Sex hormones and autoimmunity.

Autoimmune diseases occur more in women than in men, and this may be attributable to the role of estrogens. Androgens promote autoimmune diseases with a profile of type 1 cytokines, such as rheumatoid arthritis, whereas estrogens promote autoimmune diseases with a type 2 cytokine profile, like systemic lupus erythematosus. Both androgens and estrogens regulate the Th1/Th2 balance. Type 1 autoimmune diseases are improved when decrease type 1 cytokines (i.e. during fasting), or when there is a rise in type 2 cytokines (increased estrogens, as in pregnancy). Type 2 autoimmune diseases improve when type 2 cytokines are diminished (decreased estrogen, as in post-partum period) or when type 1 response is stimulated.

[1]  K. Tamaki,et al.  Estrogen enhances immunoglobulin production by human PBMCs. , 1999, The Journal of allergy and clinical immunology.

[2]  H. Schunkert,et al.  The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2000 by The Endocrine Society Hormone Replacement Therapy and Interrelation between Serum Interleukin-6 and Body Mass Index in Postmenopausal Women: A Population-Based Study , 2022 .

[3]  M. Kaminishi,et al.  Gender differences in cytokine secretion by human peripheral blood mononuclear cells: role of estrogen in modulating LPS-induced cytokine secretion in an ex vivo septic model. , 2001, Shock.

[4]  K. Tamaki,et al.  Testosterone suppresses anti-DNA antibody production in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. , 1997, Arthritis and rheumatism.

[5]  A. Masi,et al.  Estrogens, the immune response and autoimmunity. , 1995, Clinical and experimental rheumatology.

[6]  F. Wunderlich,et al.  B cells express intracellular but not surface receptors for testosterone and estradiol , 2002, Steroids.

[7]  J. Cannon,et al.  Hormonal modulation of interleukin-6, tumor necrosis factor and associated receptor secretion in postmenopausal women. , 2002, Cytokine.

[8]  C. O'Herlihy,et al.  Menstrual Cycle Dependent Fluctuations in NK and T‐Lymphocyte Subsets from Non‐Pregnant Human Endometrium , 2000, American journal of reproductive immunology.

[9]  M. Piccinni,et al.  Defective production of LIF, M-CSF and Th2-type cytokines by T cells at fetomaternal interface is associated with pregnancy loss. , 2001, Journal of reproductive immunology.

[10]  F. J. Grundbacher.  Human X Chromosome Carries Quantitative Genes for Immunoglobulin M , 1972, Science.

[11]  R. S. Lord,et al.  Estrogen metabolism and the diet-cancer connection: rationale for assessing the ratio of urinary hydroxylated estrogen metabolites. , 2002, Alternative medicine review : a journal of clinical therapeutic.

[12]  A. Bamberger,et al.  Transcriptional regulation of the human `leukemia inhibitory factor' gene: modulation by glucocorticoids and estradiol , 1997, Molecular and Cellular Endocrinology.

[13]  S. Ahmed,et al.  Sex hormones and the immune system--Part 2. Animal data. , 1990, Bailliere's clinical rheumatology.

[14]  I. Sargent,et al.  Flow cytometric measurement of intracellular Th1 and Th2 cytokine production by human villous and extravillous cytotrophoblast. , 2001, Placenta.

[15]  J. Féher,et al.  In vitro effects of different steroid hormones on superoxide anion production of human neutrophil granulocytes , 2000, Steroids.

[16]  A. Schuurs,et al.  Effects of gender and sex steroids on the immune response. , 1990, Journal of steroid biochemistry.

[17]  Griffin Jf,et al.  Humoral immunity in oral contraceptive users. II. In vitro immunoglobulin production. , 1988 .

[18]  Y. Sasaki,et al.  Interleukin‐12 Secretion by Peripheral Blood Mononuclear Cells is Decreased in Normal Pregnant Subjects and Increased in Preeclamptic Patients , 2002, American journal of reproductive immunology.

[19]  J. Wither,et al.  Activated B cells express increased levels of costimulatory molecules in young autoimmune NZB and (NZB x NZW)F(1) mice. , 2000, Clinical immunology.

[20]  W. H. Stimson.  Oestrogen and Human T Lymphocytes: Presence of Specific Receptors in the T‐Suppressor/Cytotoxic Subset , 1988, Scandinavian journal of immunology.

[21]  L. De Cecco,et al.  Immune cell circulating subsets are affected by gonadal function. , 1994, Life sciences.

[22]  A. D. de León,et al.  Inverse Association Between Obesity and Antinuclear Antibodies in Women , 2008, The Journal of Rheumatology.

[23]  C. Grimaldi,et al.  Estrogen up-regulates Bcl-2 and blocks tolerance induction of naive B cells. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[24]  C. Grimaldi,et al.  Estrogen alters thresholds for B cell apoptosis and activation. , 2002, The Journal of clinical investigation.

[25]  R. Straub,et al.  Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity , 2004, Lupus.

[26]  C. Alpers,et al.  Decrease in glomerulonephritis and Th1-associated autoantibody production after progesterone treatment in NZB/NZW mice. , 2009, Arthritis and rheumatism.

[27]  B. Weill,et al.  Progesterone receptors in lymphocytes of liver-transplanted and transfused patients. , 1989, Immunology letters.

[28]  B. Polgár,et al.  The Role of γ/δ T Cell Receptor Positive Cells in Pregnancy , 1999 .

[29]  D. Verthelyi,et al.  Estrogen increases the number of plasma cells and enhances their autoantibody production in nonautoimmune C57BL/6 mice. , 1998, Cellular immunology.

[30]  O. Sandra,et al.  Th1/Th2 Paradigm in Pregnancy: Paradigm Lost? , 2004, International Archives of Allergy and Immunology.

[31]  K. Tamaki,et al.  Estrogen enhancement of anti-double-stranded DNA antibody and immunoglobulin G production in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. , 1999, Arthritis and rheumatism.

[32]  G. Yovel,et al.  The effects of sex, menstrual cycle, and oral contraceptives on the number and activity of natural killer cells. , 2001, Gynecologic oncology.

[33]  C. Watson,et al.  Membrane estrogen and glucocorticoid receptors--implications for hormonal control of immune function and autoimmunity. , 2001, International immunopharmacology.

[34]  M. Heineman,et al.  The immune response during the luteal phase of the ovarian cycle: increasing sensitivity of human monocytes to endotoxin. , 2001, Fertility and sterility.

[35]  I. Elenkov,et al.  Hormonal Regulation of Tumor Necrosis Factor‐α, Interleukin‐12 and Interleukin‐10 Production by Activated Macrophages: A Disease‐modifying Mechanism in Rheumatoid Arthritis and Systemic Lupus Erythematosus? , 1999, Annals of the New York Academy of Sciences.

[36]  S. Ansar Ahmed,et al.  Sex hormones, immune responses, and autoimmune diseases. Mechanisms of sex hormone action. , 1985, The American journal of pathology.

[37]  C. Lau,et al.  Increased apoptotic neutrophils and macrophages and impaired macrophage phagocytic clearance of apoptotic neutrophils in systemic lupus erythematosus. , 2003, Arthritis and rheumatism.

[38]  C. Wira,et al.  Oestradiol regulation of antigen presentation by uterine stromal cells: role of transforming growth factor‐β production by epithelial cells in mediating antigen‐presenting cell function , 2003, Immunology.

[39]  I. Gavilán,et al.  Consistent production of a higher TH1:TH2 cytokine ratio by stimulated T cells in men compared with women. , 2000, European journal of endocrinology.

[40]  M. Irahara,et al.  B cell subsets in postmenopausal women and the effect of hormone replacement therapy. , 2001, Maturitas.

[41]  A. Strasser,et al.  Estrogen influences the differentiation, proliferation, and survival of early B-lineage precursors. , 2000, Blood.

[42]  M. Clerici,et al.  Characterization of type 1 and type 2 cytokine production profile in physiologic and pathologic human pregnancy , 1996, Clinical and experimental immunology.

[43]  P. Husslein,et al.  Production of Pro- and Anti-Inflammatory Cytokines of Human Placental Trophoblasts in Response to Pathogenic Bacteria , 2001, The Journal of the Society for Gynecologic Investigation: JSGI.

[44]  H. Offner,et al.  Estradiol Treatment Redirects the Isotype of the Autoantibody Response and Prevents the Development of Autoimmune Arthritis 1 , 2003, The Journal of Immunology.

[45]  R. Shames.  Gender differences in the development and function of the immune system. , 2002, The Journal of adolescent health : official publication of the Society for Adolescent Medicine.

[46]  M. Álvarez-Mon,et al.  Increased IgM B cell differentiation lymphokine production by T lymphocytes from patients with primary biliary cirrhosis. , 1994, Journal of hepatology.

[47]  L. Ackerman.  Sex hormones and the genesis of autoimmunity. , 2006, Archives of dermatology.

[48]  R. Lahita.  The role of sex hormones in systemic lupus erythematosus. , 1999, Current opinion in rheumatology.

[49]  M. Christiaens,et al.  Evaluation of progesterone receptor expression in eosinophils using real-time quantitative PCR. , 2002, Biochimica et biophysica acta.

[50]  D. Rachoń,et al.  Effects of oestrogen deprivation on interleukin-6 production by peripheral blood mononuclear cells of postmenopausal women. , 2002, The Journal of endocrinology.

[51]  J. Griffin,et al.  Humoral immunity in oral contraceptive users. I. Plasma immunoglobulin levels. , 1988, Contraception.

[52]  R. Vollenhoven.  Dehydroepiandrosterone for the treatment of systemic lupus erythematosus. , 2002 .

[53]  F. G. McDonald,et al.  Oestrogen as an inhibitor of human NK cell cytolysis , 1985, FEBS letters.

[54]  J. Uksila.  Human NK cell activity is not inhibited by pregnancy and cord serum factors and female steroid hormones in vitro. , 1985, Journal of reproductive immunology.

[55]  S. Ansar Ahmed,et al.  Estrogen induces normal murine CD5+ B cells to produce autoantibodies. , 1989, Journal of immunology.

[56]  R. Holmdahl,et al.  Oestrogen is a potent disease accelerator in SLE‐prone MRL lpr/lpr mice , 1990, Clinical and experimental immunology.

[57]  I. Sargent,et al.  Changes in systemic type 1 and type 2 immunity in normal pregnancy and pre‐eclampsia may be mediated by natural killer cells , 2005, European journal of immunology.

[58]  M. Heineman,et al.  The immune response during the luteal phase of the ovarian cycle: a Th2-type response? , 2000, Fertility and sterility.

[59]  C. Grimaldi,et al.  Cutting Edge: Expansion and Activation of A Population of Autoreactive Marginal Zone B Cells in a Model of Estrogen-Induced Lupus , 2001, The Journal of Immunology.

[60]  M. Heineman,et al.  17beta-estradiol and progesterone do not influence the production of cytokines from lipopolysaccharide-stimulated monocytes in humans. , 2004, Fertility and sterility.

[61]  G. Mor,et al.  Interaction of the Estrogen Receptors with the Fas Ligand Promoter in Human Monocytes1 , 2003, The Journal of Immunology.

[62]  Bing Sun,et al.  Effects of leptin on the production of cytokines by cultured human endometrial stromal and epithelial cells. , 2003, Fertility and sterility.

[63]  K. Tamaki,et al.  Testosterone inhibits immunoglobulin production by human peripheral blood mononuclear cells , 1996, Clinical and experimental immunology.

[64]  G. Mor,et al.  Menopause Is Associated With a Significant Increase in Blood Monocyte Number and a Relative Decrease in the Expression of Estrogen Receptors in Human Peripheral Monocytes , 1995, American journal of reproductive immunology.

[65]  M. Heineman,et al.  The immunology of successful pregnancy. , 2003, Human reproduction update.

[66]  D. Jones,et al.  Variation in natural killer activity in peripheral blood during the menstrual cycle. , 1985, British medical journal.

[67]  J. Cidlowski,et al.  Molecular control of immune/inflammatory responses: interactions between nuclear factor-kappa B and steroid receptor-signaling pathways. , 1999, Endocrine reviews.

[68]  F. Annunziato,et al.  Progesterone favors the development of human T helper cells producing Th2-type cytokines and promotes both IL-4 production and membrane CD30 expression in established Th1 cell clones. , 1995, Journal of immunology.

[69]  M. Cutolo.  Estrogen metabolites: increasing evidence for their role in rheumatoid arthritis and systemic lupus erythematosus. , 2004, The Journal of rheumatology.

[70]  R. Lahita.  The connective tissue diseases and the overall influence of gender. , 1996, International journal of fertility and menopausal studies.

[71]  A. Klajman,et al.  [Sex hormones and the immune system]. , 1982, Harefuah.

[72]  G. Giese,et al.  Estradiol binding to cell surface raises cytosolic free calcium in T cells , 1998, FEBS letters.

[73]  D. Isenberg,et al.  Lymphocyte Subsets in a Large Cohort of Patients with Systemic Lupus Erythematosus , 1993, Lupus.

[74]  R. A. Cassidy.  INFLUENCE OF STEROIDS ON OXIDANT GENERATION IN ACTIVATED HUMAN GRANULOCYTES AND MONONUCLEAR LEUKOCYTES , 2003, Shock.

[75]  M. Sheridan-Pereira,et al.  Sex-specific alterations in neutrophil apoptosis: the role of estradiol and progesterone. , 2003, Blood.

[76]  K. Ndebele,et al.  Differential Effects of Sex Steroids on T and B Cells: Modulation of Cell Cycle Phase Distribution, Apoptosis and bcl-2 Protein Levels , 2001, Pathobiology.

[77]  B. Bain,et al.  Variations in leucocyte count during menstrual cycle. , 1975, British medical journal.

[78]  M. Heineman,et al.  Sex hormones and the immune response in humans. , 2005, Human reproduction update.

[79]  Y. Sasaki,et al.  The ratio of interleukin (IL)-18 to IL-12 secreted by peripheral blood mononuclear cells is increased in normal pregnant subjects and decreased in pre-eclamptic patients. , 2004, Journal of reproductive immunology.

[80]  H. Moes,et al.  Cytokine Production by Natural Killer Lymphocytes in Follicular and Luteal Phase of the Ovarian Cycle in Humans , 2001, American journal of reproductive immunology.

[81]  J. Farré,et al.  Estrogen stimulates neuronal nitric oxide synthase protein expression in human neutrophils. , 1999, Circulation research.

[82]  P. Siiteri,et al.  Sex steroids and the immune system--I. Sex difference in autoimmune disease in NZB/NZW hybrid mice. , 1980, Journal of steroid biochemistry.

[83]  F. Tanrıverdi,et al.  The hypothalamic-pituitary-gonadal axis: immune function and autoimmunity. , 2003, The Journal of endocrinology.

[84]  M. Evans,et al.  Gender differences in autoimmune diseases: estrogen increases calcineurin expression in systemic lupus erythematosus. , 1998, Clinical immunology and immunopathology.

[85]  K. Matalka.  The effect of estradiol, but not progesterone, on the production of cytokines in stimulated whole blood, is concentration-dependent. , 2003, Neuro endocrinology letters.

[86]  Philippa Marrack,et al.  Genetic and hormonal factors in female-biased autoimmunity. , 2010, Autoimmunity reviews.

[87]  J. Gustafsson,et al.  Cloning of a novel receptor expressed in rat prostate and ovary. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[88]  T. Garrett,et al.  STUDIES OF THE REGULATORY EFFECTS OF THE SEX HORMONES ON ANTIBODY FORMATION AND STEM CELL DIFFERENTIATION , 1972, The Journal of experimental medicine.

[89]  P. Siiteri,et al.  Effect of castration and sex hormone treatment on survival, anti- nucleic acid antibodies, and glomerulonephritis in NZB/NZW F1 mice , 1978, The Journal of experimental medicine.

[90]  A. Silman,et al.  Influence of oral contraception on the occurrence of rheumatoid arthritis in female sibs. , 1990, Scandinavian journal of rheumatology.

[91]  R. Norman,et al.  Variations in peripheral blood levels of immunoreactive tumor necrosis factor α (TNFα) throughout the menstrual cycle and secretion of TNFα from the human corpus luteum , 1999 .

[92]  C. Grimaldi,et al.  Bromocriptine restores tolerance in estrogen-treated mice. , 2000, The Journal of clinical investigation.

[93]  M. Polan,et al.  Interleukin-1 in human ovarian cells and in peripheral blood monocytes increases during the luteal phase: evidence for a midcycle surge in the human. , 1994, American journal of obstetrics and gynecology.

[94]  M. Heineman,et al.  Gender Difference in the Non‐Specific and Specific Immune Response in Humans , 2004, American journal of reproductive immunology.

[95]  M. Heineman,et al.  Cytokine production in natural killer cells and lymphocytes in pregnant women compared with women in the follicular phase of the ovarian cycle. , 2002, Fertility and sterility.

[96]  R. Effros,et al.  Immune effects of hormone replacement therapy in post-menopausal women , 2001, Experimental Gerontology.

[97]  R. Dinesh,et al.  PD-1, gender, and autoimmunity. , 2010, Autoimmunity reviews.

[98]  I. Sargent,et al.  Monocytes are primed to produce the Th1 type cytokine IL‐12 in normal human pregnancy: an intracellular flow cytometric analysis of peripheral blood mononuclear cells , 2003, Clinical and experimental immunology.

[99]  K. Beagley,et al.  Regulation of innate and adaptive immunity by the female sex hormones oestradiol and progesterone. , 2003, FEMS immunology and medical microbiology.

[100]  N. Olsen,et al.  Gonadal steroids and immunity. , 1996, Endocrine reviews.

[101]  H. Okamura,et al.  IL-18 in pregnancy; the elevation of IL-18 in maternal peripheral blood during labour and complicated pregnancies. , 2000, Journal of reproductive immunology.

[102]  R. Lahita.  Sex hormones and systemic lupus erythematosus. , 2000, Rheumatic diseases clinics of North America.

[103]  M. Heineman,et al.  The Effect of Testosterone on Cytokine Production in the Specific and Non‐specific Immune Response , 2004, American journal of reproductive immunology.

[104]  C. Selmi,et al.  Is autoimmunity a matter of sex? , 2008, Autoimmunity reviews.

[105]  Y. S. Yang,et al.  Hormone replacement therapy reverses the decrease in natural killer cytotoxicity but does not reverse the decreases in the T-cell subpopulation or interferon-gamma production in postmenopausal women. , 2000, Fertility and sterility.

[106]  M. Irahara,et al.  Transient Increase in the Levels of T-Helper 1 Cytokines in Postmenopausal Women and the Effects of Hormone Replacement Therapy , 2001, Gynecologic and Obstetric Investigation.

[107]  Z. Yeşilova,et al.  The effect of testosterone replacement treatment on immunological features of patients with Klinefelter's syndrome , 2000, Clinical and experimental immunology.

[108]  M. Mitchell,et al.  Cytokines, prostaglandins and parturition--a review. , 2003, Placenta.

[109]  R. Mcmurray,et al.  Estrogen, prolactin, and autoimmunity: actions and interactions. , 2001, International immunopharmacology.

[110]  M. Petri,et al.  Disassociation of sex hormone levels and cytokine production in SLE patients , 2001, Lupus.

[111]  S. Norton,et al.  Administration of dehydroepiandrosterone sulfate retards onset but not progression of autoimmune disease in NZB/W mice. , 1997, Autoimmunity.

[112]  D. Barad,et al.  Gender as risk factor for autoimmune diseases. , 2007, Journal of autoimmunity.

[113]  P. Kubes,et al.  Nitric oxide: an endogenous modulator of leukocyte adhesion. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[114]  C. Jacobs,et al.  Decreased phagocytosis of apoptotic cells in diseased SLE mice. , 2004, Journal of autoimmunity.

[115]  J. Huber,et al.  Influence of low-dose oral contraception on peripheral blood lymphocyte subsets at particular phases of the hormonal cycle. , 2002, Fertility and sterility.

[116]  R. Eastell,et al.  The effect of 17beta-estradiol on production of cytokines in cultures of peripheral blood. , 2001, Bone.

[117]  M. Evans,et al.  Estrogen increases CD40 ligand expression in T cells from women with systemic lupus erythematosus. , 2001, The Journal of rheumatology.

[118]  M. Evans,et al.  Molecular mechanisms involved in the estrogen-dependent regulation of calcineurin in systemic lupus erythematosus T cells. , 2000, Clinical immunology.

[119]  T. Bilfinger,et al.  Estradiol coupling to human monocyte nitric oxide release is dependent on intracellular calcium transients: evidence for an estrogen surface receptor. , 1999, Journal of immunology.

[120]  M. Cutolo,et al.  Different roles for androgens and estrogens in the susceptibility to autoimmune rheumatic diseases. , 2000, Rheumatic diseases clinics of North America.

[121]  A. Blakemore,et al.  Stability of Serum Interleukin‐10 Levels During the Menstrual Cycle , 1997, American journal of reproductive immunology.

[122]  S. Ahmed,et al.  17 beta-estradiol, but not 5 alpha-dihydrotestosterone, augments antibodies to double-stranded deoxyribonucleic acid in nonautoimmune C57BL/6J mice. , 1994, Endocrinology.

[123]  K. Esposito,et al.  Cytokine pattern in postmenopause. , 2002, Maturitas.

[124]  M. Beato,et al.  Steroid hormone receptors: an update. , 2000, Human reproduction update.

[125]  G. Chaouat,et al.  Lymphocytic progesterone receptors in normal and pathological human pregnancy. , 1989, Journal of reproductive immunology.

[126]  H. Vogelsang,et al.  A comparative study of the effects of two oral contraceptives containing dienogest or desogestrel on the human immune system , 2000, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.

[127]  R. Eastell,et al.  Effects of Estrogen Therapy of Postmenopausal Women on Cytokines Measured in Peripheral Blood , 1998, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[128]  S. Strober,et al.  Cutting Edge: A Role for CD1 in the Pathogenesis of Lupus in NZB/NZW Mice1 , 2000, The Journal of Immunology.

[129]  E. Giltay,et al.  In vivo effects of sex steroids on lymphocyte responsiveness and immunoglobulin levels in humans. , 2000, The Journal of clinical endocrinology and metabolism.

[130]  M. Heineman,et al.  Endotoxin-induced cytokine production of monocytes of third-trimester pregnant women compared with women in the follicular phase of the menstrual cycle. , 2003, American journal of obstetrics and gynecology.

[131]  C. Thompson,et al.  Apoptosis in the pathogenesis and treatment of disease , 1995, Science.

[132]  H. Aoyama,et al.  Effects of sex hormones on chemotaxis of human peripheral polymorphonuclear leukocytes and monocytes. , 1992, Journal of periodontology.

[133]  J. Polman,et al.  ERβ: Identification and characterization of a novel human estrogen receptor , 1996 .

[134]  H. Friedman,et al.  Practical Considerations Regarding the Influence of the Menstrual Cycle on Leukocyte Parameters in Clinical Trials , 2000, American journal of therapeutics.

[135]  N. Abdou,et al.  Gender differences in autoimmunity: molecular basis for estrogen effects in systemic lupus erythematosus. , 2001, International immunopharmacology.

[136]  C. Whitacre.  Sex differences in autoimmune disease , 2001, Nature Immunology.

[137]  I. Sargent,et al.  NK cells and human pregnancy--an inflammatory view. , 2006, Trends in immunology.

[138]  D. Jones,et al.  Hormonal modulation of human natural killer cell activity in vitro. , 1985, Journal of reproductive immunology.

[139]  K. Ndebele,et al.  Estrogen and Progesterone Modulate Monocyte Cell Cycle Progression and Apoptosis , 2003, American journal of reproductive immunology.

[140]  M. Østensen.  Sex Hormones and Pregnancy in Rheumatoid Arthritis and Systemic Lupus Erythematosus , 1999 .

[141]  J. A. D. Silva,et al.  Sex hormones, glucocorticoids and autoimmunity: facts and hypotheses. , 1995 .