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Fetal microchimerism: the cellular and immunological legacy of pregnancy

Published online by Cambridge University Press:  12 November 2009

David M. Lissauer
Affiliation:
Fetal Medicine Centre, Birmingham Women's Foundation Trust and School of Clinical and Experimental Medicine, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham, UK.
Karen P. Piper
Affiliation:
CRUK Institute for Cancer Studies, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham, UK.
Paul A.H. Moss
Affiliation:
CRUK Institute for Cancer Studies, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham, UK.
Mark D. Kilby*
Affiliation:
Fetal Medicine Centre, Birmingham Women's Foundation Trust and School of Clinical and Experimental Medicine, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham, UK.
*
*Corresponding author: Mark D. Kilby, Fetal Medicine Centre, Reproduction and Child Health, Birmingham Women's Hospital, University of Birmingham, Edgbaston, Birmingham, B15 2TG, UK. Tel: +44 121 627 2778; E-mail: [email protected]

Abstract

During pregnancy there is transplacental traffic of fetal cells into the maternal circulation. Remarkably, cells of fetal origin can then persist for decades in the mother and are detectable in the circulation and in a wide range of tissues. Maternal CD8 T cell responses directed against fetal antigens can also be detected following pregnancy. However, the impact that the persistence of allogenic cells of fetal origin and the maternal immune response towards them has on the mother's health remains unclear and is the subject of considerable investigation. The potentially harmful effects of fetal microchimerism include an association with autoimmune disease and recurrent miscarriage. Beneficial effects that have been explored include the contribution of persistent fetal cells to maternal tissue repair. A link between fetal microchimerism and cancer has also been proposed, with some results supporting a protective role and others, conversely, suggesting a role in tumour development. The phenomenon of fetal microchimerism thus provokes many questions and promises to offer further insights not only into the biology of pregnancy but fields such as autoimmunity, transplantation biology and oncology.

Type
Review Article
Copyright
Copyright © Cambridge University Press 2009

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References

References

1Lo, Y.M. et al. (1996) Two-way cell traffic between mother and fetus: biologic and clinical implications. Blood 88, 4390-4395CrossRefGoogle ScholarPubMed
2Douglas, G.W. et al. (1959) Trophoblast in the circulating blood during pregnancy. American Journal of Obstetrics and Gynecology 78, 960-973CrossRefGoogle ScholarPubMed
3Bianchi, D.W. et al. (1996) Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum. Proceedings of the National Academy of Sciences of the United States of America 93, 705-708Google Scholar
4O'Donoghue, K. et al. (2004) Microchimerism in female bone marrow and bone decades after fetal mesenchymal stem-cell trafficking in pregnancy. Lancet 364, 179-182CrossRefGoogle ScholarPubMed
5Liegeois, A. et al. (1977) Microchimerism: a stable state of low-ratio proliferation of allogeneic bone marrow. Transplantation Proceedings 9, 273-276Google Scholar
6Bazopoulou-Kyrkanidou, E. (2001) Chimeric creatures in Greek mythology and reflections in science. American Journal of Medical Genetics 100, 66-80Google Scholar
7Piper, K.P. et al. (2007) Functional HY-Specific CD8+ T Cells are found in a high proportion of women following pregnancy with a male fetus. Biology of Reproduction 76, 96-101Google Scholar
8Verdijk, R.M. et al. (2004) Pregnancy induces minor histocompatibility antigen-specific cytotoxic T cells: implications for stem cell transplantation and immunotherapy. Blood 103, 1961-1964CrossRefGoogle ScholarPubMed
9James, E. et al. (2003) Multiparity induces priming to male-specific minor histocompatibility antigen, HY, in mice and humans. Blood 102, 388-393Google Scholar
10Lo, Y.M. et al. (2000) Quantitative analysis of the bidirectional fetomaternal transfer of nucleated cells and plasma DNA. Clinical Chemistry 46, 1301-1309CrossRefGoogle ScholarPubMed
11Bianchi, D.W. (2007) Robert E. Gross Lecture. Fetomaternal cell trafficking: a story that begins with prenatal diagnosis and may end with stem cell therapy. Journal of Pediatric Surgery 42, 12-18CrossRefGoogle Scholar
12Krabchi, K. et al. (2006) Quantification of all fetal nucleated cells in maternal blood in different cases of aneuploidies. Clinical Genetics 69, 145-154CrossRefGoogle ScholarPubMed
13Guetta, E. et al. (2003) Hematopoietic progenitor cells as targets for non-invasive prenatal diagnosis: detection of fetal CD34+ cells and assessment of post-delivery persistence in the maternal circulation. Blood Cells Molecules and Diseases 30, 13-21CrossRefGoogle ScholarPubMed
14Lim, T.H., Tan, A.S. and Goh, V. H. (2001) Relationship between gestational age and frequency of fetal trophoblasts and nucleated erythrocytes in maternal peripheral blood. Prenatal Diagnosis 21, 14-21Google Scholar
15Bianchi, D.W. et al. (2001) Significant fetal-maternal hemorrhage after termination of pregnancy: implications for development of fetal cell microchimerism. American Journal of Obstetrics and Gynecology 184, 703-706CrossRefGoogle ScholarPubMed
16Zhong, X.Y., Holzgreve, W. and Hahn, S. (2006) Direct quantification of fetal cells in maternal blood by real-time PCR. Prenatal Diagnosis 26, 850-854CrossRefGoogle ScholarPubMed
17Zimmermann, B. et al. (2005) Optimized real-time quantitative PCR measurement of male fetal DNA in maternal plasma. Clinical Chemistry 51, 1598-1604CrossRefGoogle ScholarPubMed
18Lo, Y.M. et al. (1998) Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. American Journal of Human Genetics 62, 768-775CrossRefGoogle ScholarPubMed
19Lambert, N.C. et al. (2002) Male microchimerism in healthy women and women with scleroderma: cells or circulating DNA? A quantitative answer. Blood 100, 2845-2851Google Scholar
20Adams, K.M. et al. (2003) Male DNA in female donor apheresis and CD34-enriched products. Blood 102, 3845-3847Google Scholar
21Lo, Y.M. et al. (1997) Presence of fetal DNA in maternal plasma and serum. Lancet 350, 485-487CrossRefGoogle ScholarPubMed
22Bianchi, D.W. et al. (1997) PCR quantitation of fetal cells in maternal blood in normal and aneuploid pregnancies. American Journal of Human Genetics 61, 822-829CrossRefGoogle ScholarPubMed
23Ohtsuka, T. et al. (2001) Quantitative analysis of microchimerism in systemic sclerosis skin tissue. Archives of Dermatological Research 293, 387-391Google Scholar
24Stevens, A.M. et al. (2004) Liver biopsies from human females contain male hepatocytes in the absence of transplantation. Laboratory Investigation 84, 1603-1609Google Scholar
25Srivatsa, B. et al. (2001) Microchimerism of presumed fetal origin in thyroid specimens from women: a case-control study. Lancet 358, 2034-2038Google Scholar
26Klintschar, M. et al. (2001) Evidence of fetal microchimerism in Hashimoto's thyroiditis. Journal of Clinical Endocrinology and Metabolism 86, 2494-2498Google Scholar
27Klintschar, M. et al. (2006) Fetal microchimerism in Hashimoto's thyroiditis: a quantitative approach. European Journal of Endocrinology 154, 237-241Google Scholar
28Johnson, K.L. et al. (2001) Fetal cell microchimerism in tissue from multiple sites in women with systemic sclerosis. Arthritis and Rheumatism 44, 1848-1854Google Scholar
29Khosrotehrani, K. et al. (2004) Transfer of fetal cells with multilineage potential to maternal tissue. Journal of the Americal Medical Association 292, 75-80CrossRefGoogle ScholarPubMed
30Khosrotehrani, K. et al. (2005) Natural history of fetal cell microchimerism during and following murine pregnancy. Journal of Reproductive Immunology 66, 1-12Google Scholar
31Loubiere, L.S. et al. (2006) Maternal microchimerism in healthy adults in lymphocytes, monocyte/macrophages and NK cells. Laboratory Investigation 86, 1185-1192CrossRefGoogle ScholarPubMed
32Khosrotehrani, K. et al. (2003) The influence of fetal loss on the presence of fetal cell microchimerism: a systematic review. Arthritis and Rheumatism 48, 3237-3241Google Scholar
33Yan, Z. et al. (2005) Male microchimerism in women without sons: quantitative assessment and correlation with pregnancy history. American Journal of Medicine 118, 899-906Google Scholar
34Wang, X. et al. (2003) Conception, early pregnancy loss and time to clinical pregnancy: a population-based prospective study. Fertility and Sterility 79, 577-584Google Scholar
35Holzgreve, W. et al. (1998) Disturbed feto-maternal cell traffic in preeclampsia. Obstetrics and Gynecology 91, 669-672Google ScholarPubMed
36Leung, T.N. et al. (1998) Maternal plasma fetal DNA as a marker for preterm labour. Lancet 352, 1904-1905CrossRefGoogle ScholarPubMed
37Aractingi, S. et al. (1998) Fetal DNA in skin of polymorphic eruptions of pregnancy. Lancet 352, 1898-1901Google Scholar
38Rossi, G. (2004) Nature of stem cell involved in fetomaternal microchimerism. Lancet 364, 1936Google Scholar
39Khosrotehrani, K. et al. (2008) Pregnancy allows the transfer and differentiation of fetal lymphoid progenitors into functional T and B cells in mothers. Journal of Immunology 180, 889-897CrossRefGoogle Scholar
40O'donoghue, K. et al. (2003) Identification of fetal mesenchymal stem cells in maternal blood: implications for non-invasive prenatal diagnosis. Molecular Human Reproduction 9, 497-502Google Scholar
41Tafuri, A. et al. (1995) T cell awareness of paternal alloantigens during pregnancy. Science 270, 630-633Google Scholar
42Constantin, C.M. et al. (2007) Normal establishment of virus-specific memory CD8 T cell pool following primary infection during pregnancy. Journal of Immunology 179, 4383-4389CrossRefGoogle ScholarPubMed
43Nelson, J.L. (2002) Microchimerism: incidental byproduct of pregnancy or active participant in human health? Trends in Molecular Medicine 8, 109-113Google Scholar
44Walker, L.S. and Abbas, A.K. (2002) The enemy within: keeping self-reactive T cells at bay in the periphery. Nature Reviews Immunology 2, 11-19Google Scholar
45Wood, K.J. and Sakaguchi, S. (2003) Regulatory T cells in transplantation tolerance. Nature Reviews Immunology 3, 199-210Google Scholar
46Lubaroff, D.M. and Silvers, W.K. (1973) Importance of chimerism in maintaining tolerance of skin allografts in mice. Journal of Immunology 111, 65-71Google Scholar
47Cosimi, A.B. and Sachs, D.H. (2004) Mixed chimerism and transplantation tolerance. Transplantation 77, 943-946CrossRefGoogle ScholarPubMed
48Ehl, S. et al. (1998) Antigen persistence and time of T-cell tolerization determine the efficacy of tolerization protocols for prevention of skin graft rejection. Nature Medicine 4, 1015-1019CrossRefGoogle ScholarPubMed
49Claas, F. (2004) Chimerism as a tool to induce clinical transplantation tolerance. Current Opinion in Immunology 16, 578-583CrossRefGoogle ScholarPubMed
50Monaco, A.P. (2002) Tolerance and chimerism: separate and unequal concepts. Transplantation Proceedings 34, 1991-1997CrossRefGoogle ScholarPubMed
51Simpson, E., Benjamin, D. and Chandler, P. (1981) Nonresponsiveness to H-Y: tolerance in H-2b mice. Transplantation Proceedings 13, 1880-1883Google Scholar
52Aluvihare, V.R., Kallikourdis, M. and Betz, A.G. (2004) Regulatory T cells mediate maternal tolerance to the fetus. Nature Immunology 5, 266-271Google Scholar
53Somerset, D.A. et al. (2004) Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset. Immunology 112, 38-43Google Scholar
54van Halteren, A.G. et al. (2009) Naturally acquired tolerance and sensitization to minor histocompatibility antigens in healthy family members. Blood 114, 2263-2272CrossRefGoogle ScholarPubMed
55Bonilla, W.V. et al. (2006) Microchimerism maintains deletion of the donor cell-specific CD8+ T cell repertoire. Journal of Clinical Investigation 116, 156-162CrossRefGoogle ScholarPubMed
56Kollman, C. et al. (2001) Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood 98, 2043-2051CrossRefGoogle ScholarPubMed
57Flowers, M.E. et al. (1990) Previous donor pregnancy as a risk factor for acute graft-versus-host disease in patients with aplastic anaemia treated by allogeneic marrow transplantation. British Journal of Haematology 74, 492-496CrossRefGoogle ScholarPubMed
58Mutis, T. et al. (1999) Tetrameric HLA class I-minor histocompatibility antigen peptide complexes demonstrate minor histocompatibility antigen-specific cytotoxic T lymphocytes in patients with graft-versus-host disease. Nature Medicine 5, 839-842Google Scholar
59Dazzi, F. and Goldman, J. (1999) Donor lymphocyte infusions. Current Opinion in Hematology 6, 394-399CrossRefGoogle ScholarPubMed
60Gratwohl, A. et al. (2001) Female donors influence transplant-related mortality and relapse incidence in male recipients of sibling blood and marrow transplants. Hematology Journal 2, 363-370Google Scholar
61Randolph, S.S. et al. (2004) Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched, related hematopoietic stem cell transplants. Blood 103, 347-352CrossRefGoogle ScholarPubMed
62Gahrton, G. et al. (2005) The impact of donor gender on outcome of allogeneic hematopoietic stem cell transplantation for multiple myeloma: reduced relapse risk in female to male transplants. Bone Marrow Transplantation 35, 609-617Google Scholar
63Gratwohl, A. et al. (2008) H-Y as a minor histocompatibility antigen in kidney transplantation: a retrospective cohort study. Lancet 372, 49-53CrossRefGoogle ScholarPubMed
64Rai, R. and Regan, L. (2006) Recurrent miscarriage. Lancet 368, 601-611CrossRefGoogle ScholarPubMed
65Kruse, C. et al. (2004) A study of HLA-DR and -DQ alleles in 588 patients and 562 controls confirms that HLA-DRB1*03 is associated with recurrent miscarriage. Human Reproduction 19, 1215-1221Google Scholar
66Nielsen, H.S. et al. (2008) A firstborn boy is suggestive of a strong prognostic factor in secondary recurrent miscarriage: a confirmatory study. Fertility and Sterility 89, 907-911Google Scholar
67Christiansen, O.B. et al. (2004) Impact of the sex of first child on the prognosis in secondary recurrent miscarriage. Human Reproduction 19, 2946-2951Google Scholar
68Nielsen, H.S. et al. (2009) Association of HY-restricting HLA class II alleles with pregnancy outcome in patients with recurrent miscarriage subsequent to a firstborn boy. Human Molecular Genetics 18, 1684-1691Google Scholar
69Chosidow, O. et al. (1992) Sclerodermatous chronic graft-versus-host disease. Analysis of seven cases. Journal of the American Academy of Dermatology 26, 49-55CrossRefGoogle ScholarPubMed
70Jaffee, B.D. and Claman, H.N. (1983) Chronic graft-versus-host disease (GVHD) as a model for scleroderma. I. Description of model systems. Cellular Immunology. 77, 1-12Google Scholar
71Nelson, J.L. (1996) Maternal-fetal immunology and autoimmune disease: is some autoimmune disease auto-alloimmune or allo-autoimmune? Arthritis and Rheumatism 39, 191-194CrossRefGoogle ScholarPubMed
72Nelson, J.L. et al. (1998) Microchimerism and HLA-compatible relationships of pregnancy in scleroderma. Lancet 351, 559-562CrossRefGoogle ScholarPubMed
73Artlett, C.M., Smith, J.B. and Jimenez, S.A. (1998) Identification of fetal DNA and cells in skin lesions from women with systemic sclerosis. New England Journal of Medicine 338, 1186-1191Google Scholar
74Ichikawa, N. et al. (2001) Microchimerism in Japanese patients with systemic sclerosis. Arthritis and Rheumatism 44, 1226-12283.0.CO;2-Q>CrossRefGoogle ScholarPubMed
75McNallan, K.T. et al. (2007) Immunophenotyping of chimeric cells in localized scleroderma. Rheumatology 46, 398-402CrossRefGoogle ScholarPubMed
76Scaletti, C. et al. (2002) Th2-oriented profile of male offspring T cells present in women with systemic sclerosis and reactive with maternal major histocompatibility complex antigens. Arthritis and Rheumatism 46, 445-450CrossRefGoogle ScholarPubMed
77Selva-O'Callaghan, A. et al. (2003) Lack of evidence of foetal microchimerism in female Spanish patients with systemic sclerosis. Lupus 12, 15-20CrossRefGoogle ScholarPubMed
78Murata, H., Nakauchi, H. and Sumida, T. (1999) Microchimerism in Japanese women patients with systemic sclerosis. Lancet 354, 220CrossRefGoogle ScholarPubMed
79Gannage, M. et al. (2002) Feto-maternal microchimerism in connective tissue diseases. European Journal of Immunology 32, 3405-3413Google Scholar
80Rak, J.M. et al. (2009) Male microchimerism and HLA compatibility in French women with sclerodema: a different profile in limited and diffuse subset. Rheumatology 48, 363-366CrossRefGoogle ScholarPubMed
81Fanning, P.A. et al. (2000) Detection of male DNA in the liver of female patients with primary biliary cirrhosis. Journal of Hepatology 33, 690-695CrossRefGoogle ScholarPubMed
82Tanaka, A. et al. (1999) Fetal microchimerism alone does not contribute to the induction of primary biliary cirrhosis. Hepatology 30, 833-838CrossRefGoogle ScholarPubMed
83Rubbia-Brandt, L. et al. (1999) FISH for Y chromosome in women with primary biliary cirrhosis: lack of evidence for leukocyte microchimerism. Hepatology 30, 821-822CrossRefGoogle ScholarPubMed
84Corpechot, C. et al. (2000) Fetal microchimerism in primary biliary cirrhosis. Journal of Hepatology 33, 696-700CrossRefGoogle ScholarPubMed
85Invernizzi, P. et al. (2000) Blood fetal microchimerism in primary biliary cirrhosis. Clinical and Experimental Immunology 122, 418-422Google Scholar
86Schoniger-Hekele, M. et al. (2002) Lack of evidence for involvement of fetal microchimerism in pathogenesis of primary biliary cirrhosis. Digestive Diseases and Sciences 47, 1909-1914Google Scholar
87Kuroki, M. et al. (2002) Detection of maternal-fetal microchimerism in the inflammatory lesions of patients with Sjogren's syndrome. Annals of the Rheumatic Diseases 61, 1041-1046CrossRefGoogle ScholarPubMed
88Toda, I. et al. (2001) Lack of evidence for an increased microchimerism in the circulation of patients with Sjogren's syndrome. Annals of the Rheumatic Diseases 60, 248-253CrossRefGoogle ScholarPubMed
89Endo, Y., Negishi, I. and Ishikawa, O. (2002) Possible contribution of microchimerism to the pathogenesis of Sjogren's syndrome. Rheumatology 41, 490-495CrossRefGoogle Scholar
90Imaizumi, M. et al. (2002) Intrathyroidal fetal microchimerism in pregnancy and postpartum. Endocrinology 143, 247-253CrossRefGoogle ScholarPubMed
91Ando, T. et al. (2002) Intrathyroidal fetal microchimerism in Graves' disease. Journal of Clinical Endocrinology and Metabolism 87, 3315-3320Google Scholar
92Johnson, K.L. et al. (2001) Microchimerism in a female patient with systemic lupus erythematosus. Arthritis and Rheumatism 44, 2107-21113.0.CO;2-9>CrossRefGoogle Scholar
93Abbud, F.M. et al. (2002) Systemic lupus erythematosus and microchimerism in autoimmunity. Transplantation Proceedings 34, 2951-2952CrossRefGoogle Scholar
94Mosca, M. et al. (2003) Correlations of Y chromosome microchimerism with disease activity in patients with SLE: analysis of preliminary data. Annals of the Rheumatic Diseases 62, 651-654Google Scholar
95Gadi, V.K. et al. (2008) Case-control study of fetal microchimerism and breast cancer. PLoS ONE 3, e1706Google Scholar
96Cha, D. et al. (2003) Cervical cancer and microchimerism. Obstetrics and Gynecology 102, 774-781Google Scholar
97Cirello, V. et al. (2008) Fetal cell microchimerism in papillary thyroid cancer: a possible role in tumor damage and tissue repair. Cancer Research 68, 8482-8488CrossRefGoogle ScholarPubMed
98O'donoghue, K. et al. (2008) Microchimeric fetal cells cluster at sites of tissue injury in lung decades after pregnancy. Reproductive Biomedicine Online 16, 382-390CrossRefGoogle Scholar
99Dubernard, G. et al. (2009) Increased fetal cell microchimerism in high grade breast carcinomas occurring during pregnancy. International Journal of Cancer 124, 1054-1059Google Scholar
100Dubernard, G. et al. (2008) Breast cancer stroma frequently recruits fetal derived cells during pregnancy. Breast Cancer Research 10, R14Google Scholar
101Nguyen Huu, S. et al. (2009) Fetal microchimeric cells participate in tumour angiogenesis in melanomas occurring during pregnancy. American Journal of Pathology 174, 630-637CrossRefGoogle ScholarPubMed
102Nguyen Huu, S. et al. (2007) Maternal neoangiogenesis during pregnancy partly derives from fetal endothelial progenitor cells. Proceedings of the National Academy of Sciences of the United States of America 104, 1871-1876Google Scholar
103Bianchi, D.W. (2000) Fetal cells in the mother: from genetic diagnosis to diseases associated with fetal cell microchimerism. European Journal of Obstetrics Gynecology and Reproductive Biology 92, 103-108Google Scholar
104Johnson, K.L. et al. (2002) Significant fetal cell microchimerism in a nontransfused woman with hepatitis C: Evidence of long-term survival and expansion. Hepatology 36, 1295-1297Google Scholar
105Khosrotehrani, K. et al. (2007) Fetal cells participate over time in the response to specific types of murine maternal hepatic injury. Human Reproduction 22, 654-661Google Scholar
106Wang, Y. et al. (2004) Fetal cells in mother rats contribute to the remodeling of liver and kidney after injury. Biochemical and Biophysical Research Communications 325, 961-967Google Scholar
107Tan, X.W. et al. (2005) Fetal microchimerism in the maternal mouse brain: a novel population of fetal progenitor or stem cells able to cross the blood-brain barrier? Stem Cells 23, 1443-1452Google Scholar
108Santos, M.A. et al. (2008) Fetal cells in the maternal appendix: a marker of inflammation or fetal tissue repair? Human Reproduction 23, 2319-2325Google Scholar
109Evans, P.C. et al. (1999) Long-term fetal microchimerism in peripheral blood mononuclear cell subsets in healthy women and women with scleroderma. Blood 93, 2033-2037Google Scholar
110Miyashita, Y. et al. (2000) Y chromosome microchimerism in rheumatic autoimmune disease. Annals of the Rheumatic Diseases 59, 655-656CrossRefGoogle ScholarPubMed
111Lambert, N.C. et al. (2005) Male microchimerism in women with systemic sclerosis and healthy women who have never given birth to a son. Annals of the Rheumatic Diseases 64, 845-848CrossRefGoogle ScholarPubMed

Further reading, resources and contacts

The Fred Hutchinson Cancer Research Center provides background information on microchimerism and information on research being undertaken in their institution:

Nelson, J.L. (2008) Your cells are my cells. Scientific American 298, 64-71Google Scholar
Nelson, J.L. (2008) Your cells are my cells. Scientific American 298, 64-71Google Scholar