Estrogen’s role in immunity
Estrogen is a very important hormone, particularly in the context of autoimmune disease. Many scientists believe that estrogen may be one of the reasons why autoimmune diseases are more prevalent in women than men. Estrogen may interplay with certain immune factors that enhance the action of the inflammatory response by increasing antibodies that attack certain tissues in the body (Connections, n.d.). Several theories indicate that estrogen enhances the inflammatory process of the immune system, and changes in estrogen levels can be associated with more pronounced autoimmune conditions. However, there is not a direct correlation to estrogen levels and autoimmune disease, since some conditions are exacerbated by drops in estrogen (such as RA) while others are aggravated by higher estrogen levels (such as systemic lupus erythematosus) (Andersson et al., 2015).
Estrogens generally favor immune processes involving CD4+Th2 cells and B cells, thereby promoting B-cell-mediated autoimmune diseases (Farage et al, 2012). Physiologic levels of estrogen, however, also stimulate the expansion of CD4+ CD25+ Tregs, which help maintain tolerance to self-antigens. Estrogen also stimulate the expression of the Foxp3 gene, a marker for Treg function. Estrogen provokes involution of the thymus gland which is associated with reduction in number of immature T-lymphocytes. Moreover, oral estrogen has been shown to restore T-cell function. Estrogen depletion, as seen in menopause, is associated with reductions in B and T cells as well as impaired immunity to infections. Estrogen deficiency renders postmenopausal women vulnerable to degenerative conditions such as osteoarthritis, osteoporosis, atherosclerosis, and Alzheimer’s disease (Shivers et al., 2015).
According to Farage et al, the fact that estrogen favors a stronger overall immune response, particularly with regard to antibody response in women, is a mixed blessing. “Although it produces a superior resistance to infection compared with men it also increases the risk in women of autoimmune disease” (Farage et al, 2012). However, it appears to be more of a “Goldilocks situation”-both too much or too little estrogen can cause problems, and the right amount is needed for appropriate immune regulation (Connections, n.d.). Interestingly, low doses of estrogen can promote enhanced TH-1 responses and increased cell-mediated immunity, while high doses can increase Th-2 responses (Kassi & Moutsatsou, 2010). “Indeed estrogen is a potent immunomodulatory agent and can exert stimulatory as well as regulatory effects on the immune system, such as enhancing B cell antibody production, reducing B and T lymphopoiesis and inhibiting T cell-dependent inflammation” (Andersson et al., 2015)
Here is chart that describes some of the cytokine changes with estrogen from the literature.
|IFN-gamma(pro- Inflammatory)||decreased with increased estrogen|
|IL-1 (pro-inflammatory)||decreased with increased estrogen|
|IL-2 (pro-inflammatory)||decreased with increased estrogen|
|IL-4 (anti-inflammatory)||increased with increased estrogen|
|IL-1B (pro-inflammatory)||decreased with increased estrogen|
|IL-5 (TH-2)||increased with increased estrogen|
|IL-6 (pro-inflammatory)||decreased with increased estrogen|
|IL-10 (anti-inflammatory)||increased with increased estrogen|
|IL-12 (pro-inflammatory)||increased with increased estrogen|
|IL-13||increased with increased estrogen|
|IL-17||increased or decreased.|
|TGF-beta (anti-inflammatory)||increased with increased estrogen|
|TNF-a (pro-inflammatory)||decreased with increased estrogen|
Andersson, A., Stubelius, A., Karlsson, M. N., Engdahl, C., Erlandsson, M., Grahnemo, L., . . . Islander, U. (2015). Estrogen regulates T helper 17 phenotype and localization in experimental autoimmune arthritis. Arthritis Res Ther, 17, 32. doi:10.1186/s13075-015-0548-y
Connections (n.d.). Autoimmune Disease: When our immune system goes haywire. Retrieved (2018, July 23) from https://www.womensinternational.com/portfolio-items/autoimmune-disease/ (Links to an external site.)
Farage, M., Miller, K. Maibach, H. (2012). Effects of Menopause on Autoimmune Diseases. Retrieved (2018, July 23) from https://www.medscape.com/viewarticle/775536 (Links to an external site.)
Kassi, E., & Moutsatsou, P. (2010). Estrogen receptor signaling and its relationship to cytokines in systemic lupus erythematosus. J Biomed Biotechnol, 2010, 317452. doi:10.1155/2010/317452
Shivers, K. Y., Amador, N., Abrams, L., Hunter, D., Jenab, S., & Quinones-Jenab, V. (2015). Estrogen alters baseline and inflammatory-induced cytokine levels independent from hypothalamic-pituitary-adrenal axis activity. Cytokine, 72(2), 121-129. doi:10.1016/j.cyto.2015.01.007