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Pathophysiology of fetal microchimeric cells
Clinica Chimica Acta 360 (2005) 1 – 8 www.elsevier.com/locate/clinchim
Review
Pathophysiology of fetal microchimeric cells Carol M. Artlett* Division of Rheumatology, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA Received 9 December 2004; received in revised form 8 February 2005; accepted 11 April 2005 Available online 24 June 2005
Abstract Microchimerism has been defined by the presence of a low number of circulating cells transferred from one individual to another. The transfer of microchimeric cells naturally takes place during pregnancy and occurs bi-directionally between the mother and fetus. Further, microchimerism can also be a result of blood transfusions and organ transplants. Microchimeric cells have been implicated in health and disease. Fetal microchimerism has been correlated with the hyporesponsiveness of the maternal immune system towards a fetal allograft and with the longevity of organ transplants. However, microchimeric cells have been implicated in the pathogenesis of autoimmune diseases including systemic sclerosis. In contrast, microchimeric cells were found to contribute to tissue repair. Much controversy exists around the role of microchimeric cells in the pathogenesis of certain diseases, and these cells in tissues may be a consequence rather than the cause of disease. D 2005 Elsevier B.V. All rights reserved. Keywords: Microchimerism; Autoimmune disease; Fetal cells; Prenatal diagnosis; Organ transplantation; Transfusion
Contents 1. Fetal microchimerism and pregnancy . . . . . . . . . . . . . . . . . 2. Fetal microchimerism may contribute to some diseases of pregnancy 3. Fetal microchimerism and autoimmune diseases . . . . . . . . . . . 4. The microchimeric mouse . . . . . . . . . . . . . . . . . . . . . . 5. Fetal microchimerism and tissue repair . . . . . . . . . . . . . . . . 6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Fetal microchimerism and pregnancy
* Tel.: +1 215 503 5700; fax: +1 215 923 4649. E-mail address: [email protected]. 0009-8981/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.cccn.2005.04.019
The trafficking of fetal cells into the maternal circulation starts very early during pregnancy at approximately 4 weeks gestation [1]. A greater number of
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fetal cells transfer into the maternal circulation than do maternal cells into the fetal circulation [2,3]. A critical threshold of the numbers of fetal cells in the maternal circulation may be necessary for the establishment and maintenance of the pregnancy. Not enough fetal cells and the pregnancy is aborted, or, too many fetal cells may be predictive of pregnancy complications later in gestation and may predispose to autoimmune diseases. Indeed, the fetus, due to paternal HLA cell surface antigens, is a foreign entity. However, this natural allograft is not normally rejected by the maternal immune system due to antibodies that are generated against the paternally inherited HLA antigens on her fetus. Studies in mice suggest that there is clonal deletion in the immune system during gestation. This deletion serves as a mechanism for specific peripheral antigen-specific tolerance to the fetus [4]. This study suggested that there are several mechanisms of peripheral tolerance during gestation and that the maternal immune cells, which are not clonally deleted, become unresponsive to the antigenic challenge of the fetal microchimeric cells [4]. Detection of fetal cells in the maternal circulation has clinical significance as it has been employed for non-invasive prenatal diagnosis. It is frequently used to determine fetal gender and inherited genetic disorders. Analysis of fetal cells in the maternal circulation is labor intensive and requires enrichment techniques such as ficoll density gradients, with subsequent magnetic cell sorting [5,6]. However, residual fetal cells from a previous pregnancy can cause a false-positive result, as some fetal cells are long-lived [7]. The exchange of fetal microchimeric cells between non-HLA identical twins is a common event and was first described in bovines [8]. Approximately 8% of human twin pregnancies and 21% of triplets are chimeric in their blood cell populations from their siblings [9]. Investigations employing mixed lymphocyte reactions have shown that twins are non-reactive towards each other, even when the chimeric cell population from the twin is approximately 10%, whereas, a normal response towards cells from other individuals remains [10]. Microchimeric cells from a previous pregnancy may influence the gender of a subsequent pregnancy. This may reflect the antibody response towards the microchimeric cells from the current pregnancy. Of interest, the sex of previous offspring appears to influ-
ence the sex of subsequent offspring. In 16 families whose first offspring was a son, the next offspring was found to be a daughter 75% of cases [11]. Furthermore, studies suggest that in male offspring, there is a sexcorrelated difference of parentally transmitted HLA alleles, when compared to female offspring [12]. Therefore, it has been suggested that the sharing of paternal HLA antigens between brothers may contribute to a decreased maternal immune response to malespecific H-Y fetal antigen on microchimeric cells [11]; however, it has been demonstrated by mixed lymphocyte reactions that women are still more reactive towards their male offspring as opposed to their female offspring [13,14].
2. Fetal microchimerism may contribute to some diseases of pregnancy Instances of increased numbers of microchimeric fetal cells have been identified in pre-term labor [15], pre-eclampsia [16–18] and aneuploidy [19,20]. However, there is speculation that the increased number of fetal microchimeric cells in the maternal circulation is a reflection of the abnormalities within the structure of the placenta, and not directly related to the disease process. The concentration of microchimeric fetal DNA was found to be higher in women who had pre-term labor when compared to women without pre-term labor [15]. In women with threatened pre-term labor that were successfully treated by tocolysis there was a lower concentration of fetal DNA compared to women who did not respond to treatment [15]. This suggests that higher concentrations of fetal DNA prior to a spontaneous pre-term delivery may differentiate between true and false pre-term labor [15]. Pre-eclampsia is a multisystem disorder specific to pregnancy. Women with pre-eclampsia also have increased circulating fetal cells [16,17,21]. The pathogenesis of pre-eclampsia is not understood, but is widely accepted that vascular endothelial dysfunction with poor placentation are the cause. In patients, matched for gestational age, the concentration of microchimeric cells in women with pre-eclampsia was found to be five times greater than in women without pre-eclampsia [16]. Furthermore, the increase in circulating fetal cells was detected early in gesta-
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tion, prior to clinical manifestations of the disease [17]. In some aneuploid pregnancies, there are placental vasculature and hematological abnormalities [22]. This hypothesis was confirmed when Bianchi et al. found fetal cells to be elevated in women with some forms of aneuploid pregnancies [19]. It was found that women who were carrying male fetuses with the karyotypes 47,XY,21 and 47,XY,+inv(dup)15 had higher numbers of fetal microchimeric cells than women who were carrying normal karyotype fetuses [19]. In addition, women carrying the 47,XY,+18, or the 47, XXY karyotypes did not have an increased number of fetal cells [19]. Polymorphic eruptions of pregnancy generally occur after 34 weeks gestation and present as pruritic, non-follicular erythematous papules on the abdomen, arms, buttocks and thighs. The histology of the eruptions demonstrates a perivascular lymphocytic infiltration in the dermis. These lesions heal spontaneously after pregnancy but can recur in subsequent pregnancies. Aractingi et al. [23] detected male fetal cells in the dermis and epidermis from skin lesions of pregnant women with polymorphic eruptions of pregnancy [23]. This suggests that fetal cells in some instances can be involved in a short-lived inflammatory response in the maternal tissues. It has been postulated that women with recurrent spontaneous abortion (RSA) do not receive adequate numbers of microchimeric fetal cells during their pregnancy to retain the fetus. Antibodies against fetal HLA antigens are frequently observed in the sera of multiparous women [24,25] and antibodies directed against maternal HLA antigens have been demonstrated in some offspring [26]. Reed et al. [27] found that pregnant women produce antibodies against some mismatched HLA antigens of the fetus as early as the eighth week of pregnancy and that these antibodies were found to be complexed with soluble HLA alloantigens. It was speculated that the exposure of the maternal immune system to allogeneic antigens on fetal microchimeric cells would produce lymphocytotoxic antibodies and that these antibodies are required to retain the fetus [28]. Furthermore, these antibodies were found to decrease during pregnancy, presumably due to the antibodies binding to the placenta, to circulating fetal cells, and/or to soluble antigen [28]. The etiology of RSA remains unknown, however, women
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with RSA have been successfully treated with killed paternal leukocytes [28]. Pre-immunization titers of maternal anti-paternal antibodies in women with RSA are frequently found to be negative [28]. Subsequently, post-immunization titers in women with RSA who successfully carried a fetus to term were found to be positive [28]. The timing of the immunization with paternal leukocytes also appears to be critical, as treatment of women with RSA in the third week of gestation increased the success rate to 94% for retaining the fetus compared to 58% with 1–3 immunizations prior to pregnancy [29].
3. Fetal microchimerism and autoimmune diseases Recently, microchimerism has been implicated in the pathogenesis of some autoimmune diseases such as systemic sclerosis (SSc) to its similarity with GVHD. However, it has not yet been determined if these cells are integrally involved in the pathogenesis of SSc, or if fetal microchimeric cells are just a marker of inflammation. GVHD occurs when T-cells present in transplanted donor bone marrow or other tissues or in transfused blood react with the recipient’s cell surface antigens. HLA disparities, the immunologic competence of the host, and the numbers and characteristics of the T-cells in the graft are factors that play an important role in the development of GVHD [30]. In the case of SSc, the fetal microchimeric cells are immunologically competent and have been found to express CD3 [31] and CD4 [32], the host appears foreign to these cells in HLA class I [33,34], and the host is incapable of mounting an immune response to these cells, most likely due to tolerance established during gestation. Scott Pereira first proposed that fetal microchimeric cells might be involved in SSc [35,36]. In publications by Black and Stevens, and Silman and Black, he was quoted as stating that bScleroderma has been postulated as a type of chronic GVHD resulting from transplacental transfer of cells between mother and fetus [35] and that b. . . this could lead to a state of microchimerism and activation of such cells to cause a chronic GVHD-type of diseaseQ [36]. Subsequently, other investigators [37] proposed and demonstrated the involvement of fetal cells in the pathogenesis of SSc but it was not until the discovery of the presence
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of male fetal cells in a normal woman 27 years after the birth of her infant [38] that the involvement of fetal cells in SSc was given credence [39]. SSc is a complex heterogeneous disease with similarities to GVHD [40–42]. It is characterized by humoral and cell-mediated immune responses against constituents of the body’s own tissues. SSc and chronic GVHD closely resemble each other and it has been speculated that SSc may be a form of GVHD [31,34– 36,40,41,43,44]. Skin, lung, and esophageal involvement [45–47], with lymphocytic infiltration into the affected tissues [45,48,49], cytokine abnormalities [50–53], and fibrosis in the dermis and lungs [54] are all prominent features of both SSc and GVHD. The activation of the immune system is an early event in both SSc and chronic GVHD, and T cells are central to the development of tissue damage and dominate the inflammatory infiltrates [55,56]. Microchimeric cells of fetal origin have been identified in the peripheral blood of patients with SSc [31,34]. However, if microchimeric cells are involved in the disease process, it is important to demonstrate the presence of these cells in the lesions [31]. These results indicated that non-autologous cells might be mediating a GVHD-like reaction in patients with SSc and the presence of Y chromosome DNA correlated with a history of having male offspring. Fetal microchimeric cells isolated from the peripheral blood of women with SSc were found to express CD3 [31]. Furthermore, analysis of microchimerism in the CD4+ and CD8+ T cell populations revealed that SSc patients had significantly more microchimeric CD4+ T cells but not CD8+ T cells compared to the controls [32]. There is speculation that the microchimeric CD4+ and CD8+ T cells are activated and express the IL-2 receptor and therefore would have undergone clonal expansion. Studies investigating the TCR repertoire in the microchimeric cells will need to be performed to determine whether these cells are indeed activated in SSc. Studies have also demonstrated that microchimeric CD4+ and CD8+ cells are involved in GVHD responses and these cells are found in skin lesions from individuals who developed GVHD following a bone marrow transplantation [57– 59]. The presence of microchimerism in these functionally different cell populations supports the hypothesis that SSc may represent a GVHD-like response mediated by activated fetal microchimeric T cells.
Women with SSc are more likely to have HLA class II compatible offspring than controls, suggesting that there is tolerance to the fetal microchimeric cell [33]. Scaletti et al., in an elegant study, demonstrated that male-derived fetal microchimeric T cell clones isolated from an active lesion from a patients with SSc were primarily TH2 in origin and reacted with maternal HLA antigens [60]. If microchimeric cells are involved in the pathogenesis of SSc and other autoimmune diseases, it is possible that the microchimeric cells have become activated by a subsequent event such as, for example, an environmental exposure (viral, chemical, or other factor). Once activated, the fetal cells would traffic to the skin and may initiate a cascade of events including the recruitment of autologous cells through the secretion of pro-inflammatory cytokines resulting in the fibro-proliferative and vascular alterations, which are typical of SSc. Stastny et al. [61] reported the first animal model for SSc by characterizing GVHD in a mouse. The model was established by injecting immunologically tolerant neonatal rats with allogeneic lymphoid cells. The resulting severe dermal fibrosis displayed similarities to the histopathological skin changes characteristic of human SSc. Sjogren’s syndrome and SLE studies identified fetal cells in the peripheral blood in some patients but were unable to demonstrate a strong association between microchimeric cells and these diseases [62,63]. Interestingly, in one study, microchimeric cells were not identified in the salivary gland of patients with Sjogren’s syndrome but were only identified in the salivary glands of patients with SSc who had Sjogren’s secondary to their disease [64]. Fetal microchimeric cells were detected in the liver of patients with PBC, however microchimeric cells were also frequently found in the liver of control individuals and therefore this finding remains unclear [65]. A study by Liegeois et al., in mice demonstrated that the liver is a natural repository for fetal microchimeric cells [66]. To clarify the involvement of microchimeric cells in PBC, activation and functional studies on these microchimeric cells are required. It is also possible that fetal microchimeric cells could be involved in thyroid disease, which occurs in 10% of all women in the early postpartum period. Furthermore, up to 60% of reproductive Grave’s patients report onset in the postpartum period [67].
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Indeed, the presence of fetal microchimerism was identified in Hashimoto’s thyroiditis but not in patients with nodular goiters [68]. In studies of patients with SSc, it appears that a pregnancy is protective for the disease and delays onset [69,70]. Within this hypothesis, the etiology of SSc in non-pregnant women is unclear, however, there is speculation that maternal microchimeric cells are driving the disease. Given the more severe clinical course and progression of SSc in non-pregnant women and in males, our results would suggest that the activated maternal microchimeric cells are more aggressive or require a lower threshold of stimulation to become activated [69].
4. The microchimeric mouse In an attempt to elucidate the correlation between SSc and fetal microchimerism, a mouse model for SSc that integrally involved the presence of fetal cells was developed [71]. Retired female mice bred to generate H-2K genetic crosses were used. PCR analysis for the paternal H-2Kb allele demonstrated a 48-fold increase in the fetal cells in the peripheral blood after the vinyl chloride treatment [71]. Histopathological changes were associated with the increase in fetal cells and the mice developed cutaneous inflammatory changes, fibrosis and splenomegaly. Furthermore, the fibrosis displayed similarities to the fibrosis observed in SSc or chronic GVHD. These histopathological changes were absent in virgin mice injected with vinyl chloride [71].
5. Fetal microchimerism and tissue repair The possibility that fetal cells may have a beneficial effect role rather than a detrimental one was demonstrated in an elegant study by Wang et al. [72]. Wang et al. employed rats that had been bred to GFP males. Ethanol and gentamycin were used to induce injury in liver and kidney of the post-partum females. Wang et al. found that fetal cells were engrafted into the bone marrow with resulting detection of these cells in the peripheral blood of the rats. This study also demonstrated that the engrafted GFPpositive fetal cells were hepatocytes in the liver and
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tubular epithelial cells in the kidney [72]. The fetal cells in the liver were found to express albumin confirming that they were hepatocytes. Furthermore, Wang et al. observed fetal cells expressing GFP in the cytoplasm of cells in the tubular basement membrane. The GFP-positive cells were not found in the organs of the rats that were not injured. These findings suggest that in a state where the tissue injury is chronic, fetal cell microchimerism may be established more frequently, or more easily, and also suggests that microchimeric cells are involved in tissue repair.
6. Conclusion The roles that microchimeric cells potentially play in disease of pregnancy, transplantation, autoimmune disease, and tissue repair are yet to be fully elucidated. The immune system appears to require microchimeric cells for the maintenance of a pregnancy; however, this may result in the activation of the microchimeric cells later in life and lead to the establishment of an autoimmune disease. These findings suggest that the immunopathogenesis in some autoimmune diseases may involve differentiation and activation of foreign cells from a pregnancy remote in time and that these cells are then able to initiate GVHD. These microchimeric cells have persisted either as stem cells or as inactive lymphocytes. If microchimeric cells are involved in the pathogenesis of autoimmune diseases, why some individuals have one autoimmune disease and not another, is yet to be understood. Breakdown of tolerance of the microchimeric cell towards the recipient, caused by an undetermined event, probably environmental in origin, could result in the activation of these cells to cause an allograft reaction, which manifests clinically as SSc or another autoimmune disease. Currently, we do not know whether the increased frequency of microchimeric cells in the autoimmune patient is due to the expression of pro-inflammatory cytokines that drive a generalized inflammatory response in that patient, or whether microchimeric cells are elevated due to specific activation of these cells recognizing recipient HLA antigens, or if they are aiding in tissue repair. Further studies will need to be performed to clarify the role of the microchi-
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meric cells within lesions and its involvement in the pathogenesis of autoimmune diseases.
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[54] Janin-Mercier A, Devergie A, van Cauwenberge D, Bourges M, Lapiere ChM, Guckman E. Immunohistologic and ultrastructural study of the sclerotic skin in chronic graft-versus-host disease in man. Am J Pathol 1984;115: 296 – 306. [55] Roumm AD, Whiteside TL, Medsger TA, Rodnan GP. Lymphocytes in the skin of patients with progressive systemic sclerosis. Quantification, subtyping, and clinical correlations. Arthritis Rheum 1984;27:645 – 53. [56] Saurat JH, Piguet PF. Human and murine cutaneous graftversus-host diseases. Potential models for the study of immunologically mediated skin diseases. Br J Dermatol 1984; 111(Suppl. 27):213 – 8. [57] Gaschet J, Trevino MA, Cherel M, et al. HLA-target antigens and T-cell receptor diversity of activated T cells invading the skin during graft-versus-host disease. Blood 1996;87:2345 – 53. [58] Schultz KR, Paquet J, Bader S, HayGlass KT. Requirement for B cells in T cell priming to minor histocompatibility antigens and development of graft-versus-host disease. Bone Marrow Transplant 1995;16:289 – 95. [59] Datta AR, Barrett AJ, Jiang YZ, et al. Distinct T cell populations distinguish chronic myeloid leukaemia cells from lymphocytes in the same individual: a model for separating GVHD from GVL reactions. Bone Marrow Transplant 1994;14:517 – 24. [60] Scaletti C, Vultaggio A, Bonifacio S, et al. TH2-Oriented profile of male offspring T cells present in women with systemic sclerosis and reactive with maternal major histocompatibility complex antigens. Arthritis Rheum 2002;46:445 – 50. [61] Stastny P, Stembridge VA, Ziff M. Homologous disease in the adult rat, a model for autoimmune disease. Ann NY Acad Sci 1965;124:158 – 61. [62] Toda I, Kuwana M, Tsubota K, Kawakami Y. Lack of evidence for increased microchimerism in the circulation of patients with Sjogren’s syndrome. Ann Rheum Dis 2001; 60:248 – 53. [63] Miyashita Y, Ono M, Ueki H, Kurasawa K. Y chromosome microchimerism in rheumatic autoimmune disease. Ann Rheum Dis 2000;59:655 – 6. [64] Aractingi S, Sibilia J, Meignin V, et al. Presence of microchimerism in labial salivary glands in systemic sclerosis but not in Sjogren’s syndrome. Arthritis Rheum 2002;46:1039 – 43. [65] Tanaka A, Lindor K, Gish R, et al. Fetal microchimerism alone does not contribute to the induction of primary biliary cirrhosis. Hepatology 1999;30:833 – 8. [66] Liegeois A, Gaillard MC, Ouvre E, Lewin D. Microchimerism in pregnant mice. Transplant Proc 1981;XIII:1250 – 2. [67] Davies TF. The thyroid immunology of the postpartum period. Thyroid 1999;9:675 – 84. [68] Klintschar M, Schwaiger P, Mannweiler S, Regauer S, Kleiber M. Evidence of fetal microchimerism in Hashimoto’s thyroiditis. J Clin Endocrinol Metab 2001;86:2494 – 8. [69] Artlett CM, Rasheed M, Russo-Stieglitz KE, Sawaya HHB, Jimenez SA. Influence of prior pregnancies on disease course and cause of death in systemic sclerosis. Ann Rheum Dis 2002;61:346 – 50.
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[70] Pisa FE, Bovenzi M, Romeo L, et al. Reproductive factors and the risk of scleroderma. Arthritis Rheum 2002;46: 51 – 456. [71] Christner PJ, Artlett CM, Conway RF, Jimenez SA. Increased numbers of microchimeric cells of fetal origin and dermal
fibrosis in mice following injection of vinyl chloride. Arthritis Rheum 2000;43:2598 – 605. [72] Wang Y, Iwatani H, Ito T, et al. Fetal cells in mother rats contribute to the remodeling of liver and kidney after injury. Biochem Biophys Res Commun 2004;325:961 – 7.
Review
Pathophysiology of fetal microchimeric cells Carol M. Artlett* Division of Rheumatology, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA Received 9 December 2004; received in revised form 8 February 2005; accepted 11 April 2005 Available online 24 June 2005
Abstract Microchimerism has been defined by the presence of a low number of circulating cells transferred from one individual to another. The transfer of microchimeric cells naturally takes place during pregnancy and occurs bi-directionally between the mother and fetus. Further, microchimerism can also be a result of blood transfusions and organ transplants. Microchimeric cells have been implicated in health and disease. Fetal microchimerism has been correlated with the hyporesponsiveness of the maternal immune system towards a fetal allograft and with the longevity of organ transplants. However, microchimeric cells have been implicated in the pathogenesis of autoimmune diseases including systemic sclerosis. In contrast, microchimeric cells were found to contribute to tissue repair. Much controversy exists around the role of microchimeric cells in the pathogenesis of certain diseases, and these cells in tissues may be a consequence rather than the cause of disease. D 2005 Elsevier B.V. All rights reserved. Keywords: Microchimerism; Autoimmune disease; Fetal cells; Prenatal diagnosis; Organ transplantation; Transfusion
Contents 1. Fetal microchimerism and pregnancy . . . . . . . . . . . . . . . . . 2. Fetal microchimerism may contribute to some diseases of pregnancy 3. Fetal microchimerism and autoimmune diseases . . . . . . . . . . . 4. The microchimeric mouse . . . . . . . . . . . . . . . . . . . . . . 5. Fetal microchimerism and tissue repair . . . . . . . . . . . . . . . . 6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Fetal microchimerism and pregnancy
* Tel.: +1 215 503 5700; fax: +1 215 923 4649. E-mail address: [email protected]. 0009-8981/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.cccn.2005.04.019
The trafficking of fetal cells into the maternal circulation starts very early during pregnancy at approximately 4 weeks gestation [1]. A greater number of
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fetal cells transfer into the maternal circulation than do maternal cells into the fetal circulation [2,3]. A critical threshold of the numbers of fetal cells in the maternal circulation may be necessary for the establishment and maintenance of the pregnancy. Not enough fetal cells and the pregnancy is aborted, or, too many fetal cells may be predictive of pregnancy complications later in gestation and may predispose to autoimmune diseases. Indeed, the fetus, due to paternal HLA cell surface antigens, is a foreign entity. However, this natural allograft is not normally rejected by the maternal immune system due to antibodies that are generated against the paternally inherited HLA antigens on her fetus. Studies in mice suggest that there is clonal deletion in the immune system during gestation. This deletion serves as a mechanism for specific peripheral antigen-specific tolerance to the fetus [4]. This study suggested that there are several mechanisms of peripheral tolerance during gestation and that the maternal immune cells, which are not clonally deleted, become unresponsive to the antigenic challenge of the fetal microchimeric cells [4]. Detection of fetal cells in the maternal circulation has clinical significance as it has been employed for non-invasive prenatal diagnosis. It is frequently used to determine fetal gender and inherited genetic disorders. Analysis of fetal cells in the maternal circulation is labor intensive and requires enrichment techniques such as ficoll density gradients, with subsequent magnetic cell sorting [5,6]. However, residual fetal cells from a previous pregnancy can cause a false-positive result, as some fetal cells are long-lived [7]. The exchange of fetal microchimeric cells between non-HLA identical twins is a common event and was first described in bovines [8]. Approximately 8% of human twin pregnancies and 21% of triplets are chimeric in their blood cell populations from their siblings [9]. Investigations employing mixed lymphocyte reactions have shown that twins are non-reactive towards each other, even when the chimeric cell population from the twin is approximately 10%, whereas, a normal response towards cells from other individuals remains [10]. Microchimeric cells from a previous pregnancy may influence the gender of a subsequent pregnancy. This may reflect the antibody response towards the microchimeric cells from the current pregnancy. Of interest, the sex of previous offspring appears to influ-
ence the sex of subsequent offspring. In 16 families whose first offspring was a son, the next offspring was found to be a daughter 75% of cases [11]. Furthermore, studies suggest that in male offspring, there is a sexcorrelated difference of parentally transmitted HLA alleles, when compared to female offspring [12]. Therefore, it has been suggested that the sharing of paternal HLA antigens between brothers may contribute to a decreased maternal immune response to malespecific H-Y fetal antigen on microchimeric cells [11]; however, it has been demonstrated by mixed lymphocyte reactions that women are still more reactive towards their male offspring as opposed to their female offspring [13,14].
2. Fetal microchimerism may contribute to some diseases of pregnancy Instances of increased numbers of microchimeric fetal cells have been identified in pre-term labor [15], pre-eclampsia [16–18] and aneuploidy [19,20]. However, there is speculation that the increased number of fetal microchimeric cells in the maternal circulation is a reflection of the abnormalities within the structure of the placenta, and not directly related to the disease process. The concentration of microchimeric fetal DNA was found to be higher in women who had pre-term labor when compared to women without pre-term labor [15]. In women with threatened pre-term labor that were successfully treated by tocolysis there was a lower concentration of fetal DNA compared to women who did not respond to treatment [15]. This suggests that higher concentrations of fetal DNA prior to a spontaneous pre-term delivery may differentiate between true and false pre-term labor [15]. Pre-eclampsia is a multisystem disorder specific to pregnancy. Women with pre-eclampsia also have increased circulating fetal cells [16,17,21]. The pathogenesis of pre-eclampsia is not understood, but is widely accepted that vascular endothelial dysfunction with poor placentation are the cause. In patients, matched for gestational age, the concentration of microchimeric cells in women with pre-eclampsia was found to be five times greater than in women without pre-eclampsia [16]. Furthermore, the increase in circulating fetal cells was detected early in gesta-
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tion, prior to clinical manifestations of the disease [17]. In some aneuploid pregnancies, there are placental vasculature and hematological abnormalities [22]. This hypothesis was confirmed when Bianchi et al. found fetal cells to be elevated in women with some forms of aneuploid pregnancies [19]. It was found that women who were carrying male fetuses with the karyotypes 47,XY,21 and 47,XY,+inv(dup)15 had higher numbers of fetal microchimeric cells than women who were carrying normal karyotype fetuses [19]. In addition, women carrying the 47,XY,+18, or the 47, XXY karyotypes did not have an increased number of fetal cells [19]. Polymorphic eruptions of pregnancy generally occur after 34 weeks gestation and present as pruritic, non-follicular erythematous papules on the abdomen, arms, buttocks and thighs. The histology of the eruptions demonstrates a perivascular lymphocytic infiltration in the dermis. These lesions heal spontaneously after pregnancy but can recur in subsequent pregnancies. Aractingi et al. [23] detected male fetal cells in the dermis and epidermis from skin lesions of pregnant women with polymorphic eruptions of pregnancy [23]. This suggests that fetal cells in some instances can be involved in a short-lived inflammatory response in the maternal tissues. It has been postulated that women with recurrent spontaneous abortion (RSA) do not receive adequate numbers of microchimeric fetal cells during their pregnancy to retain the fetus. Antibodies against fetal HLA antigens are frequently observed in the sera of multiparous women [24,25] and antibodies directed against maternal HLA antigens have been demonstrated in some offspring [26]. Reed et al. [27] found that pregnant women produce antibodies against some mismatched HLA antigens of the fetus as early as the eighth week of pregnancy and that these antibodies were found to be complexed with soluble HLA alloantigens. It was speculated that the exposure of the maternal immune system to allogeneic antigens on fetal microchimeric cells would produce lymphocytotoxic antibodies and that these antibodies are required to retain the fetus [28]. Furthermore, these antibodies were found to decrease during pregnancy, presumably due to the antibodies binding to the placenta, to circulating fetal cells, and/or to soluble antigen [28]. The etiology of RSA remains unknown, however, women
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with RSA have been successfully treated with killed paternal leukocytes [28]. Pre-immunization titers of maternal anti-paternal antibodies in women with RSA are frequently found to be negative [28]. Subsequently, post-immunization titers in women with RSA who successfully carried a fetus to term were found to be positive [28]. The timing of the immunization with paternal leukocytes also appears to be critical, as treatment of women with RSA in the third week of gestation increased the success rate to 94% for retaining the fetus compared to 58% with 1–3 immunizations prior to pregnancy [29].
3. Fetal microchimerism and autoimmune diseases Recently, microchimerism has been implicated in the pathogenesis of some autoimmune diseases such as systemic sclerosis (SSc) to its similarity with GVHD. However, it has not yet been determined if these cells are integrally involved in the pathogenesis of SSc, or if fetal microchimeric cells are just a marker of inflammation. GVHD occurs when T-cells present in transplanted donor bone marrow or other tissues or in transfused blood react with the recipient’s cell surface antigens. HLA disparities, the immunologic competence of the host, and the numbers and characteristics of the T-cells in the graft are factors that play an important role in the development of GVHD [30]. In the case of SSc, the fetal microchimeric cells are immunologically competent and have been found to express CD3 [31] and CD4 [32], the host appears foreign to these cells in HLA class I [33,34], and the host is incapable of mounting an immune response to these cells, most likely due to tolerance established during gestation. Scott Pereira first proposed that fetal microchimeric cells might be involved in SSc [35,36]. In publications by Black and Stevens, and Silman and Black, he was quoted as stating that bScleroderma has been postulated as a type of chronic GVHD resulting from transplacental transfer of cells between mother and fetus [35] and that b. . . this could lead to a state of microchimerism and activation of such cells to cause a chronic GVHD-type of diseaseQ [36]. Subsequently, other investigators [37] proposed and demonstrated the involvement of fetal cells in the pathogenesis of SSc but it was not until the discovery of the presence
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of male fetal cells in a normal woman 27 years after the birth of her infant [38] that the involvement of fetal cells in SSc was given credence [39]. SSc is a complex heterogeneous disease with similarities to GVHD [40–42]. It is characterized by humoral and cell-mediated immune responses against constituents of the body’s own tissues. SSc and chronic GVHD closely resemble each other and it has been speculated that SSc may be a form of GVHD [31,34– 36,40,41,43,44]. Skin, lung, and esophageal involvement [45–47], with lymphocytic infiltration into the affected tissues [45,48,49], cytokine abnormalities [50–53], and fibrosis in the dermis and lungs [54] are all prominent features of both SSc and GVHD. The activation of the immune system is an early event in both SSc and chronic GVHD, and T cells are central to the development of tissue damage and dominate the inflammatory infiltrates [55,56]. Microchimeric cells of fetal origin have been identified in the peripheral blood of patients with SSc [31,34]. However, if microchimeric cells are involved in the disease process, it is important to demonstrate the presence of these cells in the lesions [31]. These results indicated that non-autologous cells might be mediating a GVHD-like reaction in patients with SSc and the presence of Y chromosome DNA correlated with a history of having male offspring. Fetal microchimeric cells isolated from the peripheral blood of women with SSc were found to express CD3 [31]. Furthermore, analysis of microchimerism in the CD4+ and CD8+ T cell populations revealed that SSc patients had significantly more microchimeric CD4+ T cells but not CD8+ T cells compared to the controls [32]. There is speculation that the microchimeric CD4+ and CD8+ T cells are activated and express the IL-2 receptor and therefore would have undergone clonal expansion. Studies investigating the TCR repertoire in the microchimeric cells will need to be performed to determine whether these cells are indeed activated in SSc. Studies have also demonstrated that microchimeric CD4+ and CD8+ cells are involved in GVHD responses and these cells are found in skin lesions from individuals who developed GVHD following a bone marrow transplantation [57– 59]. The presence of microchimerism in these functionally different cell populations supports the hypothesis that SSc may represent a GVHD-like response mediated by activated fetal microchimeric T cells.
Women with SSc are more likely to have HLA class II compatible offspring than controls, suggesting that there is tolerance to the fetal microchimeric cell [33]. Scaletti et al., in an elegant study, demonstrated that male-derived fetal microchimeric T cell clones isolated from an active lesion from a patients with SSc were primarily TH2 in origin and reacted with maternal HLA antigens [60]. If microchimeric cells are involved in the pathogenesis of SSc and other autoimmune diseases, it is possible that the microchimeric cells have become activated by a subsequent event such as, for example, an environmental exposure (viral, chemical, or other factor). Once activated, the fetal cells would traffic to the skin and may initiate a cascade of events including the recruitment of autologous cells through the secretion of pro-inflammatory cytokines resulting in the fibro-proliferative and vascular alterations, which are typical of SSc. Stastny et al. [61] reported the first animal model for SSc by characterizing GVHD in a mouse. The model was established by injecting immunologically tolerant neonatal rats with allogeneic lymphoid cells. The resulting severe dermal fibrosis displayed similarities to the histopathological skin changes characteristic of human SSc. Sjogren’s syndrome and SLE studies identified fetal cells in the peripheral blood in some patients but were unable to demonstrate a strong association between microchimeric cells and these diseases [62,63]. Interestingly, in one study, microchimeric cells were not identified in the salivary gland of patients with Sjogren’s syndrome but were only identified in the salivary glands of patients with SSc who had Sjogren’s secondary to their disease [64]. Fetal microchimeric cells were detected in the liver of patients with PBC, however microchimeric cells were also frequently found in the liver of control individuals and therefore this finding remains unclear [65]. A study by Liegeois et al., in mice demonstrated that the liver is a natural repository for fetal microchimeric cells [66]. To clarify the involvement of microchimeric cells in PBC, activation and functional studies on these microchimeric cells are required. It is also possible that fetal microchimeric cells could be involved in thyroid disease, which occurs in 10% of all women in the early postpartum period. Furthermore, up to 60% of reproductive Grave’s patients report onset in the postpartum period [67].
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Indeed, the presence of fetal microchimerism was identified in Hashimoto’s thyroiditis but not in patients with nodular goiters [68]. In studies of patients with SSc, it appears that a pregnancy is protective for the disease and delays onset [69,70]. Within this hypothesis, the etiology of SSc in non-pregnant women is unclear, however, there is speculation that maternal microchimeric cells are driving the disease. Given the more severe clinical course and progression of SSc in non-pregnant women and in males, our results would suggest that the activated maternal microchimeric cells are more aggressive or require a lower threshold of stimulation to become activated [69].
4. The microchimeric mouse In an attempt to elucidate the correlation between SSc and fetal microchimerism, a mouse model for SSc that integrally involved the presence of fetal cells was developed [71]. Retired female mice bred to generate H-2K genetic crosses were used. PCR analysis for the paternal H-2Kb allele demonstrated a 48-fold increase in the fetal cells in the peripheral blood after the vinyl chloride treatment [71]. Histopathological changes were associated with the increase in fetal cells and the mice developed cutaneous inflammatory changes, fibrosis and splenomegaly. Furthermore, the fibrosis displayed similarities to the fibrosis observed in SSc or chronic GVHD. These histopathological changes were absent in virgin mice injected with vinyl chloride [71].
5. Fetal microchimerism and tissue repair The possibility that fetal cells may have a beneficial effect role rather than a detrimental one was demonstrated in an elegant study by Wang et al. [72]. Wang et al. employed rats that had been bred to GFP males. Ethanol and gentamycin were used to induce injury in liver and kidney of the post-partum females. Wang et al. found that fetal cells were engrafted into the bone marrow with resulting detection of these cells in the peripheral blood of the rats. This study also demonstrated that the engrafted GFPpositive fetal cells were hepatocytes in the liver and
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tubular epithelial cells in the kidney [72]. The fetal cells in the liver were found to express albumin confirming that they were hepatocytes. Furthermore, Wang et al. observed fetal cells expressing GFP in the cytoplasm of cells in the tubular basement membrane. The GFP-positive cells were not found in the organs of the rats that were not injured. These findings suggest that in a state where the tissue injury is chronic, fetal cell microchimerism may be established more frequently, or more easily, and also suggests that microchimeric cells are involved in tissue repair.
6. Conclusion The roles that microchimeric cells potentially play in disease of pregnancy, transplantation, autoimmune disease, and tissue repair are yet to be fully elucidated. The immune system appears to require microchimeric cells for the maintenance of a pregnancy; however, this may result in the activation of the microchimeric cells later in life and lead to the establishment of an autoimmune disease. These findings suggest that the immunopathogenesis in some autoimmune diseases may involve differentiation and activation of foreign cells from a pregnancy remote in time and that these cells are then able to initiate GVHD. These microchimeric cells have persisted either as stem cells or as inactive lymphocytes. If microchimeric cells are involved in the pathogenesis of autoimmune diseases, why some individuals have one autoimmune disease and not another, is yet to be understood. Breakdown of tolerance of the microchimeric cell towards the recipient, caused by an undetermined event, probably environmental in origin, could result in the activation of these cells to cause an allograft reaction, which manifests clinically as SSc or another autoimmune disease. Currently, we do not know whether the increased frequency of microchimeric cells in the autoimmune patient is due to the expression of pro-inflammatory cytokines that drive a generalized inflammatory response in that patient, or whether microchimeric cells are elevated due to specific activation of these cells recognizing recipient HLA antigens, or if they are aiding in tissue repair. Further studies will need to be performed to clarify the role of the microchi-
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meric cells within lesions and its involvement in the pathogenesis of autoimmune diseases.
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