Tamoxifen blocks estrogen-induced B cell maturation but not survival.
Estrogen treatment has been shown not only to exacerbate disease activity and accelerate death in spontaneous murine models of lupus but also to induce a lupus-like phenotype in non-spontaneously autoimmune mice. In mice transgenic for the H chain of an anti-DNA Ab, estrogen rescues naive autoreactive B cells that normally are deleted and causes them to mature to a marginal zone phenotype. Estrogen further leads to the activation of this population causing an elevation of serum anti-DNA Ab titers and renal disease. This study was designed to evaluate the therapeutic potential of tamoxifen, a selective estrogen receptor modulator, on estrogen-induced lupus. Mice treated with both estradiol and tamoxifen showed no elevation in anti-DNA Ab titers and consequently no glomerular IgG. The DNA-reactive B cell population that is rescued by estrogen was present in an anergic state in mice treated with both estradiol and tamoxifen. Estradiol enhances transitional B cell resistance to apoptosis and expands the population of marginal zone B cells; tamoxifen did not impede the enhanced resistance to apoptosis, but prevented the development of autoreactive cells as marginal zone B cells. Thus, estrogen-induced autoimmunity proceeds through two distinct molecular pathways, one affecting survival and the other maturation. Activation, but not survival, of autoreactive B cells can be abrogated by tamoxifen. Drugs that modulate even some of the effects of estrogen may be beneficial in patients with lupus. Eventually, understanding the pathways involved in survival and activation of autoreactive B cells will permit the development of therapeutics that target all relevant pathways.
Peeva
Elena
E
Department of Microbiology and Immunology and Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Venkatesh
Jeganathan
J
Diamond
Betty
B
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D015703:Antigens, CD / Q000096:biosynthesis; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology*; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D004958:Estradiol / Q000008:administration & dosage*; D004965:Estrogen Antagonists / Q000008:administration & dosage; D005260:Female; D006825:Hybridomas; D007074:Immunoglobulin G / Q000096:biosynthesis; D016130:Immunophenotyping; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis; D051918:Sialic Acid Binding Ig-like Lectin 2; D013629:Tamoxifen / Q000008:administration & dosage*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D000974:Antibodies, Antinuclear; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; C497868:Cd22 protein, mouse; D015815:Cell Adhesion Molecules; D004965:Estrogen Antagonists; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; D008070:Lipopolysaccharides; D051918:Sialic Acid Binding Ig-like Lectin 2; D013629:Tamoxifen; D004958:Estradiol; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse