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Immunological adaptations in pregnancy that modulate rheumatoid arthritis disease activity

A Publisher Correction to this article was published on 17 February 2020

This article has been updated


During pregnancy, the fetus that grows within the maternal uterus is not rejected by the maternal immune system. To enable both tolerance towards the fetus and defence against pathogens, modifications of the maternal immune system occur during gestation. These modifications are able to bring about a natural improvement in disease activity of some autoimmune diseases, such as rheumatoid arthritis (RA). Various mechanisms of the immune system contribute to the phenomenon of pregnancy-related improvement of RA, and the cessation of these immunomodulatory mechanisms after delivery correlates with postpartum disease flare. HLA disparity between mother and fetus, glycosylation of IgG, immunoregulatory pathways, and alterations in innate and adaptive immune cells and their cytokines have important roles in pregnancy and in pregnancy-related amelioration of RA.

Key points

  • Immune tolerance during pregnancy is most pronounced at the feto-maternal interface, but also has a systemic effect that supports amelioration of rheumatoid arthritis (RA) by rebalancing pro-inflammatory and anti-inflammatory influences.

  • A pro-inflammatory microenvironment is crucial for normal implantation and parturition, whereas a tolerogenic environment is induced during the course of pregnancy to enable normal placentation and fetal growth.

  • With regard to innate immune cells, monocyte gene activity in the peripheral blood is higher during pregnancy than postpartum, and a tolerogenic subset of innate cells is at work in the placenta during pregnancy.

  • With regard to adaptive immune cells, there is no definite predominance of T helper 2 cells but a downregulation of effector T cell activity and an expansion of regulatory T cells, which support pregnancy-related RA improvement.

  • Galactosylation of IgG is a pregnancy-related phenomenon that renders disease-specific autoantibodies less pathogenic and could explain why a gestational increase in anti-cyclic citrullinated peptide antibody IgG galactosylation is associated with improved RA.

  • After delivery, the immunomodulatory effects mediated by fetal antigens and pregnancy hormones disappear, giving rise to T cell activity that, together with persisting monocyte activity, correlates with postpartum disease flares.

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Fig. 1: Immune events in pregnancy.
Fig. 2: Rebalance of pro-inflammatory and anti-inflammatory factors during pregnancy in rheumatoid arthritis.

Change history


  1. 1.

    Ince-Askan, H. & Dolhain, R. J. Pregnancy and rheumatoid arthritis. Best Pract. Res. Clin. Rheumatol. 29, 580–596 (2015).

    PubMed  Google Scholar 

  2. 2.

    Østensen, M., Villiger, P. M. & Förger, F. Interaction of pregnancy and autoimmune rheumatic disease. Autoimmun. Rev. 11, A437–A446 (2012).

    PubMed  Google Scholar 

  3. 3.

    Hench, P. S. The ameliorating effect of pregnancy on chronic atrophic (infectious, rheumatoid) arthritis, fibrositis, and intermittent hydrarthrosis. Mayo Clin. Proc. 13, 161–167 (1938).

    Google Scholar 

  4. 4.

    Østensen, M. & Husby, G. A prospective clinical study of the effect of pregnancy on rheumatoid arthritis and ankylosing spondylitis. Arthritis Rheum. 26, 1155–1159 (1983).

    PubMed  Google Scholar 

  5. 5.

    Neely, N. T. & Persellin, R. H. Activity of rheumatoid arthritis during pregnancy. Tex. Med. 73, 59–63 (1977).

    CAS  PubMed  Google Scholar 

  6. 6.

    Østensen, M., Aune, B. & Husby, G. Effect of pregnancy and hormonal changes on the activity of rheumatoid arthritis. Scand. J. Rheumatol. 12, 69–72 (1983).

    PubMed  Google Scholar 

  7. 7.

    Zbinden, A., van den Brandt, S., Østensen, M., Villiger, P. M. & Förger, F. Risk for adverse pregnancy outcome in axial spondyloarthritis and rheumatoid arthritis: disease activity matters. Rheumatology 57, 1235–1242 (2018).

    PubMed  Google Scholar 

  8. 8.

    Förger, F. et al. Discontinuing TNF-inhibitors before gestational week 20 in well-controlled rheumatoid arthritis and juvenile arthritis is not associated with a disease worsening in late pregnancy. Arthritis Rheumatol. (2019).

    Article  PubMed  Google Scholar 

  9. 9.

    de Man, Y. A., Dolhain, R. J., van de Geijn, F. E., Willemsen, S. P. & Hazes, J. M. Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study. Arthritis Rheum. 59, 1241–1248 (2008).

    PubMed  Google Scholar 

  10. 10.

    Barrett, J. H., Brennan, P., Fiddler, M. & Silman, A. J. Does rheumatoid arthritis remit during pregnancy and relapse postpartum? Results from a nationwide study in the United Kingdom performed prospectively from late pregnancy. Arthritis Rheum. 42, 1219–1227 (1999).

    CAS  PubMed  Google Scholar 

  11. 11.

    de Man, Y. A. et al. Women with rheumatoid arthritis negative for anti-cyclic citrullinated peptide and rheumatoid factor are more likely to improve during pregnancy, whereas in autoantibody-positive women autoantibody levels are not influenced by pregnancy. Ann. Rheum. Dis. 69, 420–423 (2010).

    PubMed  Google Scholar 

  12. 12.

    de Man, Y. A. et al. Association of higher rheumatoid arthritis disease activity during pregnancy with lower birth weight: results of a national prospective study. Arthritis Rheum. 60, 3196–3206 (2009).

    PubMed  Google Scholar 

  13. 13.

    Spector, T. D. Rheumatoid arthritis. Rheum. Dis. Clin. North Am. 16, 513–537 (1990).

    CAS  PubMed  Google Scholar 

  14. 14.

    Robertson, S. A. & Sharkey, D. J. Seminal fluid and fertility in women. Fertil. Steril. 106, 511–519 (2016).

    PubMed  Google Scholar 

  15. 15.

    Saito, S., Shima, T., Nakashima, A., Inada, K. & Yoshino, O. Role of paternal antigen-specific Treg cells in successful implantation. Am. J. Reprod. Immunol. 75, 310–316 (2016).

    CAS  PubMed  Google Scholar 

  16. 16.

    Chaouat, G., Dubanchet, S. & Ledee, N. Cytokines: important for implantation? J. Assist. Reprod. Genet. 24, 491–505 (2007).

    PubMed Central  PubMed  Google Scholar 

  17. 17.

    Robertson, S. A., Care, A. S. & Moldenhauer, L. M. Regulatory T cells in embryo implantation and the immune response to pregnancy. J. Clin. Invest. 128, 4224–4235 (2018).

    PubMed Central  PubMed  Google Scholar 

  18. 18.

    Arck, P. C. & Hecher, K. Fetomaternal immune cross-talk and its consequences for maternal and offspring's health. Nat. Med. 19, 548–556 (2013).

    CAS  PubMed  Google Scholar 

  19. 19.

    Medawar, P. B. Some immunological and endocrinological problems, raised by the evolution of viviparity in vertebrates. Nature 172, 603–606 (1953).

    PubMed  Google Scholar 

  20. 20.

    Lei, K. I., Chan, L. Y., Chan, W. Y., Johnson, P. J. & Lo, Y. M. Quantitative analysis of circulating cell-free Epstein-Barr virus (EBV) DNA levels in patients with EBV-associated lymphoid malignancies. Br. J. Haematol. 111, 239–246 (2000).

    CAS  Google Scholar 

  21. 21.

    Triche, E. W. et al. Sharing and preeclampsia: variation in effects by seminal fluid exposure in a case-control study of nulliparous women in Iowa. J. Reprod. Immunol. 101–102, 111–119 (2014).

    Google Scholar 

  22. 22.

    Ober, C. Current topic: HLA and reproduction: lessons from studies in the Hutterites. Placenta 16, 569–577 (1995).

    CAS  Google Scholar 

  23. 23.

    Gonzalez, D. A., de Leon, A. C., Moncholi, C. V., Cordova Jde, C. & Hernandez, L. B. Arthritis in mice: allogeneic pregnancy protects more than syngeneic by attenuating cellular immune response. J. Rheumatol. 31, 30–34 (2004).

    Google Scholar 

  24. 24.

    Nelson, J. L. et al. Remission of rheumatoid arthritis during pregnancy and maternal-fetal class II alloantigen disparity. Am. J. Reprod. Immunol. 28, 226–227 (1992).

    CAS  Google Scholar 

  25. 25.

    Nelson, J. L. et al. Maternal-fetal disparity in HLA class II alloantigens and the pregnancy-induced amelioration of rheumatoid arthritis. N. Engl. J. Med. 329, 466–471 (1993).

    CAS  Google Scholar 

  26. 26.

    van der Horst-Bruinsma, I. E. et al. Influence of HLA-class II incompatibility between mother and fetus on the development and course of rheumatoid arthritis of the mother. Ann. Rheum. Dis. 57, 286–290 (1998).

    PubMed  Google Scholar 

  27. 27.

    Zrour, S. H. et al. The impact of pregnancy on rheumatoid arthritis outcome: the role of maternofetal HLA class II disparity. Joint Bone Spine 77, 36–40 (2010).

    PubMed  Google Scholar 

  28. 28.

    Brennan, P. et al. Maternal-fetal HLA incompatibility and the course of inflammatory arthritis during pregnancy. J. Rheumatol. 27, 2843–2848 (2000).

    CAS  PubMed  Google Scholar 

  29. 29.

    McInnes, I. B. & Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 365, 2205–2219 (2011).

    CAS  PubMed  Google Scholar 

  30. 30.

    Reiding, K. R. et al. Serum protein N-glycosylation changes with rheumatoid arthritis disease activity during and after pregnancy. Front. Med. 4, 241 (2017).

    Google Scholar 

  31. 31.

    Nesspor, T. C., Raju, T. S., Chin, C. N., Vafa, O. & Brezski, R. J. Avidity confers FcγR binding and immune effector function to aglycosylated immunoglobulin G1. J. Mol. Recognit. 25, 147–154 (2012).

    CAS  PubMed  Google Scholar 

  32. 32.

    Zenclussen, A. C., Gentile, T., Kortebani, G., Mazzolli, A. & Margni, R. Asymmetric antibodies and pregnancy. Am. J. Reprod. Immunol. 45, 289–294 (2001).

    CAS  PubMed  Google Scholar 

  33. 33.

    van Zeben, D. et al. Early agalactosylation of IgG is associated with a more progressive disease course in patients with rheumatoid arthritis: results of a follow-up study. Br. J. Rheumatol. 33, 36–43 (1994).

    PubMed  Google Scholar 

  34. 34.

    Rademacher, T. W., Williams, P. & Dwek, R. A. Agalactosyl glycoforms of IgG autoantibodies are pathogenic. Proc. Natl Acad. Sci. USA 91, 6123–6127 (1994).

    CAS  PubMed Central  PubMed  Google Scholar 

  35. 35.

    van de Geijn, F. E. et al. Immunoglobulin G galactosylation and sialylation are associated with pregnancy-induced improvement of rheumatoid arthritis and the postpartum flare: results from a large prospective cohort study. Arthritis Res. Ther. 11, R193 (2009).

    PubMed Central  PubMed  Google Scholar 

  36. 36.

    Bondt, A., Wuhrer, M., Kuijper, T. M., Hazes, J. M. & Dolhain, R. J. Fab glycosylation of immunoglobulin G does not associate with improvement of rheumatoid arthritis during pregnancy. Arthritis Res. Ther. 18, 274 (2016).

    PubMed Central  PubMed  Google Scholar 

  37. 37.

    Bondt, A. et al. ACPA IgG galactosylation associates with disease activity in pregnant patients with rheumatoid arthritis. Ann. Rheum. Dis. 77, 1130–1136 (2018).

    CAS  PubMed  Google Scholar 

  38. 38.

    Van Dijk, W. & Mackiewicz, A. Interleukin-6-type cytokine-induced changes in acute phase protein glycosylation. Ann. NY Acad. Sci. 762, 319–330 (1995).

    PubMed  Google Scholar 

  39. 39.

    Ercan, A. et al. Estrogens regulate glycosylation of IgG in women and men. JCI Insight 2, e89703 (2017).

    PubMed Central  PubMed  Google Scholar 

  40. 40.

    Fettke, F. et al. Maternal and fetal mechanisms of B cell regulation during pregnancy: human chorionic gonadotropin stimulates B cells to produce IL-10 while alpha-fetoprotein drives them into apoptosis. Front. Immunol. 7, 495 (2016).

    PubMed Central  PubMed  Google Scholar 

  41. 41.

    Miranda, S., Canellada, A., Gentile, T. & Margni, R. Interleukin-6 and dexamethasone modulate in vitro asymmetric antibody synthesis and UDP-Glc glycoprotein glycosyltransferase activity. J. Reprod. Immunol. 66, 141–150 (2005).

    CAS  PubMed  Google Scholar 

  42. 42.

    Haupl, T. et al. Reactivation of rheumatoid arthritis after pregnancy: increased phagocyte and recurring lymphocyte gene activity. Arthritis Rheum. 58, 2981–2992 (2008).

    PubMed  Google Scholar 

  43. 43.

    Goin, D. E. et al. Pregnancy-induced gene expression changes in vivo among women with rheumatoid arthritis: a pilot study. Arthritis Res. Ther. 19, 104 (2017).

    PubMed Central  PubMed  Google Scholar 

  44. 44.

    Weix, J. et al. Influence of pregnancy on the adipocytokine and peroxisome proliferator-activated receptor pathways in peripheral blood mononuclear cells from healthy donors and rheumatoid arthritis patients. Arthritis Rheum. 64, 2095–2103 (2012).

    CAS  PubMed  Google Scholar 

  45. 45.

    Lima, J. et al. Serum markers of B-cell activation in pregnancy during late gestation, delivery, and the postpartum period. Am. J. Reprod. Immunol. 81, e13090 (2019).

    CAS  PubMed Central  PubMed  Google Scholar 

  46. 46.

    Weix, J., Haupl, T., Raio, L., Villiger, P. M. & Forger, F. The physiologic increase in expression of some type I IFN-inducible genes during pregnancy is not associated with improved disease activity in pregnant patients with rheumatoid arthritis. Transl. Res. 161, 505–512 (2013).

    CAS  PubMed  Google Scholar 

  47. 47.

    Schumacher, A. et al. Human chorionic gonadotropin attracts regulatory T cells into the fetal-maternal interface during early human pregnancy. J. Immunol. 182, 5488–5497 (2009).

    CAS  PubMed  Google Scholar 

  48. 48.

    Nagaeva, O., Jonsson, L. & Mincheva-Nilsson, L. Dominant IL-10 and TGF-β mRNA expression in γδT cells of human early pregnancy decidua suggests immunoregulatory potential. Am. J. Reprod. Immunol. 48, 9–17 (2002).

    PubMed  Google Scholar 

  49. 49.

    Bissenden, J. G., Ling, N. R. & Mackintosh, P. Suppression of mixed lymphocyte reactions by pregnancy serum. Clin. Exp. Immunol. 39, 195–202 (1980).

    CAS  PubMed Central  PubMed  Google Scholar 

  50. 50.

    Nancy, P. et al. Chemokine gene silencing in decidual stromal cells limits T cell access to the maternal-fetal interface. Science 336, 1317–1321 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  51. 51.

    Rieger, L. et al. Specific subsets of immune cells in human decidua differ between normal pregnancy and preeclampsia-a prospective observational study. Reprod. Biol. Endocrinol. 7, 132 (2009).

    PubMed Central  PubMed  Google Scholar 

  52. 52.

    Ishihara, K. & Hirano, T. Molecular basis of the cell specificity of cytokine action. Biochim. Biophys. Acta 1592, 281–296 (2002).

    CAS  PubMed  Google Scholar 

  53. 53.

    Yockey, L. J. & Iwasaki, A. Interferons and proinflammatory cytokines in pregnancy and fetal development. Immunity 49, 397–412 (2018).

    CAS  PubMed Central  PubMed  Google Scholar 

  54. 54.

    Racicot, K., Kwon, J. Y., Aldo, P., Silasi, M. & Mor, G. Understanding the complexity of the immune system during pregnancy. Am. J. Reprod. Immunol. 72, 107–116 (2014).

    PubMed Central  PubMed  Google Scholar 

  55. 55.

    Vacca, P., Chiossone, L., Mingari, M. C. & Moretta, L. Heterogeneity of NK cells and other innate lymphoid cells in human and murine decidua. Front. Immunol. 10, 170 (2019).

    CAS  PubMed Central  PubMed  Google Scholar 

  56. 56.

    Gomez-Lopez, N., StLouis, D., Lehr, M. A., Sanchez-Rodriguez, E. N. & Arenas-Hernandez, M. Immune cells in term and preterm labor. Cell Mol. Immunol. 11, 571–581 (2014).

    CAS  PubMed Central  PubMed  Google Scholar 

  57. 57.

    Alijotas-Reig, J., Esteve-Valverde, E., Ferrer-Oliveras, R., Llurba, E. & Gris, J. M. Tumor necrosis factor-alpha and pregnancy: focus on biologics. An updated and comprehensive review. Clin. Rev. Allergy Immunol. 53, 40–53 (2017).

    CAS  PubMed  Google Scholar 

  58. 58.

    Logiodice, F. et al. Decidual interleukin-22-producing CD4+ T Cells (Th17/Th0/IL-22+ and Th17/Th2/IL-22+, Th2/IL-22+, Th0/IL-22+), which also produce IL-4, are involved in the success of pregnancy. Int. J. Mol. Sci. 20, 428 (2019).

    PubMed Central  Google Scholar 

  59. 59.

    Nicola, N. A. & Babon, J. J. Leukemia inhibitory factor (LIF). Cytokine Growth Factor Rev. 26, 533–544 (2015).

    CAS  PubMed Central  PubMed  Google Scholar 

  60. 60.

    Winship, A., Correia, J., Zhang, J. G., Nicola, N. A. & Dimitriadis, E. Leukemia inhibitory factor (LIF) inhibition during mid-gestation impairs trophoblast invasion and spiral artery remodelling during pregnancy in mice. PLOS ONE 10, e0129110 (2015).

    PubMed Central  PubMed  Google Scholar 

  61. 61.

    Ashkar, A. A., Di Santo, J. P. & Croy, B. A. Interferon gamma contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy. J. Exp. Med. 192, 259–270 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  62. 62.

    Murphy, S. P. et al. Interferon gamma in successful pregnancies. Biol. Reprod. 80, 848–859 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  63. 63.

    Giaglis, S. et al. Neutrophil migration into the placenta: good, bad or deadly? Cell Adh. Migr. 10, 208–225 (2016).

    CAS  PubMed Central  PubMed  Google Scholar 

  64. 64.

    Chen, C. P. et al. Expression of interferon gamma by decidual cells and natural killer cells at the human implantation site: implications for preeclampsia, spontaneous abortion, and intrauterine growth restriction. Reprod. Sci. 22, 1461–1467 (2015).

    CAS  PubMed Central  PubMed  Google Scholar 

  65. 65.

    Jena, M. K., Nayak, N., Chen, K. & Nayak, N. R. Role of macrophages in pregnancy and related complications. Arch. Immunol. Ther. Exp. 67, 295–309 (2019).

    CAS  Google Scholar 

  66. 66.

    Ziegler, S. M. et al. Innate immune responses to toll-like receptor stimulation are altered during the course of pregnancy. J. Reprod. Immunol. 128, 30–37 (2018).

    CAS  PubMed  Google Scholar 

  67. 67.

    Sur Chowdhury, C. et al. Enhanced neutrophil extracellular trap generation in rheumatoid arthritis: analysis of underlying signal transduction pathways and potential diagnostic utility. Arthritis Res. Ther. 16, R122 (2014).

    PubMed Central  PubMed  Google Scholar 

  68. 68.

    Wegmann, T. G., Lin, H., Guilbert, L. & Mosmann, T. R. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol. Today 14, 353–356 (1993).

    CAS  PubMed  Google Scholar 

  69. 69.

    Fallon, P. G. et al. IL-4 induces characteristic Th2 responses even in the combined absence of IL-5, IL-9, and IL-13. Immunity 17, 7–17 (2002).

    CAS  PubMed  Google Scholar 

  70. 70.

    Ng, S. C. et al. Expression of intracellular Th1 and Th2 cytokines in women with recurrent spontaneous abortion, implantation failures after IVF/ET or normal pregnancy. Am. J. Reprod. Immunol. 48, 77–86 (2002).

    PubMed  Google Scholar 

  71. 71.

    Ostensen, M. et al. Pregnancy in patients with rheumatic disease: anti-inflammatory cytokines increase in pregnancy and decrease post partum. Ann. Rheum. Dis. 64, 839–844 (2005).

    CAS  PubMed  Google Scholar 

  72. 72.

    Santner-Nanan, B. et al. Fetal-maternal alignment of regulatory T cells correlates with IL-10 and Bcl-2 upregulation in pregnancy. J. Immunol. 191, 145–153 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  73. 73.

    Saito, S., Nakashima, A., Shima, T. & Ito, M. Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy. Am. J. Reprod. Immunol. 63, 601–610 (2010).

    CAS  PubMed  Google Scholar 

  74. 74.

    Liu, Z. Z., Sun, G. Q., Hu, X. H., Kwak-Kim, J. & Liao, A. H. The transdifferentiation of regulatory T and Th17 cells in autoimmune/inflammatory diseases and its potential implications in pregnancy complications. Am. J. Reprod. Immunol. (2017).

    Article  PubMed  Google Scholar 

  75. 75.

    Chaouat, G. et al. Th1/Th2 paradigm in pregnancy: paradigm lost? Cytokines in pregnancy/early abortion: reexamining the Th1/Th2 paradigm. Int. Arch. Allergy Immunol. 134, 93–119 (2004).

    PubMed  Google Scholar 

  76. 76.

    Roeleveld, D. M. & Koenders, M. I. The role of the Th17 cytokines IL-17 and IL-22 in rheumatoid arthritis pathogenesis and developments in cytokine immunotherapy. Cytokine 74, 101–107 (2015).

    CAS  PubMed  Google Scholar 

  77. 77.

    Furst, D. E. & Emery, P. Rheumatoid arthritis pathophysiology: update on emerging cytokine and cytokine-associated cell targets. Rheumatology 53, 1560–1569 (2014).

    CAS  PubMed Central  PubMed  Google Scholar 

  78. 78.

    McInnes, I. B. & Schett, G. Pathogenetic insights from the treatment of rheumatoid arthritis. Lancet 389, 2328–2337 (2017).

    CAS  Google Scholar 

  79. 79.

    Huizinga, T. W., van der Linden, M. W., Deneys-Laporte, V. & Breedveld, F. C. Interleukin-10 as an explanation for pregnancy-induced flare in systemic lupus erythematosus and remission in rheumatoid arthritis. Rheumatology 38, 496–498 (1999).

    CAS  PubMed  Google Scholar 

  80. 80.

    de Steenwinkel, F. D. et al. Circulating maternal cytokines influence fetal growth in pregnant women with rheumatoid arthritis. Ann. Rheum. Dis. 72, 1995–2001 (2013).

    PubMed  Google Scholar 

  81. 81.

    Samstein, R. M., Josefowicz, S. Z., Arvey, A., Treuting, P. M. & Rudensky, A. Y. Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict. Cell 150, 29–38 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  82. 82.

    Hierweger, A. M. et al. Progesterone modulates the T cell response via glucocorticoid receptor-dependent pathways. Am. J. Reprod. Immunol. 81, e13084 (2019).

    CAS  PubMed Central  PubMed  Google Scholar 

  83. 83.

    Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

    CAS  PubMed  Google Scholar 

  84. 84.

    Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).

    CAS  PubMed  Google Scholar 

  85. 85.

    Habicht, A. et al. A link between PDL1 and T regulatory cells in fetomaternal tolerance. J. Immunol. 179, 5211–5219 (2007).

    CAS  PubMed  Google Scholar 

  86. 86.

    Sakaguchi, S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat. Immunol. 6, 345–352 (2005).

    CAS  PubMed  Google Scholar 

  87. 87.

    Aluvihare, V. R., Kallikourdis, M. & Betz, A. G. Regulatory T cells mediate maternal tolerance to the fetus. Nat. Immunol. 5, 266–271 (2004).

    CAS  PubMed  Google Scholar 

  88. 88.

    Tilburgs, T. et al. Evidence for a selective migration of fetus-specific CD4+CD25bright regulatory T cells from the peripheral blood to the decidua in human pregnancy. J. Immunol. 180, 5737–5745 (2008).

    CAS  PubMed  Google Scholar 

  89. 89.

    Somerset, D. A., Zheng, Y., Kilby, M. D., Sansom, D. M. & Drayson, M. T. Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset. Immunology 112, 38–43 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

  90. 90.

    Sasaki, Y. et al. Decidual and peripheral blood CD4+CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases. Mol. Hum. Reprod. 10, 347–353 (2004).

    CAS  PubMed  Google Scholar 

  91. 91.

    Toldi, G. et al. The frequency of peripheral blood CD4+ CD25high FoxP3+ and CD4+ CD25 FoxP3+ regulatory T cells in normal pregnancy and pre-eclampsia. Am. J. Reprod. Immunol. 68, 175–180 (2012).

    CAS  PubMed  Google Scholar 

  92. 92.

    Marcoli, N. et al. Differential influence of maternal and fetal pregnancy factors on the in-vitro induction of human regulatory T cells: a preliminary study. Swiss Med. Wkly 145, w14172 (2015).

    PubMed  Google Scholar 

  93. 93.

    Metcalfe, S. M. LIF in the regulation of T-cell fate and as a potential therapeutic. Genes Immun. 12, 157–168 (2011).

    CAS  PubMed  Google Scholar 

  94. 94.

    Hosseini, A., Dolati, S., Hashemi, V., Abdollahpour-Alitappeh, M. & Yousefi, M. Regulatory T and T helper 17 cells: Their roles in preeclampsia. J. Cell Physiol. 233, 6561–6573 (2018).

    CAS  PubMed  Google Scholar 

  95. 95.

    Morgan, M. E. et al. Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+ regulatory T cells. Arthritis Rheum. 52, 2212–2221 (2005).

    CAS  PubMed  Google Scholar 

  96. 96.

    Morgan, M. E. et al. CD25+ cell depletion hastens the onset of severe disease in collagen-induced arthritis. Arthritis Rheum. 48, 1452–1460 (2003).

    PubMed  Google Scholar 

  97. 97.

    Förger, F. et al. Pregnancy induces numerical and functional changes of CD4+CD25high regulatory T cells in patients with rheumatoid arthritis. Ann. Rheum. Dis. 67, 984–990 (2008).

    PubMed  Google Scholar 

  98. 98.

    Munoz-Suano, A., Kallikourdis, M., Sarris, M. & Betz, A. G. Regulatory T cells protect from autoimmune arthritis during pregnancy. J. Autoimmun. 38, J103–J108 (2012).

    CAS  PubMed  Google Scholar 

  99. 99.

    Koenen, H. J. et al. Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood 112, 2340–2352 (2008).

    CAS  PubMed  Google Scholar 

  100. 100.

    Wang, T. et al. Regulatory T cells in rheumatoid arthritis showed increased plasticity toward Th17 but retained suppressive function in peripheral blood. Ann. Rheum. Dis. 74, 1293–1301 (2015).

    CAS  Google Scholar 

  101. 101.

    Santner-Nanan, B. et al. Systemic increase in the ratio between Foxp3+ and IL-17-producing CD4+ T cells in healthy pregnancy but not in preeclampsia. J. Immunol. 183, 7023–7030 (2009).

    CAS  Google Scholar 

  102. 102.

    Sakaguchi, S., Vignali, D. A., Rudensky, A. Y., Niec, R. E. & Waldmann, H. The plasticity and stability of regulatory T cells. Nat. Rev. Immunol. 13, 461–467 (2013).

    CAS  Google Scholar 

  103. 103.

    Ehrenstein, M. R. et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFα therapy. J. Exp. Med. 200, 277–285 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

  104. 104.

    Komatsu, N. et al. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat. Med. 20, 62–68 (2014).

    CAS  Google Scholar 

  105. 105.

    Jorgensen, K. T., Harpsoe, M. C., Jacobsen, S., Jess, T. & Frisch, M. Increased risk of rheumatoid arthritis in women with pregnancy complications and poor self-rated health: a study within the Danish National Birth Cohort. Rheumatology 53, 1513–1519 (2014).

    Google Scholar 

  106. 106.

    Ma, K. K., Nelson, J. L., Guthrie, K. A., Dugowson, C. E. & Gammill, H. S. Adverse pregnancy outcomes and risk of subsequent rheumatoid arthritis. Arthritis Rheumatol. 66, 508–512 (2014).

    PubMed Central  PubMed  Google Scholar 

  107. 107.

    Hayday, A. C. γδ T cells and the lymphoid stress-surveillance response. Immunity 31, 184–196 (2009).

    CAS  Google Scholar 

  108. 108.

    Bonneville, M., O'Brien, R. L. & Born, W. K. γδ T cell effector functions: a blend of innate programming and acquired plasticity. Nat. Rev. Immunol. 10, 467–478 (2010).

    CAS  Google Scholar 

  109. 109.

    Carding, S. R. & Egan, P. J. γδ T cells: functional plasticity and heterogeneity. Nat. Rev. Immunol. 2, 336–345 (2002).

    CAS  PubMed Central  Google Scholar 

  110. 110.

    Toussirot, E. et al. Increased production of soluble CTLA-4 in patients with spondylarthropathies correlates with disease activity. Arthritis Res. Ther. 11, R101 (2009).

    PubMed Central  PubMed  Google Scholar 

  111. 111.

    Kimura, M., Hanawa, H., Watanabe, H., Ogawa, M. & Abo, T. Synchronous expansion of intermediate TCR cells in the liver and uterus during pregnancy. Cell Immunol. 162, 16–25 (1995).

    CAS  PubMed  Google Scholar 

  112. 112.

    Terzieva, A. et al. Early pregnancy human decidua is enriched with activated, fully differentiated and pro-inflammatory Gamma/Delta T Cells with diverse TCR repertoires. Int. J. Mol. Sci. 20, 687 (2019).

    CAS  PubMed Central  Google Scholar 

  113. 113.

    Barakonyi, A., Polgar, B. & Szekeres-Bartho, J. The role of gamma/delta T-cell receptor-positive cells in pregnancy: part II. Am. J. Reprod. Immunol. 42, 83–87 (1999).

    CAS  PubMed  Google Scholar 

  114. 114.

    Szereday, L., Barakonyi, A., Miko, E., Varga, P. & Szekeres-Bartho, J. γ/δT-cell subsets, NKG2A expression and apoptosis of Vδ2+ T cells in pregnant women with or without risk of premature pregnancy termination. Am. J. Reprod. Immunol. 50, 490–496 (2003).

    PubMed  Google Scholar 

  115. 115.

    Szekeres-Bartho, J. The role of progesterone in feto-maternal immunological cross talk. Med. Princ. Pract. 27, 301–307 (2018).

    PubMed Central  PubMed  Google Scholar 

  116. 116.

    Szekeres-Bartho, J. & Wegmann, T. G. A progesterone-dependent immunomodulatory protein alters the Th1/Th2 balance. J. Reprod. Immunol. 31, 81–95 (1996).

    CAS  PubMed  Google Scholar 

  117. 117.

    Peterman, G. M., Spencer, C., Sperling, A. I. & Bluestone, J. A. Role of gamma delta T cells in murine collagen-induced arthritis. J. Immunol. 151, 6546–6558 (1993).

    CAS  PubMed  Google Scholar 

  118. 118.

    Smith, M. D. et al. Tγδ cells and their subsets in blood and synovial tissue from rheumatoid arthritis patients. Scand. J. Immunol. 32, 585–593 (1990).

    CAS  PubMed  Google Scholar 

  119. 119.

    Tham, M. et al. Reduced pro-inflammatory profile of γδT cells in pregnant patients with rheumatoid arthritis. Arthritis Res. Ther. 18, 26 (2016).

    PubMed Central  PubMed  Google Scholar 

  120. 120.

    Ito, Y. et al. Gamma/delta T cells are the predominant source of interleukin-17 in affected joints in collagen-induced arthritis, but not in rheumatoid arthritis. Arthritis Rheum. 60, 2294–2303 (2009).

    CAS  PubMed  Google Scholar 

  121. 121.

    Shen, Y. et al. TCR γ/δ+ cell subsets in the synovial membranes of patients with rheumatoid arthritis and juvenile rheumatoid arthritis. Scand. J. Immunol. 36, 533–540 (1992).

    CAS  PubMed  Google Scholar 

  122. 122.

    Förger, F., Østensen, M., Schumacher, A. & Villiger, P. M. Impact of pregnancy on health related quality of life evaluated prospectively in pregnant women with rheumatic diseases by the SF-36 health survey. Ann. Rheum. Dis. 64, 1494–1499 (2005).

    PubMed Central  PubMed  Google Scholar 

  123. 123.

    Østensen, M., Fuhrer, L., Mathieu, R., Seitz, M. & Villiger, P. M. A prospective study of pregnant patients with rheumatoid arthritis and ankylosing spondylitis using validated clinical instruments. Ann. Rheum. Dis. 63, 1212–1217 (2004).

    PubMed Central  PubMed  Google Scholar 

  124. 124.

    Unger, A., Kay, A., Griffin, A. J. & Panayi, G. S. Disease activity and pregnancy associated alpha 2-glycoprotein in rheumatoid arthritis during pregnancy. Br. Med. J. 286, 750–752 (1983).

    CAS  Google Scholar 

  125. 125.

    Jethwa, H., Lam, S., Smith, C. & Giles, I. Does rheumatoid arthritis really improve during pregnancy? A systematic review and metaanalysis. J. Rheumatol. 46, 245–250 (2019).

    PubMed  Google Scholar 

  126. 126.

    Østensen, M., Sicher, P., Forger, F. & Villiger, P. M. Activation markers of peripheral blood mononuclear cells in late pregnancy and after delivery: a pilot study. Ann. Rheum. Dis. 64, 318–320 (2005).

    PubMed Central  PubMed  Google Scholar 

  127. 127.

    Recalde, G. et al. Contribution of sex steroids and prolactin to the modulation of T and B cells during autoimmunity. Autoimmun. Rev. 17, 504–512 (2018).

    CAS  PubMed  Google Scholar 

  128. 128.

    Vieira Borba, V. & Shoenfeld, Y. Prolactin, autoimmunity, and motherhood: when should women avoid breastfeeding? Clin. Rheumatol. 38, 1263–1270 (2019).

    PubMed  Google Scholar 

  129. 129.

    Pereira Suarez, A. L., Lopez-Rincon, G., Martinez Neri, P. A. & Estrada-Chavez, C. Prolactin in inflammatory response. Adv. Exp. Med. Biol. 846, 243–264 (2015).

    PubMed  Google Scholar 

  130. 130.

    Pellegrini, I., Lebrun, J. J., Ali, S. & Kelly, P. A. Expression of prolactin and its receptor in human lymphoid cells. Mol. Endocrinol. 6, 1023–1031 (1992).

    CAS  PubMed  Google Scholar 

  131. 131.

    Tang, M. W. et al. Rheumatoid arthritis and psoriatic arthritis synovial fluids stimulate prolactin production by macrophages. J. Leukoc. Biol. 102, 897–904 (2017).

    CAS  PubMed  Google Scholar 

  132. 132.

    Tang, M. W. et al. The prolactin receptor is expressed in rheumatoid arthritis and psoriatic arthritis synovial tissue and contributes to macrophage activation. Rheumatology 55, 2248–2259 (2016).

    CAS  PubMed Central  PubMed  Google Scholar 

  133. 133.

    Ince-Askan, H., Hazes, J. M. W. & Dolhain, R. Breastfeeding among women with rheumatoid arthritis compared with the general population: results from a nationwide prospective cohort study. J. Rheumatol. 46, 1067–1074 (2019).

    CAS  PubMed  Google Scholar 

  134. 134.

    Zhang, F. et al. Are prolactin levels linked to suction pressure? Breastfeed. Med. 11, 461–468 (2016).

    PubMed  Google Scholar 

  135. 135.

    Chen, H., Wang, J., Zhou, W., Yin, H. & Wang, M. Breastfeeding and risk of rheumatoid arthritis: a systematic review and metaanalysis. J. Rheumatol. 42, 1563–1569 (2015).

    PubMed  Google Scholar 

  136. 136.

    Andreoli, L. et al. EULAR recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Ann. Rheum. Dis. 76, 476–485 (2017).

    CAS  PubMed  Google Scholar 

  137. 137.

    Buyon, J. P. et al. Predictors of pregnancy outcomes in patients with lupus: a cohort study. Ann. Intern. Med. 163, 153–163 (2015).

    PubMed Central  PubMed  Google Scholar 

  138. 138.

    Moroni, G. et al. Fetal outcome and recommendations of pregnancies in lupus nephritis in the 21st century. A prospective multicenter study. J. Autoimmun. 74, 6–12 (2016).

    PubMed  Google Scholar 

  139. 139.

    Gotestam Skorpen, C. et al. Disease activity during pregnancy and the first year postpartum in women with systemic lupus erythematosus. Arthritis Care Res. 69, 1201–1208 (2017).

    Google Scholar 

  140. 140.

    Crow, M. K. & Ronnblom, L. Type I interferons in host defence and inflammatory diseases. Lupus Sci. Med. 6, e000336 (2019).

    PubMed Central  PubMed  Google Scholar 

  141. 141.

    Kirou, K. A. et al. Activation of the interferon-alpha pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease. Arthritis Rheum. 52, 1491–1503 (2005).

    CAS  PubMed  Google Scholar 

  142. 142.

    Andrade, D. et al. Interferon-alpha and angiogenic dysregulation in pregnant lupus patients who develop preeclampsia. Arthritis Rheumatol. 67, 977–987 (2015).

    CAS  PubMed Central  PubMed  Google Scholar 

  143. 143.

    Ursin, K., Lydersen, S., Skomsvoll, J. F. & Wallenius, M. Disease activity during and after pregnancy in women with axial spondyloarthritis: a prospective multicentre study. Rheumatology 57, 1064–1071 (2018).

    PubMed  Google Scholar 

  144. 144.

    Lories, R. J. & Baeten, D. L. Differences in pathophysiology between rheumatoid arthritis and ankylosing spondylitis. Clin. Exp. Rheumatol. 27, S10–S14 (2009).

    CAS  PubMed  Google Scholar 

  145. 145.

    Förger, F., Villiger, P. M. & Østensen, M. Pregnancy in patients with ankylosing spondylitis: do regulatory T cells play a role? Arthritis Rheum. 61, 279–283 (2009).

    PubMed  Google Scholar 

  146. 146.

    Bhalla, A., Stone, P. R., Liddell, H. S., Zanderigo, A. & Chamley, L. W. Comparison of the expression of human leukocyte antigen (HLA)-G and HLA-E in women with normal pregnancy and those with recurrent miscarriage. Reproduction 131, 583–589 (2006).

    CAS  PubMed  Google Scholar 

  147. 147.

    Morandi, F. & Pistoia, V. Interactions between HLA-G and HLA-E in physiological and pathological conditions. Front. Immunol. 5, 394 (2014).

    PubMed Central  PubMed  Google Scholar 

  148. 148.

    Li, S. et al. Estrogen induces indoleamine 2,3-dioxygenase expression via suppressors of cytokine signaling 3 in the chorionic villi and decidua of women in early pregnancy. Am. J. Reprod. Immunol. (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  149. 149.

    Liu, W. et al. Relationship of SOCS3 and TGF-β with IDO expression in early pregnancy chorionic villi and decidua. Exp. Ther. Med. 14, 4817–4824 (2017).

    CAS  PubMed Central  PubMed  Google Scholar 

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Correspondence to Frauke Förger.

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The maternal part of the placenta.

Semiallogeneic graft

A transplant sharing half of its genes with the recipient


An organ, tissue or cells transplanted between genetically non-identical members of the same species.


The presence of a small number of genetically distinct cells in a host individual.


A complication of pregnancy characterized by hypertension and proteinuria and signs of damage to other organs, usually occurring after 20 weeks of pregnancy.

Mixed lymphocyte reaction

The proliferation response following co-culture of two populations of lymphocytes, used as a surrogate measure of T cell activation

Trophoblast invasion

Invasion of the uterus by fetal cells during human placentation.

Spiral artery remodelling

Transformation of spiral arteries into vessels of low resistance by trophoblast invasion.


The process of labour and delivery.

Chorioamniotic membranes

Fetal membranes (amnion and chorion) making up the amniotic sac that surrounds and protects the fetus.

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Förger, F., Villiger, P.M. Immunological adaptations in pregnancy that modulate rheumatoid arthritis disease activity. Nat Rev Rheumatol 16, 113–122 (2020).

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