THE ROLE OF ESTROGEN IN THE INDUCTION AND MODULATION OF SYSTEMIC LUPUS ERYTHROMATOSUS (SLE)

Feng, Feng

THE ROLE OF ESTROGEN IN THE INDUCTION AND MODULATION OF SYSTEMIC LUPUS ERYTHROMATOSUS (SLE)

Abstract

Systemic lupus erythematous (SLE) is a systemic autoimmune disease, characterized by circulating auto-antibodies to nuclear and cytoplasmic self antigens. A striking female predominance has been documented in SLE, with a female to male occurrence ratio of 9:1. Although the sex discrepancy in SLE has been attributed to sex hormones especially the female sex steroid estrogen, its importance is still controversial and other mechanisms are proposed, such as X inactivation, imprinting, differential exposures, etc. The present studies were undertaken to investigate the role of estrogen in inducing and accelerating lupus in lupus-prone and non-autoimmune mice and identify the possible mechanisms involved. We first ovariectomized or castrated female or male lupus-prone SNF1 mice in order to determine the impact that removal of physiological levels of sex hormones would have on the pathogenesis of lupus nephritis; exogenous 17?-estradiol (E-2) at a dose of 1mg/kg was also administrated to male mice. The results suggested that E-2 accelerated and exacerbated SNF1 lupus nephritis by inducing pathogenic idiotypic-reactive T cell populations that led to increased production of IdLNF1+ IgG which was deposited in the kidneys, resulting in nephritis. In, contrast, the removal of physiological level of testosterone had no effect. E-2 was also shown to induce the lupus phenotype and disease in the non-autoimmune mice, DBF1 mice. Further, the development of lupus nephritis in bone marrow chimeras derived from SNF1 mice of different genders or between SNF1 mice and the nonautoimmune-prone DBF1 cross, required either a female host and/or the addition of exogenous E-2. The possible mechanism(s) underlying the effect of estrogen were also investigated. Thymectomy of SNF1 mice (at 30 days of age) delayed disease onset; however E-2 treatment induced disease in thymectomized mice, suggesting that the thymus was not required for E-2 induced upregulation of pathogenic idiotypic-reactive T cell populations. Lastly, our data suggest that estrogen?s effects on lupus nephritis were ER-? dependent; E-2 exposure led to decreased survival and nephritis in WT (ER?+/+) but not ER?-/-, and SNF1 immune cells constitutively expressed more ER? compared to DBF1, which was upregulated after E-2 exposure.

Description

Ph.D. Dissertation

Sponsorship

Jerrie Gavalchin

Date Issued

2006-10-20T12:12:03Z

Keywords

estrogen; lupus; autoimmune disease; pathogenesis

Has Other Format(s)

bibid: 6476218

Types

dissertation or thesis