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Bi-Directional Cell Trafficking During Pregnancy: Long-term Consequences for Human Health

and .

During pregnancy some cells traffic between the fetus and mother and recent studies indicate low levels persist in the respective hosts decades later. Microchimerism (Mc) refers to a small population of cells or DNA harbored by one individual that derive from a genetically distinct individual. Persistent Mc can also arise from cell transfer between twins in utero or after a blood transfusion. Because women are preferentially affected by autoimmune disease, often with an increased incidence in post-reproductive years, fetal Mc has been investigated in diseases such as systemic sclerosis (SSc), autoimmune thyroiditis, primary biliary cirrhosis, Sjögren's syndrome and systemic lupus erythematosus. Maternal Mc has been investigated in SSc, myositis and neonatal lupus. Evidence implicating fetal Mc is strongest in SSc where quantitatively higher levels of fetal Mc have been found and particular human leukocyte antigen (HLA) relationships of mother and child are associated with increased risk of subsequent SSc in the mother. Maternal Mc is implicated in myositis and neonatal lupus. It is unknown how Mc might be involved in autoimmune disease. Mc could play a role in the effector arm of immune responses either directly or indirectly. Microchimeric cells could be targets of an immune response, an intriguing possibility suggested by a recent study in which maternal cells identified in hearts of infants with neonatal lupus congenital heart block were predominantly cardiac myocytes. Alternatively microchimeric cells could be recruited secondarily to diseased tissues and function in tissue repair. The long-term consequences of naturally acquired Mc deriving from pregnancy are not yet known. Because persistent fetal and maternal Mc are not uncommon in healthy individuals it seems likely that beneficial effects may also accrue to the host. Recent advances in this active frontier of scientific research are discussed.

Introduction

The application of molecular techniques to the study of human pregnancy has revealed that bi-directional cell trafficking occurs between the mother and the fetus.1 The long-term persistence of fetal cells in the mother and maternal cells in her progeny leads to the coexistence of at least two cell populations in a single person.2,3 Microchimerism (Mc) refers to a small nonhost cell population (or DNA quantity) from one individual harbored by another individual. Other potential sources of Mc can occur as a result of cell trafficking between twins in utero and after a nonirradiated blood transfusion.4,5 Substantial levels of fetal DNA have been detected in the circulation of women undergoing elective termination and it is presumed that persistent fetal Mc occurs after spontaneous or induced abortion.6 Theoretically, cells could transfer from an older to a younger sibling via the maternal circulation or from sexual intercourse, although these possibilities remain to be investigated.

The concept that naturally acquired Mc from pregnancy might contribute to autoimmune disease arose in part from observations of iatrogenic chimerism in transplantation.7 After hematopoietic cell transplantation, donor cells may attack the recipient resulting in graft-versus-host-disease (GVHD). Chronic GVHD shares many clinical similarities with autoimmune diseases including SSc (also called scleroderma), primary biliary cirrhosis, Sjögren's syndrome, and sometimes myositis and systemic lupus erythematosus.8 Other observations contributing to the hypothesis included the predominance of autoimmune diseases in women especially after reproductive years and the observation that the donor-recipient human leukocyte antigen (HLA) relationship is a critical component of both chronic GVHD and graft rejection.7 The particular HLA genes and the HLA-relationship of host and microchimeric cells likely represent important factors in whether Mc has a detrimental, neutral or possibly even beneficial effect on the host. Although beneficial effects of Mc have not been specifically shown, it seems likely that fetal and maternal Mc provide benefits to the host as both are commonly found in healthy individuals. This chapter reviews recent investigations of fetal and maternal Mc and considers implications of these studies to human health and disease (fig. 1).

Figure 1

Figure 1

Microchimerism in Human Health and Disease Footnote: SSc = systemic sclerosis, PBC = primary biliary cirrhosis, PBMC = peripheral blood mononuclear cells, T = small series of autopsy cases

Fetal Mc in SSc

Most studies of fetal Mc test for male DNA or male cells as a marker of fetal Mc in women with sons, although not all studies provide the pregnancy history of study subjects. Initial studies of fetal Mc in autoimmune disease focused on SSc, a disease with clinical similarities to chronic GVHD. The first report described a prospective blinded study of women with SSc and healthy women who had given birth to at least one son.9 An assay that had previously been standardized for use in prenatal diagnosis was employed to test DNA extracted from whole peripheral blood and provide a quantitative assessment of male DNA. Women with SSc were found to harbor significantly higher levels of male DNA than controls (11 vs. 0.4 mean male DNA cell equivalents per 16cc of whole blood, respectively). In some women with SSc, levels of male DNA were within the highest quartile of fetal Mc observed in women currently pregnant with a normal male fetus, even though the women with SSc had given birth to their sons decades previously. A quantitative approach was used in the initial study investigating fetal Mc in autoimmune disease because an earlier report suggested persistent fetal Mc is frequent among healthy women (positive in 6 of 8 healthy women with sons).2 When nonquantitative techniques are used only the Mc frequency can be reported i.e., any positive result in cases versus controls. Most, although not all, subsequent studies have been consistent with an increase in levels of fetal Mc without necessarily an increase in frequency when women with SSc are compared to controls.10-15

Further characterization of fetal Mc in peripheral blood necessitated development of additional techniques to allow quantitative testing of different blood compartments and isolated cellular subsets. Studies were made possible by the application of real-time quantitative PCR (Q-PCR) methods to the study of fetomaternal cell transfer.1 In peripheral blood, fetal Mc could be due to circulating cells or to release of breakdown products from disease damaged tissues. Employing real-time Q-PCR for a Y-chromosome specific sequence, increased levels of fetal Mc were found in the cellular component but not in plasma from peripheral blood of women with SSc compared to controls.10 Of initial studies examining peripheral blood cellular subsets, an earlier study used a nonquantitative technique and described the presence of fetal Mc within T and B lymphocytes, monocytes and natural killer cell populations of women with SSc and healthy women.11 There was no significant difference of Mc frequency in the different cellular subsets in the women with SSc compared to healthy women. More recently, two studies have employed Q-PCR, examining cellular subsets. One report described a decrease in fetal Mc within maternal CD3-positive T lymphocytes including CD8+ cells but noted the majority of patients were taking immune suppressive medication.10 Another report described an increase of fetal Mc within CD4-positive T lymphocytes in the diffuse form of SSc but did not provide medication use.12 Further studies of immunologically active peripheral blood subsets are needed—ideally studies of patients who are early in the disease course, including evaluation of immunosuppressive medication use and categorization according to clinical disease characteristics. In addition, other variables will need to be considered that have not yet been established for healthy women, as this is a new investigative frontier. For example, does length of time from pregnancy, number of pregnancies, or type of pregnancy outcome (spontaneous or induced abortion, preeclampsia, preterm birth, etc.) affect fetal Mc levels and/or cellular subset distribution in the mother?

Lesional skin of women with SSc has been tested for male DNA in two studies, both with positive results.16,17 The reports differed in that the former used a nonquantitative technique and described an increased frequency16 whereas the latter employed a quantitative technique and reported no difference in frequency but did find quantitatively significant differences in women with SSc compared to controls.17 In the latter study, the male DNA cell equivalents were 4.6 compared to 1.8 in 80 ng of tissue in cases and controls, respectively. In another study, autopsy tissues from a limited number of women with SSc and controls who had given birth to sons were studied for male cells by fluorescence in situ hybridization (FISH) for Y- and X-chromosome specific markers.18 Male cells were identified in lung, kidney, skin (SSc disease sites), liver, adrenal gland and lymph node of some patients, with particularly high numbers in the spleen. High levels of male cells in the spleen were of interest in light of a previous study reporting marked splenomegaly in a murine model of Mc in SSc.19 Mice were treated with vinyl chloride, an agent associated with SSc; significantly increased levels of fetal Mc were observed and correlated with splenomegaly and dermal fibrosis.

The hypothesis linking fetal Mc to autoimmune disease incorporated the proposal that particular HLA genes and the HLA-relationships between host and microchimeric cell populations is likely a key determinant of the effect of Mc on the host. To investigate this aspect of the hypothesis, women and all their children were studied for the HLA class II genes DRB1 (encoding HLA-DR), DQA1 and DQB1 (encoding HLA-DQ). An increased risk of subsequent SSc in the mother was observed when a previously born child was not distinguishable, from the mother's perspective, for genes encoding the HLA-DR molecule.9 Another study purported to show compatibility of either a patient's mother or child as a risk factor for SSc, but unfortunately was not interpretable due to a number of methodological problems, including use of controls with an HLA-associated disease and comparison across different HLA-gene families that were not independent of each other.20 A subsequent study examined HLA-compatibility of the patient's mother in studies of men with SSc and found no difference compared to healthy men.21

Additional studies are needed with serial testing of fetal Mc levels and comparison to other inflammatory autoimmune and non-autoimmune diseases. Overall studies in SSc may be summarized as generally showing a significant difference in the quantity of fetal Mc in blood and tissues compared to controls without necessarily showing an increased frequency of fetal Mc. Results available to date lend support to the importance of HLA genes as likely key determinants of whether long-term persistent fetal Mc has the potential for adverse consequences to the host.

How Might Fetal Mc Contribute to Disease Pathogenesis in SSc?

Whether Mc contributes to the pathogenesis of SSc and what mechanisms may be involved are unknown. Differences in Mc between women with SSc and controls could be interpreted as a secondary event in the pathogenic process. Increased risk of subsequent SSc in women who previously gave birth to an HLA-DRB1 compatible child, however, argues against this interpretation. A number of possibilities may be considered. Fetal microchimeric cells could potentially function as effectors or targets of an immune response. Other investigators have described T cell clones, presumably of fetal origin, which react specifically with maternal (mismatched) HLA antigens, expressing a pattern of cytokine production consistent with T-helper type 2.22 However, caution should accompany direct analogy with mechanisms involved in chronic GVHD, where circulating cells are essentially completely replaced by donor cells, as levels of naturally acquired fetal Mc are very low (generally far less than 1% of circulating cells). The effect of a small number of cells could be amplified, for example, by presentation of fetal peptides by one host cell to other another host cell, analogous to the “indirect” pathway of recognition, thought to play a role in chronic rejection of organ grafts. A small number of microchimeric cells could potentially dysregulate host-to-host cell interactions in a paracrine fashion through cytokine secretion. The possibilities are not mutually exclusive as more than one mechanism could be contributory. With respect to the contribution of HLA genes, an excess HLA similarity of fetal cells to the mother without complete HLA-identity could hamper the recognition of cells as foreign while promoting autoimmunity by simultaneous presentation of peptides derived from HLA that are similar and dissimilar to self. Thus, Mc could have adverse, neutral (or beneficial) effects on the host, depending upon particular HLA genes and the HLA-relationship between the different cell populations.

Fetal Mc in Autoimmune Thyroid Disease

A disproportionate incidence of autoimmune thyroid disease in women and frequent onset postpartum prompted investigation of fetal Mc.23,24 In a study of thyroid tissues, the frequency of male DNA was greater in Hashimoto's disease compared to nodular goiter and positive results correlated with women who had sons.25 Male DNA was likewise more frequent in thyroid tissues from women with Graves' disease compared to controls with adenoma.26 Employing FISH to identify male cells in thyroidectomy and autopsy specimens from women with multiple thyroid disorders, male cells were found in thyroids from more than half of women with a thyroid disease compared to none in autopsy controls.27 Women with Hashimoto's thyroiditis harbored male cells at a somewhat greater frequency than women with other thyroid diseases; however, male cells were almost as frequent in some non-autoimmune conditions. Suggesting Mc could contribute to tissue repair, one tissue section had male cells that were indistinguishable from differentiated thyroid follicles. The concept that fetal Mc may be recruited to the thyroid during immunologic injury is supported by observations from a murine model of experimental autoimmune thyroiditis (EAT).28 Fetal T cells and dendritic cells accumulated within the thyroids of mice with EAT during pregnancy and the early postpartum period. After mating females to males with green fluorescent protein expression, offspring cells expressing the protein could be found in thyroid glands from experimentally immunized pregnant and postpartum mice and not in control nonimmunized mice.

Fetal Mc in Other Autoimmune Diseases

Studies of fetal Mc in other autoimmune diseases have examined Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), and primary biliary cirrhosis (PBC). Direct comparison of study results within a particular disease is often limited by differences in techniques for measuring Mc and in study design (discussed later). In contrast to SSc and thyroid diseases, where studies generally lend support to a potential role for fetal Mc in SS and SLE, results are conflicting, and in PBC, mostly negative. Earlier studies of SS reported no significant difference of fetal Mc in peripheral blood samples between women with SS and controls.29 Subsequent studies examined DNA extracted from salivary glands with differing results. Nonquantitative methods were used in all studies. One report described an increased frequency of male DNA in minor salivary gland biopsies from women with SS compared to controls (55% vs. 13%).30 Another study testing for male DNA in labial salivary glands found none in primary SS, but positive results were found in a small number of women with SSc and with SSc and secondary SSc.31 A third study reported male DNA more often in labial salivary glands of SS patients than controls (36% vs. 0%) and also found positive results in some bronchoalveoloar lavage specimens from a limited number of women with SS.32 Modest sample sizes were assessed in these studies, and future studies of larger numbers of subjects in different clinical disease subsets using quantitative techniques are needed.

In one series of SLE patients, when nonquantitative methods were used no significant difference of fetal Mc was observed in women with SLE compared to controls; however, when real-time Q-PCR methods were employed, SLE patients differed significantly from controls.33 In another series of similar size also employing real-time Q-PCR, no difference of frequency or quantity was observed.34 The latter study, although finding no correlation with disease activity, did report a higher mean fetal Mc level in patients with a history of lupus nephritis. A case report of a woman who died from SLE described male cells in multiple disease-affected tissues including kidney, lung, heart, skin and intestine.35 SLE has extensive and varied clinical manifestations so that additional studies of large populations of well-characterized patients will be necessary to determine whether fetal Mc plays an role in this disease. From an experimental perspective, rationale exists for exploring a possible role of maternal Mc in SLE since a murine model of SLE is created by the infusion of parental cells into the F1 progeny.36

PBC is a chronic, progressive autoimmune liver disease that has features similar to chronic GVHD of the liver. An initial study of PBC found male DNA in the majority of livers of women with PBC but also in the majority of livers affected by other diseases, without a difference of frequency, although the quantity was somewhat greater in PBC.37 Most studies have reported no significant difference in fetal Mc of women with PBC when compared to other liver disorders.38-41 The frequency of positive results when testing for male DNA varied over a wide range (18% to 70%), but may be explained at least in part by differences in patient selection as some studies were limited to women with sons while others were not. Although no overall association was observed, another study found fetal Mc more often in PBC patients who had anti-centromere antibodies, an antibody that is associated with the CREST variant of SSc.39 Overall evidence is lacking to support a causal role for fetal Mc in PBC. However, whether immunologic consequences of fetal Mc might differ depending upon pregnancy type, e.g., spontaneous or induced abortion, or whether the total number of sexual partners correlates with MC has not been investigated in any autoimmune disease. This gap in knowledge is especially evident in studies of PBC since a recent report described an increasing risk of PBC with increasing gravidity with double the percentage of PBC patients reporting five or more children compared to controls.42

Maternal Mc in Autoimmune Disease

The transfer of maternal cells into newborn infants has been appreciated at least since the 1960's when routine karyotyping of male infants demonstrated sex chromosome mosaicism.43 Maternal transfer of erythrocytes, leukocytes, and platelets into the infant's circulation was demonstrated when maternal blood labeled with a tracer was found in the newborn infant's cord blood.44,45 Although studies of fetal Mc can employ a single PCR assay for male DNA in women with sons, no similar simple approach has been available to study maternal Mc. The FISH technique can be used to visually identify and quantify female cells in a male but is laborious and time intensive. An alternative approach is to target a noninherited nonshared genetic polymorphism. Using this approach, the estimated frequency of maternal cells in cord blood was 42%.46 Using FISH maternal cells have been detected in multiple newborn tissues including liver, spleen, thymus, thyroid, and skin.47

Maternal Mc is implicated in myositis. The frequency of maternal Mc was significantly increased both in peripheral blood mononuclear cells and in muscle biopsies of children with juvenile dermatomyositis as compared to unrelated controls and to unaffected siblings.48 Inclusion of unaffected siblings as a control group is a study design strength as environmental, and to some extent genetic background are similar. Although not limited to autoimmune myositis, other studies of children with idiopathic inflammatory myopathy also reported an increased frequency of maternal Mc in peripheral blood and in muscle biopsies.49 The phenotype of maternal cells in muscle tissues was not determined in these studies.

In an early study of SSc maternal-specific DNA was detected using a nonquantitative technique in more than half of all study subjects without a significant difference in patients and controls.3 A more recent report described an approach in which a panel of HLA-specific real-time Q-PCR assays was developed targeting noninherited nonshared maternal-specific HLA sequences.50 Employing the panel of quantitative assays and studying a larger number of subjects, maternal Mc was significantly more frequent among SSc patients than healthy women (72% vs. 22%). Quantitative differences were not significantly different in the two groups. As described previously, HLA-compatibility of the mother has also been investigated in men with SSc. Mothers of men with SSc were not compatible more often than mothers of healthy men.21

How Might Maternal Mc Contribute to Disease Pathogenesis?

Whether maternal Mc is involved with disease pathogenesis and any mechanism of involvement is not known. However, an intriguing possibility is suggested by a recent report that investigated maternal Mc in neonatal lupus erythematosus syndrome.51 A technique was developed by which the same cells in a tissue section could be evaluated for phenotype and for sex with concomitant immunohistochemistry and FISH for X- and Y-chromosomes. Autopsy samples from male infants were examined, and maternal cells were identified in the atrioventricular node and myocardium (up to 2% of all cells in some sections). Interestingly, the majority of maternal cells lacked hematopoietic cell markers, instead expressing markers of cardiac myocytes. This finding suggests that microchimeric cells can transdifferentiate, which is consistent with many other recent reports of unexpected cellular plasticity in cells thought to have undergone terminal differentiation (i.e., neurons, hepatocytes).52 Thus, microchimeric cells could be the target of a host immune response with subsequent fibrosis of the conduction system and eventual heart block. Alternatively, transdifferentiation of maternal microchimeric cells could contribute to tissue repair. The two possibilities cannot be distinguished in this study.

Technical and Study Design Considerations

In studies of Mc, experimental design and techniques are of paramount importance in drawing valid conclusions, because it is a low frequency event and occurs frequently in healthy individuals. Interpretation of studies employing PCR for detection of microchimeric DNA requires knowledge of the sensitivity and specificity of the particular assay employed in addition to specific methodological information such as the number of DNA aliquots tested and number of times testing was conducted. PCR assay specificity may be compromised by cross-reactivity of some Y-chromosome sequences with autosomal sequences yielding false-positive results. Nested PCR techniques are nonquantitative and subject to greater risk of contamination than closed PCR systems (e.g., kinetic PCR). Despite good sensitivity of assays targeting Y-chromosome multi-copy sequences, some Y-sequences vary in copy number between individual men so that only multi-copy Y-chromosome sequences that have a stable copy number between men should be used for quantitative purposes.

Additional sources of variation arise depending upon the compartment of blood being investigated and specific technique used during blood processing. For example, during pregnancy fetal DNA is much higher in maternal plasma than PBMC.53 In contrast, long-term persistent Mc was essentially limited to the cellular component (and not plasma) in a study of women with SSc and healthy women.10 The speed of centrifugation and presence of a filtration step during blood processing alters the total DNA detected in the sample and may affect results of testing for Mc.54 DNA extracted from paraffin-embedded tissues could be subject to contamination because paraffin baths are not routinely changed between samples. Other technological issues arise when studying tissues by FISH as overlapping cells can produce artifacts; only cells with two signals in a well-defined nucleus should be counted.

The preferable study design for investigation of Mc is prospective with inclusion of pregnancy history and other potential sources of Mc. Some studies assayed for male DNA in a female host and reported results as fetal Mc but lacked pregnancy history. Sources of male DNA in a woman to be considered include a prior pregnancy, twin, or blood transfusion, with other potential sources from anolder brother passed via the maternal circulation or possibly sometimes from sexual intercourse. Testing using assays to identify unique genetic polymorphisms will be especially useful in future studies, for example to support fetal origin of male DNA. Finally, disease stage and medications, notably immunologically-active medications at the time of blood draw, should be queried as either could confound a potential association between Mc and disease.

Summary

Bi-directional cell traffic occurs between a mother and child during pregnancy, and Mc persists in respective hosts decades later. Recent studies examining fetal and maternal Mc provide support for the possibility that Mc could contribute to the pathogenesis of selected diseases, particularly SSc, autoimmune thyroid disease, myositis and neonatal lupus. Microchimeric cells could also benefit the host through tissue repair. It is likely that Mc can have adverse, neutral, or beneficial effects on the host, depending upon other factors with HLA genes and the HLA-relationship among cells probably of key importance. Elucidating the mechanisms by which naturally acquired Mc is permitted without detriment to the host may lead to novel strategies with application to prevention and/or treatment of autoimmune diseases. Further investigations in this area of research may also be of benefit in advancing understanding of iatrogenic chimerism, notably in organ and stem cell transplantation.

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