The Immune side of Endometriosis


“One is not born, but rather becomes, a woman.” – Simone de Beauvoir.

Throughout the years, young girls have been taught that with their first bleeding they will become ‘women. Even though that is not exactly what Simone meant when she uttered her very famous words, menstruation does bring certain differences in the life of a young person. Unfortunately, while being in their reproductive years, 10% of females will experience endometriosis.

Endometriosis is a chronically painful disease. Women with endometriosis carry tissues (endometrium) and glands that lines the inner surface of the uterus, growing outside it. It usually manifests itself as cysts dominantly placed in fallopian tubes or ovaries. It can also be present in distant areas (deep endometriosis) affecting urinary tract or sometimes, less commonly, lymph nodes, heart, or bones. There are four theories of its development:

1) The regurgitation theory- blood flows backwards towards the pelvis instead of flowing out

2) The benign metastases theory-  endometrial tissue gets spread via blood vessels and lymphatics

3) The metaplastic theory- terminally differenced cells outside the uterus differentiate into endometrium

4) The extrauterine stem/progenitor cell theory- circulating stem cell differentiates into endometrial tissue

Over the years it has been argued that endometriotic cells are able to escape the immune surveillance. Preventing that escape from immune system will offer a better understanding of the disease and even potential better treatments. Currently, endometriosis is regulated with hormonal therapy, or with surgical removal of the cysts if they outgrow 5 cm. Since endometriosis can highly lead to infertility in young women, early diagnostics and treatment are important. Usually, endometriosis is diagnosed during the routine gynecologist check-up, or if a person starts experiencing extremely painful menstruation, painful intercourse, or excruciating pain in the lesions area.

Not only is it painful, but compared to the healthy counterparts, females with endometriosis express higher levels of inflammatory mediators which can establish lesions and evade the immune system. Han and colleagues have reported that intracellular estrogen receptor-beta (ERbeta) activity gets enhanced in endometriotic tissues to stimulate the endometriosis pathology. ERbeta receptor signaling blocks TNF-alpha mediated apoptosis and induces inflammasome to increase IL-1beta production. This will result in higher endometriotic cell adherence and proliferation.

There are four phases of the menstrual cycle: menstruation (shedding of uterine lining/periods), follicular phase (preparation of egg release), proliferative phase (build up of uterine lining), ovulation (egg release from ovary), luteal phase (preparation for possible pregnancy), and secretory phase (release of biochemicals by uterine lining to either support pregnancy or help break down lining). Although there is a lot of knowledge about the anatomy and biology of these phases, there are fewer studies on the role of immune cells during these phases.

Agostinis and colleagues reviewed immune cell involvement in the endometriosis. For example, during the secretory phase in the healthy endometrium, there is an increase of macrophages proposed to be clearing excess endometrial tissue, while in endometriosis such increase is not seen. Furthermore, levels of uterine natural killer cells surges during the secretory and menstrual phase to establish suitable environment for implantation of the embryo, on the other hand, you guessed it, in endometriosis the natural killer cells will have lower activity. Contrary to healthy people, neutrophils of endometriosis patients show more activity with higher reactive oxygen species production, and they also produce angiogenic factors and cytokines like VEGF and IL-8 that can support disease progression. Let’s have a look at lymphocytes now. T cell cytotoxicity against endometriotic cells drops in endometriosis. For B lymphocytes, there has been evidence of the presence of autoantibodies in endometriosis, swinging this disease into autoimmune direction.

Now the question arises, how can endometriosis lead to infertility? Considering that the autoantibodies produced could also bind to embryo or sperm, they could be a cause of infertility in endometriosis by activating immune response against the sperm or embryo and attacking them. Agostinis and team further talk about the complement involvement in endometriosis. They argue that women with endometriosis have endometrial tissue-specific complement activation, possible via coagulation cascade triggered by periodic bleeding of endometriotic tissue.

Involvement of the immune system in endometriosis for sure is as fascinating as it is essential. Research on endometriosis presents an insight in the endocrine-immune system communication causing a hormone dependent, immune-related disease. It would be great to see if this could potentially lead to new long-lasting, and preferably, less invasive treatment in the future. Finding a replacement for the surgical treatment is definitely something to look forward to!

Sources:

Han SJ, Jung SY, Wu SP, et al. Estrogen Receptor β Modulates Apoptosis Complexes and the Inflammasome to Drive the Pathogenesis of Endometriosis. Cell. 2015;163(4):960-974. doi:10.1016/j.cell.2015.10.034

Agostinis C, Balduit A, Mangogna A, et al. Immunological Basis of the Endometriosis: The Complement System as a Potential Therapeutic Target. Front Immunol. 2021;11:599117. Published 2021 Jan 11. doi:10.3389/fimmu.2020.599117

Robbins Basic Pathology, Elsevier, 2018

Article author: Ines Poljak. Ines is a MSc graduate from University of Copenhangen who worked on multiple myeloma bone disease. She worked in several clinical laboratories before committing herself completely to research.

Editor: Sutonuka Bhar. Sutonuka is a PhD candidate at the University of Florida. Her work focuses on host immune responses against viruses and bacterial membrane vesicles.

Check out Antibuddies’ blog post “The Immune side of Endometriosis.”


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