If you read my previous post on how endometriosis cells develop, you know you need an endo-like cell to start the process of getting endo. You can be born with it, or perhaps develop it over time. However, this pesky cell is not necessarily a problem until it becomes endometriosis.

So, how did that happen??

If you want to thank someone for establishing your endometriosis lesion, thank your immune system! That’s right, it’s your confused immune system that establishes and integrates a lost endo-like cell into your healthy tissue, complete with blood, oxygen, and nutrient supply.

Why would your immune system do such a thing? Basically, it’s confused.

A Confused Immune System Establishes Endometriosis

Immune dysfunction is very different than thinking your immune system needs extra support, say, by taking zinc and Vitamin C to shorten the duration of a cold. It actually indicates that it’s not behaving properly. It’s often doing things it shouldn’t, while not doing things that it should. You may be surprised how many diseases you’re familiar with that are also rooted in immune dysfunction.

For example, nearly all conditions associated with chronic inflammation are involved with immune dysfunction to some extent. This is why well known conditions like acne, kidney stones, asthma, rosacea, and some forms of arthritis arise from immune dysfunction to some degree. Even chronic allergies present an aspect of immune dysfunction, and another part of the immune picture that many of us with endo deal with on a regular basis. 

When it comes to more serious diseases of immune dysfunction, I’m sure you’ve heard of autoimmune disorders. These are chronic diseases that occur when the immune system becomes so confused that it begins to inflame and attack a normal part of your body—your healthy cells, tissues, or organs. There’s really no better example of a confused immune system than one that attacks your own body. And while endometriosis is not considered an autoimmune disorder (as of now there are no known auto-antibodies specifically associated with endo) it is still considered an “autoimmune-associated” disorder due to its chronic inflammatory nature and link with other autoimmune diseases.

Cancer is another potent example of immune dysfunction, wherein your immune system can no longer distinguish an aggressive, destructive, and abnormal cell (the types of cells your immune system should be cleaning up) from the healthy one next door. Moreover, it’s often the immune system that established the cancerous cells as full blown cancer, connecting them to blood supply and (mistakenly) fostering its growth—similar to how it behaves with endo. In fact, endometriosis behaves so much like cancer that we sometimes see it described as a benign (non-lethal) cancer-like tissue. [But don’t worry, as painful as endo can be, it is not cancer and it will not kill you]

So, where exactly does endometriosis fit into this immune dysfunction picture? How is it a disease of chronic inflammation that, despite not being acne, cancer, or autoimmune, behaves similarly to each in some ways? It turns out that it’s a unique disease, with specific facets of dysfunction that turn an endo-like cell into an endo lesion, and continues with a  progression of lesions once established. Immune dysfunction is actually so implicated in endometriosis that it appears no matter how the original endo-cells came to be, the disease can’t come to fruition without the participation of a dysfunctional immune response, including these four components:

Part 1) Your Immune System Establishes your endo lesion

There are many factors that led to the creation of an endo-like cell. It’s similar to an endometrial cell, but very different…and not in a good way (on how you get an endo-like cell, see this post). BUT, the big takeaway is that it’s not causing problems just yet. It’s just a bizarre cell in the body.

Unfortunately, inflammatory immune factors in the pelvis (or wherever your endo is) see this endo-like cell and are confused. Rather than destroying it, the immune factors think it needs saving and establish it into your healthy tissue. Congrats, you now have endometriosis lesion thanks to a confused immune response.

(1,2,3,4,5)

Part 2) Your immune system allows endometriosis to stay

Once established, our immune system “janitors” should really be clearing away these cells. If that sounds odd, you must know that this is a normal part of your immune function. “See a bizarre, mutated, dead, or damaged cell? Get it out of the body. This is one of my immune jobs.”

That means, in the case of endo, our immune system should be hard at work clearing up the endo lesions. They are bizarre, and it’s up to the immune system to get rid of them. Instead, immune surveillance seems to ignore them, let them hang out—another way in which the immune system is dysfunctional.

(6,7,8)

Part 3) Beyond endometriosis lesions - a full body immune issue

Having endo does not just equate immune dysfunction at the site of the endo, it actually is much bigger than that. Instead there appears to be whole-body immune dysfunction with numerous immune components misbehaving in measurable ways.

While it’s not totally clear whether the immune dysfunction witnessed in the endo body began before or after the endometriosis lesions took hold, it’s obvious that endo-related immune dysfunction affects the entire body, with widespread abnormalities in the levels and behavior of circulating immune factors. Development may be different for each sufferer, that perhaps systemic inflammation before endo triggered this misbehaving immune system and set the stage for endo’s growth, or was caused by the high amount of inflammation produced within the endo environment post lesion establishment, feeding into itself cycle after cycle. Maybe both.

Systemic inflammation and immune dysfunction also helps us account for the myriad of other, not-so-obviously-related endo symptoms that drive many of us crazy. For example, women with endo are more prone to developing allergies, skin problems, hypothyroidism, celiac disease, chronic fatigue syndrome, fibromyalgia, chronic joint pain and frequent headaches - all diseases and symptoms associated with chronic inflammation and immune system dysregulation.

This widespread immune dysfunction can create a sort of “whack-a-mole” situation where endo patients feel like they’re struggling to manage all of their symptoms at once, contributing to what feels like a body falling apart.

(9,10,11)

Part 4) Endometriosis Lesions Create a Unique Immune Environment

Once endo-like cells are established as endometriosis lesions, you officially have endometriosis as the disease you know. Now these lesions produce their own estrogen and inflammatory immune factors, exacerbating the progression, pain, inflammation, and immune dysfunction. They also produce increased lactic acid, which acts as a kind of “invisibility cloak” so janitorial immune factors get confused, contributing to the immune system’s ability to clean up the cells or lesions.

This means that endometriosis lesions are no longer just responding to immune factors. They are also producing them and confusing them—thus becoming an integral part of the immune equation. And because all this is happening within the peritoneal fluid, increased levels of oxidative stress may begin to affect your surrounding organs, creating either pain (such as when urinating or defecating), or intra-abdominal adhesions.

Re-Training the Immune System, Heal Endometriosis

The biggest reason to care about the immune dysfunction aspect of endometriosis is that you have it in your power to do something about it, and may in the process reduce your endo, either the disease or simply the symptoms. Many inflammatory triggers related to endometriosis can actually be addressed and, for many of us, a dysfunctional immune response can be retrained. If you’ve had friends or family members who put their issues of immune dysfunction into remission (whether it be cancer, autoimmune, or, heck, quelled their acne), you can understand that this is possible.

For a more endo-specific example, one review study found that while 29 percent of those with endo had disease that ended up progressing, 42 percent actually showed disease regression and 29 percent remained stable. Another review of healthy, fertile women having their “tubes tied” to prevent pregnancy found asymptomatic endo in nearly 6 percent of these women at the time of surgery—with lesions that were established but not causing problems.

“When the immune system works, it is capable of inactivating, stabilizing, and clearing endometriosis. If we can harness the innate ability of the immune system, we may improve the lives of women and transgender men.” Dr. Dan Martin

Where to start? This site is a good place! There are thousands of studies showing how diet and lifestyle shifts can greatly impact immune function, from regulating blood sugar and infusing nutrients, to limiting your distress levels and screen time. Yes, these simple factors play a big role in immune re-regulation. [Of course endo is complex, and you may indeed require the help of additional integrative care! Everything from naturopaths and skilled doctors, to a wide-excision surgery play roles in many of our endo stories.]

By adopting a new endo lifestyle, you may be able to join the 42 percent of those with endo who show natural disease regression, or the 29 percent who remain stable. 

References

1)  Capobianco, A., & Rovere-Querini, P. (2013). Endometriosis, a disease of the macrophage. Frontiers in immunology, 4, 9. https://doi.org/10.3389/fimmu.2013.00009

2) Hogg, C., Horne, A. W., & Greaves, E. (2020). Endometriosis-Associated Macrophages: Origin, Phenotype, and Function. Frontiers in endocrinology, 11, 7. https://doi.org/10.3389/fendo.2020.00007

3)  Paul Dmowski, W., & Braun, D. P. (2004). Immunology of endometriosis. Best practice & research. Clinical obstetrics & gynaecology, 18(2), 245–263. https://doi.org/10.1016/j.bpobgyn.2004.02.001 

4)  Qi, Q., Liu, X., Zhang, Q., & Guo, S. W. (2020). Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells. Scientific reports, 10(1), 1281. https://doi.org/10.1038/s41598-020-57997-6

5)   Zhou, W. J., Yang, H. L., Shao, J., Mei, J., Chang, K. K., Zhu, R., & Li, M. Q. (2019). Anti-inflammatory cytokines in endometriosis. Cellular and molecular life sciences : CMLS, 76(11), 2111–2132. https://doi.org/10.1007/s00018-019-03056-x

6)  Thiruchelvam, U., Wingfield, M., & O’Farrelly, C. (2015). Natural Killer Cells: Key Players in Endometriosis. American journal of reproductive immunology (New York, N.Y. : 1989), 74(4), 291–301. https://doi.org/10.1111/aji.12408

7)  Wu, M. H., Shoji, Y., Wu, M. C., Chuang, P. C., Lin, C. C., Huang, M. F., & Tsai, S. J. (2005). Suppression of matrix metalloproteinase-9 by prostaglandin E(2) in peritoneal macrophage is associated with severity of endometriosis. The American journal of pathology, 167(4), 1061–1069. https://doi.org/10.1016/S0002-9440(10)61195-9

8)  Xu H. (2019). Expressions of natural cytotoxicity receptor, NKG2D and NKG2D ligands in endometriosis. Journal of reproductive immunology, 136, 102615. https://doi.org/10.1016/j.jri.2019.102615

9)  Laganà, A. S., Garzon, S., Götte, M., Viganò, P., Franchi, M., Ghezzi, F., & Martin, D. C. (2019). The Pathogenesis of Endometriosis: Molecular and Cell Biology Insights. International journal of molecular sciences, 20(22), 5615. https://doi.org/10.3390/ijms20225615

10)  Symons, L. K., Miller, J. E., Tyryshkin, K., Monsanto, S. P., Marks, R. M., Lingegowda, H., Vanderbeck, K., Childs, T., Young, S. L., Lessey, B. A., Koti, M., & Tayade, C. (2020). Neutrophil recruitment and function in endometriosis patients and a syngeneic murine model. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 34(1), 1558–1575. https://doi.org/10.1096/fj.201902272R

11)  Porpora, M. G., Scaramuzzino, S., Sangiuliano, C., Piacenti, I., Bonanni, V., Piccioni, M. G., Ostuni, R., Masciullo, L., & Benedetti Panici, P. L. (2020). High prevalence of autoimmune diseases in women with endometriosis: a case-control study. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology, 36(4), 356–359. https://doi.org/10.1080/09513590.2019.1655727

12) Evers, J.L.H. (2013). Is adolescent endometriosis a progressive disease that needs to be diagnosed and treated? Human Reproduction, 28(8), 2023.  https://doi.org/10.1093/humrep/det298

13) Fuentes A, Escalona J, Céspedes P, Espinoza A, Johnson MC. (2014). Prevalencia de la endometriosis en mujeres sometidas a esterilización quirúrgica laparoscópica en un hospital de Santiago de Chile [Prevalence of endometriosis in 287 women undergoing surgical sterilization in Santiago Chile].  Rev Med Chil, 142(1), 16-9. Spanish.  https://doi.org/10.4067/S0034-98872014000100003.