Background Systemic sclerosis is a disease of unknown originwhich often occurs in women after their childbearing years.It has many clinical and histopathological similarities to chronicgraft-versus-host disease. Recent studies indicate that fetalstem cells can survive in the maternal circulation for manyyears post partum. This finding suggests that fetal cells persistingin the maternal circulation or tissues could be involved inthe pathogenesis of systemic sclerosis by initiating a graft-versus-hostreaction.
Methods We used the polymerase chain reaction (PCR) to identifyY-chromosome sequences in DNA extracted from peripheral-bloodcells and skin lesions from women with systemic sclerosis ofrecent onset. To confirm the PCR findings, we used fluorescencein situ hybridization of peripheral-blood cells and cells withinchronic inflammatory-cell infiltrates in biopsy specimens ofaffected skin.
Results Y-chromosome sequences were found in DNA from peripheral-bloodcells in 32 of 69 women with systemic sclerosis (46 percent),as compared with 1 of 25 normal women (4 percent, P<0.001),and in T lymphocytes from 3 women with systemic sclerosis whohad male offspring. Furthermore, Y-chromosome sequences wereidentified in skin-biopsy specimens from 11 of 19 women withsystemic sclerosis (58 percent); 9 of the 11 were known to havecarried male fetuses. Nucleated cells containing Y chromosomeswere detected by fluorescence in situ hybridization in paraffin-embeddedsections of skin lesions from all seven women we tested whoseskin-biopsy specimens contained Y-chromosome sequences.
Conclusions Fetal antimaternal graft-versus-host reactions maybe involved in the pathogenesis of systemic sclerosis in somewomen.
Source Information
From the Department of Medicine, Division of Rheumatology, Jefferson Medical College, Thomas Jefferson University, Philadelphia.
Address reprint requests to Dr. Jimenez at the Department of Medicine, Division of Rheumatology, Thomas Jefferson University, Rm. 509, Bluemle Life Sciences Bldg., 233 S. 10th St., Philadelphia, PA 19107-5541.
Gabrielli, A., Avvedimento, E. V., Krieg, T.
(2009). Scleroderma. NEJM
360: 1989-2003
[Full Text]
RAMARAJ, R., SORRELL, V. L.
(2009). Peripartum cardiomyopathy: Causes, diagnosis, and treatment. Cleveland Clinic Journal of Medicine
76: 289-296
[Abstract][Full Text]
Hongling Du, , Taylor, H. S.
(2009). Reviews: Stem Cells and Female Reproduction. Reproductive Sciences
16: 126-139
[Abstract]
O'Donoghue, K.
(2008). Fetal microchimerism and maternal health during and after pregnancy. Obstet Med
1: 56-64
[Abstract][Full Text]
Cirello, V., Recalcati, M. P., Muzza, M., Rossi, S., Perrino, M., Vicentini, L., Beck-Peccoz, P., Finelli, P., Fugazzola, L.
(2008). Fetal Cell Microchimerism in Papillary Thyroid Cancer: A Possible Role in Tumor Damage and Tissue Repair. Cancer Res.
68: 8482-8488
[Abstract][Full Text]
Bartynski, W.S.
(2008). Posterior Reversible Encephalopathy Syndrome, Part 2: Controversies Surrounding Pathophysiology of Vasogenic Edema. Am. J. Neuroradiol.
29: 1043-1049
[Abstract][Full Text]
Lipsker, D., Flory, E., Wiesel, M.-L., Hanau, D., de la Salle, H.
(2008). Between Light and Dark, the Chimera Comes Out. Arch Dermatol
144: 327-330
[Abstract][Full Text]
Bustos, M. L., Frias, S., Ramos, S., Estrada, A., Arreola, J. L., Mendoza, F., Gaxiola, M., Salcedo, M., Pardo, A., Selman, M.
(2007). Local and Circulating Microchimerism Is Associated with Hypersensitivity Pneumonitis. Am. J. Respir. Crit. Care Med.
176: 90-95
[Abstract][Full Text]
Svegliati, S., Olivieri, A., Campelli, N., Luchetti, M., Poloni, A., Trappolini, S., Moroncini, G., Bacigalupo, A., Leoni, P., Avvedimento, E. V., Gabrielli, A.
(2007). Stimulatory autoantibodies to PDGF receptor in patients with extensive chronic graft-versus-host disease. Blood
110: 237-241
[Abstract][Full Text]
Khosrotehrani, K., Reyes, R.R., Johnson, K.L., Freeman, R.B., Salomon, R.N., Peter, I., Stroh, H., Guegan, S., Bianchi, D.W.
(2007). Fetal cells participate over time in the response to specific types of murine maternal hepatic injury. Hum Reprod
22: 654-661
[Abstract][Full Text]
McNallan, K. T., Aponte, C., el-Azhary, R., Mason, T., Nelson, A. M., Paat, J. J., Crowson, C. S., Reed, A. M.
(2007). Immunophenotyping of chimeric cells in localized scleroderma. Rheumatology (Oxford)
46: 398-402
[Abstract][Full Text]
Nguyen Huu, S., Oster, M., Uzan, S., Chareyre, F., Aractingi, S., Khosrotehrani, K.
(2007). Maternal neoangiogenesis during pregnancy partly derives from fetal endothelial progenitor cells. Proc. Natl. Acad. Sci. USA
104: 1871-1876
[Abstract][Full Text]
Kremer Hovinga, I. C. L., Koopmans, M., de Heer, E., Bruijn, J. A., Bajema, I. M.
(2007). Chimerism in systemic lupus erythematosus--three hypotheses. Rheumatology (Oxford)
46: 200-208
[Abstract][Full Text]
Piper, K. P., McLarnon, A., Arrazi, J., Horlock, C., Ainsworth, J., Kilby, M. D., Martin, W. L., Moss, P. A.
(2007). Functional HY-Specific CD8+ T Cells Are Found in a High Proportion of Women Following Pregnancy with a Male Fetus. Biol. Reprod.
76: 96-101
[Abstract][Full Text]
Zuber, J.-P., Spertini, F.
(2006). Immunological basis of systemic sclerosis. Rheumatology (Oxford)
45: iii23-iii25
[Abstract][Full Text]
Klintschar, M., Immel, U.-D., Kehlen, A., Schwaiger, P., Mustafa, T., Mannweiler, S., Regauer, S., Kleiber, M., Hoang-Vu, C.
(2006). Fetal microchimerism in Hashimoto's thyroiditis: a quantitative approach. Eur J Endocrinol
154: 237-241
[Abstract][Full Text]
Khosrotehrani, K., Bianchi, D. W.
(2005). Multi-lineage potential of fetal cells in maternal tissue: a legacy in reverse. J. Cell Sci.
118: 1559-1563
[Abstract][Full Text]
Vernochet, C., Caucheteux, S. M., Gendron, M.-C., Wantyghem, J., Kanellopoulos-Langevin, C.
(2005). Affinity-Dependent Alterations of Mouse B Cell Development by Noninherited Maternal Antigen. Biol. Reprod.
72: 460-469
[Abstract][Full Text]
Johnson, K. L., Bianchi, D. W.
(2004). Fetal cells in maternal tissue following pregnancy: what are the consequences?. Hum Reprod Update
10: 497-502
[Abstract][Full Text]
Sawaya, H. H. B., Jimenez, S. A., Artlett, C. M.
(2004). Quantification of fetal microchimeric cells in clinically affected and unaffected skin of patients with systemic sclerosis. Rheumatology (Oxford)
43: 965-968
[Abstract][Full Text]
Khosrotehrani, K., Johnson, K. L., Cha, D. H., Salomon, R. N., Bianchi, D. W.
(2004). Transfer of Fetal Cells With Multilineage Potential to Maternal Tissue. JAMA
292: 75-80
[Abstract][Full Text]
Polan, M. L., Yao, M. W. M.
(2004). Stem Cell Transfer and the Uterus: The Egg Teaches the Chicken. JAMA
292: 104-105
[Full Text]
Spyridonidis, A., Schmitt-Graff, A., Tomann, T., Dwenger, A., Follo, M., Behringer, D., Finke, J.
(2004). Epithelial Tissue Chimerism after Human Hematopoietic Cell Transplantation Is a Real Phenomenon. Am. J. Pathol.
164: 1147-1155
[Abstract][Full Text]
Adams, K. M., Nelson, J. L.
(2004). Microchimerism: An Investigative Frontier in Autoimmunity and Transplantation. JAMA
291: 1127-1131
[Abstract][Full Text]
Jimenez, S. A., Derk, C. T.
(2004). Following the Molecular Pathways toward an Understanding of the Pathogenesis of Systemic Sclerosis. ANN INTERN MED
140: 37-50
[Full Text]
Deguchi, M., Whitaker-Menezes, D., Jones, S. C., Aiba, S., Nakagawa, S., Tagami, H., Korngold, R., Murphy, G. F.
(2003). 12E2: A Cloned Murine Dermal Cell with Features of Dermal Dendrocytes and Capacity to Produce Pathologic Changes Resembling Early Kaposi's Sarcoma. Am. J. Pathol.
163: 1817-1825
[Abstract][Full Text]
O'Donoghue, K., Choolani, M., Chan, J., de la Fuente, J., Kumar, S., Campagnoli, C., Bennett, P.R., Roberts, I.A.G., Fisk, N.M.
(2003). Identification of fetal mesenchymal stem cells in maternal blood: implications for non-invasive prenatal diagnosis. Mol Hum Reprod
9: 497-502
[Abstract][Full Text]
Ando, T., Davies, T. F.
(2003). Postpartum Autoimmune Thyroid Disease: The Potential Role of Fetal Microchimerism. J. Clin. Endocrinol. Metab.
88: 2965-2971
[Abstract][Full Text]
Mosca, M, Curcio, M, Lapi, S, Valentini, G, D'Angelo, S, Rizzo, G, Bombardieri, S
(2003). Correlations of Y chromosome microchimerism with disease activity in patients with SLE: analysis of preliminary data. Ann Rheum Dis
62: 651-654
[Abstract][Full Text]
Cox, L. A., Ramos, R. C., Dennis, T. N., Jimenez, S. A., Smith, J. B., Artlett, C. M.
(2003). Detection of Microchimeric Cells in the Peripheral Blood of Nonpregnant Women Is Enhanced by Magnetic Cell Sorting before PCR. Clin. Chem.
49: 309-312
[Full Text]
Selva-O'Callaghan, A, Mijares-Boeckh-Behrens, T, Prades, E B., Solans-Laque, R, Simeon-Aznar, C P, Fonollosa-Pla, V, Vilardell-Tarres, M
(2003). Lack of evidence of foetal microchimerism in female Spanish patients with systemic sclerosis. Lupus
12: 15-20
[Abstract]
Giacomelli, R, Matucci-Cerinic, M, Bombardieri, S
(2002). Microchimerism in Sjogren's syndrome. Ann Rheum Dis
61: 1039-1040
[Full Text]
Kuroki, M, Okayama, A, Nakamura, S, Sasaki, T, Murai, K, Shiba, R, Shinohara, M, Tsubouchi, H
(2002). Detection of maternal-fetal microchimerism in the inflammatory lesions of patients with Sjogren's syndrome. Ann Rheum Dis
61: 1041-1046
[Abstract][Full Text]
Nelson, J L
(2002). Microchimerism and human autoimmune diseases. Lupus
11: 651-654
[Abstract]
Lambert, N. C., Lo, Y. M. D., Erickson, T. D., Tylee, T. S., Guthrie, K. A., Furst, D. E., Nelson, J. L.
(2002). Male microchimerism in healthy women and women with scleroderma: cells or circulating DNA? A quantitative answer. Blood
100: 2845-2851
[Abstract][Full Text]
Ando, T., Imaizumi, M., Graves, P. N., Unger, P., Davies, T. F.
(2002). Intrathyroidal Fetal Microchimerism in Graves' Disease. J. Clin. Endocrinol. Metab.
87: 3315-3320
[Abstract][Full Text]
Penas, P. F., Jones-Caballero, M., Aragues, M., Fernandez-Herrera, J., Fraga, J., Garcia-Diez, A.
(2002). Sclerodermatous Graft-vs-Host Disease: Clinical and Pathological Study of 17 Patients. Arch Dermatol
138: 924-934
[Abstract][Full Text]
Endo, Y., Negishi, I., Ishikawa, O.
(2002). Possible contribution of microchimerism to the pathogenesis of Sjogren's syndrome. Rheumatology (Oxford)
41: 490-495
[Abstract][Full Text]
Sakkas, L. I., Xu, B., Artlett, C. M., Lu, S., Jimenez, S. A., Platsoucas, C. D.
(2002). Oligoclonal T Cell Expansion in the Skin of Patients with Systemic Sclerosis. J. Immunol.
168: 3649-3659
[Abstract][Full Text]
Artlett, C M, Rasheed, M, Russo-Stieglitz, K E, Sawaya, H H B, Jimenez, S A
(2002). Influence of prior pregnancies on disease course and cause of death in systemic sclerosis. Ann Rheum Dis
61: 346-350
[Abstract][Full Text]
Zhang, Y., McCormick, L. L., Desai, S. R., Wu, C., Gilliam, A. C.
(2002). Murine Sclerodermatous Graft-Versus-Host Disease, a Model for Human Scleroderma: Cutaneous Cytokines, Chemokines, and Immune Cell Activation. J. Immunol.
168: 3088-3098
[Abstract][Full Text]
Imaizumi, M., Pritsker, A., Unger, P., Davies, T. F.
(2002). Intrathyroidal Fetal Microchimerism in Pregnancy and Postpartum. Endocrinology
143: 247-253
[Abstract][Full Text]
Stevens, A., Nelson, J. L.
(2002). Maternal and Fetal Microchimerism: Implications for Human Diseases. NeoReviews
3: e11-19
[Full Text]
Artlett, C. M., Miller, F. W., Rider, L. G.
(2001). Persistent maternally derived peripheral microchimerism is associated with the juvenile idiopathic inflammatory myopathies. Rheumatology (Oxford)
40: 1279-1284
[Abstract][Full Text]
MIJARES-BOECKH-BEHRENS, T, SELVA-O'CALLAGHAN, A, SOLANS-LAQUE, R, BOSCH-GIL, J A., VILARDELL-TARRES, M, BALADA-PRADES, E, KUWANA, M, OGAWA, Y, TODA, I
(2001). Fetal microchimerism in Sjogren's syndrome. Ann Rheum Dis
60: 897a-898
[Full Text]
Kruskall, M. S., Lee, T.-H., Assmann, S. F., Laycock, M., Kalish, L. A., Lederman, M. M., Busch, M. P.
(2001). Survival of transfused donor white blood cells in HIV-infected recipients. Blood
98: 272-279
[Abstract][Full Text]
Klintschar, M., Schwaiger, P., Mannweiler, S., Regauer, S., Kleiber, M.
(2001). Evidence of Fetal Microchimerism in Hashimoto's Thyroiditis. J. Clin. Endocrinol. Metab.
86: 2494-2498
[Abstract][Full Text]
Bree, A. F., Siegfried, E., Sotelo-Avila, C., Nahass, G.
(2001). Infantile Hemangiomas: Speculation on Placental Trophoblastic Origin. Arch Dermatol
137: 573-577
[Abstract][Full Text]
Toda, I, Kuwana, M, Tsubota, K, Kawakami, Y
(2001). Lack of evidence for an increased microchimerism in the circulation of patients with Sjogren's syndrome. Ann Rheum Dis
60: 248-253
[Abstract][Full Text]
Imaizumi, M., Pritsker, A., Kita, M., Ahmad, L., Unger, P., Davies, T. F.
(2001). Pregnancy and Murine Thyroiditis: Thyroglobulin Immunization Leads to Fetal Loss in Specific Allogeneic Pregnancies. Endocrinology
142: 823-829
[Abstract][Full Text]
Boneva, R. S., Folks, T. M., Chapman, L. E.
(2001). Infectious Disease Issues in Xenotransplantation. Clin. Microbiol. Rev.
14: 1-14
[Abstract][Full Text]
Lo, Y.M. D.
(2000). Fetal DNA in Maternal Plasma: Biology and Diagnostic Applications. Clin. Chem.
46: 1903-1906
[Abstract][Full Text]
Arvola, M., Gustafsson, E., Svensson, L., Jansson, L., Holmdahl, R., Heyman, B., Okabe, M., Mattsson, R.
(2000). Immunoglobulin-Secreting Cells of Maternal Origin Can Be Detected in B Cell-Deficient Mice. Biol. Reprod.
63: 1817-1824
[Abstract][Full Text]
Stummvoll, G. H., Aringer, M., Smolen, J. S., Koller, M., Kiener, H. P., Steiner, C. W., Bohle, B., Knobler, R., Graninger, W. B.
(2000). Derangement of apoptosis-related lymphocyte homeostasis in systemic sclerosis. Rheumatology (Oxford)
39: 1341-1350
[Abstract][Full Text]
Lo, Y.M. D., Lau, T. K., Chan, L. Y.S., Leung, T. N., Chang, A. M.Z.
(2000). Quantitative Analysis of the Bidirectional Fetomaternal Transfer of Nucleated Cells and Plasma DNA. Clin. Chem.
46: 1301-1309
[Abstract][Full Text]
MIYASHITA, Y., ONO, M., ONO, M., UEKI, H., KURASAWA, K.
(2000). Y chromosome microchimerism in rheumatic autoimmune disease. Ann Rheum Dis
59: 654b-654
[Full Text]
Lambert, N. C., Evans, P. C., Hashizumi, T. L., Maloney, S., Gooley, T., Furst, D. E., Nelson, J. L.
(2000). Cutting Edge: Persistent Fetal Microchimerism in T Lymphocytes Is Associated with HLA-DQA1*0501: Implications in Autoimmunity. J. Immunol.
164: 5545-5548
[Abstract][Full Text]
Vietor, H. E., Hallensleben, E., van Bree, S. P. M. J., van der Meer, E. M. W., Kaal, S. E. J., Bennebroek-Gravenhorst, J., Kanhai, H. H. H., Brand, A., Claas, F. H. J.
(2000). Survival of donor cells 25 years after intrauterine transfusion. Blood
95: 2709-2714
[Abstract][Full Text]
Pearson, G. D., Veille, J.-C., Rahimtoola, S., Hsia, J., Oakley, C. M., Hosenpud, J. D., Ansari, A., Baughman, K. L.
(2000). Peripartum Cardiomyopathy: National Heart, Lung, and Blood Institute and Office of Rare Diseases (National Institutes of Health) Workshop Recommendations and Review. JAMA
283: 1183-1188
[Abstract][Full Text]
McCormick, L. L., Zhang, Y., Tootell, E., Gilliam, A. C.
(1999). Anti-TGF-{beta} Treatment Prevents Skin and Lung Fibrosis in Murine Sclerodermatous Graft-Versus-Host Disease: A Model for Human Scleroderma. J. Immunol.
163: 5693-5699
[Abstract][Full Text]
Kaal, S. E. J., Van den Hoogen, F. H. J., De Jong, E. M. G. J., Viëtor, H. E.
(1999). Systemic Sclerosis: New Insights in Autoimmunity. Exp. Biol. Med.
222: 1-8
[Abstract][Full Text]
Bodo, I., Peters, M., Radich, J. P., Hess, J., Blinder, M., Watson, M. S., Van Rheeden, R., Natarajan, S., Lowell, J. A., Brown, R., DiPersio, J., Adkins, D.
(1999). Donor-Derived Acute Promyelocytic Leukemia in a Liver-Transplant Recipient. NEJM
341: 807-813
[Full Text]
Sakkas, L. I., Tourtellotte, C., Berney, S., Myers, A. R., Platsoucas, C. D.
(1999). Increased Levels of Alternatively Spliced Interleukin 4 (IL-4delta 2) Transcripts in Peripheral Blood Mononuclear Cells from Patients with Systemic Sclerosis. CVI
6: 660-664
[Abstract][Full Text]
Nelson, J L.
(1999). Autoimmune disease and the long-term persistence of fetal and maternal microchimerism. Lupus
8: 493-496
NELSON, J L.
(1999). Non-host cells in the pathogenesis of autoimmune disease: a new paradigm?. Ann Rheum Dis
58: 518-520
[Full Text]
Nelson, J L
(1999). Microchimerism: implications for autoimmune disease. Lupus
8: 370-374
[Abstract]
Starzl, T. E., Zinkernagel, R. M.
(1998). Antigen Localization and Migration in Immunity and Tolerance. NEJM
339: 1905-1913
[Full Text]
van der Horst-Bruinsma, I E, Hazes, J M W, Schreuder, G M T., Radstake, T R D J, Barrera, P, van de Putte, L B A, Mustamu, D, van Schaardenburg, D, Breedveld, F C, de Vries, R R P
(1998). Influence of non-inherited maternal HLA-DR antigens on susceptibility to rheumatoid arthritis. Ann Rheum Dis
57: 672-675
[Abstract][Full Text]
Connolly, M. K., McCalmont, T. H., Daniell, H. W., Artlett, C. M., Smith, J. B., Jimenez, S. A.
(1998). Fetal DNA and Cells in Women with Systemic Sclerosis. NEJM
339: 771-772
[Full Text]
Nelson, J. L.
(1998). Microchimerism and Autoimmune Disease. NEJM
338: 1223-1225
[Full Text]
Lockshin, M.D.
(1998). Review : Pregnancy loss and antiphospholipid antibodies. Lupus
7: S86-S89
[Abstract]