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Postpartum Autoimmune Thyroid Disease: The Potential Role of Fetal Microchimerism

Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029

Address all correspondence and requests for reprints to: Takao Ando, M.D., Mount Sinai School of Medicine, Box 1055, 1 Gustave L. Levy Place, New York, New York 10029. E-mail: takao.ando{at}mssm.edu.

	Abstract

Top Abstract Introduction Establishing fetal... Cell constituents of fetal... Indirect evidence of fetal... Nonthyroidal diseases AITD and pregnancy Intrathyroidal fetal... An animal model of... Potential immunological role of... Maternal cell microchimerism Summary References

 
Fetal microchimerism is defined as the presence of fetal cells in maternal tissues established during pregnancy. Immune suppression of maternal immunity during pregnancy by the placenta may play an important role in allowing the establishment of such fetal microchimerism. However, peripheral blood fetal microchimerism that persists in the postpartum period is considered a natural event and implies the induction of tolerance during pregnancy. Identification of fetal cells that persist preferentially in maternal tissues subject to autoimmunity, such as skin and thyroid, has also suggested the possible immune modulation of the autoimmune response at the target tissue by fetal cells. Accumulating evidence suggests that fetal immune cells may be reactive to maternal antigens and, therefore, have the capacity to trigger graft vs. host reactions. This would provide a mechanism for the initiation and/or exacerbation of autoimmune disease.

The course and severity of autoimmune thyroid disease have long been known to be profoundly influenced by pregnancy, with disease suppression prepartum and exacerbation postpartum. However, the precise mechanisms involved have not been fully understood. Here we have reviewed recent information on the possible role of fetal microchimerism in autoimmune thyroid disease, focusing on the immunological consequences of intrathyroidal fetal cells and their contribution to postpartum exacerbations.

	Introduction

Top Abstract Introduction Establishing fetal... Cell constituents of fetal... Indirect evidence of fetal... Nonthyroidal diseases AITD and pregnancy Intrathyroidal fetal... An animal model of... Potential immunological role of... Maternal cell microchimerism Summary References

 
MICROCHIMERISM HAS BEEN defined as a chimera (i.e. a mixture) of small numbers of cells from different individuals coexisting within tissues, including the peripheral blood. Microchimerism has been demonstrated after organ transplantation (such as bone marrow, kidney, and heart) by demonstrating a persistent mixture of cell populations from both donor and recipient. The chimeric donor immune cells are believed to play a role in modulating the immune responses in a recipient. Indeed, donor cells may initiate not only graft vs. host disease (GvHD), but may also have an important role in the induction of host tolerance to graft tissue (1). Fetal microchimerism is also seen as a natural consequence of an established pregnancy and results from a mixture of cells of maternal and fetal origin seen in maternal tissues during and after pregnancy. The strategy to identify such fetal cells has been varied, but one simple method in women with a previous male pregnancy has been to assay for male fetal cells using male-specific gene markers. Using this approach, fetal microchimerism has been shown to persist in some women for more than 27 yr after delivery (2, 3). As easily achieved, male cell makers have been used in most of the studies to detect fetal microchimerism, but it is important to note that fetal microchimerism could also be female in origin. Such female fetal cells can only be assessed by human leukocyte antigen (HLA)-based detection and are more difficult to study because this system requires multiple detection probes.

	Establishing fetal microchimerism

Top Abstract Introduction Establishing fetal... Cell constituents of fetal... Indirect evidence of fetal... Nonthyroidal diseases AITD and pregnancy Intrathyroidal fetal... An animal model of... Potential immunological role of... Maternal cell microchimerism Summary References

 
In pregnancy, a fetal "graft" that carries paternal antigens as well as maternal antigens is by definition partially allogeneic. For a successful pregnancy outcome, the maternal immune system must not overreact to the fetus. The feto-placental unit, therefore, suppresses maternal immunity, allowing it to tolerate fetal antigens.

Trophoblast cells located in the placenta and subject to maternal immune surveillance serve as physical barriers between mother and fetus and have been shown to express several immune-modulating molecules, such as HLA-G, Fas ligand, and indoleamine 2,3-dioxygenase, as well as secrete a variety of humeral factors, such as leukemia inhibitory factor and progesterone (4). HLA-G is one of the members of the major histocompatibility complex (MHC) class I family and is known to inhibit natural killer function (5, 6) and dendritic cell maturation (7). Fas ligand interacts with Fas antigen and induces apoptotic cell death of fetal antigen-reactive maternal lymphocytes (8). Indoleamine 2,3-dioxygenase, which catalyzes tryptophan in lymphocytes, has proven to be critical in the maintenance of allogeneic pregnancy in the mouse (9). Leukemia inhibitory factor secretion from the maternal placenta and Th2 lymphocytes is required for blastocyst implantation and also considered to have an immunological role(s) in fetomaternal tolerance (4). Other than these local modulators, progesterone and estrogen produced by the placenta affect cytokine profiles across the whole maternal immune system (4).

The net effect of these immune modulations affects maternal T helper (Th) cell differentiation. Th0 precursor cells have the potential to differentiate into Th1 or Th2 cells depending on the cytokine signals provided during antigen presentation. IL-12 and interferon- promote Th1 differentiation, while IL-4 promotes Th2. Th1 cells produce IL-2 and interferon-, whereas Th2 cells synthesize IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13 (4). Th1 cell induction generates cellular inflammation, in contrast to the allergic and humeral immune response induced by Th2 cells. The placenta-driven immune modulation mentioned above promotes suppression of Th1 immunity and a relative enhancement of Th2 immunity during pregnancy. A failure to suppress the activity of Th1 cells has been correlated with miscarriage (4), and the altered immune condition during pregnancy must be favorable to survival of the fetus. Hence, once fetal cells migrate into the maternal circulation and take up residence in maternal tissues, they may survive without being destroyed by the suppressed maternal immune system. This immune suppression of pregnancy may remain for some months after delivery (10), allowing fetal cells to establish themselves and to survive the postpartum period, but under normal circumstances most fetal cells are lost during this time.

	Cell constituents of fetal microchimerism

Top Abstract Introduction Establishing fetal... Cell constituents of fetal... Indirect evidence of fetal... Nonthyroidal diseases AITD and pregnancy Intrathyroidal fetal... An animal model of... Potential immunological role of... Maternal cell microchimerism Summary References

 
Cell transfer between fetus and mother, especially from the fetus to the mother, is a common finding during pregnancy. In humans, this transfer has been detected as early as 4–5 wk postconception when assessed by male DNA (11). Several types of fetal cells have been demonstrated in the maternal circulation during pregnancy, including CD34⁺ and CD34⁺CD38⁺ hemopoietic progenitor cells, nucleated erythrocytes, trophoblasts, and leukocytes (12). As trophoblastic cells serve as lining cells in contact with the maternal circulation, it is not surprising to find these cells in the maternal blood as a result of cell shedding. However, the presence of fetal blood cells in the maternal circulation also denotes imperfection in the physical barrier of the placenta.

As fetal microchimerism in peripheral blood is an almost universal finding during normal pregnancy (13), and the postpartum period (14, 15, 16, 17), the presence of fetal cells in the circulation does not indicate an aberrant immune response by the mother. However, as fetal microchimerism can persist for more than 27 yr (2, 3), it is possible that fetal cells themselves also play an active role in determining the immune repertoire. Based on these assumptions, we hypothesize that fetal immune cells have immune interaction with their maternal counterparts in the postpartum period and may precipitate the onset of postpartum autoimmune thyroid disease (AITD) (17, 18, 19).

	Indirect evidence of fetal microchimerism in nonthyroidal human autoimmunity

Top Abstract Introduction Establishing fetal... Cell constituents of fetal... Indirect evidence of fetal... Nonthyroidal diseases AITD and pregnancy Intrathyroidal fetal... An animal model of... Potential immunological role of... Maternal cell microchimerism Summary References

 
Most human autoimmune diseases develop preferentially in women of childbearing age and are modulated by pregnancy (20). The marked immune changes described above, i.e. suppression during pregnancy and exacerbation postpartum, may contribute to the high frequency of autoimmune disorders in middle-aged women. As the maternal immune system must tolerate allogeneic paternal antigens on fetal tissues, the immune tolerance induced during pregnancy may be more profound when the male is more disparate from the female. In humans, rheumatoid arthritis has tended to show improvement or remission in the presence of more maternal-fetal disparity in HLA class II antigens (21), thus supporting this concept. Hence, paternal antigens are likely to affect the degree of maternal immune suppression during pregnancy. In addition, similar histological features seen in both GvHD and autoimmune disease have raised the possibility of a role for fetal microchimerism in such diseases. For example, lymphocytic infiltration seen in skin and liver affected by GvHD is similar to the findings in certain autoimmune skin and liver diseases (see below).

	Nonthyroidal diseases

Top Abstract Introduction Establishing fetal... Cell constituents of fetal... Indirect evidence of fetal... Nonthyroidal diseases AITD and pregnancy Intrathyroidal fetal... An animal model of... Potential immunological role of... Maternal cell microchimerism Summary References

 
The first direct discovery of fetal cells in autoimmune disease was obtained from patients with the human autoimmune skin disease scleroderma. Fetal cells were identified as male DNA in the peripheral blood and also in the inflammatory skin lesions of these patients (14, 22). Similarly, male cells in female autoimmune patients have been discovered in the lesions of primary biliary cirrhosis (15, 23, 24), systemic lupus erythematosus (25), and Sjögren’s syndrome (26).

Scleroderma.

This is an autoimmune disorder that affects vascular and connective tissues, primarily in women of reproductive age. In scleroderma, fetal cell invasion into the skin lesions was exclusively found in affected patients, but not in healthy controls (22). In addition, the frequent occurrence of pulmonary fibrosis in such patients after multiple pregnancies has further suggested a profound relationship between scleroderma and pregnancy (27). Prolonged peripheral fetal microchimerism in scleroderma was associated with a specific MHC class II allele (HLA DQA1*0501) from either the mother or the offspring (28). In addition, Christner et al. (29) demonstrated that in a mouse model of scleroderma induced by a chemical (vinyl chloride), severe inflammation and fibrosis of the skin were observed only in females that had been mated with another strain, not in virgin mice. In pregnant mice with experimental scleroderma, the number of peripheral blood fetal cells was remarkably increased after vinyl chloride treatment, suggesting that microchimeric cells proliferated in response to the chemical stimulus and may have initiated autoimmune skin disease (29). Moreover, Scaletti et al. (30) recently studied male T cell clones from the peripheral blood and skin lesions of female patients with scleroderma. They showed that some T cell clones from patients and controls had a proliferative response to maternal non-T peripheral blood cells. About 10% of the maternal MHC antigen-reactive clones were Y-chromosome positive, as shown by the fluorescent in situ hybridization (FISH) technique. This was also associated with a significantly stronger IL-4 response, which is relevant in Th2-dominant scleroderma, to maternal MHC antigens compared with other clones (30). These results suggested that the fetal cells were immunologically active and able to proliferate, rather than innocent bystander cells, and that one of the immune targets of these fetal immune cells were maternal antigens and not exclusively the MHC (HLA) antigens.

Primary biliary cirrhosis (PBC).

PBC is an autoimmune liver disease in which intrahepatic small biliary ducts are destroyed by infiltrating immune cells, leading to intrahepatic cholestasis. Tissue findings in PBC are similar to that in GvHD. The liver of such patients has also been shown to harbor fetal cells, but this has been seen in both patients and healthy controls in some reports (15, 23), while others (24) have shown intrahepatic fetal male cells, by FISH, only in PBC patients. Intrahepatic fetal cells expressed leukocyte common antigen CD45 and HLA-DR, but not CD34 or -fetoprotein (24). These studies showed that the liver is one of the human organs with marked fetal microchimerism. Functional studies of intrahepatic fetal cells have not been reported.

Polymorphic eruption in late pregnancy.

This transient skin disease has been shown to be associated with intradermal fetal microchimerism (31). In contrast to autoimmune diseases, this skin disorder develops in late pregnancy and usually improves after delivery quite spontaneously, and the skin lesions have been shown to contain fetal DNA (31). Thus, it could be that loss or reduction of fetal cells after delivery may have aided recovery. However, the pathological mechanisms of this disorder remain uncertain.

	AITD and pregnancy

Top Abstract Introduction Establishing fetal... Cell constituents of fetal... Indirect evidence of fetal... Nonthyroidal diseases AITD and pregnancy Intrathyroidal fetal... An animal model of... Potential immunological role of... Maternal cell microchimerism Summary References

 
Like other autoimmune diseases, AITD affects women in the reproductive age range. As AITD commonly initiates and/or exacerbates in the postpartum, we suspected the involvement of fetal microchimerism (18). Indeed, AITD is one of the best characterized groups of autoimmune diseases to have a profound relationship with pregnancy (32). Autoimmune antigens involved in AITD are the primary thyroid antigens, such as the TSH receptor (TSHR), thyroglobulin (Tg), and thyroid peroxidase (TPO). In cases of autoimmunity against the TSHR, the thyrocytes may be overstimulated and generate excess thyroid hormone secondary to activating autoantibodies (Graves’ disease). Autoimmunity against Tg and TPO is seen most actively in Hashimoto’s disease, where the thyroid cells are apoptosed and which is associated with dense lymphocytic infiltration and germinal centers. Thyroid hormone synthesis is gradually reduced due to loss of the thyrocytes.

AITD and pregnancy.

The relationship between pregnancy and AITD has been well documented (32). As mentioned earlier, placental immune suppression during pregnancy lessens the activity of AITD, as seen in the remission of Graves’ disease and reduced titers of autoantibodies against the major thyroid autoantigens; Tg, TPO (18, 33), and TSHR (34). However, exacerbation of preexisting AITD or initiation of AITD are also common postpartum (18). Increased titers of thyroid autoantibodies, a reversed ratio of CD4⁺/CD8⁺ T cells, and a change in cytokine profiles to favor Th1 responses have all been observed in the postpartum (10). In AITD, Graves’ disease has been shown to be most markedly suppressed by pregnancy itself, but up to 60% of Graves’ disease patients of childbearing age have been reported to develop this disease within 1 yr of delivery (35). In addition, postpartum thyroiditis has been found in approximately 8–10% of all women and increases to more than 40% in women with TPO autoantibodies (33). In general, this increased incidence of AITD in the postpartum has been attributed to altered immunity during and after pregnancy (10), but the precise mechanism(s) have not been fully elucidated.

Pregnancy loss and AITD.

AITD has also been shown to be one of the risk factors contributing to spontaneous abortion. Untreated thyroid dysfunction, hyperthyroidism, and hypothyroidism due to AITD may also influence pregnancy outcome. Even the presence of thyroid antibodies against Tg and/or TPO without evidence of thyroid dysfunction has been repeatedly recognized as a risk factor for miscarriage (36, 37). The precise mechanisms that may explain this phenomenon are unclear, but three hypotheses have been proposed (38). 1) Pregnancy loss seen in patients with thyroid antibodies may be due to subtle deficiency of thyroid hormone. 2) There may be a direct effect(s) of thyroid antibodies, for example on the placenta. 3) Thyroid antibodies may just represent an abnormal immune state responsible for an unstable implant.

	Intrathyroidal fetal microchimerism

Top Abstract Introduction Establishing fetal... Cell constituents of fetal... Indirect evidence of fetal... Nonthyroidal diseases AITD and pregnancy Intrathyroidal fetal... An animal model of... Potential immunological role of... Maternal cell microchimerism Summary References

 
Non-AITD.

Three laboratories, including our own (17, 39, 40), have studied intrathyroidal fetal microchimerism in non-AITD. Although Klintschar et al. (40) could not find any male cell-positive thyroid adenoma specimens taken from women, others have reported low numbers of male cells in thyroid adenoma (17, 39), adenomatous goiter, and thyroid cancer (39). Whether such accumulation was secondary to minor degrees of lymphocytic infiltration is unclear. However, we also found intrathyroidal fetal microchimerism with low numbers of male cells in normal mice during pregnancy consistent with a low level of nonspecific accumulation (Fig. 1A; see below).

Graves’ disease.

To investigate the potential role of fetal microchimerism in AITD, we first studied the presence of male DNA in thyroid tissue from patients with human Graves’ disease (17). We established a male cell assay using a PCR-ELISA optimized to detect human sex-determining region Y (SRY) DNA. A single male cell was detectable in this assay within a background of 10⁵ female cells. No male SRY gene was amplified from blood samples taken from women who had never been pregnant. In contrast, about 30–45% of normal women and those with Graves’ disease who had given birth to boys were positive for male cells. These results simply confirmed that peripheral blood fetal microchimerism can be found in both healthy controls and patients with AITD. However, fetal microchimerism was also identified in human Graves’ thyroid tissue using both paraffin-embedded and fresh frozen Graves’ thyroid tissues, although there was some DNA fragmentation in the former resulting in weaker PCR signals. Unexpectedly, some of these male cell-positive Graves’ thyroid specimens were taken from women reported never to have been pregnant. It is likely that unrecognized miscarriages had occurred in such cases, although the possibility that male cells were derived from seminal lymphocytes cannot be ruled out (17).

Hashimoto’s disease.

Intrathyroidal fetal microchimerism in Hashimoto’s disease has also been identified (39, 40). Klintschar et al. (40) used a PCR-based semiquantitative technique to detect intrathyroidal male fetal cells. Male DNA was identified in 50% of paraffin-embedded female thyroid specimens. Srivatsa et al. (39) used a Y-chromosome-specific probe for FISH to locate male cells in Hashimoto’s specimens. They found male cells sparsely spread throughout the thyroid specimens, rather than accumulating within a lymphocytic infiltrate (39).

Conclusions.

These studies indicated that the thyroid gland is an organ with fetal microchimerism that was more common in AITD than non-AITD. As studied by Jansson et al. (35), the time lag between pregnancy and the onset of Graves’ disease is within 1 yr in up to 60% of the cases. To date, there are no data to explain whether this time sequence could be related to the presence of activated intrathyroidal fetal cells or due to factors other than fetal microchimerism. However, the presence of residual fetal cells within the maternal thyroid gland, which become activated in the postpartum period as maternal immune suppression is lost, remains an attractive explanation for the postpartum exacerbation of AITD (see below).

	An animal model of thyroiditis during pregnancy and the postpartum

Top Abstract Introduction Establishing fetal... Cell constituents of fetal... Indirect evidence of fetal... Nonthyroidal diseases AITD and pregnancy Intrathyroidal fetal... An animal model of... Potential immunological role of... Maternal cell microchimerism Summary References

 
To further elucidate the immunological impact of pregnancy on AITD, we recently studied experimental autoimmune thyroiditis (EAT) in both syngeneic and allogeneic murine pregnancies (19, 20, 41). EAT has been extensively studied as an animal model of autoimmune thyroiditis and is initiated by immunization with Tg.

Pregnancy loss in an animal model of thyroiditis.

To study the impact of paternal antigens on pregnancy success, EAT-susceptible female mice (CBA/J, H2^k), previously immunized with murine Tg, were mated with a different strain of nonimmunized males, and the percentage of successful pregnancies (pregnancy was determined by vaginal plugs) was evaluated. Among several strains tested, we found that in female CBA/J mice mated with male BALB/c (H2^d) there was a significantly increased spontaneous abortion rate in early pregnancy compared with nonimmunized controls (20) (Table 2). In addition, these female mice showed exacerbated thyroiditis during persisting pregnancy, which was associated with enhanced Th1 responses to BALB/c paternal antigens. We concluded that the increase in spontaneous abortion resulted from exposure to paternal antigens, and this may also exacerbate concomitant thyroiditis (20).

We then expanded our study into the postpartum period to determine whether this allogeneic exacerbation might further exacerbate EAT in the postpartum period (41) as seen in women. In contrast to an exacerbated EAT in the CBA/J x BALB/c pregnancies, a postpartum exacerbation of EAT was also observed in both syngeneic (CBA/J x CBA/J) and allogeneic (CBA/J x BALB/c) pregnancies, with enhanced IL-4 secretion in response to mitogen. We concluded that the postpartum exacerbation of EAT was probably due to loss of placental immune suppression rather than maternal exposure to specific allogeneic fetal antigens during pregnancy (41). Hence, the exacerbation of EAT seen in this mouse model was similar to that seen in the human postpartum period.

In summary, an exacerbation of EAT was triggered by 1) specific paternal (i.e. fetal) MHC antigen exposure to the mother during pregnancy and 2) nonspecifically enhanced maternal immunity in the postpartum period.

Fetal microchimerism in murine thyroiditis.

To further explore involvement of fetal alloantigens in EAT during pregnancy and the postpartum, we examined the maternal host for the presence of fetal microchimerism (19). We chose a combination of CBA/J x BALB/c, because an influence of paternal antigens on maternal EAT was observed. We established a similar PCR-ELISA to estimate the amount of murine SRY gene, which allowed us again to detect one male cell in a background of 10⁵ female cells. Male fetal DNA was easily detected in peripheral blood in both nonimmunized controls and EAT pregnant mice. In contrast, intrathyroidal fetal microchimerism was most easily seen in the EAT animals during pregnancy and only rarely in the controls. The abundant fetal cells within the thyroid gland of mice with EAT during pregnancy decreased in the postpartum and were hardly detectable by 10 wk postpartum (19) (Fig. 1A). Low numbers of fetal cells present in the nonimmunized animal thyroid glands were consistent with the presence of fetal cells in nonautoimmune thyroid disease in human tissues (17, 39).

View larger version (24K): [in this window] [in a new window]   FIG. 1. Intrathyroidal fetal microchimerism in a murine model of EAT during pregnancy and postpartum. A, The number of male cells (determined by SRY PCR transcripts) in each positive sample is illustrated. The numbers below the panel indicate the number of male fetal cell-positive thyroid specimens per number of total thyroid specimens examined in each group. Specimens were obtained at 2 wk of pregnancy and at 5 and 10 wk of the postpartum period, as indicated at the bottom. This figure was adapted and modified from Table 1B in Ref. 19 . Permission was obtained from The Endocrine Society. B, An intrathyroidal fetal green cell seen in the murine model of EAT during pregnancy by mating with a male green mouse.

To more readily detect fetal cells in the thyroid gland, a modified EAT model was developed by mating a susceptible female mouse strain with male "green" mice. This green mouse was engineered to express green fluorescent protein (GFP) in most cells, driven under the control of a ß-actin promoter and a cytomegalovirus enhancer (42). This model has proven to be a useful tool to study chimerism, as chimeric cells can be easily detected by direct observation under the fluorescent microscope. In addition, the frequency and cell type of GFP-expressing cells can be determined by flow cytometry or GFP-PCR. Using male green mice we identified fetal cell microchimerism in the circulation and the thyroid gland of murine Tg-immunized pregnant mice (19) (Fig. 1B), confirming the presence of intact fetal cells and not just DNA fragments.

Intrathyroidal immune fetal cells.

To understand the putative immunological role(s) of fetal cells in EAT, the male-specific SRY DNA fragment was PCR-amplified from the intrathyroidal fetal cells bearing immune markers. This was performed using magnetic beads coated with monoclonal antibodies against a lineage antigen. Male DNA was strongly amplified from CD4⁺ and CD11c⁺ cells, and weakly from CD8⁺, but not from B220/CD45R⁺, CD11b⁺, or Sca-1⁺ cells. These data indicated that intrathyroidal fetal cells obtained during pregnancy included T cell and dendritic cell lineages (19). This direct evidence of immune fetal cell involvement in intrathyroidal fetal microchimerism provided evidence compatible with potential fetal cell-induced modulation of autoimmune thyroiditis during pregnancy and the postpartum. However, functional studies of intrathyroidal fetal immune cells are still needed, and it will be important to monitor any changes in the lineage of intrathyroidal fetal cells during pregnancy and the postpartum.

	Potential immunological role of fetal microchimerism

Top Abstract Introduction Establishing fetal... Cell constituents of fetal... Indirect evidence of fetal... Nonthyroidal diseases AITD and pregnancy Intrathyroidal fetal... An animal model of... Potential immunological role of... Maternal cell microchimerism Summary References

 
Having reviewed several autoimmune diseases associated with tissue fetal microchimerism, including the thyroid, there are a number of potential mechanisms by which fetal immune and nonimmune cells may influence the autoimmune status of the mother. Fetal microchimerism, detected even many years after delivery (2, 3), indicates insufficient elimination of fetal cells secondary to sustained immune tolerance to the fetal graft and by the fetal cells to the host (10). Of course this status may not have been achieved immediately. Hence, when these allogeneic fetal cells take up residence in maternal tissues and remain there after delivery, it is not unreasonable to assume that they should modulate or even initiate early maternal immune responses in a graft vs. host response, especially after loss of the immune suppression of pregnancy. Indeed, the fact that they do not appear to provoke disease in human pregnancy indicates the success of placental immune suppression. However, the accumulating evidence, summarized above, suggests that target tissue fetal microchimerism has the potential for initiating a local immune response after pregnancy. Furthermore, fetal immune cells seem immunologically competent (30). Thus, we hypothesize that such cells may modulate AITD in the postpartum (17). This concept is illustrated in Fig. 2. A maternal antigen(s) may be presented from either fetus to mother or vice versa by graft vs. host reactions and also by bystander mechanisms, as seen in other situations (43). This may initiate and/or exacerbate AITD. However, as most of the evidence of immune competency of fetal cells within an autoimmune target has been obtained from the study of patients with scleroderma, it remains possible that intrathyroidal fetal cells, even immune cells, are only the reflection of an ongoing local immune reaction and thus do not participate in modulation or initiation of AITD.

View larger version (35K): [in this window] [in a new window]   FIG. 2. Hypothetical mechanism by which fetal cells modulate AITD postpartum. A, Fetal microchimerism is established during pregnancy by placental immune suppression. The mechanism that attracts fetal immune cells to migrate into the maternal thyroid gland has not been studied. Cytokines, chemokines, and adherent factors may be involved (19 ). B, Due to placental immune suppression, immunological interaction between maternal and fetal immune cells should be minimal and/or neglectful. C, After delivery, partially sustained immunosuppressive effects (10 ) facilitate the survival of fetal cells, and loss of placental immune suppression activates intrathyroidal fetal immune cells. D, Activated fetal immune cells initiate graft vs. host reaction against maternal antigens by secreting immunomodulatory cytokines and/or expressing immunomodulatory molecules, which activates intrathyroidal maternal autoreactive T cells and eventually initiates and/or exacerbates AITD postpartum.

	Maternal cell microchimerism

Top Abstract Introduction Establishing fetal... Cell constituents of fetal... Indirect evidence of fetal... Nonthyroidal diseases AITD and pregnancy Intrathyroidal fetal... An animal model of... Potential immunological role of... Maternal cell microchimerism Summary References

	Summary

Top Abstract Introduction Establishing fetal... Cell constituents of fetal... Indirect evidence of fetal... Nonthyroidal diseases AITD and pregnancy Intrathyroidal fetal... An animal model of... Potential immunological role of... Maternal cell microchimerism Summary References

 
We have reviewed fetal microchimerism as it occurs naturally and in the context of autoimmune conditions, including AITD. Accumulating evidence suggests a possible role(s) for fetal cells in modulating autoimmune disease, and one of the most important issues to be addressed is whether intrathyroidal fetal microchimerism impacts human postpartum thyroiditis. Based on our model of murine EAT, our data suggest that intrathyroidal fetal microchimerism may be involved in precipitation of the postpartum thyroid diseases, and it will be important to determine the kind of fetal cell interactions performing this modulatory role.

	Footnotes

Abbreviations: AITD, Autoimmune thyroid disease; EAT, experimental autoimmune thyroiditis; FISH, fluorescent in situ hybridization; GFP, green fluorescent protein; GvHD, graft vs. host disease; HLA, human leukocyte antigen; MHC, major histocompatibility complex; PBC, primary biliary cirrhosis; SRY, sex-determining region Y; Tg, thyroglobulin; Th, T helper; TPO, thyroid peroxidase; TSHR, TSH receptor.

Received December 4, 2002.

Accepted March 28, 2003.

	References

Top Abstract Introduction Establishing fetal... Cell constituents of fetal... Indirect evidence of fetal... Nonthyroidal diseases AITD and pregnancy Intrathyroidal fetal... An animal model of... Potential immunological role of... Maternal cell microchimerism Summary References

 

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