Systemic lupus erythematosus (SLE) is an autoimmune disease that preferentially affects women (9:1) in their reproductive years, indicating that sex specific factors including the sex hormone estradiol play an important role in lupus pathogenesis. Murine models of lupus show natural earlier expression of disease and ensuing mortality in female mice. The Sle1 and Sle3 lupus susceptibility loci present in NZM2410 mice direct increased penetrance of disease in females, which is consistent with studies showing that elevation of systemic estradiol or exposure to estrogenic environmental compounds accelerate lupus development. An understanding of the mechanisms underlying the female preponderance of SLE requires that we precisely determine how endogenous estrogens and estrogen receptors (ER) regulate the function of immune cells such as B lymphocytes and dendritic cells (DC), which express ER and have been implicated in lupus pathogenesis. However, current models for the study of estrogen effects on immune cells often have involved systemic exposure to supra-physiological levels of estradiol or global loss of ER, which creates hormonal imbalances. Elevated systemic levels of estradiol result in a profound depletion of hematopoietic progenitors, leading to alterations in numbers and phenotype of B cells and DC. To circumvent these effects of ER ligands on immune cell development, we propose to develop and use a novel model of murine lupus in which ERalpha expression may be specifically ablated in differentiated B cells or DC. We will use lentiviral transgenesis to deliver Cre recombinase driven by the CD19 or CD11c promoters to lupus prone B6.Sle13 bicongenic mice bearing a conditional ERalpha allele. This approach will allow us to determine whether aberrant DC or post-bone marrow B cell phenotypes associated with the sex sensitive Sle1 and Sle3 loci are mediated by direct effects of endogenous estrogens on B cells or DC. In Aim 1, we will determine if the elevated DC numbers or hyper-activated DC phenotypes leading to pro-inflammatory cytokine production in female B6.Sle13 bicongenic mice are a result of the direct action of endogenous estrogen on DC. In Aim 2, we will determine whether perturbations in transitional B cell subsets and subsequent enhanced loss of serologic tolerance in female B6.Sle13 bicongenic mice are a result of the direct action of endogenous estrogen on committed B cells and/or DC. The successful implementation of this lentiviral transgenesis strategy to delete ERalpha in specific cell types will establish a versatile model that could be used to study the role of ERalpha signaling in any cell type during the development of lupus nephritis. PUBLIC HEALTH RELEVANCE Cells of the human and murine immune systems are capable of responding to estrogens, phytoestrogens and drugs used for treatment of breast cancer and osteoporosis. We seek to understand how estrogens control the development and function of key regulatory cells of the immune system, termed dendritic cells and B cells, during the autoimmune disease Systemic Lupus Erythematosus. This knowledge will help to understand why autoimmune diseases preferentially afflict women.

R21AI079616

2008-08-15

2011-07-31