Doctor of Philosophy (PhD)
Genetics, Cell Biology & Anatomy
Karen A. Gould
Lupus is a chronic autoimmune disease characterized by the presence of autoimmune B and T cells and the production of pathogenic antibodies against nuclear antigens. Lupus predominately affects women between menarche and menopause. There are both genetic and environmental risk factors which affect an individuals’ risk of developing lupus. Estrogens are a risk factor for developing lupus and are thought to contribute significantly to the initiation and progression of disease. In lupus-prone mice, genetic knockout of a receptor for estrogen, estrogen receptor alpha (ERα), causes significant attenuation of lupus. Previous studies have not identified the cell type or types which mediate the effects of ERα on lupus. Estrogen has many effects on the immune system which could contribute to the development of autoimmunity in susceptible individuals. Particularly, estrogen promotes the survival of highly autoreactive B cells. Therefore, we hypothesized that ERα expression in hematopoietic cells promotes lupus, and more specifically, that ERα in B cells promotes lupus.
To test this hypothesis, we created two different murine models of lupus on the lupus-prone (NZB x NZW)F1 genetic background. To investigate the role of ERα in hematopoietic cells, we created chimeric mice with hematopoietic and non-hematopoietic cells with different ERα genotypes. Due to issues with the creation of successful chimeras, we were not able to use these mice to fully address our hypothesis. However, these studies revealed that estrogen plays a role in the success of hematopoietic reconstitution in females.
To address the hypothesis that ERα expression in B cells promotes lupus, we created a (NZB x NZW)F1 model with B cell specific deletion of ERα. Although only a moderate proportion of B cells had successful deletion of ERα, this was sufficient to cause a significant attenuation of lupus. Mice with B cell specific ERα deletion had fewer activated B cells, produced fewer pathogenic autoantibodies, and had significantly prolonged survival compared to control mice. Therefore, these studies have shown that ERα expression in B cells promotes lupus in the (NZB x NZW)F1 model of lupus.
Tabor, Dana E., "Role of B cell and hematopoietic cell intrinsic actions of ERα in lupus pathogenesis" (2016). Theses & Dissertations. 116.