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SLE and pregnancy: the potential role for regulatory T cells

Nature Reviews Rheumatology volume 7, pages 124–128 (2011)Cite this article

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Abstract

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder that disproportionally affects women, especially in their reproductive years. SLE is associated with considerable pregnancy-related morbidity—including fetal loss, preterm birth, fetal growth restriction and pre-eclampsia. CD4+CD25+ regulatory T (TREG) cells have a potent immunosuppressive function and contribute to immunological self-tolerance. These cells might be essential for successful placental development by ensuring fetal tolerance. The numbers of TREG cells are augmented during normal pregnancy and, conversely, diminished numbers are associated with pregnancy loss and pre-eclampsia. Several studies have shown that patients with SLE have decreased numbers of TREG cells that might be functionally defective. This defective TREG cell functioning could predispose women with SLE to pregnancy complications. This article provides an overview of current knowledge of the role and function of TREG cells in SLE and pregnancy and how these cells might contribute to improving pregnancy-related outcomes in patients with SLE in the future.

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Figure 1: Maternal tolerance of the fetus.
Figure 2: The origins of TREG cells.

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References

  1. Dachenko, N., Satia, J. A. & Anthony, M. S. Epidemiology of systemic lupus erythematosus: a comparison of worldwide disease burden. Lupus 15, 308–318 (2006).

    Article  Google Scholar 

  2. Clowse, M. E., Jamison, M., Myers, E. & James, A. H. A national study of the complications of lupus in pregnancy. Am. J. Obstet. Gynecol. 199, 127.e1–127.e6 (2008).

    Article  Google Scholar 

  3. Yacobi, S., Ornoy, A., Blumenfeld, Z. & Miller, R. K. Effect of sera from women with systemic lupus erythematosus or antiphospholipid syndrome and recurrent abortions on human placental explants in culture. Teratology 66, 300–308 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Sakaguchi, S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol. 22, 531–562 (2004).

    Article  CAS  Google Scholar 

  6. Bennett, C. L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20–21 (2001).

    Article  CAS  Google Scholar 

  7. Wu, H. Y. & Staines, N. A. A deficiency of CD4+CD25+ T cells permits the development of spontaneous lupus-like disease in mice, and can be reversed by induction of mucosal tolerance to histone peptide autoantigen. Lupus 13, 192–200 (2004).

    Article  CAS  Google Scholar 

  8. Barath, S. et al. The severity of systemic lupus erythematosus negatively correlates with the increasing number of CD4+CD25highFoxP3+ regulatory T cells during repeated plasmapheresis treatments of patients. Autoimmunity 40, 521–528 (2007).

    Article  CAS  Google Scholar 

  9. Bonelli, M. et al. Quantitative and qualitative deficiencies of regulatory T cells in patients with systemic lupus erythematosus (SLE). Int. Immunol. 20, 861–868 (2008).

    Article  CAS  Google Scholar 

  10. Valencia, X., Yarboro, C., Illei, G. & Lipsky, P. E. Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J. Immunol. 178, 2579–2588 (2007).

    Article  CAS  Google Scholar 

  11. Suárez, A., López, P., Gómez, J. & Gutierréz, C. Enrichment of CD4+CD25high T cell population in patients with systemic lupus erythematosus treated with glucocorticoids. Ann. Rheum. Dis. 65, 1512–1517 (2006).

    Article  Google Scholar 

  12. Yan, B. et al. Dysfunctional CD4+CD25+ regulatory T cells in untreated active systemic lupus erythematosus secondary to interferon-alpha-producing antigen-presenting cells. Arthritis Rheum. 58, 801–812 (2008).

    Article  CAS  Google Scholar 

  13. Lee, H. Y. et al. Altered frequency and migration capacity of CD4+CD25+ regulatory T cells in systemic lupus erythematosus. Rheumatology (Oxford) 47, 789–794 (2008).

    Article  CAS  Google Scholar 

  14. Vargas-Rojas, M. I., Crispin, J. C., Richaud-Patin, Y. & Alcocer-Varela, J. Quantitative and qualitative normal regulatory T cells are not capable of inducing suppression in SLE patients due to T-cell resistance. Lupus 17, 289–294 (2008).

    Article  CAS  Google Scholar 

  15. Zhang, B. et al. Clinical significance of increased CD4+CD25−FOXP3+ T cells in patients with new-onset systemic lupus erythematosus. Ann. Rheum. Dis. 67, 1037–1040 (2008).

    Article  CAS  Google Scholar 

  16. Cepika, A. M., Marinic, I., Morovic-Vergles, J., Soldo-Juresa, D. & Gagro, A. Effect of steroids on the frequency of regulatory T cells and expression of FOXP3 in a patient with systemic lupus erythematosus: a two-year follow-up. Lupus 16, 374–377 (2007).

    Article  Google Scholar 

  17. Zhang, B., Zhang, X., Tang, F., Zhu, L. & Liu, Y. Reduction of forkhead box P3 levels in CD4+CD25high T cells in patients with new-onset systemic lupus erythematosus. Clin. Exp. Immunol. 153, 182–187 (2008).

    Article  CAS  Google Scholar 

  18. Chirico, D., Bruce, I., Baker, P. & Tower, C. Predictors of pregnancy complications in women with systemic lupus erythematosus [abstract]. BJOG 116, 1407–1408 (2009).

    Google Scholar 

  19. Horwitz, D. A., Zheng, S. G. & Gray, J. D. Natural and TGF-beta-induced Foxp3+CD4+CD25+ regulatory T cells are not mirror images of each other. Trends Immunol. 29, 429–435 (2008).

    Article  CAS  Google Scholar 

  20. Marie, J. C., Letterio, J. J., Gavin, M. & Rudensky, A. Y. TGF-β1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J. Exp. Med. 201, 1061–1067 (2005).

    Article  CAS  Google Scholar 

  21. Dang, H. et al. SLE-like autoantibodies and Sjogren's syndrome-like lymphoproliferation in TGF-β knockout mice. J. Immunol. 155, 3205–3212 (1995).

    CAS  PubMed  Google Scholar 

  22. Ohtsuka, K., Gray, J. D., Stimmler, M. M., Toro, B. & Horwitz, D. A. Decreased production of TGF-β by lymphocytes from patients with systemic lupus erythematosus. J. Immunol. 160, 2539–2545 (1998).

    CAS  PubMed  Google Scholar 

  23. Ohtsuka, K., Gray, J. D., Stimmler, M. M. & Horwitz, D. A. The relationship between defects in lymphocyte production of transforming growth factor-β1 in systemic lupus erythematosus and disease activity or severity. Lupus 8, 90–94 (1999).

    Article  CAS  Google Scholar 

  24. Jackson, M., Ahmad, Y., Bruce, I. N., Coupes, B. & Brenchley, P. E. Activation of transforming growth factor-β1 and early atherosclerosis in systemic lupus erythematosus. Arthritis Res. Ther. 8, R81 (2006).

    Article  Google Scholar 

  25. Blaauw, J. et al. Increased intima-media thickness after early-onset pre-eclampsia. Obstet. Gynecol. 107, 1345–1351 (2006).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  27. 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).

    Article  CAS  Google Scholar 

  28. Tilburgs, T. et al. Differential distribution of CD4+CD25bright and CD8+CD28− T-cells in decidua and maternal blood during human pregnancy. Placenta 27 (Suppl. A), S47–S53 (2006).

    Article  Google Scholar 

  29. 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).

    Article  CAS  Google Scholar 

  30. Sasaki, Y. et al. Proportion of peripheral blood and decidual CD4+CD25bright regulatory T cells in pre-eclampsia. Clin. Exp. Immunol. 149, 139–145 (2007).

    Article  CAS  Google Scholar 

  31. Darmochwal-Kolarz, D. et al. Activated T lymphocytes in pre-eclampsia. Am. J. Reprod. Immunol. 58, 39–45 (2007).

    Article  CAS  Google Scholar 

  32. Clausen, T. et al. Altered plasma concentrations of leptin, transforming growth factor-β1 and plasminogen activator inhibitor type 2 at 18 weeks of gestation in women destined to develop pre-eclampsia. Circulating markers of disturbed placentation? Placenta 23, 380–385 (2002).

    Article  CAS  Google Scholar 

  33. Clark, D. A., Fernandes, J. & Banwatt, D. Prevention of spontaneous abortion in the CBA × DBA/2 mouse model by intravaginal TGF-β and local recruitment of CD4+8+FOXP3+ cells. Am. J. Reprod. Immunol. 59, 525–534 (2008).

    Article  Google Scholar 

  34. Scarpellini, F. & Sbracia, M. Effectiveness of GM-CSF 1 in the treatment of habitual abortion in a controlled study [abstract 6.7]. Am. J. Reprod. Immunol. 51, 433–434 (2004).

    Google Scholar 

  35. Scarpellini, F. & Sbracia, M. G-CSF treatment in unexplained recurrent spontaneous abortion mobilized different lymphocytes and dendritic cells in peripheral blood [abstract 1171570850]. Am. J. Reprod. Immunol. 57, 327 (2007).

    Google Scholar 

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Acknowledgements

The authors acknowledge the support of the Manchester Wellcome Trust Clinical Research Facility, UK. I. Bruce and the Maternal Fetal Health Research Group are supported by the Manchester Academic Health Sciences Center and the Manchester National Institute for Health Research Biomedical Research Center, UK.

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Authors and Affiliations

  1. Maternal and Fetal Health Research Center,

    Clare Tower, Ian Crocker, Debora Chirico & Philip Baker

  2. Arthritis Research UK Epidemiology Unit, Manchester Academic Health Sciences Center, The University of Manchester, Brunswick Street, Manchester, M13 9PL, UK

    Ian Bruce

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  1. Clare Tower
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Contributions

C. Tower, I. Crocker and D. Chirico contributed equally to researching the data for the article and to writing the article. C. Tower, I. Crocker, D. Chirico and I. Bruce provided a substantial and equal contribution to discussions of the content. C. Tower, I. Crocker, P. Baker and I. Bruce contributed equally to reviewing and/or editing of the manuscript before submission.

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Correspondence to Clare Tower.

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Tower, C., Crocker, I., Chirico, D. et al. SLE and pregnancy: the potential role for regulatory T cells. Nat Rev Rheumatol 7, 124–128 (2011). https://doi.org/10.1038/nrrheum.2010.124

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