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.


CONCLUSIONS
Raloxifene suppressed estrogen-mediated effects on the survival, maturation, and activation of autoreactive B cells in NZB/W F1 mice.
Zhang
Yu
Y
Department of Medicine and Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA. peeva.elena@gmail.com
Saha
Subhrajit
S
Rosenfeld
Gabriel
G
Gonzalez
Juana
J
Pepeljugoski
Kiril P
KP
Peeva
Elena
E
D000818:Animals; D000974:Antibodies, Antinuclear; D000936:Antigen-Antibody Complex / Q000187:drug effects / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000097:blood; D004359:Drug Therapy, Combination; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007074:Immunoglobulin G / Q000032:analysis / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008814:Mice, Inbred NZB; D010052:Ovariectomy; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology / Q000276:immunology
D000974:Antibodies, Antinuclear; D000936:Antigen-Antibody Complex; D019013:CD40 Antigens; D004965:Estrogen Antagonists; D004967:Estrogens; D007074:Immunoglobulin G; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D004247:DNA