentrations increase with advancing gestation and that male sequences were not detected postpartum. These data support the use of this primate species as a model to investigate fetomaternal cell trafficking and microchimerism. While the ethical issues are more complex when using primates as opposed to mice, the rhesus monkey may be a superior model as, like humans, it has a haemochorial placenta. Nevertheless, animal models will prove to be a powerful tool for future studies of fetomaternal cell trafficking.
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Conclusions and future directions |
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Fetal cell microchimerism is a burgeoning field of inquiry, although the data are contradictory relative to the health consequences of persistent fetal cells in maternal tissues. Initially, the hypothesis that fetal cells induce a graft-versus-host-like immune response in mothers was investigated and led to a concentration of reports on the involvement of microchimerism in autoimmune disease. However, to date no investigators have proven that fetal cells cause autoimmune disease. Indeed, some researchers have demonstrated a lack of association between fetal cell microchimerism and autoimmunity. Due to these variable associations of fetal cells with maternal tissues, the relationship between autoimmunity and microchimerism remains unclear.
The relationship between fetal cell microchimerism and non-autoimmune disorders, including infectious disease and cancer, has led to speculation that fetal cells provide a rejuvenating source of fetal progenitor cells that may have the capacity to participate in maternal tissue repair processes. Two components are necessary to demonstrate this occurrence: homing to areas of tissue damage and plasticity (differentiation). The presence of precursor cells (e.g. CD34+ lymphoid progenitor cells) has been demonstrated in the circulation of women during and following pregnancy (Bianchi et al., 1996). Apparently fetal cells with epithelial and hepatic markers have also been found in maternal tissues (Khosrotehrani et al., 2003b), suggesting their capacity to migrate from the circulation, home to various tissue types, and differentiate or fuse. In addition, others have suggested that umbilical cord blood is a source of transplantable progenitor cells that may be useful for stem cell therapy (Kakinuma et al., 2003). While the capacity of fetal cells acquired during pregnancy to differentiate (and function appropriately) has yet to be shown, research efforts are taking place to investigate this possibility. The most powerful means to demonstrate differentiation of fetal cells in maternal tissues are animal models. For example, through breeding transgenic male mice to wild-type females, fetal cells acquired during pregnancy can be tracked by identifying the transgene or its protein product, which are not found in wild-type animals. These fetal cells could be assessed for function in situ by immunohistochemistry, or they could be microdissected from the maternal tissue and assayed for gene expression or protein expression by microarray profiling. Regardless of the analytical methods used to assess function of the microchimeric cells in the future, the presence and persistence of fetal cells in maternal tissues following pregnancy has been reproducibly demonstrated. Therefore, the main objective of fetal cell microchimerism research remains: what are the cells doing there?
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