Current Rheumatology Reports

, Volume 3, Issue 3, pp 222–229 | Cite as

Microchimerism and hla relationships of pregnancy: Implications for autoimmune diseases

  • J. Lee Nelson


The application of molecular techniques to the study of human pregnancy has resulted in knowledge that the placenta is only a relative barrier to traffic of fetal and maternal cells. Moreover, long-term persistence of fetal cells in the maternal circulation and maternal cells in her progeny have been described. Harboring of cells from another individual is referred to as chimerism and microchimerism indicates low levels of non-host cells. The clinical features of a known condition of human chimerism, chronic graft-versus-host disease that occurs after stem cell transplantation, resemble spontaneously occurring autoimmune diseases including systemic sclerosis, Sjögren’s syndrome, primary biliary cirrhosis, and sometimes myositis and systemic lupus. A critical determinant of chronic graft-versus-host disease is the HLA relationship of donor and host cells. When considered together, these observations have led to a new area of research investigating whether microchimerism and HLA-relationships are involved in the pathogenesis of some autoimmune diseases.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Bianchi DW: Current knowledge about fetal blood cells in the maternal circulation. J Perinat Med 1998, 16:175–185.Google Scholar
  2. 2.
    Hall JM, Lingenfelter P, Adams SL, et al.: Detection of maternal cells in human umbilical cord blood using fluorescence in situ hybridization. Blood 1995, 86:2829–2832.PubMedGoogle Scholar
  3. 3.
    Bianchi DW, Zickwolf GK, Weil GJ, Sylvester S, DeMaria MA: Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum. Proc Natl Acad Sci USA 1996, 93:705–708. A study of healthy women in which the seminal observation was reported that fetal cells persist for decades after pregnancy completion.PubMedCrossRefGoogle Scholar
  4. 4.
    Maloney S, Smith AG, Furst DE, et al.: Microchimerism of maternal origin persists into adult life. J Clin Invest 1999, 104:41–47. The first description of long-term persistence of maternal microchimerism in immunocompetent individuals.PubMedCrossRefGoogle Scholar
  5. 5.
    De Moor G, De Bock G, Noens L, De Bic S: A new case of human chimerism detected after pregnancy: 46,XY karyotype in the lymphocytes of a woman. Acta Clin Belg 1988, 43:231–235.PubMedGoogle Scholar
  6. 6.
    Lee TH, Paglieroni T, Ohto H, Holland PV, Busch MP: Survival of donor leukocyte subpopulations in immunocompetent transfusion recipients: frequent long-term microchimerism in severe trauma patients. Blood 1999, 93:3127–3139. Description of long-term persistence of donor cells in trauma patients who have received multiple transfusions.PubMedGoogle Scholar
  7. 7.
    Nelson JL: Maternal-fetal immunology and autoimmune disease. Is some autoimmune disease auto-alloimmune or allo-autoimmune? Arthritis Rheum 1996, 39:191–194. Presentation of the hypothesis that non-host cells are involved in the pathogenesis of autoimmune disease, providing the rationale for the hypothesis and the corollary hypothesis that HLA compatibility of a child increases risk of subsequent autoimmune disease in the mother.PubMedCrossRefGoogle Scholar
  8. 8.
    Thomas MR, Williamson R, Craft I, Yazdani N, Rodeck CH: Y chromosome sequence DNA amplified from peripheral blood of women in early pregnancy. Lancet 1994, 343:413–414.PubMedCrossRefGoogle Scholar
  9. 9.
    Lo YMD, Lau TK, Chan LYS, Leung TN, Chang AMZ: Quantitative analysis of the bidirectional fetomaternal transfer of nucleated cells and plasma DNA. Clin Chem 2000, 46:1301–1309.PubMedGoogle Scholar
  10. 10.
    Lo YMD, Lo ESF, Watson N, et al.: Two-way cell traffic between mother and fetus: biologic and clinical implications. Blood 1996, 88:4390–4395. Describes the application of PCR-based techniques and documents traffic of cells during human pregnancy from fetus to mother and mother to fetus.PubMedGoogle Scholar
  11. 11.
    Petit T, Dommergues M, Socie G, et al.: Detection of maternal cells in human fetal blood during the third trimester of pregnancy using allele-specific PCR amplification. Br J Haematol 1997, 100:767–771.CrossRefGoogle Scholar
  12. 12.
    Lo ESF, Lo YMD, Hjelm NM, Thilaganathan B: Transfer of nucleated maternal cells into fetal circulation during the second trimester of pregnancy [letter]. Br J Haematol 1998, 100:605–606.PubMedCrossRefGoogle Scholar
  13. 13.
    Piotrowski P, Croy BA: Maternal cells are widely distributed in murine fetuses in utero. Biol Reprod 1996, 54:1103–1110. Maternal cells were widely distributed in immunodeficient fetuses and were routinely found in the bone marrow of immune competent fetuses.PubMedCrossRefGoogle Scholar
  14. 14.
    Pollack MS, Kirpatrick D, Kapoor N, Dupont B, O’Reilly RJ: Identification by HLA typing of intrauterine-derived maternal T cells in four patients with severe combined immunodeficiency. N Engl J Med 1982, 307:662–666.PubMedCrossRefGoogle Scholar
  15. 15.
    Shulman HM, Sullivan KM: Graft-versus-host disease. Auto and allo immunity after bone marrow transplantation. Concepts Immunopathol 1988, 6:141–165.PubMedGoogle Scholar
  16. 16.
    Urbano-Marquez A, Estruch R, Grau J, et al.: Inflammatory myopathy associated with chronic graft-versus-host disease. Neurology 1986, 36:1091–1093.PubMedGoogle Scholar
  17. 17.
    Anasetti C, Rybka W, Sullivan KM, Banaji M, Slichter SJ: Graft-vs-host disease is associated with autoimmune-like thrombocytopenia. Blood 1989, 73:1054–1058.PubMedGoogle Scholar
  18. 18.
    Klumpp TR, Herman JH: Autoimmune neutropenia after bone marrow transplantation. Blood 1993, 82:1035.PubMedGoogle Scholar
  19. 19.
    Smith C, Norberg R, Moller G, Lonnqvist B, Hammarstrom L: Autoantibody formation after bone marrow transplantation. Eur Neurol 1989, 29:128–134.PubMedGoogle Scholar
  20. 20.
    Lister J, Messner H, Keysonte E, Miller R, Fritzler M: Autoantibody analysis of patients with graft versus host disease. J Clin Lab Immunol 1987, 24:19–20. Includes the description of antibodies to dsDNA in patients with graft-versus-host disease.PubMedGoogle Scholar
  21. 21.
    Nelson JL, Furst DE, Maloney S, et al.: Microchimerism and HLA-compatible relationships of pregnancy in SSc. Lancet 1998, 351:559–562. First report of microchimerism in patients with SSc showing fetal microchimerism was quantitatively greater in women with SSc than in healthy women. HLA-DRB1 compatibility of a previously born child was identified as a risk factor for subsequent SSc in the mother.PubMedCrossRefGoogle Scholar
  22. 22.
    Artlett CM, Smith JB, Jimenez SA: Identification of fetal DNA and cells in skin lesions from women with systemic sclerosis. N Engl J Med 1998, 338:1186–1191. A significant difference in the frequency of microchimerism in DNA extracted from skin was found in DNA extracted from biopsies of SSc patients compared with controls.PubMedCrossRefGoogle Scholar
  23. 23.
    Murata H, Nakauchi H, Sumida T: Microchimerism in Japanese women patients with systemic sclerosis. Lancet 1999, 354:220.PubMedCrossRefGoogle Scholar
  24. 24.
    Evans PC, Lambert N, Maloney S, et al.: Long-term fetal microchimerism in peripheral blood mononuclear cell subsets in healthy women and women with scleroderma. Blood 1999, 93:1–6.Google Scholar
  25. 25.
    McMilin KD, Johnson RL: HLA homozygosity and the risk of related-donor transfusion-associated graft-versus-host disease. Transfus Med Rev 1993, 7:37–41.PubMedGoogle Scholar
  26. 26.
    Lambert NC, Evans PC, Hashizumi TL, Maloney S, Gooley T, Furst DE, Nelson JL.: Cutting edge: persistent fetal microchimerism in T lymphocytes is associated with HLA-DQA1*0501: implications in autoimmunity. J Immunol 2000, 164:5545–5548.PubMedGoogle Scholar
  27. 27.
    Aractingi S, Berkane N, Bertheau P, et al.: Fetal DNA in skin of polymorphic eruptions of pregnancy. Lancet 1999, 352:1898–1901. An elegant and carefully conducted study in which pregnant women suffering from a skin disease were found to have microchimerism in skin biopsy samples that was not found in matched controls.CrossRefGoogle Scholar
  28. 28.
    Tanaka A, Lindor K, Gish R, et al.: Fetal microchimerism alone does not contribute to the induction of primary biliary cirrhosis. Hepatology 1999, 30:833–838.PubMedCrossRefGoogle Scholar
  29. 29.
    Negishi I, Endo Y, Maebashi OI: Identification of fetal lymphocytes infiltrating in the salivary glands of patients with Sjögren’s syndrome [abstract]. Arthritis Rheum 1999, 42:S140.Google Scholar
  30. 30.
    Reed AM, Picornell YJ, Harwood A, Kredich DW: Chimerism in children with juvenile dermatomyositis [letter]. Lancet 2000, 356:2156–2157. A study of patients with juvenile dermatomyositis with a strong study design using unaffected siblings as controls. Maternal microchimerism was found more often in patients than in unaffected siblings.PubMedCrossRefGoogle Scholar
  31. 31.
    Artlett CM, Ramos R, Jiminez SA, et al.: Chimeric cells of maternal origin in juvenile idiopathic inflammatory myopathies [letter]. Lancet 2000, 356:2155–2156. A study of patients with juvenile idiopathic inflammatory myopathy in whom maternal microchimerism was found more often than in controls.PubMedCrossRefGoogle Scholar
  32. 32.
    Christner PJ, Artlett CM, Conway RF, Jiminez SA: Increased numbers of microchimeric cells of fetal origin are associated with dermal fibrosis in mice following injection of vinyl chloride. Arthritis Rheum 2000, 43:2598–2605. An experimental model of SSc that brings together microchimerism, pathologic changes in tissues and the exogenous agent and vinyl chloride, in disease pathogenesis.PubMedCrossRefGoogle Scholar
  33. 33.
    Nelson JL, Hughes KA, Smith AG, et al.: Maternal-fetal disparity in HLA class II alloantigens and the pregnancy-induced amelioration of rheumatoid arthritis. N Engl J Med 1993, 329:466–471.PubMedCrossRefGoogle Scholar
  34. 34.
    Mullinax F: Chimerism and autoimmunity. In Proceedings of the Fourth ASEAN Congress. Rheumatology 1993:39–40. A patient with systemic lupus and a patient with scleroderma are described in which chimerism was suspected to be involved in the disease.Google Scholar
  35. 35.
    Gleichman E, Van Elven H, Van der Veen JP: A systemic lupus erythematosus (SLE)-like disease in mice induced by abnormal T-B cell cooperation. Eur J Immunol 1982, 12:152–155.CrossRefGoogle Scholar
  36. 36.
    Portanova JP, Claman HN, Kotzin BL: Autoimmunization in murine graft-vs-host disease, I: Selective production of antibodies to histones and DNA. J Immunol 1985, 135:3580–3586.Google Scholar
  37. 37.
    Portanova JP, Ebling FM, Hammond WS, Hahn BH, Kotzin BL: Allogeneic MHC antigen requirements for lupus-like autoantibody production and nephritis in murine graft-vs-host disease. J Immunol 1988, 141:3370–3376.PubMedGoogle Scholar
  38. 38.
    Nelson JL: Microchimerism and autoimmune disease. N Engl J Med 1998, 338:1224–1225.PubMedCrossRefGoogle Scholar
  39. 39.
    Buyon JP: Neonatal lupus syndromes. In Systemic Lupus rythematosus, edn 3. Edited by Lahita R. San Diego: Academic Press; 1998:337–359.Google Scholar
  40. 40.
    Claas FHJ, Gijbels Y, van der Velden-de Munck J, van Rood JJ: Induction of B cell unresponsiveness to noninherited maternal HLA antigens during fetal life. Science 1988, 241:1815–1817.PubMedCrossRefGoogle Scholar
  41. 41.
    Holzgreve W, Ghezzi F, Di Naro E, et al.: Disturbed feto-maternal cell traffic in preeclampsia. Obstet Gynecol 1998, 91:669–672.PubMedCrossRefGoogle Scholar
  42. 42.
    Nelson JL, Tsao B, Hahn B, et al.: Microchimerism: a new etiology for autoimmune disease? FASEB J 1999, 13:A958.Google Scholar
  43. 43.
    Lambert N, Distler O, Muller-Ladner U, et al.: HLA DQA1*0501 is associated with diffuse systemic sclerosis in men. Arthritis Rheum 2000, 43:2005–2010.PubMedCrossRefGoogle Scholar
  44. 44.
    Starzl TE, Demetris AJ, Murase N, et al.: The lost chord: microchimerism and allograft survival. Immunol Today 1996, 17:577–584.PubMedCrossRefGoogle Scholar
  45. 45.
    Hakim FT, Mackall CL: The immune system: effector and target of graft-versus-host disease In Graft-vs-Host Disease, edn 2. Edited by Ferrara JL, Deeg HJ, Burakof ST. New York: Marcel Dekker; 1997:274–289.Google Scholar
  46. 46.
    Suzuki K, Narita T, Yui R, Asakura H, Fujiwara M: Mechanism of the induction of autoimmune disease by graft-versus-host reaction. Role of CD8+ cells in the development of hepatic and ductal lesions induced by CD4+ cells in MHC class I plus II different host. Lab Invest 1994, 70:609–619.PubMedGoogle Scholar
  47. 47.
    Sayegh MH, Carpenter CB: Role of indirect allorecognition in allograft rejection. Int Rev Immunol 1996, 13:221–229.PubMedGoogle Scholar
  48. 48.
    Miller RG: The veto phenomenon and T-cell regulation. Immunol Today 1986, 7:112–114.CrossRefGoogle Scholar

Copyright information

© Current Science Inc 2001

Authors and Affiliations

  • J. Lee Nelson
    • 1
  1. 1.Immunogenetics D2-100Fred Hutchinson Cancer Research CenterSeattleUSA

Personalised recommendations