Date of Award
Doctor of Philosophy (PhD)
Genetics, Cell Biology & Anatomy
Karen A. Gould, PhD
The autoimmune disease lupus shows a significant female sex bias. This sex bias may be due to the ability of estrogens to promote loss of tolerance to chromatin, the initial loss of tolerance event in lupus. Previously, we demonstrated that the ability of estrogens to promote lupus in (NZBxNZW) F1 mice is dependent on signaling via estrogen receptor alpha (ERα). The Sle1 lupus susceptibility allele controls loss of tolerance to chromatin, and C57BL/6 (B6) mice carrying the Sle1 lose tolerance and develop anti-chromatin autoantibodies and spontaneously activated immune cells. Loss of tolerance occurs earlier and with a higher penetrance in B6.Sle1 females than in males, illustrating a sex bias, although the specific impact of estrogens/ERα signaling in this phenotype has not been described. Furthermore, nothing is known about the impact of sex and estrogen signaling on Sle1-induced immune cell hyperactivation. Here, we show that a deficiency of either estrogens or ERα attenuates loss of tolerance and autoantibody development in B6.Sle1 female mice. Additionally, we found Sle1-associated immune cell hyperactivation shows a female sex bias, and furthermore, that ERα deficiency diminishes Sle1-associated immune cell hyperactivation in B6.Sle1 females. Furthermore, our preliminary data indicate that the actions of Sle1 subloci Sle1a and Sle1b are modulated to ERα signaling. Finally, we demonstrate that ERα may influence the Sle1 phenotype in females by modulating the expression of Pbx1, a gene that lies within the Sle1 interval. Altogether, estrogen signaling via ERα controls the female sex bias in the Sle1 phenotype.
Yoachim, Shayla D., "Impact of Estrogen Receptor Alpha on SLE1-Induced Loss of Tolerance" (2015). Theses & Dissertations. 3.