Shruti Revankar

Introduction: Systemic Lupus Erythematous (SLE) is a systemic autoimmune disease that is characterized, broadly, by chronic inflammation, complement activation, auto-antibody production and immune-complex deposition¹. SLE exhibits a strong gender bias, 10:1, skewed towards females. Some recent studies have discovered that trans-women were experiencing similar rates of SLE, post hormone therapy, which further directs suspicion towards estrogen as a key player in the development of SLE². Multiple studies support this hypothesis through their finding of a connection between B-cell Activating Factor (BAFF), which has been implicated in autoimmune diseases, and estrogen^3,4,5 Methods: The main studies establishing the BAFF/estrogen connection used healthy donor cells or mice cells that were BAFF+ or BAFF knockouts. The cells were all administered varying levels of estrogen and results were derived through immunoblotting or ELISA^3,4,5 Results: The presence of IgG-BAFF complexes were strongly associated with consumption of complement proteins, anti-dsDNA levels, presence of SLE activity and lupus induced nephritis⁴.When healthy mice and donor human cells were treated with estrogen, there was up to a five-fold increase in BAFF expression³. An additional study suggested another player in the estrogen/BAFF interaction: p202 protein. P202 protein was shown to have a strong association with BAFF while also indirectly regulated by it via IL-6. Similarly, estrogen was also seen to have an effect on p202 expression⁵. Conclusion: Studies showed that an active SLE disease state was linked to the presence of IgG-BAFF immune complexes which is due to an increased circulating BAFF concentration⁴. Studies also showed a strong positive correlation between the administration of estrogen and BAFF concentration – implying that estrogen lead to the upregulation and activation of BAFF^3,5. Finally, some preliminary findings suggested that estrogen may be a part of a positive feedback loop consisting of BAFF and p202 protein⁵. Although none of these findings necessarily narrow down estrogen as the main driver of SLE, the presence of the potential feedback loop and strong associations with BAFF & SLE expression point to the fact that estrogen is a powerful factor in one’s susceptibility to SLE.

1. Wang S, Chen Y, Xu X, Hu W, Shen H, Chen J. Prevalence of hepatitis B virus and hepatitis C virus infection in patients with systemic lupus erythematosus: a systematic review and meta-analysis. Oncotarget. 2017;8(60):102437-102445. doi:10.18632/oncotarget.22261.
2. Rekvig OP. Systemic Lupus Erythematosus: Definitions, Contexts, Conflicts, Enigmas. Frontiers in Immunology. 2018;9:387. doi:10.3389/fimmu.2018.00387.
3. Drehmer MN, Suterio DG, Muniz YCN, Souza IRD, Löfgren SE. BAFF Expression is Modulated by Female Hormones in Human Immune Cells. Biochemical Genetics. 2016;54(5):722-730. doi:10.1007/s10528-016-9752-y.
4. Friebus-Kardash J, Branco L, Ribi C, et al. Immune complexes containing serum B-cell activating factor and immunoglobulin G correlate with disease activity in systemic lupus erythematosus. Nephrology Dialysis Transplantation. 2017;33(1):54-64. doi:10.1093/ndt/gfx220.
5. Panchanathan R, Choubey D. Murine BAFF expression is up-regulated by estrogen and interferons: Implications for sex bias in the development of autoimmunity. Molecular Immunology. 2013;53(1-2):15-23. doi:10.1016/j.molimm.2012.06.013.