Advertisement

Clinical Reviews in Allergy & Immunology

, Volume 40, Issue 1, pp 16–26 | Cite as

The Multi-faceted Influences of Estrogen on Lymphocytes: Toward Novel Immuno-interventions Strategies for Autoimmunity Management

  • Ebru Karpuzoglu
  • Moncef ZoualiEmail author
Article

Abstract

Early studies of the immune system disclosed that, generally, females exhibit stronger responses to a variety of antigens than males. Perhaps as a result of this response, women are more prone to developing autoimmune diseases than men. Yet, the precise cellular and molecular mechanisms remain under investigation. Recently, interferon-gamma and the related pro-inflammatory interleukin-12 were found to be under effects of sex steroid hormones, with potential implications in regulating immune cells and autoimmune responses. In B lymphocytes, functional binding sites for estrogen receptors were identified in the promoter of the gene encoding activation-induced deaminase, an enzyme required for somatic hypermutation, and class-switch recombination. The observation that estrogen exerts direct impacts on antibody affinity-maturation provides a potential mechanism that could account for generating pathogenic high-affinity auto-antibodies. Further deciphering the multi-faceted influences of sex hormones on the responsiveness of immune cells could lead to novel therapeutic interventions for autoimmunity management.

Keywords

SLE Lupus IFN-γ Estrogen Immunity B cells 

References

  1. 1.
    Ahmed SA, Hissong BD, Verthelyi D, Donner K, Becker K, Karpuzoglu-Sahin E (1999) Gender and risk of autoimmune diseases: possible role of estrogenic compounds. Environ Health Perspect 107(Suppl 5):681–686PubMedCrossRefGoogle Scholar
  2. 2.
    Jacobson DL, Gange SJ, Rose NR, Graham NM (1997) Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 84:223–243PubMedCrossRefGoogle Scholar
  3. 3.
    Walsh SJ, Rau LM (2000) Autoimmune diseases: a leading cause of death among young and middle-aged women in the United States. Am J Public Health 90:1463–1466PubMedCrossRefGoogle Scholar
  4. 4.
    Zouali M (2005) Taming lupus. Sci Am 292:58–65PubMedCrossRefGoogle Scholar
  5. 5.
    Millet A, Decaux O, Perlat A, Grosbois B, Jego P (2009) Systemic lupus erythematosus and vaccination. Eur J Intern Med 20:236–241PubMedCrossRefGoogle Scholar
  6. 6.
    Rider V, Abdou NI (2001) Gender differences in autoimmunity: molecular basis for estrogen effects in systemic lupus erythematosus. Int Immunopharmacol 1:1009–1024PubMedCrossRefGoogle Scholar
  7. 7.
    Hill P, Wynder EL, Helman P, Hickman R, Rona G, Kuno K (1976) Plasma hormone levels in different ethnic populations of women. Cancer Res 36:2297–2301PubMedGoogle Scholar
  8. 8.
    Wilder RL, Elenkov IJ (1999) Hormonal regulation of tumor necrosis factor-alpha, interleukin-12 and interleukin-10 production by activated macrophages. A disease-modifying mechanism in rheumatoid arthritis and systemic lupus erythematosus? Ann N Y Acad Sci 876:14–31PubMedCrossRefGoogle Scholar
  9. 9.
    Whitelaw DA, Hall D, Kotze T (2008) Pregnancy in systemic lupus erythematosus: a retrospective study from a developing community. Clin Rheumatol 27:577–580PubMedCrossRefGoogle Scholar
  10. 10.
    Whitelaw DA, Jessop SJ (2007) Major flares in women with SLE on combined oral contraception. Clin Rheumatol 26:2163–2165PubMedCrossRefGoogle Scholar
  11. 11.
    Sanchez-Guerrero J, Karlson EW, Liang MH, Hunter DJ, Speizer FE, Colditz GA (1997) Past use of oral contraceptives and the risk of developing systemic lupus erythematosus. Arthritis Rheum 40:804–808PubMedCrossRefGoogle Scholar
  12. 12.
    Carlsten H, Nilsson N, Jonsson R, Backman K, Holmdahl R, Tarkowski A (1992) Estrogen accelerates immune complex glomerulonephritis but ameliorates T cell-mediated vasculitis and sialadenitis in autoimmune MRL lpr/lpr mice. Cell Immunol 144:190–202PubMedCrossRefGoogle Scholar
  13. 13.
    Grimaldi CM, Cleary J, Dagtas AS, Moussai D, Diamond B (2002) Estrogen alters thresholds for B cell apoptosis and activation. J Clin Invest 109:1625–1633PubMedGoogle Scholar
  14. 14.
    Peeva E, Grimaldi C, Spatz L, Diamond B (2000) Bromocriptine restores tolerance in estrogen-treated mice. J Clin Invest 106:1373–1379PubMedCrossRefGoogle Scholar
  15. 15.
    Roubinian JR, Talal N, Greenspan JS, Goodman JR, Siiteri PK (1978) Effect of castration and sex hormone treatment on survival, anti-nucleic acid antibodies, and glomerulonephritis in NZB/NZW F1 mice. J Exp Med 147:1568–1583PubMedCrossRefGoogle Scholar
  16. 16.
    Wu WM, Lin BF, Su YC, Suen JL, Chiang BL (2000) Tamoxifen decreases renal inflammation and alleviates disease severity in autoimmune NZB/W F1 mice. Scand J Immunol 52:393–400PubMedCrossRefGoogle Scholar
  17. 17.
    Svenson JL, EuDaly J, Ruiz P, Korach KS, Gilkeson GS (2008) Impact of estrogen receptor deficiency on disease expression in the NZM2410 lupus prone mouse. Clin Immunol 128:259–268PubMedCrossRefGoogle Scholar
  18. 18.
    Bynote KK, Hackenberg JM, Korach KS, Lubahn DB, Lane PH, Gould KA (2008) Estrogen receptor-alpha deficiency attenuates autoimmune disease in (NZB x NZW)F1 mice. Genes Immun 9:137–152PubMedCrossRefGoogle Scholar
  19. 19.
    Shtrichman R, Samuel CE (2001) The role of gamma interferon in antimicrobial immunity. Curr Opin Microbiol 4:251–259PubMedCrossRefGoogle Scholar
  20. 20.
    Young HA, Bream JH (2007) IFN-gamma: recent advances in understanding regulation of expression, biological functions, and clinical applications. Curr Top Microbiol Immunol 316:97–117PubMedCrossRefGoogle Scholar
  21. 21.
    McMurray RW, Hoffman RW, Nelson W, Walker SE (1997) Cytokine mRNA expression in the B/W mouse model of systemic lupus erythematosus—analyses of strain, gender, and age effects. Clin Immunol Immunopathol 84:260–268PubMedCrossRefGoogle Scholar
  22. 22.
    Maret A, Coudert JD, Garidou L, Foucras G, Gourdy P, Krust A et al (2003) 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 33:512–521PubMedCrossRefGoogle Scholar
  23. 23.
    Karpuzoglu-Sahin E, Zhi-Jun Y, Lengi A, Sriranganathan N, Ansar Ahmed S (2001) Effects of long-term estrogen treatment on IFN-gamma, Il-2 and Il-4 gene expression and protein synthesis in spleen and thymus of normal c57bl/6 mice. Cytokine 14:208–217PubMedCrossRefGoogle Scholar
  24. 24.
    Karpuzoglu E, Fenaux JB, Phillips RA, Lengi AJ, Elvinger F, Ansar Ahmed S (2006) Estrogen up-regulates inducible nitric oxide synthase, nitric oxide, and cyclooxygenase-2 in splenocytes activated with T cell stimulants: role of interferon-gamma. Endocrinology 147:662–671PubMedCrossRefGoogle Scholar
  25. 25.
    Matalka KZ, Ali DA (2005) Stress-induced versus preovulatory and pregnancy hormonal levels in modulating cytokine production following whole blood stimulation. Neuroimmunomodulation 12:366–374PubMedCrossRefGoogle Scholar
  26. 26.
    Kruse N, Greif M, Moriabadi NF, Marx L, Toyka KV, Rieckmann P (2000) Variations in cytokine mRNA expression during normal human pregnancy. Clin Exp Immunol 119:317–322PubMedCrossRefGoogle Scholar
  27. 27.
    Matalka KZ (2003) The effect of estradiol, but not progesterone, on the production of cytokines in stimulated whole blood, is concentration-dependent. Neuroendocrinol Lett 24:185–191PubMedGoogle Scholar
  28. 28.
    Breckler LA, Hale J, Jung W, Westcott L, Dunstan JA, Thornton CA, et al. (2009), Modulation of in vivo and in vitro cytokine production over the course of pregnancy in allergic and non-allergic mothers. Pediatr Allergy Immunol 2009 Mar 23 (in press)Google Scholar
  29. 29.
    Mullen AC, High FA, Hutchins AS, Lee HW, Villarino AV, Livingston DM et al (2001) Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science 292:1907–1910PubMedCrossRefGoogle Scholar
  30. 30.
    Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH (2000) A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100:655–669PubMedCrossRefGoogle Scholar
  31. 31.
    Karpuzoglu E, Phillips RA, Gogal RM Jr, Ansar Ahmed S (2007) IFN-gamma-inducing transcription factor, T-bet is upregulated by estrogen in murine splenocytes: role of IL-27 but not IL-12. Mol Immunol 44:1819–1825CrossRefGoogle Scholar
  32. 32.
    Kawana K, Kawana Y, Schust DJ (2005) Female steroid hormones use signal transducers and activators of transcription protein-mediated pathways to modulate the expression of T-bet in epithelial cells: a mechanism for local immune regulation in the human reproductive tract. Mol Endocrinol 19:2047–2059PubMedCrossRefGoogle Scholar
  33. 33.
    Fox HS, Bond BL, Parslow TG (1991) Estrogen regulates the IFN-gamma promoter. J Immunol 146:4362–4367PubMedGoogle Scholar
  34. 34.
    Reininger L, Santiago ML, Takahashi S, Fossati L, Izui S (1996) T helper cell subsets in the pathogenesis of systemic lupus erythematosus. Ann Med Interne (Paris) 147:467–471Google Scholar
  35. 35.
    Carvalho-Pinto CE, Garcia MI, Mellado M, Rodriguez-Frade JM, Martin-Caballero J, Flores J et al (2002) Autocrine production of IFN-gamma by macrophages controls their recruitment to kidney and the development of glomerulonephritis in MRL/lpr mice. J Immunol 169:1058–1067PubMedGoogle Scholar
  36. 36.
    Lawson BR, Prud’homme GJ, Chang Y, Gardner HA, Kuan J, Kono DH et al (2000) Treatment of murine lupus with cDNA encoding IFN-gammaR/Fc. J Clin Invest 106:207–215PubMedCrossRefGoogle Scholar
  37. 37.
    Haas C, Ryffel B, Le Hir M (1998) IFN-gamma receptor deletion prevents autoantibody production and glomerulonephritis in lupus-prone (NZB × NZW)F1 mice. J Immunol 160:3713–3718PubMedGoogle Scholar
  38. 38.
    Kikawada E, Lenda DM, Kelley VR (2003) IL-12 deficiency in MRL-Fas(lpr) mice delays nephritis and intrarenal IFN-gamma expression, and diminishes systemic pathology. J Immunol 170:3915–3925PubMedGoogle Scholar
  39. 39.
    Tucci M, Lombardi L, Richards HB, Dammacco F, Silvestris F (2008) Overexpression of interleukin-12 and T helper 1 predominance in lupus nephritis. Clin Exp Immunol 154:247–254PubMedCrossRefGoogle Scholar
  40. 40.
    Lit LC, Wong CK, Li EK, Tam LS, Lam CW, Lo YM (2007) Elevated gene expression of Th1/Th2 associated transcription factors is correlated with disease activity in patients with systemic lupus erythematosus. J Rheumatol 34:89–96PubMedGoogle Scholar
  41. 41.
    Peng SL, Szabo SJ, Glimcher LH (2002) T-bet regulates IgG class switching and pathogenic autoantibody production. Proc Natl Acad Sci U S A 99:5545–5550PubMedCrossRefGoogle Scholar
  42. 42.
    Harigai M, Kawamoto M, Hara M, Kubota T, Kamatani N, Miyasaka N (2008) Excessive production of IFN-gamma in patients with systemic lupus erythematosus and its contribution to induction of B lymphocyte stimulator/B cell-activating factor/TNF ligand superfamily-13B. J Immunol 181:2211–2219PubMedGoogle Scholar
  43. 43.
    Mo C, Chearwae W, O’Malley JT, Kaplan M, Bright JJ (2007) Distinct roles of STAT4{alpha} and STAT4beta in the pathogenesis of experimental allergic encephalomyelitis. J Immunol 178:5681–5690Google Scholar
  44. 44.
    Lawless VA, Zhang S, Ozes ON, Bruns HA, Oldham I, Hoey T et al (2000) Stat4 regulates multiple components of IFN-gamma-inducing signaling pathways. J Immunol 165:6803–6808PubMedGoogle Scholar
  45. 45.
    Lezama-Davila CM, Isaac-Marquez AP, Barbi J, Cummings HE, Lu B, Satoskar AR (2008) Role of phosphatidylinositol-3-kinase-gamma (PI3Kgamma)-mediated pathway in 17beta-estradiol-induced killing of L. mexicana in macrophages from C57BL/6 mice. Immunol Cell Biol 86:539–543PubMedCrossRefGoogle Scholar
  46. 46.
    Karpuzoglu E, Phillips RA, Dai R, Graniello C, Gogal RM Jr, Ahmed SA (2009) Signal transducer and activation of transcription (STAT) 4beta, a shorter isoform of interleukin-12-induced STAT4, is preferentially activated by estrogen. Endocrinology 150:1310–1320PubMedCrossRefGoogle Scholar
  47. 47.
    Offner H, Adlard K, Zamora A, Vandenbark AA (2000) Estrogen potentiates treatment with T-cell receptor protein of female mice with experimental encephalomyelitis. J Clin Invest 105:1465–1472PubMedCrossRefGoogle Scholar
  48. 48.
    Elenkov IJ, Wilder RL, Bakalov VK, Link AA, Dimitrov MA, Fisher S et al (2001) IL-12, TNF-alpha, and hormonal changes during late pregnancy and early postpartum: implications for autoimmune disease activity during these times. J Clin Endocrinol Metab 86:4933–4938PubMedCrossRefGoogle Scholar
  49. 49.
    Germain SJ, Sacks GP, Sooranna SR, Sargent IL, Redman CW (2007) Systemic inflammatory priming in normal pregnancy and preeclampsia: the role of circulating syncytiotrophoblast microparticles. J Immunol 178:5949–5956PubMedGoogle Scholar
  50. 50.
    Hewagama A, Patel D, Yarlagadda S, Strickland FM, Richardson BC (2009) Stronger inflammatory/cytotoxic T-cell response in women identified by microarray analysis. Genes Immun 10:509–516PubMedCrossRefGoogle Scholar
  51. 51.
    Fan X, Oertli B, Wuthrich RP (1997) Up-regulation of tubular epithelial interleukin-12 in autoimmune MRL-Fas(lpr) mice with renal injury. Kidney Int 51:79–86PubMedCrossRefGoogle Scholar
  52. 52.
    Schwarting A, Tesch G, Kinoshita K, Maron R, Weiner HL, Kelley VR (1999) IL-12 drives IFN-gamma-dependent autoimmune kidney disease in MRL-Fas(lpr) mice. J Immunol 163:6884–6891PubMedGoogle Scholar
  53. 53.
    Yasuda T, Yoshimoto T, Tsubura A, Matsuzawa A (2001) Clear suppression of Th1 responses but marginal amelioration of autoimmune manifestations by IL-12p40 transgene in MRL-FAS(lprcg)/FAS(lprcg) mice. Cell Immunol 210:77–86PubMedCrossRefGoogle Scholar
  54. 54.
    Xu Z, Duan B, Croker BP, Morel L (2006) STAT4 deficiency reduces autoantibody production and glomerulonephritis in a mouse model of lupus. Clin Immunol 120:189–198PubMedCrossRefGoogle Scholar
  55. 55.
    Singh RR, Saxena V, Zang S, Li L, Finkelman FD, Witte DP et al (2003) Differential contribution of IL-4 and STAT6 vs STAT4 to the development of lupus nephritis. J Immunol 170:4818–4825PubMedGoogle Scholar
  56. 56.
    Jacob CO, Zang S, Li L, Ciobanu V, Quismorio F, Mizutani A et al (2003) Pivotal role of Stat4 and Stat6 in the pathogenesis of the lupus-like disease in the New Zealand mixed 2328 mice. J Immunol 171:1564–1571PubMedGoogle Scholar
  57. 57.
    Wilder RL (1998) Hormones, pregnancy, and autoimmune diseases. Ann N Y Acad Sci 840:45–50PubMedCrossRefGoogle Scholar
  58. 58.
    Tokano Y, Morimoto S, Kaneko H, Amano H, Nozawa K, Takasaki Y et al (1999) Levels of IL-12 in the sera of patients with systemic lupus erythematosus (SLE)—relation to Th1- and Th2-derived cytokines. Clin Exp Immunol 116:169–173PubMedCrossRefGoogle Scholar
  59. 59.
    Su DL, Wang HJ, Ji XH, Li YY, Xuan HB, Heng C et al (2006) Mycophenolic acid inhibits SLE-associated cytokine expression and promotes apoptosis of peripheral blood mononuclear cells from patients with systemic lupus erythematosus. Acta Pharmacol Sin 27:1051–1057PubMedCrossRefGoogle Scholar
  60. 60.
    Zouali M (1998) Signaling in human lupus T lymphocytes. Lupus 7:499–502PubMedCrossRefGoogle Scholar
  61. 61.
    Tenbrock K, Juang YT, Kyttaris VC, Tsokos GC (2007) Altered signal transduction in SLE T cells. Rheumatology (Oxford) 46:1525–1530CrossRefGoogle Scholar
  62. 62.
    Rider V, Jones SR, Evans M, Abdou NI (2000) Molecular mechanisms involved in the estrogen-dependent regulation of calcineurin in systemic lupus erythematosus T cells. Clin Immunol 95:124–134PubMedCrossRefGoogle Scholar
  63. 63.
    Gorjestani S, Rider V, Kimler BF, Greenwell C, Abdou NI (2008) Extracellular signal-regulated kinase 1/2 signalling in SLE T cells is influenced by oestrogen and disease activity. Lupus 17:548–554PubMedCrossRefGoogle Scholar
  64. 64.
    Katagiri C, Kawamura T, Matsuzawa S, Mizuno Y, Matsumura S, Kikuchi K (1993) Increases in protein phosphatase 2B activity in lymphoid tissues and T-lymphocytes of autoimmune MRL/MpJ-lpr/lpr mice. J Biochem (Tokyo) 114:874–878Google Scholar
  65. 65.
    Inui A, Ogasawara H, Naito T, Sekigawa I, Takasaki Y, Hayashida Y et al (2007) Estrogen receptor expression by peripheral blood mononuclear cells of patients with systemic lupus erythematosus. Clin Rheumatol 26:1675–1678PubMedCrossRefGoogle Scholar
  66. 66.
    Peeva E, Zouali M (2005) Spotlight on the role of hormonal factors in the emergence of autoreactive B-lymphocytes. Immunol Lett 101:123–143PubMedCrossRefGoogle Scholar
  67. 67.
    Nalbandian G, Kovats S (2005) Understanding sex biases in immunity: effects of estrogen on the differentiation and function of antigen-presenting cells. Immunol Res 31:91–106PubMedCrossRefGoogle Scholar
  68. 68.
    Grimaldi CM, Hill L, Xu X, Peeva E, Diamond B (2005) Hormonal modulation of B cell development and repertoire selection. Mol Immunol 42:811–820PubMedCrossRefGoogle Scholar
  69. 69.
    Medina KL, Strasser A, Kincade PW (2000) Estrogen influences the differentiation, proliferation, and survival of early B-lineage precursors. Blood 95:2059–2067PubMedGoogle Scholar
  70. 70.
    Medina KL, Garrett KP, Thompson LF, Rossi MI, Payne KJ, Kincade PW (2001) Identification of very early lymphoid precursors in bone marrow and their regulation by estrogen. Nat Immunol 2:718–724PubMedCrossRefGoogle Scholar
  71. 71.
    Kincade PW, Medina KL, Payne KJ, Rossi MI, Tudor KS, Yamashita Y et al (2000) Early B-lymphocyte precursors and their regulation by sex steroids. Immunol Rev 175:128–137PubMedCrossRefGoogle Scholar
  72. 72.
    Smithson G, Couse JF, Lubahn DB, Korach KS, Kincade PW (1998) The role of estrogen receptors and androgen receptors in sex steroid regulation of B lymphopoiesis. J Immunol 161:27–34PubMedGoogle Scholar
  73. 73.
    Erlandsson MC, Jonsson CA, Islander U, Ohlsson C, Carlsten H (2003) Oestrogen receptor specificity in oestradiol-mediated effects on B lymphopoiesis and immunoglobulin production in male mice. Immunology 108:346–351PubMedCrossRefGoogle Scholar
  74. 74.
    Thurmond TS, Murante FG, Staples JE, Silverstone AE, Korach KS, Gasiewicz TA (2000) Role of estrogen receptor alpha in hematopoietic stem cell development and B lymphocyte maturation in the male mouse. Endocrinology 141:2309–2318PubMedCrossRefGoogle Scholar
  75. 75.
    Giglio T, Imro MA, Filaci G, Scudeletti M, Puppo F, De Cecco L et al (1994) Immune cell circulating subsets are affected by gonadal function. Life Sci 54:1305–1312PubMedCrossRefGoogle Scholar
  76. 76.
    Kanda N, Tamaki K (1999) Estrogen enhances immunoglobulin production by human PBMCs. J Allergy Clin Immunol 103:282–288PubMedCrossRefGoogle Scholar
  77. 77.
    Verthelyi DI, Ahmed SA (1998) Estrogen increases the number of plasma cells and enhances their autoantibody production in nonautoimmune C57BL/6 mice. Cell Immunol 189:125–134PubMedCrossRefGoogle Scholar
  78. 78.
    Han D, Denison MS, Tachibana H, Yamada K (2002) Effects of estrogenic compounds on immunoglobulin production by mouse splenocytes. Biol Pharm Bull 25:1263–1267PubMedCrossRefGoogle Scholar
  79. 79.
    Nakaya M, Yamasaki M, Tachibana H, Yamada K (2005) IgM production of lymphocytes from C57BL/6N mice was stimulated by estrogen treated splenic adherent cells. Immunol Lett 98:225–231PubMedCrossRefGoogle Scholar
  80. 80.
    Lagerquist MK, Erlandsson MC, Islander U, Svensson L, Holmdahl R, Carlsten H (2008) 17Beta-estradiol expands IgA-producing B cells in mice deficient for the mu chain. Scand J Immunol 67:12–17PubMedGoogle Scholar
  81. 81.
    Erlandsson MC, Jonsson CA, Lindberg MK, Ohlsson C, Carlsten H (2002) Raloxifene- and estradiol-mediated effects on uterus, bone and B lymphocytes in mice. J Endocrinol 175:319–327PubMedCrossRefGoogle Scholar
  82. 82.
    Grimaldi CM, Michael DJ, Diamond B (2001) Cutting edge: expansion and activation of a population of autoreactive marginal zone B cells in a model of estrogen-induced lupus. J Immunol 167:1886–1890PubMedGoogle Scholar
  83. 83.
    Forsberg JG (2000) Neonatal estrogen treatment and its consequences for thymus development, serum level of autoantibodies to cardiolipin, and the delayed-type hypersensitivity response. J Toxicol Environ Health A 60:185–213PubMedCrossRefGoogle Scholar
  84. 84.
    Verthelyi D, Ansar Ahmed S (1997) Characterization of estrogen-induced autoantibodies to cardiolipin in non-autoimmune mice. J Autoimmun 10:115–125PubMedCrossRefGoogle Scholar
  85. 85.
    Kanda N, Tsuchida T, Tamaki K (1999) Estrogen enhancement of anti-double-stranded DNA antibody and immunoglobulin G production in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. Arthritis Rheum 42:328–337PubMedCrossRefGoogle Scholar
  86. 86.
    Bynoe MS, Grimaldi CM, Diamond B (2000) Estrogen up-regulates Bcl-2 and blocks tolerance induction of naive B cells. Proc Natl Acad Sci U S A 97:2703–2708PubMedCrossRefGoogle Scholar
  87. 87.
    Jenkins JK, Suwannaroj S, Elbourne KB, Ndebele K, McMurray RW (2001) 17-beta-estradiol alters Jurkat lymphocyte cell cycling and induces apoptosis through suppression of Bcl-2 and cyclin A. Int Immunopharmacol 1:1897–1911PubMedCrossRefGoogle Scholar
  88. 88.
    Dong L, Wang W, Wang F, Stoner M, Reed JC, Harigai M et al (1999) Mechanisms of transcriptional activation of bcl-2 gene expression by 17beta-estradiol in breast cancer cells. J Biol Chem 274:32099–32107PubMedCrossRefGoogle Scholar
  89. 89.
    Kanda N, Tsuchida T, Tamaki K (1996) Testosterone inhibits immunoglobulin production by human peripheral blood mononuclear cells. Clin Exp Immunol 106:410–415PubMedCrossRefGoogle Scholar
  90. 90.
    Carlsten H, Holmdahl R, Tarkowski A, Nilsson LA (1989) Oestradiol- and testosterone-mediated effects on the immune system in normal and autoimmune mice are genetically linked and inherited as dominant traits. Immunology 68:209–214PubMedGoogle Scholar
  91. 91.
    Viselli SM, Reese KR, Fan J, Kovacs WJ, Olsen NJ (1997) Androgens alter B cell development in normal male mice. Cell Immunol 182:99–104PubMedCrossRefGoogle Scholar
  92. 92.
    Ellis TM, Moser MT, Le PT, Flanigan RC, Kwon ED (2001) Alterations in peripheral B cells and B cell progenitors following androgen ablation in mice. Int Immunol 13:553–558PubMedCrossRefGoogle Scholar
  93. 93.
    Altuwaijri S, Chuang KH, Lai KP, Lai JJ, Lin HY, Young FM et al (2009) Susceptibility to autoimmunity and B cell resistance to apoptosis in mice lacking androgen receptor in B cells. Mol Endocrinol 23:444–453PubMedCrossRefGoogle Scholar
  94. 94.
    Peeva E, Michael D, Cleary J, Rice J, Chen X, Diamond B (2003) Prolactin modulates the naive B cell repertoire. J Clin Invest 111:275–283PubMedGoogle Scholar
  95. 95.
    Viau M, Zouali M (2005) B-lymphocytes, innate immunity, and autoimmunity. Clin Immunol 114:17–26PubMedCrossRefGoogle Scholar
  96. 96.
    Subhrajit S, Gonzalez J, Rosenfeld G, Keiser H, Peeva E (2009) Prolactin alters the mechanisms of B cell tolerance induction. Arthritis Rheum 60:1743–1752CrossRefGoogle Scholar
  97. 97.
    Elbourne KB, Keisler D, McMurray RW (1998) Differential effects of estrogen and prolactin on autoimmune disease in the NZB/NZW F1 mouse model of systemic lupus erythematosus. Lupus 7:420–427PubMedCrossRefGoogle Scholar
  98. 98.
    Saha S, Gonzalez J, Rosenfeld G, Keiser H, Peeva E (2009) Prolactin alters the mechanisms of B cell tolerance induction. Arthritis Rheum 60:1743–1752PubMedCrossRefGoogle Scholar
  99. 99.
    Desai-Mehta A, Lu L, Ramsey-Goldman R, Datta SK (1996) Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production. J Clin Invest 97:2063–2073PubMedCrossRefGoogle Scholar
  100. 100.
    Li X, Rider V, Kimler BF, Abdou NI (2006) Estrogen does not regulate CD154 mRNA stability in systemic lupus erythematosus T cells. Lupus 15:852–857PubMedCrossRefGoogle Scholar
  101. 101.
    Diaz-Alderete A, Crispin JC, Vargas-Rojas MI, Alcocer-Varela J (2004) IL-10 production in B cells is confined to CD154+ cells in patients with systemic lupus erythematosus. J Autoimmun 23:379–383PubMedCrossRefGoogle Scholar
  102. 102.
    Tokunaga M, Fujii K, Saito K, Nakayamada S, Tsujimura S, Nawata M et al (2005) Down-regulation of CD40 and CD80 on B cells in patients with life-threatening systemic lupus erythematosus after successful treatment with rituximab. Rheumatology (Oxford) 44:176–182CrossRefGoogle Scholar
  103. 103.
    Nagafuchi H, Shimoyama Y, Kashiwakura J, Takeno M, Sakane T, Suzuki N (2003) Preferential expression of B7.2 (CD86), but not B7.1 (CD80), on B cells induced by CD40/CD40L interaction is essential for anti-DNA autoantibody production in patients with systemic lupus erythematosus. Clin Exp Rheumatol 21:71–77PubMedGoogle Scholar
  104. 104.
    Dolff S, Wilde B, Patschan S, Durig J, Specker C, Philipp T et al (2007) Peripheral circulating activated B-cell populations are associated with nephritis and disease activity in patients with systemic lupus erythematosus. Scand J Immunol 66:584–590PubMedCrossRefGoogle Scholar
  105. 105.
    Higuchi T, Aiba Y, Nomura T, Matsuda J, Mochida K, Suzuki M et al (2002) Cutting Edge: ectopic expression of CD40 ligand on B cells induces lupus-like autoimmune disease. J Immunol 168:9–12PubMedGoogle Scholar
  106. 106.
    Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T (2000) Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102:553–563PubMedCrossRefGoogle Scholar
  107. 107.
    Crouch EE, Li Z, Takizawa M, Fichtner-Feigl S, Gourzi P, Montano C et al (2007) Regulation of AID expression in the immune response. J Exp Med 204:1145–1156PubMedCrossRefGoogle Scholar
  108. 108.
    Bombardieri M, Barone F, Humby F, Kelly S, McGurk M, Morgan P et al (2007) Activation-induced cytidine deaminase expression in follicular dendritic cell networks and interfollicular large B cells supports functionality of ectopic lymphoid neogenesis in autoimmune sialoadenitis and MALT lymphoma in Sjogren’s syndrome. J Immunol 179:4929–4938PubMedGoogle Scholar
  109. 109.
    Hsu HC, Wu Y, Yang P, Wu Q, Job G, Chen J et al (2007) Overexpression of activation-induced cytidine deaminase in B cells is associated with production of highly pathogenic autoantibodies. J Immunol 178:5357–5365PubMedGoogle Scholar
  110. 110.
    Jiang C, Foley J, Clayton N, Kissling G, Jokinen M, Herbert R et al (2007) Abrogation of lupus nephritis in activation-induced deaminase-deficient MRL/lpr mice. J Immunol 178:7422–7431PubMedGoogle Scholar
  111. 111.
    Pauklin S, Sernandez IV, Bachmann G, Ramiro AR, Petersen-Mahrt SK (2009) Estrogen directly activates AID transcription and function. J Exp Med 206:99–111PubMedCrossRefGoogle Scholar
  112. 112.
    Demaison C, Chastagner P, Theze J, Zouali M (1994) Somatic diversification in the heavy chain variable region genes expressed by human autoantibodies bearing a lupus-associated nephritogenic anti-DNA idiotype. Proc Natl Acad Sci U S A 91:514–518PubMedCrossRefGoogle Scholar
  113. 113.
    Brodnicki TC (2007) Somatic mutation and autoimmunity. Cell 131:1220–1221PubMedCrossRefGoogle Scholar
  114. 114.
    Xu X, Hsu HC, Chen J, Grizzle WE, Chatham WW, Stockard CR et al (2009) Increased expression of activation-induced cytidine deaminase is associated with anti-CCP and rheumatoid factor in rheumatoid arthritis. Scand J Immunol 70:309–316PubMedCrossRefGoogle Scholar
  115. 115.
    Meeker JD, Sathyanarayana S, Swan SH (2009) Phthalates and other additives in plastics: human exposure and associated health outcomes. Philos Trans R Soc Lond B Biol Sci 364:2097–2113PubMedCrossRefGoogle Scholar
  116. 116.
    Talsness CE, Andrade AJ, Kuriyama SN, Taylor JA, vom Saal FS (2009) Components of plastic: experimental studies in animals and relevance for human health. Philos Trans R Soc Lond B Biol Sci 364:2079–2096PubMedCrossRefGoogle Scholar
  117. 117.
    Muncke J (2009) Exposure to endocrine disrupting compounds via the food chain: Is packaging a relevant source? Sci Total Environ 407:4549–4559PubMedCrossRefGoogle Scholar
  118. 118.
    Bogh IB, Christensen P, Dantzer V, Groot M, Thofner IC, Rasmussen RK et al (2001) Endocrine disrupting compounds: effect of octylphenol on reproduction over three generations. Theriogenology 55:131–150PubMedCrossRefGoogle Scholar
  119. 119.
    Miller KP, Gupta RK, Flaws JA (2006) Methoxychlor metabolites may cause ovarian toxicity through estrogen-regulated pathways. Toxicol Sci 93:180–188PubMedCrossRefGoogle Scholar
  120. 120.
    Symonds DA, Tomic D, Miller KP, Flaws JA (2005) Methoxychlor induces proliferation of the mouse ovarian surface epithelium. Toxicol Sci 83:355–362PubMedCrossRefGoogle Scholar
  121. 121.
    Toyama Y, Suzuki-Toyota F, Maekawa M, Ito C, Toshimori K (2004) Adverse effects of bisphenol A to spermiogenesis in mice and rats. Arch Histol Cytol 67:373–381PubMedCrossRefGoogle Scholar
  122. 122.
    Kim SK, Kim JH, Lee HJ, Yoon YD (2007) Octylphenol reduces the expressions of steroidogenic enzymes and testosterone production in mouse testis. Environ Toxicol 22:449–458PubMedCrossRefGoogle Scholar
  123. 123.
    McKinney JD, Waller CL (1994) Polychlorinated biphenyls as hormonally active structural analogues. Environ Health Perspect 102:290–297PubMedGoogle Scholar
  124. 124.
    Bergeron JM, Crews D, McLachlan JA (1994) PCBs as environmental estrogens: turtle sex determination as a biomarker of environmental contamination. Environ Health Perspect 102:780–781PubMedCrossRefGoogle Scholar
  125. 125.
    Vandenberg LN, Maffini MV, Sonnenschein C, Rubin BS, Soto AM (2009) Bisphenol-A and the great divide: a review of controversies in the field of endocrine disruption. Endocr Rev 30:75–95PubMedCrossRefGoogle Scholar
  126. 126.
    Forsell JH, Witt MF, Tai JH, Jensen R, Pestka JJ (1986) Effects of 8-week exposure of the B6C3F1 mouse to dietary deoxynivalenol (vomitoxin) and zearalenone. Food Chem Toxicol 24:213–219PubMedCrossRefGoogle Scholar
  127. 127.
    Pestka JJ, Tai JH, Witt MF, Dixon DE, Forsell JH (1987) Suppression of immune response in the B6C3F1 mouse after dietary exposure to the Fusarium mycotoxins deoxynivalenol (vomitoxin) and zearalenone. Food Chem Toxicol 25:297–304PubMedCrossRefGoogle Scholar
  128. 128.
    Guo TL, Zhang XL, Bartolucci E, McCay JA, White KL Jr, You L (2002) Genistein and methoxychlor modulate the activity of natural killer cells and the expression of phenotypic markers by thymocytes and splenocytes in F0 and F1 generations of Sprague-Dawley rats. Toxicology 172:205–215PubMedCrossRefGoogle Scholar
  129. 129.
    Nair-Menon JU, Campbell GT, Blake CA (1996) Toxic effects of octylphenol on cultured rat and murine splenocytes. Toxicol Appl Pharmacol 139:437–444PubMedCrossRefGoogle Scholar
  130. 130.
    Blake CA, Nair-Menon JU, Campbell GT (1997) Estrogen can protect splenocytes from the toxic effects of the environmental pollutant 4-tert-octylphenol. Endocr 6:243–249CrossRefGoogle Scholar
  131. 131.
    Ruh MF, Bi Y, Cox L, Berk D, Howlett AC, Bellone CJ (1998) Effect of environmental estrogens on IL-1beta promoter activity in a macrophage cell line. Endocr 9:207–211CrossRefGoogle Scholar
  132. 132.
    Lee MH, Kim E, Kim TS (2004) Exposure to 4-tert-octylphenol, an environmentally persistent alkylphenol, enhances interleukin-4 production in T cells via NF-AT activation. Toxicol Appl Pharmacol 197:19–28PubMedCrossRefGoogle Scholar
  133. 133.
    Ohnishi T, Yoshida T, Igarashi A, Muroi M, Tanamoto K (2008) Effects of possible endocrine disruptors on MyD88-independent TLR4 signaling. FEMS Immunol Med Microbiol 52:293–295PubMedCrossRefGoogle Scholar
  134. 134.
    Yoshitake J, Kato K, Yoshioka D, Sueishi Y, Sawa T, Akaike T et al (2008) Suppression of NO production and 8-nitroguanosine formation by phenol-containing endocrine-disrupting chemicals in LPS-stimulated macrophages: involvement of estrogen receptor-dependent or -independent pathways. Nitric Oxide 18:223–228PubMedCrossRefGoogle Scholar
  135. 135.
    Calemine J, Zalenka J, Karpuzoglu-Sahin E, Ward DL, Lengi A, Ahmed SA (2003) The immune system of geriatric mice is modulated by estrogenic endocrine disruptors (diethylstilbestrol, alpha-zearalanol, and genistein): effects on interferon-gamma. Toxicology 194:115–128PubMedCrossRefGoogle Scholar
  136. 136.
    Sobel ES, Gianini J, Butfiloski EJ, Croker BP, Schiffenbauer J, Roberts SM (2005) Acceleration of autoimmunity by organochlorine pesticides in (NZB × NZW)F1 mice. Environ Health Perspect 113:323–328PubMedCrossRefGoogle Scholar
  137. 137.
    Yurino H, Ishikawa S, Sato T, Akadegawa K, Ito T, Ueha S et al (2004) Endocrine disruptors (environmental estrogens) enhance autoantibody production by B1 cells. Toxicol Sci 81:139–147PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Biomedical Sciences and Pathobiology, Center for Molecular Medicine and Infectious DiseaseVirginia-Maryland Regional College of Veterinary Medicine, Virginia TechBlacksburgUSA
  2. 2.Institute of Genes and TransplantationBaskent UniversityAnkaraTurkey
  3. 3.Inserm U606Centre Viggo Petersen, Hôpital LariboisièreParis CEDEX 10France
  4. 4.University Denis Diderot Paris 7ParisFrance

Personalised recommendations