Raloxifene Modulates Estrogen-mediated B Cell Autoreactivity in NZB/W F1 Mice

Objective. Estrogen has been found to exacerbate disease activity in murine lupus and to induce a lupus-like syndrome in nonspontaneously autoimmune mice. This has led to the consideration that estrogen may be a risk factor for the development of systemic lupus erythematosus (SLE), and selective estrogen receptor modulators (SERM) may serve to ameliorate lupus activity. We evaluated the effects and mechanism of action of the SERM raloxifene in murine lupus. Methods. Effects of raloxifene on the development of lupus in NZB/W F1 mice were evaluated in the presence and absence of estrogen by assessing the serum DNA reactivity, glomerular IgG deposition and kidney damage, B cell maturation and selection, and activation status of marginal zone and follicular B cells. Results. Compared to estradiol-treated mice, mice treated with estradiol and raloxifene had significantly lower serum anti-DNA antibody levels and less kidney damage. These effects of raloxifene were due, at least in part, to antagonism of the influence of estrogen on DNA-reactive B cells. Raloxifene was found to prevent estrogen-mediated suppression of autoreactive B cell elimination at the T1/T2 selection checkpoint, to reduce estrogen-induced CD40 overexpression on follicular B cells, making them less responsive to T cell costimulation, and to ameliorate estrogen-mediated CD22 downregulation on marginal zone B cells, thereby decreasing their responsiveness to B cell antigen receptor-mediated stimuli. Conclusion. Raloxifene suppressed estrogen-mediated effects on the survival, maturation, and activation of autoreactive B cells in NZB/W F1 mice.

[1]  T. Austin.  Precursors. , 2020, Bulletin of the World Health Organization.

[2]  M. Petri,et al.  Frequency of lupus flare in pregnancy. The Hopkins Lupus Pregnancy Center experience. , 2010, Arthritis and rheumatism.

[3]  A. Tatum,et al.  The induction of the lupus phenotype by estrogen is via an estrogen receptor-alpha-dependent pathway. , 2010, Clinical immunology.

[4]  A. Hasenburg,et al.  The effect of exemestane or tamoxifen on markers of bone turnover: results of a German sub-study of the Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial. , 2009, Breast.

[5]  K. Korach,et al.  Impact of estrogen receptor deficiency on disease expression in the NZM2410 lupus prone mouse. , 2008, Clinical immunology.

[6]  C. Mok.  Hormone replacement therapy in systemic lupus erythematosus. , 2008, Nature clinical practice. Rheumatology.

[7]  Y. Shoenfeld,et al.  Gender and autoimmunity. , 2007, Autoimmunity reviews.

[8]  E. Zenteno,et al.  Effect of Prolactin on Lymphocyte Activation from Systemic Lupus Erythematosus Patients , 2007, Annals of the New York Academy of Sciences.

[9]  Jing Li,et al.  Effects of estrogen receptor subtype-selective agonists on autoimmune disease in lupus-prone NZB/NZW F1 mouse model. , 2007, Clinical immunology.

[10]  C. Maric,et al.  Renoprotective Effects of a Selective Estrogen Receptor Modulator, Raloxifene, in an Animal Model of Diabetic Nephropathy , 2007, American Journal of Nephrology.

[11]  C. Hermenegildo,et al.  Estrogen Receptor Agonists and Immune System in Ovariectomized Mice , 2006, International journal of immunopathology and pharmacology.

[12]  E. Sternberg.  Faculty Opinions recommendation of The selective estrogen receptor modulators, tamoxifen and raloxifene, impair dendritic cell differentiation and activation. , 2006 .

[13]  C. Grimaldi,et al.  Hormonal Regulation of B Cell Development: 17β-Estradiol Impairs Negative Selection of High-Affinity DNA-Reactive B Cells at More Than One Developmental Checkpoint1 , 2006, The Journal of Immunology.

[14]  J. Reginster,et al.  Raloxifene reduces fractures in postmenopausal women with osteoporosis. , 2006, Clinical orthopaedics and related research.

[15]  C. Mok,et al.  Raloxifene for postmenopausal women with systemic lupus erythematosus: a pilot randomized controlled study. , 2005, Arthritis and rheumatism.

[16]  B. Diamond,et al.  Tamoxifen Blocks Estrogen-Induced B Cell Maturation but Not Survival1 , 2005, The Journal of Immunology.

[17]  D. Allman,et al.  Models for peripheral B cell development and homeostasis. , 2005, Seminars in immunology.

[18]  C. Grimaldi,et al.  Mechanism of Action of Transmembrane Activator and Calcium Modulator Ligand Interactor-Ig in Murine Systemic Lupus Erythematosus1 , 2004, The Journal of Immunology.

[19]  Sung Yeon Kim,et al.  Genotoxic Mechanism of Tamoxifen in Developing Endometrial Cancer , 2004, Drug metabolism reviews.

[20]  M. Kronenberg,et al.  Activation of natural killer T cells in NZB/W mice induces Th1-type immune responses exacerbating lupus. , 2003, The Journal of clinical investigation.

[21]  J. Gustafsson,et al.  Estrogen signaling: a subtle balance between ER alpha and ER beta. , 2003, Molecular interventions.

[22]  H. Zinger,et al.  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 , 2003, Annals of the rheumatic diseases.

[23]  C. Ohlsson,et al.  Raloxifene- and estradiol-mediated effects on uterus, bone and B lymphocytes in mice. , 2002, The Journal of endocrinology.

[24]  J. Dwyer,et al.  Estrogen inhibition of EAE involves effects on dendritic cell function , 2002, Journal of neuroscience research.

[25]  R. Furie,et al.  The effect of anti-CD40 ligand antibody on B cells in human systemic lupus erythematosus. , 2002, Arthritis and rheumatism.

[26]  Donald P. McDonnell,et al.  Connections and Regulation of the Human Estrogen Receptor , 2002, Science.

[27]  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.

[28]  J. Cline,et al.  Assessment of Hormonally Active Agents in the Reproductive Tract of Female Nonhuman Primates , 2001, Toxicologic pathology.

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

[30]  B. Chiang,et al.  Tamoxifen Decreases Renal Inflammation and Alleviates Disease Severity in Autoimmune NZB/W F1 Mice , 2000, Scandinavian journal of immunology.

[31]  C K Osborne,et al.  Selective estrogen receptor modulators: structure, function, and clinical use. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  J. Kearney,et al.  B‐cell subsets and the mature ­preimmune repertoire. Marginal zone and B1 B cells as part of a “natural immune memory” , 2000, Immunological reviews.

[33]  C. Hermenegildo,et al.  The endometrial effects of SERMs. , 2000, Human reproduction update.

[34]  B. Chiang,et al.  Tamoxifen alleviates disease severity and decreases double negative T cells in autoimmune MRL‐lpr/lpr mice , 2000, Immunology.

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

[36]  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.

[37]  Chisato Miyaura,et al.  Comparative Effects of Estrogen and Raloxifene on B Lymphopoiesis and Bone Loss Induced by Sex Steroid Deficiency in Mice , 2000, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[38]  U. Thienel,et al.  T cells in the pathogenesis of systemic lupus erythematosus: Potential roles of CD154-CD40 interactions and costimulatory molecules , 2000, Current rheumatology reports.

[39]  S. Cummings,et al.  The Effect of Raloxifene on Risk of Breast Cancer in Postmenopausal Women: Results From the MORE Randomized Trial , 2000 .

[40]  L. Plouffe,et al.  Uterine Effects of 3‐Year Raloxifene Therapy in Postmenopausal Women Younger Than Age 60 , 2000, Obstetrics and gynecology.

[41]  S. Cummings,et al.  The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. , 1999, JAMA.

[42]  K. Korach,et al.  Estrogen receptor null mice: what have we learned and where will they lead us? , 1999, Endocrine reviews.

[43]  M. Neuberger,et al.  Deficiency in CD22, a B Cell–specific Inhibitory Receptor, Is Sufficient to Predispose to Development of High Affinity Autoantibodies , 1999, The Journal of experimental medicine.

[44]  S. Datta.  Production of pathogenic antibodies: Cognate interactions between autoimmune T and B cells , 1998, Lupus.

[45]  H. Jick,et al.  Postmenopausal estrogen replacement therapy and the risk of developing systemic lupus erythematosus or discoid lupus. , 1998, The Journal of rheumatology.

[46]  K. Korach,et al.  The role of estrogen receptors and androgen receptors in sex steroid regulation of B lymphopoiesis. , 1998, Journal of immunology.

[47]  W. Huster,et al.  Effects of raloxifene hydrochloride on the endometrium of postmenopausal women. , 1997, American journal of obstetrics and gynecology.

[48]  G. Köhler,et al.  CD22 is a negative regulator of B-cell receptor signalling , 1997, Current Biology.

[49]  F. Kalush,et al.  The beneficial effects of treatment with tamoxifen and anti‐oestradiol antibody on experimental systemic lupus erythematosus are associated with cytokine modulations , 1997, Immunology.

[50]  M. Neuberger,et al.  Hyperresponsive B Cells in CD22-Deficient Mice , 1996, Science.

[51]  C. Burns,et al.  Anti-CD40 ligand antibody treatment prevents the development of lupus-like nephritis in a subset of New Zealand black x New Zealand white mice. Response correlates with the absence of an anti-antibody response. , 1996, Journal of immunology.

[52]  G. Köhler,et al.  Transitional B cells are the target of negative selection in the B cell compartment , 1995, The Journal of experimental medicine.

[53]  G. Colditz,et al.  Postmenopausal Estrogen Therapy and the Risk for Developing Systemic Lupus Erythematosus , 1995, Annals of Internal Medicine.

[54]  C. Turner,et al.  Raloxifene preserves bone strength and bone mass in ovariectomized rats. , 1994, Endocrinology.

[55]  H. Carlsten,et al.  Estrogen induces suppression of natural killer cell cytotoxicity and augmentation of polyclonal B cell activation. , 1994, Cellular immunology.

[56]  T. Bourne,et al.  Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial , 1994, The Lancet.

[57]  T. Spector,et al.  Safety of Hormone Replacement Therapy (HRT) in Systemic Lupus Erythematosus (SLE) , 1994, Lupus.

[58]  A. Tarkowski,et al.  Histocompatibility Complex Gene Products and Exposure to Oestrogen: Two Independent Disease Accelerating Factors in Murine Lupus , 1993, Scandinavian journal of immunology.

[59]  S. Ahmed,et al.  Antibodies to cardiolipin in normal C57BL/6J mice: induction by estrogen but not dihydrotestosterone. , 1993, Journal of autoimmunity.

[60]  A. Young,et al.  Cardiovascular effects , 1991, Experimental Gerontology.

[61]  S. Takahashi,et al.  IgG3 production in MRL/lpr mice is responsible for development of lupus nephritis. , 1991, Journal of immunology.

[62]  M. Baum,et al.  Tamoxifen to prevent breast cancer , 1991, The Lancet.

[63]  M. Sporn,et al.  Anti-oestrogens induce the secretion of active transforming growth factor beta from human fetal fibroblasts. , 1990, British Journal of Cancer.

[64]  J. Wolter,et al.  Effects of tamoxifen treatment on plasma lipids and lipoprotein lipid composition. , 1990, The Journal of clinical endocrinology and metabolism.

[65]  D. Isenberg,et al.  Serial studies of the IgG subclass and functional affinity of DNA antibodies in systemic lupus erythematosus. , 1988, Journal of autoimmunity.

[66]  Bradlow Hl,et al.  Klinefelter's syndrome: hormone metabolism in hypogonadal males with systemic lupus erythematosus. , 1987, The Journal of rheumatology. Supplement.

[67]  H. Kunkel,et al.  Increased 16α-Hydroxylation of Estradiol in Systemic Lupus Erythematosus* , 1981 .

[68]  F. Dixon,et al.  The pathogenesis of glomerulonephritis. , 1968, The American journal of medicine.

[69]  P. Lambert,et al.  PATHOGENESIS OF THE GLOMERULONEPHRITIS OF NZB/W MICE , 1968, The Journal of experimental medicine.

[70]  P. Greaves,et al.  Experimental adenomyosis. , 2006, Best practice & research. Clinical obstetrics & gynaecology.

[71]  B. Thiers.  The Effect of Combined Estrogen and Progesterone Hormone Replacement Therapy on Disease Activity in Systemic Lupus Erythematosus: A Randomized Trial , 2006 .

[72]  M. Boscaro,et al.  Raloxifene: bone and cardiovascular effects. , 2005, Journal of endocrinological investigation.

[73]  D. Fowlkes,et al.  Comparative analyses of mechanistic differences among antiestrogens. , 1999, Endocrinology.

[74]  C. Lau,et al.  Safety of hormonal replacement therapy in postmenopausal patients with systemic lupus erythematosus. , 1998, Scandinavian journal of rheumatology.

[75]  K. Grandien,et al.  Comparison of the Ligand Binding Specificity and Transcript Tissue Distribution of Estrogen Receptors a and b , 1997 .

[76]  J. Gustafsson,et al.  Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. , 1997, Endocrinology.

[77]  R. Lahita,et al.  Klinefelter's syndrome: hormone metabolism in hypogonadal males with systemic lupus erythematosus. , 1987, The Journal of rheumatology. Supplement.

[78]  I. Mackay,et al.  Effects of the oestrogen antagonist tamoxifen on disease indices in systemic lupus erythematosus. , 1984, Journal of clinical & laboratory immunology.

[79]  H. Kunkel,et al.  Increased 16 alpha-hydroxylation of estradiol in systemic lupus erythematosus. , 1981, The Journal of clinical endocrinology and metabolism.

[80]  D. Perazzo,et al.  [Systemic lupus erythematosus]. , 1955, Prensa medica argentina.