Endo and immune system

The presence of endometriosis can cause disruption in the immune system:

"In the genetic regulation of Müllerian structures development, a key role is played by Hoxa and Wnt clusters, because they lead the transcription of different genes according to the different phases of the organogenesis, addressing correctly cell-to-cell interactions, allowing, finally, the physiologic morphogenesis. Accumulating evidence is suggesting that dysregulation of Wnt and/or Hox genes may affect cell migration during organogenesis and differentiation of Müllerian structures of the female reproductive tract, with possible dislocation and dissemination of primordial endometrial stem cells in ectopic regions, which have high plasticity to differentiation. We hypothesize that during postpubertal age, under the influence of different stimuli, these misplaced and quiescent ectopic endometrial cells could acquire new phenotype, biological functions, and immunogenicity. So, these kinds of cells may differentiate, specializing in epithelium, glands, and stroma to form a functional ectopic endometrial tissue. This may provoke a breakdown in the peritoneal cavity homeostasis, with the consequent processes of immune alteration, documented by peripheral mononuclear cells recruitment and secretion of inflammatory cytokines in early phases and of angiogenic and fibrogenic cytokines in the late stages of the disease." http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3697788/#!po=2.17391

Inflammatory markers and endometriosis

What can I say? It's complicated.

Endometriosis is an inflammatory disease, so a lot of people have questions about blood tests that look at inflammation. Let's look at what inflammatory markers are and specifically at CRP:

"Serum proteins that are produced in response to inflammation can be referred to as inflammatory markers. These proteins are mainly produced by the liver in response to stress and can also be called acute phase reactants. Pro-inflammatory cytokines such as IL-1, IL-6, and TNF-alpha induce synthesis of some acute phase reactants that include CRP, fibrinogen and haptoglobin. Other proteins, like albumin, are not sensitive to inflammatory cytokines for increased synthesis; instead chronic stress (inflammation) results in a lower synthesis rate with resultant decreased serum concentrations. The inflammatory markers are not diagnostic of inflammation, but reflect abnormalities that are seen in autoimmune diseases, infections, malignancies and other illnesses.

C-reactive protein (CRP)

"C-reactive protein (CRP/CRP-high sensitivity) was discovered and named for its reactivity to the C polysaccharide in the cell wall of S. pneumoniae. CRP, an innate immune protein, helps opsonize pathogens for phagocytosis and activates the complement system. CRP production is under the control of IL-1, IL-6, and TNF-alpha. Changes in serum CRP concentration change more quickly than ESR and therefore CRP may be a better reflection of current inflammation. Unlike the ESR, CRP is a fairly stable serum protein whose measurement is not time-sensitive and is not affected by other serum components. The magnitude of inflammation directly relates to the concentration of CRP. Levels < 0.2 mg/dl are considered normal, while those >1.0 mg/dL are suggestive off inflammation and/or infection. More recently, the use of high sensitivity CRP has been utilized. This test may better quantify lower levels of inflammation and has been important in evaluating cardiac disease and other inflammatory states.^{2, 3" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2832720/?report=reader}      

 

So what does this have to do with endometriosis?

Endometriosis is an inflammatory disease, so one might expect the markers to be high. But not necessarily in blood tests:

 

"Findings:

There was no significant difference between the CRP serum level in patients with endometriosis and infertile women without endometriosis. There was a significant difference in peritoneal level of CRP between case and control groups (p < 0.05).

Conclusions:

The findings suggested that measurement of this marker in patients’ serum or plasma cannot be used to diagnose endometriosis. It is further recommended that a combination of different markers might be helpful in this regard that could be studied in future."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696960/

 

So we may not see an increase in the blood test but there is a difference in the peritoneal samples:

 

"Compared to the control group, the CRP level of the peritoneal fluid were higher in patients with endometriosis (p<0.05). Pelvic endometriosis is a chronic inflammatory disease that is in association with a general inflammatory response in the peritoneal cavity.[34,35] This disease is known to have an immunological background.[36] Macrophage constitutes 82- 99% of the all the cell population of peritoneal fluid.[37–39] Literature has repeatedly reported an increase of total peritoneal fluid cell numbers, cell concentration and macrophages in endometriosis patients in compare to the control.[40–43] The study of Dunselman et al. also confirmed that there is an increase in the number and concentration of peritoneal cells in patients with endometriosis as compared to the control group.[38]" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696960/

 

While we're on the subject, let's discuss CA-125 levels:

 

It's a test that looks at markers for certain cancers, but if your doctor orders it and it's high, don't let it scare you. "...many noncancerous conditions can increase the CA 125 level.

Many different conditions can cause an increase in CA 125, including normal conditions, such as menstruation, and noncancerous conditions, such as uterine fibroids." http://www.mayoclinic.org/tests-procedures/ca-125-test/basics/definition/prc-20009524 It can also be high in people with endometriosis: "Studies published since continue to demonstrate a correlation between raised CA125 levels and endometriosis (Abrao et al., 1999; Somigliana et al., 2004; Agic et al., 2008; Seeber et al., 2008), and some imply a correlation with stage of disease (Chen et al., 1998; Amaral et al., 2006; Martinez et al., 2007; Rosa e Silva et al., 2007). One study has indicated that CA125 may be more accurate at diagnosing women with later stages of disease, in concordance with the review by Mol (Maiorana et al., 2007)." http://humupd.oxfordjournals.org/content/16/6/651.full 

Remember, all these tests might be a mere indication of endometriosis, but they are very nonspecific. The only way to accurately diagnose endometriosis is through surgery.

Mast cells:

"Mast cells may contribute to the development of pain and hyperalgesia in endometriosis
October 2006
The presence of increased activated and degranulating mast cells in deeply infiltrating endometriosis, which are the most painful lesions, and the close histological relationship between mast cells and nerves strongly suggest that mast cells could contribute to the development of pain and hyperalgesia in endometriosis, possibly by a direct effect on nerve structures.

Researchers set out to detect and quantify mast cells in peritoneal, ovarian, and deep infiltrating endometriosis and to study the relationship between mast cells and nerves in endometriosis.

Excision of endometriosis from different anatomical locations was undertaken in 69 women, who were undergoing laparoscopic excision of endometriosis for pain. Thirty-seven biopsies of normal tissue were obtained from women without endometriosis.
The women with deeply infiltrating lesions had significantly higher preoperative pain scores than women with peritoneal or ovarian endometriosis. Mast cells and degranulating mast cells are significantly more abundant in endometriotic lesions than in non-affected tissues. Deep infiltrating lesions show a significantly higher number of mast cells, activated mast cells, and mast cells located <25 mum from nerves than peritoneal and ovarian lesions. The authors found significantly more degranulating mast cells in deep infiltrating lesions than in peritoneal lesions.
Source

Anaf V, Chapron C, El Nakadi I, De Moor V, Simonart T, Noel JC. Pain, mast cells, and nerves in peritoneal, ovarian, and deep infiltrating endometriosis. Fertil Steril 2006;86(5):1336-43"

http://endometriosis.org/news/research/mast-cells-contribute-to-development-of-pain-and-hyperalgesia-in-endometriosis/

 

For a lot more on peripheral biomarkers of endometriosis see: http://humupd.oxfordjournals.org/content/16/6/651.full

  "Endometriotic lesion removal significantly alters the inflammatory profile both locally and systemically in women with endometriosis. Our findings indicate that ectopic lesions are the major drivers of systemic inflammation in endometriosis." http://www.ncbi.nlm.nih.gov/pubmed/26698677 

A few things that have helped me

Everyone is different with what will help them feel better. For me, a healthy diet with some specific changes and yoga are what I have found help me the most.

 

Specific diet changes include going gluten free (there has been research to support  this in endo patients- http://endocomprehensive.blogspot.com/2014/03/gluten-free-and-endo.html), eating food as close to nature as possible/least processed, avoiding my trigger foods (lactose, gluten, cruciferous veggies, etc- see the FODMAPs diet for IBS), and reducing sugary foods/bad carbs.

 

I also found the following items the most helpful to include in my diet:

 

Plenty of clear fresh water. Add in some lemon. Spring water seems to help the most, but I have a water filter too.

 Blueberries (probably any berry would be good)

 

Spinach. I don't whether it's the iron, the magnesium, or what, but organic spinach helps.

 

Albacore tuna. I've gotten some great deals on sustainably caught, low mercury canned tuna. Perhaps the omega-3's that help?

 

 

 

Egg white protein powder. I make a smoothie with this and spinach and I can tell I feel better. I have wondered if the l glutamine helps my gut. I can tell a difference between the egg white versus the whey.

 

I think the extra B vitamins and perhaps the low dose of vitex in this drink mix help. I drink it in the morning in my green tea.

 

Again, eating organic whenever possible, seems to help.

 

 

Again, these are things that have helped me and are not recommendations for what will work with anyone else. I can't say it made my endometriosis better, but it did help my health overall and improve my ability to deal with my endo and its ramifications.

 

 

PS Here's a link to some of the yoga poses I find most helpful to me: http://endocomprehensive.blogspot.com/2014/07/my-current-yoga-poses-that-help.html 

 

Similar stem cells, different gene exclusions

"Tissue of DIE and SE appears to have similar stem cell-related genes. Nevertheless, there are differences in gene expression between SE and DIE." So the stem cells of superficial and deep infiltrating endometriosis are similar but the gene expression is different. So what causes the deep infiltrating to be expressed differently? Hormonal influence? Diet? Toxins? http://www.ncbi.nlm.nih.gov/pubmed/26426155

Since endo is most likely laid down embryonically, I don't know that this necessarily points to pathogenesis of endo (especially as the levels decrease after the removal of the lesions) but the presence of endo certainly produces an inflammatory state.

 

J Immunol. 2015 Aug 10. pii: 1501138.

IL-17A Contributes to the Pathogenesis of Endometriosis by Triggering Proinflammatory Cytokines and Angiogenic Growth Factors.

Ahn SH¹, Edwards AK¹, Singh SS², Young SL³, Lessey BA⁴, Tayade C⁵.

Author information

• ¹Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada;
• ²Department of Obstetrics and Gynecology, University of Ottawa, Ottawa, Ontario K1H 7W9, Canada;
• ³Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, NC 27514; and.
• ⁴Department of Obstetrics and Gynecology, Greenville Health System, Greenville, SC 29605.
• ⁵Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada; tayadec@queensu.ca.

Abstract

Endometriosis is a chronic, inflammatory disease characterized by the growth of endometrial tissue in aberrant locations outside the uterus. Neoangiogenesis or establishment of new blood supply is one of the fundamental requirements of endometriotic lesion survival in the peritoneal cavity. IL-17A is emerging as a potent angiogenic and proinflammatory cytokine involved in the pathophysiology of several chronic inflammatory diseases such as rheumatoid arthritis and psoriasis. However, sparse information is available in the context of endometriosis. In this study, we demonstrate the potential importance of IL-17A in the pathogenesis and pathophysiology of endometriosis. The data show a differential expression of IL-17A in human ectopic endometriotic lesions and matched eutopic endometrium from women with endometriosis. Importantly, surgical removal of lesions resulted in significantly reduced plasma IL-17A concentrations. Immunohistochemistry revealed localization of IL-17A primarily in the stroma of matched ectopic and eutopic tissue samples. In vitro stimulation of endometrial epithelial carcinoma cells, Ishikawa cells, and HUVECs with IL-17A revealed significant increase in angiogenic (vascular endothelial growth factor and IL-8), proinflammatory (IL-6 and IL-1β), and chemotactic cytokines (G-CSF, CXCL12, CXCL1, and CX3CL1). Furthermore, IL-17A promoted tubulogenesis of HUVECs plated on Matrigel in a dose-dependent manner. Thus, we provide the first evidence, to our knowledge, that endometriotic lesions produce IL-17A and that the removal of the lesion via laparoscopic surgery leads to the significant reduction in the systemic levels of IL-17A. Taken together, our data show a likely important role of IL-17A in promoting angiogenesis and proinflammatory environment in the peritoneal cavity for the establishment and maintenance of endometriosis lesions.
Copyright © 2015 by The American Association of Immunologists, Inc.

Origins of endo

From Endometriosis Update blog (lots of good info- check it out!!):

"Several studies have focused on characterising the endometrium of women with and without endometriosis and found that; yes the endometrium in women with endometriosis is indeed different. The endometrium from women with endometriosis appears to have a higher ability to survive, proliferate and invade, seemingly filling in the missing part of the retrograde menstruation theory.

But, like all great mystery stories, the case is never wrapped up in a neat little package so early on. In recent years more and more evidence is coming to the fore, challenging the theory of retrograde menstruation. In particular there is now quite a significant amount of evidence to show the displaced endometrium that defines endometriosis is, in fact, present before you were even born. There are also rare documented cases of endometriosis in men, women who cannot menstruate and non-menstruating primates; so clearly there is the need for some radical re-thinking.

Maybe we’ve had the whole thing upside-down; maybe it is not the endometrium that dictates the fate of endometriosis, but endometriosis that dictates the fate of the endometrium. A collaborative research effort has provided some evidence to this very end (you can read the full article here). The authors of this study experimentally induced endometriosis in baboons by injecting endometrial cells into the pelvic cavity and letting them form endometriotic implants. They then compared the expression of genes within the endometrium of the baboons with experimentally induced endometriosis and disease free baboons over the course of 16 months. What they found was that the presence of endometriosis (even in its very early stages) led to marked changes (a total of 4,331 genes were altered) in the normal endometrium.

This potentially turns accepted wisdom on its head, in that women with endometriosis are not born with a defective endometrium that gives rise to endometriosis via retrograde menstruation. Rather, if we are to take all the above evidence into account, it appears endometriosis is a condition you are born with that, when the endometriotic implants ‘mature’ lead to changes in the function of the normal endometrium, thus perhaps also accounting for the fertility issues women with endo suffer from." http://www.endo-update.blogspot.co.uk/.../turning-on-its...

Peritoneal endo lesions nerve fibers

"RESULT(S): Pain-conducting substance-P-positive nerve fibers were found to be directly colocalized with human peritoneal endometriotic lesions in 74.5% of all cases. The endometriosis-associated nerve fibers are accompanied by immature blood vessels within the stroma. Nerve growth factor and neutrophin-3 are expressed by endometriotic cells. Growth-associated protein 43, a marker of neural outgrowth and regeneration, is expressed in endometriosis-associated nerve fibers but not in existing peritoneal nerves. CONCLUSION(S): The data provide the first evidence of direct contact between sensory nerve fibers and peritoneal endometriotic lesions. This implies that the fibers play an important role in the etiology of endometriosis-associated pelvic pain. Moreover, emerging evidence suggests that peritoneal endometriotic cells exhibit neurotrophic properties." http://www.ncbi.nlm.nih.gov/pubmed/17412328

 

"RESULT(S): Peritoneal endometriosis-associated nerve fibers were found significantly more frequently in group A than in group B (82.6% vs. 33.3%). CONCLUSION(S): The present study suggests that the presence of endometriosis-associated nerve fibers in the peritoneum is important for the development of endometriosis-associated pelvic pain and dysmenorrhea." http://www.ncbi.nlm.nih.gov/pubmed/18980761

 

"RESULT(S): Lesions from the rectovaginal septum were significantly more likely to be associated with a nerve fiber and report more menstrual pain than lesions from other regions. The PF glycodelin concentrations were also significantly higher in samples with an endometriotic-associated nerve. In peritoneal endometriotic lesions significantly more menstrual pain was reported when endometriotic lesions were associated with nerve fibers, although no difference was observed between the cytokine concentrations. Ovarian endometriotic lesions were rarely associated with nerve fibers.
CONCLUSION(S):
The presence of endometriosis-associated nerve fibers appear to be related to both the pain experienced by women with endometriosis and the concentration of PF cytokines; however, this association varies with the lesion location." http://www.ncbi.nlm.nih.gov/pubmed/22154765


"There was no difference in the density of nerve fibers across the menstrual cycle in peritoneal endometriotic lesions. These findings may explain why patients with peritoneal endometriosis often have painful symptoms throughout the menstrual cycle." http://www.ncbi.nlm.nih.gov/pubmed/21334610


"Progestogens and combined oral contraceptives reduced nerve fiber density and nerve growth factor and nerve growth factor receptor p75 expression in peritoneal endometriotic lesions." http://www.ncbi.nlm.nih.gov/pubmed/18976764

"Pain generation in EM is an intricate interplay of several factors such as the endometriotic lesions themselves and the pain-mediating substances, nerve fibres and cytokine-releasing immune cells such as macrophages. These interactions seem to induce a neurogenic inflammatory process. Recently published data demonstrated an increased peptidergic and decreased noradrenergic nerve fibre density in peritoneal lesions. These data could be substantiated by in vitro analyses demonstrating that the peritoneal fluids of patients suffering from EM induced an enhanced sprouting of sensory neurites from chicken dorsal root ganglia and decreased neurite outgrowth from sympathetic ganglia. These findings might be directly involved in the perpetuation of inflammation and pain. Furthermore, the evidence of EM-associated smooth muscle-like cells seems another important factor in pain generation. The peritoneal endometriotic lesion leads to reactions in the surrounding tissue and, therefore, is larger than generally believed. The identification of EM-associated nerve fibres and smooth muscle-like cells fuel discussions on the mechanisms of pain generation in EM, and may present new targets for innovative treatments." http://www.ncbi.nlm.nih.gov/pubmed/24590000

"We could detect an increased sensory and decreased sympathetic nerve fibres density in peritoneal lesions compared to healthy peritoneum. Peritoneal fluids of patients with endometriosis compared to patients without endometriosis induced an increased sprouting of sensory neurites from DRG and decreased neurite outgrowth from sympathetic ganglia. In conclusion, this study demonstrates an imbalance between sympathetic and sensory nerve fibres in peritoneal endometriosis, as well as an altered modulation of peritoneal fluids from patients with endometriosis on sympathetic and sensory innervation which might directly be involved in the maintenance of inflammation and pain." http://www.ncbi.nlm.nih.gov/pubmed/21888965