Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Estrogen receptor-α deficiency attenuates autoimmune disease in (NZB × NZW)F1 mice

Genes & Immunity volume 9, pages 137–152 (2008)Cite this article

Abstract

Estrogens promote lupus in humans and some mouse models of this disease. Nonetheless, little is known about the role of estrogen receptors in lupus pathogenesis. Here, we report that in females on the lupus-prone (NZB × NZW)F1 background, disruption of estrogen receptor-α (ERα or Esr1) attenuated glomerulonephritis and increased survival. ERα deficiency also retarded development of anti-histone/DNA antibodies, suggesting that ERα promotes loss of immunologic tolerance. Furthermore, ERα deficiency in (NZB × NZW)F1 females attenuated the subsequent development of anti-double-stranded DNA (dsDNA) IgG antibodies, which are associated with glomerulonephritis in this model. We provide evidence that ERα may promote lupus, at least in part, by inducing interferon-γ, an estrogen-regulated cytokine that impacts this disease. ERα deficiency in (NZB × NZW)F1 males increased survival and reduced anti-dsDNA antibodies, suggesting that ERα also modulates lupus in males. These studies demonstrate that ERα, rather than ERβ, plays a major role in regulating autoimmunity in (NZB × NZW)F1 mice. Furthermore, our results suggest for the first time that ERα promotes lupus, at least in part, by impacting the initial loss of tolerance. These data suggest that targeted therapy disrupting ERα, most likely within the immune system, may be effective in the prevention and/or treatment of lupus.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Lahita RG, Bradlow HL . Klinefelter's syndrome: hormone metabolism in hypogonadal males with systemic lupus erythematosus. J Rheumatol 1987; 14 (Suppl 13): 154–157.

    Google Scholar 

  2. Gilliland WR, Stashower ME . Klinefelter's syndrome and systemic lupus erythematosus. Clin Exp Rheumatol 2000; 18: 107–109.

    CAS  PubMed  Google Scholar 

  3. Lahita RG, Bradlow HL, Kunkel HG, Fishman J . Alterations of estrogen metabolism in systemic lupus erythematosus. Arthritis Rheum 1979; 22: 1195–1198.

    Article  CAS  Google Scholar 

  4. Lahita RG, Bradlow HL, Kunkel HG, Fishman J . Increased 16 alpha-hydroxylation of estradiol in systemic lupus erythematosus. J Clin Endocrinol Metab 1981; 53: 174–178.

    Article  CAS  Google Scholar 

  5. Folomeev M, Dougados M, Beaune J, Kouyoumdjian JC, Nahoul K, Amor B et al. Plasma sex hormones and aromatase activity in tissues of patients with systemic lupus erythematosus. Lupus 1992; 1: 191–195.

    Article  CAS  Google Scholar 

  6. Sanchez-Guerrero J, Liang MH, Karlson EW, Hunter DJ, Colditz GA . Postmenopausal estrogen therapy and the risk for developing systemic lupus erythematosus. Ann Intern Med 1995; 122: 430–433.

    Article  CAS  Google Scholar 

  7. Sanchez-Guerrero J, Karlson EW, Liang MH, Hunter DJ, Speizer FE, Colditz GA . Past use of oral contraceptives and the risk of developing systemic lupus erythematosus. Arthritis Rheum 1997; 40: 804–808.

    Article  CAS  Google Scholar 

  8. Meier CR, Sturkenboom MC, Cohen AS, Jick H . Postmenopausal estrogen replacement therapy and the risk of developing systemic lupus erythematosus or discoid lupus. J Rheumatol 1998; 25: 1515–1519.

    CAS  Google Scholar 

  9. Petri M . Exogenous estrogen in systemic lupus erythematosus: oral contraceptives and hormone replacement therapy. Lupus 2001; 10: 222–226.

    Article  CAS  Google Scholar 

  10. Steinberg AD, Steinberg BJ . Lupus disease activity associated with menstrual cycle. J Rheumatol 1985; 12: 816–817.

    CAS  PubMed  Google Scholar 

  11. Ruiz-Irastorza G, Lima F, Alves J, Khamashta MA, Simpson J, Hughes GR et al. Increased rate of lupus flare during pregnancy and the puerperium: a prospective study of 78 pregnancies. Br J Rheumatol 1996; 35: 133–138.

    Article  CAS  Google Scholar 

  12. Ostensen M . Sex hormones and pregnancy in rheumatoid arthritis and systemic lupus erythematosus. Ann NY Acad Sci 1999; 876: 131–143; discussion 144.

    Article  CAS  Google Scholar 

  13. Mok CC, Lau CS, Wong RW . Use of exogenous estrogens in systemic lupus erythematosus. Semin Arthritis Rheum 2001; 30: 426–435.

    Article  CAS  Google Scholar 

  14. Liu ZH, Cheng ZH, Gong RJ, Liu H, Liu D, Li LS . Sex differences in estrogen receptor gene polymorphism and its association with lupus nephritis in Chinese. Nephron 2002; 90: 174–180.

    Article  CAS  Google Scholar 

  15. Lee YJ, Shin KS, Kang SW, Lee CK, Yoo B, Cha HS et al. Association of the oestrogen receptor alpha gene polymorphisms with disease onset in systemic lupus erythematosus. Ann Rheum Dis 2004; 63: 1244–1249.

    Article  CAS  Google Scholar 

  16. Kassi E, Vlachoyiannopoulos PG, Kominakis A, Kiaris H, Moutsopoulos HM, Moutsatsou P . Estrogen receptor alpha gene polymorphism and systemic lupus erythematosus: a possible risk? Lupus 2005; 14: 391–398.

    Article  CAS  Google Scholar 

  17. Kassi EN, Vlachoyiannopoulos PG, Moutsopoulos HM, Sekeris CE, Moutsatsou P . Molecular analysis of estrogen receptor alpha and beta in lupus patients. Eur J Clin Invest 2001; 31: 86–93.

    Article  CAS  Google Scholar 

  18. Howie JB, Helyer BJ . The immunology and pathology of NZB mice. Adv Immunol 1968; 9: 215–266.

    Article  CAS  Google Scholar 

  19. Andrews BS, Eisenberg RA, Theofilopoulos AN, Izui S, Wilson CB, McConahey PJ et al. Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J Exp Med 1978; 148: 1198–1215.

    Article  CAS  Google Scholar 

  20. Walker SE, Bole GGJ . Influence of natural and synthetic estrogens on the course of autoimmune disease in the NZB/NZW mouse. Arthritis Rheum 1973; 16: 231–239.

    Article  CAS  Google Scholar 

  21. Roubinian JR, Talal N, Greenspan JS, Goodman JR, Siiteri PK . Effect of castration and sex hormone treatment on survival, anti-nucleic acid antibodies, and glomerulonephritis in NZB/NZW F1 mice. J Exp Med 1978; 147: 1568–1583.

    Article  CAS  Google Scholar 

  22. Roubinian J, Talal N, Siiteri PK, Sadakian JA . Sex hormone modulation of autoimmunity in NZB/NZW mice. Arthritis Rheum 1979; 22: 1162–1169.

    CAS  Google Scholar 

  23. Carlsten H, Tarkowski A . Histocompatibility complex gene products and exposure to oestrogen: two independent disease accelerating factors in murine lupus. Scand J Immunol 1993; 38: 341–347.

    Article  CAS  Google Scholar 

  24. Sthoeger ZM, Zinger H, Mozes E . Beneficial effects of the anti-oestrogen tamoxifen on systemic lupus erythematosus of (NZB × NZW)F1 female mice are associated with specific reduction of IgG3 autoantibodies. Ann Rheum Dis 2003; 62: 341–346.

    Article  CAS  Google Scholar 

  25. Wu WM, Lin BF, Su YC, Suen JL, Chiang BL . Tamoxifen decreases renal inflammation and alleviates disease severity in autoimmune NZB/W F1 mice. Scand J Immunol 2000; 52: 393–400.

    Article  CAS  Google Scholar 

  26. Li J, McMurray RW . Effects of estrogen receptor subtype-selective agonists on autoimmune disease in lupus-prone NZB/NZW F1 mouse model. Clin Immunol 2007; 123: 219–226.

    Article  CAS  Google Scholar 

  27. Bynoe MS, Grimaldi CM, Diamond B . Estrogen up-regulates Bcl-2 and blocks tolerance induction of naive B cells. Proc Natl Acad Sci USA 2000; 97: 2703–2708.

    Article  CAS  Google Scholar 

  28. Grimaldi CM, Cleary J, Dagtas AS, Moussai D, Diamond B . Estrogen alters thresholds for B cell apoptosis and activation. J Clin Invest 2002; 109: 1625–1633.

    Article  CAS  Google Scholar 

  29. Grimaldi CM, Jeganathan V, Diamond B . Hormonal regulation of B cell development: 17 beta-estradiol impairs negative selection of high-affinity DNA-reactive B cells at more than one developmental checkpoint. J Immunol 2006; 176: 2703–2710.

    Article  CAS  Google Scholar 

  30. Peeva E, Venkatesh J, Diamond B . Tamoxifen blocks estrogen-induced B cell maturation but not survival. J Immunol 2005; 175: 1415–1423.

    Article  CAS  Google Scholar 

  31. Lubahn DB, Moyer JS, Golding TS, Couse JF, Korach KS, Smithies O . Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc Natl Acad Sci USA 1993; 90: 11162–11166.

    Article  CAS  Google Scholar 

  32. Xie C, Sharma R, Wang H, Zhou XJ, Mohan C . Strain distribution pattern of susceptibility to immune-mediated nephritis. J Immunol 2004; 172: 5047–5055.

    Article  CAS  Google Scholar 

  33. Bygrave AE, Rose KL, Cortes-Hernandez J, Warren J, Rigby RJ, Cook HT et al. Spontaneous autoimmunity in 129 and C57BL/6 mice—implications for autoimmunity described in gene-targeted mice. PLoS Biol 2004; 2: E243.

    Article  Google Scholar 

  34. Heidari Y, Bygrave AE, Rigby RJ, Rose KL, Walport MJ, Cook HT et al. Identification of chromosome intervals from 129 and C57BL/6 mouse strains linked to the development of systemic lupus erythematosus. Genes Immun 2006; 7: 592–599.

    Article  CAS  Google Scholar 

  35. Gould KA, Tochacek M, Schaffer BS, Reindl TM, Murrin CR, Lachel CM et al. Genetic determination of susceptibility to estrogen-induced mammary cancer in the ACI rat: mapping of Emca1 and Emca2 to chromosomes 5 and 18. Genetics 2004; 168: 2113–2125.

    Article  CAS  Google Scholar 

  36. Gould KA, Pandey J, Lachel CM, Murrin CR, Flood LA, Pennington KL et al. Genetic mapping of Eutr1, a locus controlling E2-induced pyometritis in the Brown Norway rat, to RNO5. Mamm Genome 2005; 16: 854–864.

    Article  CAS  Google Scholar 

  37. Gould KA, Dietrich WF, Borenstein N, Lander ES, Dove WF . Mom1 is a semi-dominant modifier of intestinal adenoma size and multiplicity in Min/+ mice. Genetics 1996; 144: 1769–1776.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Kono DH, Burlingame RW, Owens DG, Kuramochi A, Balderas RS, Balomenos D et al. Lupus susceptibility loci in New Zealand mice. Proc Natl Acad Sci USA 1994; 91: 10168–10172.

    Article  CAS  Google Scholar 

  39. Drake CG, Babcock SK, Palmer E, Kotzin BL . Genetic analysis of the NZB contribution to lupus-like autoimmune disease in (NZB × NZW)F1 mice. Proc Natl Acad Sci USA 1994; 91: 4062–4066.

    Article  CAS  Google Scholar 

  40. Morel L, Rudofsky UH, Longmate JA, Schiffenbauer J, Wakeland EK . Polygenic control of susceptibility to murine systemic lupus erythematosus. Immunity 1994; 1: 219–229.

    Article  CAS  Google Scholar 

  41. Drake CG, Rozzo SJ, Hirschfeld HF, Smarnworawong NP, Palmer E, Kotzin BL . Analysis of the New Zealand black contribution to lupus-like renal disease. Multiple genes that operate in a threshold manner. J Immunol 1995; 154: 2441–2447.

    CAS  PubMed  Google Scholar 

  42. Rozzo SJ, Vyse TJ, Drake CG, Kotzin BL . Effect of genetic background on the contribution of New Zealand black loci to autoimmune lupus nephritis. Proc Natl Acad Sci USA 1996; 93: 15164–15168.

    Article  CAS  Google Scholar 

  43. Morel L, Mohan C, Yu Y, Schiffenbauer J, Rudofsky UH, Tian N et al. Multiplex inheritance of component phenotypes in a murine model of lupus. Mamm Genome 1999; 10: 176–181.

    Article  CAS  Google Scholar 

  44. Burlingame RW, Rubin RL . Subnucleosome structures as substrates in enzyme-linked immunosorbent assays. J Immunol Methods 1990; 134: 187–199.

    Article  CAS  Google Scholar 

  45. Mohan C, Alas E, Morel L, Yang P, Wakeland EK . Genetic dissection of SLE pathogenesis. Sle1 on murine chromosome 1 leads to a selective loss of tolerance to H2A/H2B/DNA subnucleosomes. J Clin Invest 1998; 101: 1362–1372.

    Article  CAS  Google Scholar 

  46. Steward MW, Hay FC . Changes in immunoglobulin class and subclass of anti-DNA antibodies with increasing age in N/ZBW F1 hybrid mice. Clin Exp Immunol 1976; 26: 363–370.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Lambert PH, Dixon FJ . Pathogenesis of the glomerulonephritis of NZB/W mice. J Exp Med 1968; 127: 507–522.

    Article  CAS  Google Scholar 

  48. Burlingame RW, Rubin RL, Balderas RS, Theofilopoulos AN . Genesis and evolution of antichromatin autoantibodies in murine lupus implicates T-dependent immunization with self antigen. J Clin Invest 1993; 91: 1687–1696.

    Article  CAS  Google Scholar 

  49. Burlingame RW, Boey ML, Starkebaum G, Rubin RL . The central role of chromatin in autoimmune responses to histones and DNA in systemic lupus erythematosus. J Clin Invest 1994; 94: 184–192.

    Article  CAS  Google Scholar 

  50. Mohan C, Morel L, Yang P, Watanabe H, Croker B, Gilkeson G et al. Genetic dissection of lupus pathogenesis: a recipe for nephrophilic autoantibodies. J Clin Invest 1999; 103: 1685–1695.

    Article  CAS  Google Scholar 

  51. Erlandsson MC, Ohlsson C, Gustafsson JA, Carlsten H . Role of oestrogen receptors alpha and beta in immune organ development and in oestrogen-mediated effects on thymus. Immunology 2001; 103: 17–25.

    Article  CAS  Google Scholar 

  52. McMurray RW, Hoffman RW, Nelson W, Walker SE . Cytokine mRNA expression in the B/W mouse model of systemic lupus erythematosus—analyses of strain, gender, and age effects. Clin Immunol Immunopathol 1997; 84: 260–268.

    Article  CAS  Google Scholar 

  53. Haas C, Ryffel B, Le Hir M . IFN-gamma receptor deletion prevents autoantibody production and glomerulonephritis in lupus-prone (NZB × NZW)F1 mice. J Immunol 1998; 160: 3713–3718.

    CAS  PubMed  Google Scholar 

  54. Fox HS, Bond BL, Parslow TG . Estrogen regulates the IFN-gamma promoter. J Immunol 1991; 146: 4362–4367.

    CAS  PubMed  Google Scholar 

  55. Walker SE, Besch-Williford CL, Keisler DH . Accelerated deaths from systemic lupus erythematosus in NZB × NZW F1 mice treated with the testosterone-blocking drug flutamide. J Lab Clin Med 1994; 124: 401–407.

    CAS  Google Scholar 

  56. Staples JE, Gasiewicz TA, Fiore NC, Lubahn DB, Korach KS, Silverstone AE . Estrogen receptor alpha is necessary in thymic development and estradiol-induced thymic alterations. J Immunol 1999; 163: 4168–4174.

    CAS  PubMed  Google Scholar 

  57. Yellayi S, Teuscher C, Woods JA, Welsh Jr TH, Tung KS, Nakai M et al. Normal development of thymus in male and female mice requires estrogen/estrogen receptor-alpha signaling pathway. Endocrine 2000; 12: 207–213.

    Article  CAS  Google Scholar 

  58. Werwitzke S, Trick D, Kamino K, Matthias T, Kniesch K, Schlegelberger B et al. Inhibition of lupus disease by anti-double-stranded DNA antibodies of the IgM isotype in the (NZB × NZW)F1 mouse. Arthritis Rheum 2005; 52: 3629–3638.

    Article  CAS  Google Scholar 

  59. Kramers K, Stemmer C, Monestier M, van Bruggen MC, Rijke-Schilder TP, Hylkema MN et al. Specificity of monoclonal anti-nucleosome auto-antibodies derived from lupus mice. J Autoimmun 1996; 9: 723–729.

    Article  CAS  Google Scholar 

  60. Mohan C, Adams S, Stanik V, Datta SK . Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus. J Exp Med 1993; 177: 1367–1381.

    Article  CAS  Google Scholar 

  61. Shim GJ, Kis LL, Warner M, Gustafsson JA . Autoimmune glomerulonephritis with spontaneous formation of splenic germinal centers in mice lacking the estrogen receptor alpha gene. Proc Natl Acad Sci USA 2004; 101: 1720–1724.

    Article  CAS  Google Scholar 

  62. Couse JF, Curtis SW, Washburn TF, Lindzey J, Golding TS, Lubahn DB et al. Analysis of transcription and estrogen insensitivity in the female mouse after targeted disruption of the estrogen receptor gene. Mol Endocrinol 1995; 9: 1441–1454.

    CAS  PubMed  Google Scholar 

  63. Couse JF, Yates MM, Walker VR, Korach KS . Characterization of the hypothalamic–pituitary–gonadal axis in estrogen receptor (ER) null mice reveals hypergonadism and endocrine sex reversal in females lacking ERalpha but not ERbeta. Mol Endocrinol 2003; 17: 1039–1053.

    Article  CAS  Google Scholar 

  64. Roubinian JR, Talal N, Greenspan JS, Goodman JR, Siiteri PK . Delayed androgen treatment prolongs survival in murine lupus. J Clin Invest 1979; 63: 902–911.

    Article  CAS  Google Scholar 

  65. Eddy EM, Washburn TF, Bunch DO, Goulding EH, Gladen BC, Lubahn DB et al. Targeted disruption of the estrogen receptor gene in male mice causes alteration of spermatogenesis and infertility. Endocrinology 1996; 137: 4796–4805.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge Dr Runqing Lu for helpful discussions and critical review of the paper and Drs Sara Walker, Mary Ruh and Clifford Bellone for helpful discussions in the planning stages of this work. We also thank Kelli A Peterson for assistance in handling the mice during the development of the congenic lines. KAG was supported by grants from the Lupus Foundation of America and the University of Nebraska Medical Center.

Author information

Authors and Affiliations

  1. Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA

    K K Bynoté, J M Hackenberg & K A Gould

  2. Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE, USA

    K K Bynoté & K A Gould

  3. Receptor Biology Section, National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Research Triangle Park, NC, USA

    K S Korach

  4. Department of Biochemistry, University of Missouri, Columbia, MO, USA

    D B Lubahn

  5. Department of Child Health, University of Missouri, Columbia, MO, USA

    D B Lubahn

  6. Department of Animal Sciences, University of Missouri, Columbia, MO, USA

    D B Lubahn

  7. MU Center for Phytonutrient and Phytochemical Studies, University of Missouri, Columbia, MO, USA

    D B Lubahn

  8. Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, USA

    P H Lane

Authors
  1. K K Bynoté
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J M Hackenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K S Korach
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D B Lubahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P H Lane
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K A Gould
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K A Gould.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bynoté, K., Hackenberg, J., Korach, K. et al. Estrogen receptor-α deficiency attenuates autoimmune disease in (NZB × NZW)F1 mice. Genes Immun 9, 137–152 (2008). https://doi.org/10.1038/sj.gene.6364458

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6364458

Keywords

This article is cited by

Search

Advanced search

Quick links