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  • Review Article
  • Published:

Modulation of autoimmune rheumatic diseases by oestrogen and progesterone

Key Points

  • Sexual dimorphism in the risk and expression of human autoimmune rheumatic diseases involves the immunomodulatory effects of postpubertal levels of sex steroid hormones

  • Oestrogen increases the risk of SLE in genetically susceptible women by increasing type 1 interferon production and favouring the survival of B cells that produce pathogenic IgG autoantibodies

  • Progesterone might reduce the risk of SLE in genetically predisposed women by countering these oestrogen effects—thus, the balance between oestrogen and progesterone might influence the risk of SLE

  • Pregnancy-induced amelioration of rheumatoid arthritis probably involves anti-inflammatory and tolerogenic effects of high circulating levels of progesterone, oestrogen and cortisol

  • Research into mechanisms of sex-steroid-related immunomodulation is expected to uncover novel therapeutic targets in autoimmune rheumatic conditions and to improve understanding of sexual dimorphism in risk of other diseases

Abstract

Sexual dimorphism is evident in the risk and expression of several human autoimmune diseases. Differences in disease manifestations observed between sexes are likely to involve immunomodulation by sex steroids, nonhormonal factors encoded by genes on the X and Y chromosomes, and immunological phenomena unique to pregnancy. In systemic lupus erythematosus (SLE), and perhaps other autoantibody-mediated diseases, oestrogen seems to increase the risk of disease in genetically predisposed women by targeting key immune pathways, including the type 1 interferon (IFN) response, differentiation of CD4+ T helper cells and survival of autoreactive B cells. By contrast, progesterone seems to reduce the risk of SLE by counteracting the effects of oestrogen on some of these same pathways, which suggests that the balance between oestrogen and progesterone can determine disease expression. In this Review we focus on the roles of the sex steroid hormones oestrogen and progesterone in modulating the risk and expression of SLE and rheumatoid arthritis. Intensive research in this area promises to identify novel therapeutic strategies and improve understanding of the immunological requirements and complications of pregnancy, and is expected to define the mechanisms behind sexual dimorphism in autoimmunity, immunity and other aspects of human health—a newly announced directive of the NIH.

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Figure 1: Effects of oestrogen and progesterone on the risk of systemic lupus erythematosus in women.
Figure 2: Potential contributions of oestrogen and progesterone to amelioration of rheumatoid arthritis in pregnant women.
Figure 3: Potential mechanisms through which oestrogen and progesterone might modulate the loss of immune tolerance and regulate the production of pathogenic IgG autoantibodies in systemic lupus erythematosus.
Figure 4: Potential mechanisms through which high levels of oestrogen and progesterone during pregnancy reduce disease activity in rheumatoid arthritis.

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References

  1. McCombe, P., Greer, J. & Mackay, I. Sexual dimorphism in autoimmune disease. Curr. Mol. Med. 9, 1058–1079 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Whitacre, C. Sex differences in autoimmune disease. Nat. Immunol. 2, 777–780 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Nahmias, A. J., Schollin, J. & Abramowsky, C. Evolutionary-developmental perspectives on immune system interactions among the pregnant woman, placenta, and fetus, and responses to sexually transmitted infectious agents. Ann. NY Acad. Sci. 1230, 25–47 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. Bellott, D. W. et al. Mammalian Y chromosomes retain widely expressed dosage-sensitive regulators. Nature 508, 494–499 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bouman, A., Heineman, M. & Faas, M. Sex hormones and the immune response in humans. Hum. Reprod. Update 4, 411–423 (2005).

    Article  CAS  Google Scholar 

  6. Libert, C., Dejager, L. & Pinheiro, I. The X chromosome in immune functions: when a chromosome makes the difference. Nat. Rev. Immunol. 10, 594–604 (2010).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Adams, K. A. & Nelson, J. L. Michrochimerism: an investigative frontier in autoimmunity and transplantation. JAMA 291, 1127–1131 (2009).

    Article  Google Scholar 

  9. Oertelt-Prigione, S. The influence of sex and gender on the immune response. Autoimmun. Rev. 11, A479–A485 (2012).

    Article  CAS  PubMed  Google Scholar 

  10. Clayton, J. A. & Collins, F. S. NIH to balance sex in cell and animal studies. Nature 509, 282–283 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ellman, S. et al. Estrogen and progesterone receptors: from molecular structures to clinical targets. Cell. Mol. Life Sci. 66, 2405–2426 (2009).

    Article  CAS  Google Scholar 

  12. Cunningham, M. & Gilkeson, G. Estrogen receptors in immunity and autoimmunity. Clin. Rev. Allergy Immunol. 40, 66–73 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. Schindler, A. E. et al. Classification and pharmacology of progestins. Maturitas 61, 171–180 (2008).

    Article  PubMed  Google Scholar 

  14. Petri, M. Epidemiology of systemic lupus erythematosus. Best Pract. Res. Clin. Rheumatol. 16, 847–858 (2002).

    Article  PubMed  Google Scholar 

  15. Simard, J. F. & Costenbader, K. H. What can epidemiology tell us about systemic lupus erythematosus? Int. J. Clin. Pract. 61, 1170–1180 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Arnaud, L., Mathian, A., Boddaert, J. & Amoura, Z. Late-onset systemic lupus erythematosus. Drugs Aging 29, 181–189 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Kaslow, R. & Masi, A. Age, sex, and race effects on mortality from systemic lupus erythematosus in the United States. Arthritis Rheum. 21, 473–479 (1978).

    Article  CAS  PubMed  Google Scholar 

  18. Kamphuis, S. & Silverman, E. D. Prevalence and burden of pediatric-onset systemic lupus erythematosus. Nat. Rev. Rheumatol. 6, 538–546 (2010).

    Article  CAS  PubMed  Google Scholar 

  19. Pluchinotta, F. R. et al. Distinctive clinical features of pediatric systemic lupus erythematosus in three different age classes. Lupus 16, 550–555 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Mariotti, S. et al. Puberty is associated with a marked increase of the female sex predominance in chronic autoimmune thyroiditis. Horm. Res. 72, 52–56 (2009).

    Article  CAS  PubMed  Google Scholar 

  21. Costenbader, K., Feskanich, D., Stampfer, M. & Karlson, E. Reproductive and menopausal factors and risk of systemic lupus erythematosus in women. Arthritis Rheum. 56, 1251–1262 (2007).

    Article  PubMed  Google Scholar 

  22. Medeiros, P. B. et al. Menstrual and hormonal alterations in juvenile systemic lupus erythematosus. Lupus 18, 38–43 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Shabanova, S., Ananieva, L., Alekberova, Z. & Guzov, I. Ovarian function and disease activity in patients with systemic lupus erythematosus. Clin. Exp. Rheumatol 26, 436–441 (2008).

    CAS  PubMed  Google Scholar 

  24. Ulff-Moller, C. J., Jorgensen, K. T., Pedersen, B. V., Nielsen, N. M. & Frisch, M. Reproductive factors and risk of systemic lupus erythematosus: nationwide cohort study in Denmark. J. Rheumatol. 36, 1903–1909 (2009).

    Article  PubMed  Google Scholar 

  25. Bernier, M., Mikaeloff, Y., Hudson, M. & Suissa, S. Combined oral contraceptive use and the risk of systemic lupus erythematosus. Arthritis Rheum. 61, 476–481 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Petri, M., Thompson, E., Abusuwwa, R., Huang, J. & Garrett, E. BALES: the Baltimore lupus environmental study [abstract]. Arthritis Rheum. 44, S331 (2001).

    Article  Google Scholar 

  27. Petri, M. et al. Combined oral contraceptives in women with systemic lupus erythematosus. N. Engl. J. Med. 353, 2550–2558 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Sanchez-Guerrero, J. et al. A trial of contraceptive methods in women with systemic lupus erythematosus. N. Engl. J. Med. 353, 2539–2549 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Buyon, J. P. et al. The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial. Ann. Intern. Med. 142, 953–962 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Chabbert-Buffet, N. et al. Pregnane progestin contraception in systemic lupus erythematosus: a longitudinal study of 187 patients. Contraception 83, 229–237 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Vieira, C. S. et al. Tibolone in postmenopausal women with systemic lupus erythematosus: a pilot study. Maturitas 62, 311–316 (2008).

    Article  CAS  Google Scholar 

  32. Oertelt-Prigione, S. Immunology and the menstrual cycle. Autoimmun. Rev. 11, A486–A492 (2012).

    Article  CAS  PubMed  Google Scholar 

  33. Zen, M. et al. Hormones, immune response, and pregnancy in healthy women and SLE patients. Swiss Med. Wkly 140, 187–201 (2010).

    CAS  PubMed  Google Scholar 

  34. Barbhaiya, M. & Bermas, B. L. Evaluation and management of systemic lupus erythematosus and rheumatoid arthritis during pregnancy. Clin. Immunol. 149, 225–235 (2013).

    Article  CAS  PubMed  Google Scholar 

  35. Doria, A. et al. Pregnancy, cytokines, and disease activity in systemic lupus erythematosus. Arthritis Rheum. 51, 989–995 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Roubinian, J., Talal, N., Siiteri, P. & Sadakian, J. Sex hormone modulation of autoimmunity in NZB/W mice. Arthritis Rheum. 22, 1162–1169 (1979).

    CAS  PubMed  Google Scholar 

  37. Hughes, G. C. et al. Decrease in glomerulonephritis and Th1-associated autoantibody production after progesterone treatment in NZB/NZW mice. Arthritis Rheum. 60, 1775–1784 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. Roubinian, J., Talal, N., Greenspan, J., Goodman, J. & Siiteri, P. Effect of castration and sex hormone treatment on survival, anti-nucleic acid antibodies, and glomerulonephritis in NZB/NZW F1 mice. J. Exp. Med. 147, 1568–1583 (1978).

    Article  CAS  PubMed  Google Scholar 

  39. Bynote, K. K. et al. Estrogen receptor-alpha deficiency attenuates autoimmune disease in (NZB × NZW)F1 mice. Genes Immun. 9, 137–152 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Li, J. & McMurray, R. W. Effects of estrogen receptor subtype-selective agonists on autoimmune disease in lupus-prone NZB/NZW F1 mouse model. Clin. Immunol. 123, 219–226 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Carlsten, H., Tarkowski, A., Holmdahl, R. & Nilsson, L. Oestrogen is a potent disease accelerator in SLE-prone lpr/lpr mice. Clin. Exp. Immunol. 80, 467–473 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Svenson, J. L., EuDaly, J., Ruiz, P., Korach, K. S. & Gilkeson, G. S. Impact of estrogen receptor deficiency on disease expression in the NZM2410 lupus prone mouse. Clin. Immunol. 128, 259–268 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Verheul, H. A., Stimson, W. H., Hollander, F. C. & Schuurs, A. H. The effects of nandrolone, testosterone and their decanoate esters on murine lupus. Clin. Exp. Immunol. 44, 11–17 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Roubinian, J. R., Papoian, R. & Talal, N. Androgenic hormones modulate autoantibody responses and improve survival in murine lupus. J. Clin. Invest. 59, 1066–1070 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Keisler, L., Kier, A. & Walker, S. Effects of prolonged adminstration of the 19-nor-testosterone derivatives norethindrone and norgestrel to female NZB/W mice: comparison with medroxyprogesterone and ehtinyl estradiol. Autoimmunity 9, 21–32 (1991).

    Article  CAS  PubMed  Google Scholar 

  46. Miller, L. et al. Depomedroxyprogesterone-induced hypoestrogenism and changes in vaginal flora and epithelium. Obstet. Gynecol. 96, 431–439 (2000).

    CAS  PubMed  Google Scholar 

  47. Cooper, G. S. & Stroehla, B. C. The epidemiology of autoimmune diseases. Autoimmun. Rev. 2, 119–125 (2003).

    Article  PubMed  Google Scholar 

  48. Zink, A., Listing, J., Klindworth, C., Zeidler, H. The national database of the German Collaborative Arthritis Centres: I. Structure, aims, and patients. Ann. Rheum. Dis. 60, 199–206 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Karlson, E. W., Mandl, L. A., Hankinson, S. E. & Grodstein, F. Do breast-feeding and other reproductive factors influence future risk of rheumatoid arthritis? Results from the Nurses' Health Study. Arthritis Rheum. 50, 3458–3467 (2004).

    Article  PubMed  Google Scholar 

  50. Walitt, B. et al. Effects of postmenopausal hormone therapy on rheumatoid arthritis: the women's health initiative randomized controlled trials. Arthritis Rheum. 59, 302–310 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Tedeschi, S. K., Bermas, B. & Costenbader, K. H. Sexual disparities in the incidence and course of SLE and RA. Clin. Immunol. 149, 211–218 (2013).

    Article  CAS  PubMed  Google Scholar 

  52. Kovacs, W. J. & Olsen, N. J. Sexual dimorphism of RA manifestations: genes, hormones and behavior. Nat. Rev. Rheumatol. 7, 307–310 (2011).

    Article  CAS  PubMed  Google Scholar 

  53. Guthrie, K. A., Dugowson, C. E., Voigt, L. F., Koepsell, T. D. & Nelson, J. L. Does pregnancy provide vaccine-like protection against rheumatoid arthritis? Arthritis Rheum. 7, 1842–1848 (2010).

    Google Scholar 

  54. Erlebacher, A. Mechanisms of T cell tolerance towards the allogeneic fetus. Nat. Rev. Immunol. 13, 23–33 (2013).

    Article  CAS  PubMed  Google Scholar 

  55. Robinson, D. P. & Klein, S. L. Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis. Horm. Behav. 62, 263–271 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Inoue, K., Inoue, E. & Imai, Y. Female sex hormones ameliorate arthritis in SKG mice. Biochem. Biophys. Res. Commun. 434, 740–745 (2013).

    Article  CAS  PubMed  Google Scholar 

  57. Subramanian, S. et al. Ethinyl estradiol treats collagen-induced arthritis in DBA/1LacJ mice by inhibiting the production of TNF-alpha and IL-1beta. Clin. Immunol. 115, 162–72 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Hall, J. & Rosen, A. Type 1 interferons: crucial participants in disease amplification in autoimmunity. Nat. Rev. Rheumatol. 6, 40–49 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Choubey, D. & Moudgil, K. D. Interferons in autoimmune and inflammatory diseases: regulation and roles. J. Interferon Cytokine Res. 31, 857–865 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Theofilopoulos, A., Baccala, R., Beutler, B. & Kono, D. Type 1 interferons (α/β) in immunity and autoimmunity. Ann. Rev. Immunol. 23, 307–336 (2005).

    Article  CAS  Google Scholar 

  61. Elkon, K. B. & Stone, V. V. Type I interferon and systemic lupus erythematosus. J. Interferon Cytokine Res. 31, 803–812 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Choubey, D. Interferon-inducible Ifi200-family genes as modifiers of lupus susceptibility. Immunol. Lett. 147, 10–17 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ronnblom, L. & Elkon, K. B. Cytokines as therapeutic targets in SLE. Nat. Rev. Rheumatol. 6, 339–347 (2010).

    Article  PubMed  CAS  Google Scholar 

  64. Klein, S. L., Jedlicka, A. & Pekosz, A. The Xs and Y of immune responses to viral vaccines. Lancet Infect. Dis. 10, 338–349 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Meier, A. et al. Sex differences in the Toll-like receptor-mediated response of plasmacytoid dendritic cells to HIV-1. Nat. Med. 15, 955–959 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Berghofer, B. et al. TLR7 ligands induce higher IFN-alpha production in females. J. Immunol. 177, 2088–2096 (2006).

    Article  PubMed  Google Scholar 

  67. Seillet, C. et al. The TLR-mediated response of plasmacytoid dendritic cells is positively regulated by estradiol in vivo through cell-intrinsic estrogen receptor signaling. Blood 119, 454–464 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Panchanathan, R., Liu, H. & Choubey, D. Expression of murine Unc93b1 is up-regulated by interferon and estrogen signaling: implications for sex bias in the development of autoimmunity. Int. Immunol. 25, 521–529 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Shen, H. et al. Gender-dependent expression of murine Irf5 gene: implications for sex bias in autoimmunity. J. Mol. Cell Biol. 2, 284–290 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Panchanathan, R., Shen, H., Zhang, X., Ho, S. & Choubey, D. Mutually positive regulatory feedback loop between interferons and estrogen receptor-alpha in mice: implications for sex bias in autoimmunity. PLoS ONE 5, e10868 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Shen, N. et al. Sex-specific assoctiation of X-linked toll-like receptor 7 (TLR7) with male systemic lupus erythematosus. Proc. Natl Acad. Sci. USA 107, 15838–15843 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hughes, T. et al. Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus. Ann. Rheum. Dis. 71, 694–699 (2012).

    Article  CAS  PubMed  Google Scholar 

  73. Han, S. et al. Osteopontin and systemic lupus erythematosus association: a probable gene-gender interaction. PLoS ONE 3, e0001757 (2008).

    Article  PubMed  CAS  Google Scholar 

  74. Hughes, G. C., Thomas, S., Li, C., Kaja, M. & Clark, E. A. Progesterone regulates IFN-alpha production by plasmacytoid dendritic cells. J. Immunol. 180, 2029–2033 (2008).

    Article  CAS  PubMed  Google Scholar 

  75. Huijbregts, R. P. et al. Hormonal contraception and HIV-1 infection: medroxyprogesterone acetate suppresses innate and adaptive immune mechanisms. Endocrinology 154, 1282–1295 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Tayel, S. S. et al. Progesterone suppresses interferon signaling by repressing TLR-7 and MxA expression in peripheral blood mononuclear cells of patients infected with hepatitis C virus. Arch. Virol. 158, 1755–1764 (2013).

    Article  CAS  PubMed  Google Scholar 

  77. Dosiou, C., Lathi, R., Tulac, S., Huang, S. & Giudice, L. Interferon-related and other immune genes are downregulated in periphral blood leukocytes in the luteal phase of the mentrual cycle. J. Clin. Endocrinol. Metab. 89, 2501–2504 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Yurkovetskiy, L. et al. Gender bias in autoimmunity is influenced by microbiota. Immunity 39, 400–412 (2013).

    Article  CAS  PubMed  Google Scholar 

  79. Markle, J. G. et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 339, 1084–1088 (2013).

    Article  CAS  PubMed  Google Scholar 

  80. Kawashima, T. et al. Double-stranded RNA of intestinal commensal but not pathogenic bacteria triggers production of protective interferon-beta. Immunity 38, 1187–1197 (2013).

    Article  CAS  PubMed  Google Scholar 

  81. Fung, K. Y. et al. Interferon-epsilon protects the female reproductive tract from viral and bacterial infection. Science 339, 1088–1092 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Deng, X., Berletch, J. B., Nguyen, D. K. & Disteche, C. M. X chromosome regulation: diverse patterns in development, tissues and disease. Nat. Rev. Genet. 15, 367–378 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kincade, P. W. et al. Early B-lymphocyte precursors and their regulation by sex steroids. Immunol. Rev. 175, 128–137 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Bynoe, M. S., Grimaldi, C. M. & Diamond, B. Estrogen up-regulates Bcl-2 and blocks tolerance induction of naive B cells. Proc. Natl Acad. Sci. USA 97, 2703–2708 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Hill, L., Jeganathan, V., Chinnasamy, P., Grimaldi, C. & Diamond, B. Differential roles of estrogen receptors alpha and beta in control of B-cell maturation and selection. Mol. Med. 17, 211–220 (2011).

    Article  CAS  PubMed  Google Scholar 

  86. Gubbels Bupp, M. R., Jorgensen, T. N. & Kotzin, B. L. Identification of candidate genes that influence sex hormone-dependent disease phenotypes in mouse lupus. Genes Immun. 9, 47–56 (2008).

    Article  CAS  PubMed  Google Scholar 

  87. Grimaldi, C. M., Cleary, J., Dagtas, A. S., Moussai, D. & Diamond, B. Estrogen alters thresholds for B cell apoptosis and activation. J. Clin. Invest. 109, 1625–1633 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Panchanathan, R. & Choubey, D. Murine BAFF expression is up-regulated by estrogen and interferons: implications for sex bias in the development of autoimmunity. Mol. Immunol. 53, 15–23 (2013).

    Article  CAS  PubMed  Google Scholar 

  89. Diaz, M. The role of activation-induced deaminase in lupus nephritis. Autoimmunity 46, 115–120 (2013).

    Article  CAS  PubMed  Google Scholar 

  90. Jiang, C. et al. Abrogation of lupus nephritis in activation-induce deaminase-deficient MRL/lpr mice. J. Immunol. 178, 7422–7431 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Steward, M. & Hay, F. Changes in immunoglobulin class and subclass of anti-DNA antibodies with increasing age in N/ZBW F1 hybrid mice. Clin. Exp. Immunol. 26, 363–370 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Pauklin, S., Sernandez, I., Bachmann, G., Ramiro, A. & Petersen-Mahrt, S. Estrogen directly activates AID transcription and function. J. Exp. Med. 206, 99–111 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Pauklin, S. & Petersen-Mahrt, S. Progesterone inhibits activation-induced deaminase by binding to the promoter. J. Immunol. 183, 1238–1244 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. Devey, M. E., Lee, S. R., Page, S. L., Feldman, R. & Isenberg, D. A. Serial studies of the IgG subclass and functional affinity of DNA antibodies in systemic lupus erythematosus. J. Autoimmun. 1, 483–494 (1988).

    Article  CAS  PubMed  Google Scholar 

  95. Roberts, J. L., Wyatt, R. J. & Schwartz, M. M. Differential characteristics of immune-bound antibodies in diffuse proliferative and membranous forms of lupus glomerulonephritis. Clin. Immunol. Immunopathol. 29, 223–241 (1983).

    Article  CAS  PubMed  Google Scholar 

  96. Baudino, L., Azeredo da Silveira, S., Nakata, M. & Izui, S. Molecular and cellular basis for pathogenecity of autoantibodies: lessons from murine monoclonal autoantibodies. Springer Semin. Immunopathol. 28, 175–184 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Schroeder, H. W. Jr & Cavacini, L. Structure and function of immunoglobulins. J. Allergy Clin. Immunol. 125, S41–S52 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Raju, T. S. Terminal sugars of Fc glycans influence antibody effector functions of IgGs. Curr. Opin. Immunol. 20, 471–478 (2008).

    Article  CAS  PubMed  Google Scholar 

  99. Arnold, J. N., Wormald, M. R., Sim, R. B., Rudd, P. M. & Dwek, R. A. The impact of glycosylation on the biological function and structure of human immunoglobulins. Annu. Rev. Immunol. 25, 21–50 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Bondt, A. et al. Association between galactosylation of immunoglobulin G. and improvement of rheumatoid arthritis during pregnancy is independent of sialylation. J. Proteome Res. 12, 4522–4531 (2013).

    Article  CAS  PubMed  Google Scholar 

  102. Chen, G. et al. Human IgG Fc-glycosylation profiling reveals associations with age, sex, female sex hormones and thyroid cancer. J. Proteomics 75, 2824–2834 (2012).

    Article  CAS  PubMed  Google Scholar 

  103. Staples, J. E. et al. Estrogen receptor alpha is necessary in thymic development and estradiol-induced thymic alterations. J. Immunol. 163, 4168–4174 (1999).

    CAS  PubMed  Google Scholar 

  104. Tibbetts, T., DeMayo, F., Rich, S., Conneely, O. M. & O'Malley, B. Progesterone receptors in the thymus are required for thymic involution during pregnancy and for normal fertility. Proc. Natl Acad. Sci. USA 96, 12021–12026 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Liao, W., Lin, J. X. & Leonard, W. J. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity 38, 13–25 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Moulton, V. R., Holcomb, D. R., Zajdel, M. C. & Tsokos, G. C. Estrogen upregulates cyclic AMP response element modulator alpha expression and downregulates interleukin-2 production by human T lymphocytes. Mol. Med. 18, 370–378 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Rider, V., Foster, R., Evans, M., Suenaga, R. & Abdou, N. Gender differences in autoimmune diseases: estrogen increases calcineurin expression in systemic lupus erythematosus. Clin. Immunol. Immunopathol. 89, 171–180 (1998).

    Article  CAS  PubMed  Google Scholar 

  108. Maret, A. et al. Estradiol enhances primary antigen-specific CD4 T cell responses and Th1 development in vivo. Essential role of estrogen receptor alpha expression in hematopoietic cells. Eur. J. Immunol. 33, 512–521 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. Hughes, G. C., Clark, E. A. & Wong, A. H. The intracellular progesterone receptor regulates CD4+ T cells and T cell-dependent antibody responses. J. Leukoc. Biol. 93, 369–375 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Lee, J., Ulrich, B., Cho, J., Park, J. & Kim, C. Progesterone promotes differentiation of human cord blood fetal T cells into T regulatory cells but suppresses their differentiation into Th17 cells. J. Immunol. 187, 1778–1787 (2011).

    Article  CAS  PubMed  Google Scholar 

  111. Ohkura, N., Kitagawa, Y. & Sakaguchi, S. Development and maintenance of regulatory T cells. Immunity 38, 414–423 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  113. 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).

    Article  CAS  PubMed  Google Scholar 

  114. Polanczyk, M. et al. Estrogen drives expansion of the CD4+CD25+ regulatory T cell compartment. J. Immunol. 173, 2227–2230 (2004).

    Article  CAS  PubMed  Google Scholar 

  115. Mao, G. et al. Progesterone increases systemic and local uterine proportions of CD4+CD25+ Treg cells during midterm pregnancy in mice. Endocrinology 151, 5477–5488 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Lee, J. H., Lydon, J. P. & Kim, C. H. Progesterone suppresses the mTOR pathway and promotes generation of induced regulatory T cells with increased stability. Eur. J. Immunol. 42, 1–14 (2012).

    Article  Google Scholar 

  117. Rowe, J. H., Ertelt, J. M., Xin, L. & Way, S. S. Pregnancy imprints regulatory memory that sustains anergy to fetal antigen. Nature 490, 102–106 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Hughes, G. C. & Clark, E. A. Regulation of dendritic cells by female sex steroids: relevance to immunity and autoimmunity. Autoimmunity 40, 470–481 (2007).

    Article  CAS  PubMed  Google Scholar 

  119. Seillet, C. et al. Estradiol promotes functional responses in inflammatory and steady-state dendritic cells through differential requirement for activation function-1 of estrogen receptor alpha. J. Immunol. 190, 5459–5470 (2013).

    Article  CAS  PubMed  Google Scholar 

  120. Papenfuss, T. L. et al. Estriol generates tolerogenic dendritic cells in vivo that protect against autoimmunity. J. Immunol. 186, 3346–3355 (2011).

    Article  CAS  PubMed  Google Scholar 

  121. Jones, L. A. et al. Differential modulation of TLR3- and TLR4-mediated dendritic cell maturation and function by progesterone. J. Immunol. 185, 4525–4534 (2010).

    Article  CAS  PubMed  Google Scholar 

  122. Negishi, Y. et al. Disruption of maternal immune balance maintained by innate DC subsets results in spontaneous pregnancy loss in mice. Immunobiology 217, 951–961 (2012).

    Article  CAS  PubMed  Google Scholar 

  123. Kinne, R. W., Stuhlmuller, B. & Burmester, G. R. Cells of the synovium in rheumatoid arthritis. Macrophages. Arthritis Res. Ther. 9, 224 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Miller, L. & Hunt, J. Regulation of TNF-alpha production in activated mouse macrophages by progesterone. J. Immunol. 160, 5098–5104 (1998).

    CAS  PubMed  Google Scholar 

  125. Miller, L., Alley, E. W., Murphy, W. J., Russell, S. W. & Hunt, J. S. Progesterone inhibits inducible nitric oxide synthase gene expression and nitric oxide production in murine macrophages. J. Leukoc. Biol. 59, 442–450 (1996).

    Article  CAS  PubMed  Google Scholar 

  126. Menzies, F. M., Henriquez, F. L., Alexander, J. & Roberts, C. W. Selective inhibition and augmentation of alternative macrophage activation by progesterone. Immunology 134, 281–291 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Jones, L. A. et al. Toll-like receptor-4-mediated macrophage activation is differentially regulated by progesterone via the glucocorticoid and progesterone receptors. Immunology 125, 59–69 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Ganesan, K., Balachandran, C., Manohar, B. M. & Puvanakrishnan, R. Effects of testosterone, estrogen and progesterone on TNF-alpha mediated cellular damage in rat arthritic synovial fibroblasts. Rheumatol. Int. 32, 3181–3188 (2012).

    Article  CAS  PubMed  Google Scholar 

  129. Calippe, B. et al. 17Beta-estradiol promotes TLR4-triggered proinflammatory mediator production through direct estrogen receptor alpha signaling in macrophages in vivo. J. Immunol. 185, 1169–1176 (2010).

    Article  CAS  PubMed  Google Scholar 

  130. Fox, H., Bond, B. & Parslow, T. Estrogen regulates the IFN-gamma promoter. J. Immunol. 146, 4362–4367 (1991).

    CAS  PubMed  Google Scholar 

  131. Wilcoxen, S. C., Kirkman, E., Dowdell, K. C. & Stohlman, S. A. Gender-dependent IL-12 secretion by APC is regulated by IL-10. J. Immunol. 164, 6237–6243 (2000).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank J. L. Nelson, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA and M. Wener, University of Washington, Seattle, WA, USA for their thoughtful comments during the writing of this Review. Research work in G.H.'s laboratory has been supported by NIH grant AI101564 and the Robert F. and Betty Snead Fund for Innovation in Lupus Research. Research work in D.C.'s laboratory has been supported by grants AI066261 and AI089775 from the NIH and a Veterans Administration Merit Award (5 I01 BX001133).

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Both authors contributed equally to researching data for the article, providing a substantial contribution to discussions of the content, writing the article, and to the review and/or editing of the manuscript before submission.

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Correspondence to Grant C. Hughes.

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Hughes, G., Choubey, D. Modulation of autoimmune rheumatic diseases by oestrogen and progesterone. Nat Rev Rheumatol 10, 740–751 (2014). https://doi.org/10.1038/nrrheum.2014.144

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