Doctor of Philosophy (PhD)
Molecular Genetics & Cell Biology
Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by loss of immune tolerance and the production of anti-nuclear autoantibodies. 90% of lupus patients are women, and this sex bias is due to the actions of estrogens, which promote lupus pathogenesis. Our lab has shown that estrogen receptor alpha (ERα) mediates the effect of estrogens in lupus and that ERa acts in a B cell intrinsic manner to promote the development of autoantibodies and SLE. Genetic factors also contribute to lupus. One major lupus susceptibility locus, Sle1, controls loss of tolerance and autoantibody development as well as immune cell hyperactivation. We examined the impact of ERα on Sle1a and Sle1b. While we found that ERα disruption had no impact on Sle1a, disruption of ERα abolished the female sex bias that is seen in the lupus phenotypes of B6.Sle1b mice. Importantly, we showed that without ERα signaling, Sle1b is not sufficient to induce B cell hyperactivation, suggesting a synergistic relationship between ERα and Sle1b. However, the molecular basis for this synergy was unclear. Sle1b functions as a negative regulator of B cell receptor (BCR) signaling that allows autoreactive B cells to escape tolerance checkpoints. In other cell types, ERa interacts with molecules that also participate in the BCR pathway. Therefore, we examined the impact of ERα on BCR signaling and the ability of Sle1b to modulate BCR signaling. We found that the dampened BCR signaling in naïve B cells from female B6.Sle1b mice requires ERa. Additionally, ERα modulated downstream kinase activation in the BCR cascade in female B6.Sle1b mice. We also observed that despite having reduced BCR signal strength after BCR engagement, B cells from female B6.Sle1b mice proliferate more than those from B6 females, and this enhanced proliferation was dependent on both ERα and p38 MAPK. Altogether, our data shows that ERα signaling enhances autoimmunity by allowing naïve B cells from female B6.Sle1b mice to escape tolerance induction checkpoints and proliferate robustly in the periphery, thus leading to the production of high-affinity IgG autoantibodies.
Graham, Jared H., "ERα as a Modulator of the Sle1b Lupus Susceptibility Locus and B Cell Receptor Signaling" (2022). Theses & Dissertations. 648.
Available for download on Saturday, April 27, 2024