We all know that our immune system is designed to protect our bodies from disease and illness, but what happens when our immune system fails in doing this for us? In this post, we will explore the innate immune system and discuss how abnormal levels of immune cells and proteins may contribute to painful diseases such as endometriosis.
An Brief Introduction to the Innate Immune System [1]
The immune system is a network of proteins, cells, tissues, and organs that protect the body from infection and disease. Think about a time when you got a cut on your arm or finger. The skin surrounding the cut probably swelled, turned red, and felt itchy. This inflammation is caused by the immune response, a defensive reaction that occurs when foreign objects enter the body. In this case, pathogens, or disease causing microorganisms, entered your body through the cut. Inflammation at the cut-site is usually a sign that your immune system is working hard to eliminate these pathogens.
The human immune system can be broken down into two distinct parts: (1) the innate immune system, which is the general immune response and (2) the adaptive immune system, which is the immune response specifically targeting pathogens present in the body. Both systems contain white blood cells which are cells involved in the immune system. The white blood cells of the adaptive immune response can remember the unique features of pathogens from past infections. When a pathogen re-infects the body, these cells quickly recognize the pathogen and eliminate it. But what happens when a unique pathogen infects the body for the first time? The adaptive immune response is very slow to take action when it doesn’t immediately recognize pathogens. This is where the white blood cells of the innate immune response shine. These cells recognize general features that are present in most pathogens. While both the adaptive and innate immune responses are vital in eliminating pathogens, in this post we will focus more on the innate immune system, specifically on how it relates to the pathophysiology of endometriosis.
Macrophages
Macrophages are white blood cells that patrol the body, actively looking for pathogens. Because of this, they are among the first cells to encounter these microorganisms. When a macrophage encounters a pathogen, it engulfs the pathogen through a process known as phagocytosis. Once inside of the macrophage, the pathogen is destroyed by cellular acid and enzymes.
Natural Killer Cells
It is not enough to only kill the pathogen. The immune system must also seek out human cells that were infected by the pathogen. Natural killer cells are white blood cells that identify pathogen-infected cells to induce apoptosis, or cell death.
Cytokines
In order for the different cells of the immune system to talk to one another and coordinate an immune response, they secrete proteins called cytokines. Cytokines are immunoproteins secreted by immune cells that act on neighboring immune cells to coordinate the immune response [2]. There are two main types of cytokines: (1) Proinflammatory cytokines which are secreted by macrophages and up-regulate inflammatory pathways and (2) anti-inflammatory cytokines which inhibit proinflammatory cytokines [3].
What is Endometriosis?
Endometriosis is a disease in which tissue, similar to the tissue inside the uterine cavity, grows outside the uterine cavity causing severe pain, heavy and irregular periods, and infertility [4]. Approximately 10% of women world-wide struggle with endometriosis. Despite the severe symptoms and prevalence, the cause of endometriosis has remained a mystery due to lack of awareness and research funding [5]. However, some research indicates that the body’s own immune system may play a key role.
How is the innate immune system connected to endometriosis ?
Aberrant levels of macrophages, cytokines, and natural killer cells have consistently been found in the peritoneal fluid, or liquid in the abdominal cavity, and eutopic endometrium, or uterine lining, of women with endometriosis [6,9,10]. Women with endometriosis have significantly increased amounts of macrophages in both the peritoneal fluid and eutopic endometrium [6]. Since macrophages secrete proinflammatory cytokines, the increase in macrophages causes an increase in peritoneal and endometrium cytokine concentrations. These cytokines have a variety of effects which may contribute to endometriosis disease progression [6]. Some of these effects include:
- Angiogenesis of Endometriotic Lesions: Vascular endothelial growth factor (VEGF) is a cytokine that regulates the process of developing new blood vessels known as angiogenesis. Increased levels of the angiogenic VEGF in the eutopic endometrium of women with endometriosis facilitates the implantation of endometriosis lesions outside the uterine cavity [7].
- Adhesion and Proliferation of Endometriotic Lesions: Research demonstrates that hormone prostaglandin E2 (PGE2) regulates the proliferation and adhesion of endometriotic lesions [8]. Elevated levels of proinflammatory cytokines, including interleukins (IL) 1𝛽, 6, 8, 10, 12, and 13 and tumor necrosis factor-alpha (TNF-alpha), promote the production of PGE2 in endometriotic lesions [6, 9]. This means that certains cytokines secreted by macrophages contribute to the increased levels of PGE2 in the ectopic endometrium therefore enhancing the proliferation and adhesion of these endometriosis lesions.
- Downregulation of Natural Killer Cells: Natural killer cells play an important role in removing endometriotic cells found outside of the uterine cavity by inducing apoptosis in these cells. Elevated levels of IL6, IL8, IL1𝛽, and TNF-alpha in the peritoneal fluid and endometrium downregulate natural killer cells therefore enabling endometriotic lesions to survive and implant throughout the body [9].
In Summary…
Components of the innate immune system have been implicated in the disease progression of endometriosis. However, it is important to remember that macrophages, cytokines, and natural killers have only been found to be connected to endometriosis pathogenesis. Researchers still don’t know whether or not the increased levels of macrophages and cytokines or the decreased level of natural killer cells are what cause endometriosis. Hopefully, future researchers will focus on defining the relationship between the innate immune system and endometriosis.
PELVIC PAIN IS NOT NORMAL. If you experience pelvic pain, heavy or irregular periods, and/or intense menstrual cramps, please speak to your healthcare provider and visit the following websites to learn more about the signs and symptoms of endometriosis:
https://uofrigem.wixsite.com/endoeducation
This guest post was written by Emily Schiller from iGEM 2020 team UteRus, based in Rochester, USA. Check out their social media to know more about their project!
https://www.facebook.com/rochester.igem.2020
https://twitter.com/ur_igem
https://www.instagram.com/ur.igem.2020/
https://www.youtube.com/channel/UC89g4OWlQAFBwvllSuQxhfg
References:
- Innate Immunity: https://www.ncbi.nlm.nih.gov/books/NBK26846/
- What are Cytokines?: https://www.news-medical.net/health/What-are-Cytokines.aspx
- Cytokines, Inflammation, and Pain: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785020/
- https://www.mayoclinic.org/diseases-conditions/endometriosis/symptoms-causes/syc-20354656
- Assessing research gaps and unmet needs in endometriosis: https://www.ajog.org/article/S0002-9378(19)30385-0/fulltext
- Dysfunctional Signaling Underlying Endometriosis: https://jme.bioscientifica.com/view/journals/jme/60/3/JME-17-0227.xml
- VEGF in Endometriosis: https://pubmed.ncbi.nlm.nih.gov/9688413/
- PGE2: The Master of Endometriosis?: https://pubmed.ncbi.nlm.nih.gov/20511671/
- Suppression of COUP-TFII by Proinflammatory Cytokines Contributes to the Pathogenesis of Endometriosis: https://academic-oup-com.ezp.lib.rochester.edu/jcem/article/99/3/E427/2537186
- Role of Cytokines in Endometriosis: https://www.fertstert.org/article/S0015-0282(01)01816-7/fulltext#secd416389e316
