Raloxifene modulates estrogen-mediated B cell autoreactivity in NZB/W F1 mice

Yu Zhang, Subhrajit Saha, Gabriel Rosenfeld, Juana Gonzalez, Kiril P. Pepeljugoski, Elena Peeva

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

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. The Journal of Rheumatology

Original languageEnglish (US)
Pages (from-to)1646-1657
Number of pages12
JournalJournal of Rheumatology
Volume37
Issue number8
DOIs
StatePublished - Aug 1 2010

Keywords

  • B cells
  • Estrogen
  • NZB/W F1 mice
  • Raloxifene
  • Systemic lupus erythematosus

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology

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    Zhang, Y., Saha, S., Rosenfeld, G., Gonzalez, J., Pepeljugoski, K. P., & Peeva, E. (2010). Raloxifene modulates estrogen-mediated B cell autoreactivity in NZB/W F1 mice. Journal of Rheumatology, 37(8), 1646-1657. https://doi.org/10.3899/jrheum.090911