Endometriosis – An Immunological Enigma

I. Introduction

Endometriosis is a common gynaecological disorder, affecting at least 10% of women in the reproductive age group. It is an immune-hormonal inflammatory disorder, characterised by the growth of endometrial tissue outside the uterine cavity. It is a leading cause of morbidity in premenopausal women. Endometriosis is commonly associated with pelvic pain and impaired fertility.

It is reported that 25% to 50% of women with infertility have endometriosis. Also, 30%-50% of the women with endometriosis suffer from infertility. Thus, endometriosis is an important factor in the management of women with infertility.

II. Pathophysiology

The exact cause of endometriosis is still not clear but it has been shown to have multifactorial origin. There are various theories put forward.

1. Sampson’s theory of retrograde menstruation:

This theory proposes that viable endometrial tissue is disseminated into the peritoneal cavity via the fallopian tubes during menstruation and it subsequently implants into the peritoneal cavity and other organs. However, it has been shown that 76-90% of healthy women undergo retrograde menstruation but do not develop endometriosis.

2. Coelomic Metaplasia Theory:

Endometriosis arises from the metaplasia of cells lining the peritoneum following hormonal, infectious or environmental stimuli.

3. Embryonic rest theory:

Endometriosis arises from cells remaining from mullerian duct migration during embryonic development following estrogenic stimulus.

4. Stem cell theory:

Endometrial stem/ progenitor cells from the basalis layer of endometrium can travel by retrograde menstruation, lymphatic or vascular route into the peritoneal cavity and develop into endometriotic lesion.

5. Altered eutopic endometrium in endometriosis:

The normal endometrium (eutopic) in the women with endometriosis is significantly different from that of normal women. This can be due to inherited or acquired genetic factors (risk of endometriosis is 6 times higher when a first degree relative has a severe form of endometriosis). Polymorphism of genes, involved in production of cytokines, immunomodulatory protein’s (e.g. Toll-like receptors), has been shown in these cases. Defective immune surveillance also contributes to the altered characteristic of the endometrium in women with endometriosis

Pathophysiology of Endometriosis

III. Immunopathology of Endometriosis

Endometriosis is an enigmatic disease. Though endometriosis is considered as an inflammatory disease, it is now clear that immune system plays an important role in the pathogenesis and progress of the disease. Immune cells appear to be the key factor in the development of this disease.

The women that develop endometriosis have a defective immune system that is unable to recognize and properly mount immune response to the endometrial fragments within the peritoneal cavity. This is controlled by complex immunological mechanism involving both innate and adaptive immunity.

Immunopathogenesis of endometriosis

IV. Role of Immunosurveillance in endometriosis

The phenomenon of retrograde menstruation has been thought to be responsible for the development of endometriosis (Sampson’s theory). However, this phenomenon occurs in most of the women of reproductive age, but not all of them develop the disease. Once the endometrial tissue reaches the peritoneal cavity, it does not get implanted in healthy women and is eliminated through a system known as “Immunosurveillance” using the process of “Apoptosis”.

The exact mechanism of Immuno-surveillance evasion by ectopic endometrial tissue is still unclear. The possible mechanisms are as follows

1. Effect on leucocytes:

2. Role of FAS / FASL signalling pathway: Fas ligand (FasL) is a protein from TNF family. Its binding with its receptors induces apoptosis

3. Role of Mitogen activated protein kinase (MAPK) signalling pathway:

MAPK pathways are chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cells. The chronic inflammation of endometriosis plays a role through MAPK signalling pathway. MAPK is dysregulated in endometriosis, leading to increased inflammatory response and generation of anti-apoptotic signal. This leads to escape of immunosurveillance.

V. Role of Immune cells in Endometriosis

The immune system plays a significant role in initiation and progression of endometriosis. Immune cells appear to be key factors in the development of this disease. Peritoneal flow contains different types of immune cells. In endometriosis their numbers and function are dysregulated.

1. Role of Macrophages – Macrophages are the most prevalent type of immune cells in the peritoneal fluid.  The activated macrophages normally remove the blood cells, and damaged tissue fragments by phagocytosis and enzymes. Through this immune mediator they can induce inflammation and tissue repair and also activate T & B cells.

                In endometriosis, in spite of activation, the phagocytic activity of macrophages is reduced and they fail to eliminate the ectopic endometrial tissue. In addition, the amount of regurgitated endometrial cells is higher than the capacity of the macrophages to remove them.

             There are two types of macrophages. M& M2. The Mmacrophages specialize in elimination of defective cells through inflammatory cytokines. The Mmacrophages promote angiogenesis and tissue repair. There is an excess of Mmacrophages in the ectopic endometrium in women with endometriosis. This excess of Mmacrophages plays a key role in endometriotic grafting, development and persistence. Thus, macrophages play a key role in the development of endometriosis.

Role of macrophages in endometriosis

2. NK Cells – NK cells are lymphocyte of the innate immune system that can distinguish and kill stressed cells that have undergone injury. The NK cells detection system consists of cell surface activating (KAR) and inhibitory (KIR) receptors which regulate the NK cell activities. NK cells destroy abnormal or stressed cells by a mechanism called antibody-dependent cell-mediated cytotoxicity. Also, IL-2 increases the toxicity of NK cells. The NK cells preferentially kill target cells with lower than normal expression of MHC class I protein. (known as “Missing self-hypothesis”)

In endometriosis the ectopic endometrial cells in the peritoneal cavity are not targeted or removed by NK Cells through mechanism called “Immunoescaping”.

The expression of natural cytotoxicity receptor (NCR) NKp46 on the NK cell is reduced in RPL / RIF. The expression of NKp46 on peritoneal fluid NK cells is significantly lower in endometriosis, indicating the association of endometriosis with RPL/RIF. There is also an increase of TNF-alpha and IFN-gamma producing peritoneal NK cells, leading to proliferation and angiogenesis of the endometriotic cells.

Endometriosis is commonly associated with CD57+ endometrial NK cells. CD56+ cells in the endometrium maturate into CD57+ cells. These cells are cytotoxic and are responsible for recurrent implantation failure (RIF) associated with endometriosis.

3. Dendritic cells – It has been shown that the number of mature dendritic cells (DC) CD83significantly declines in endometriosis. Under normal circumstances, immature DC mature and travel to the lymph nodes in response to foreign antigens, where the antigens are presented to the T cells. However, this process is altered in endometriosis due to significant decline in mature DC. This leads to the masking of endometrial antigens in the ectopic endometrial tissue by the circulating anti-endometrial antibodies. Due to this, endometrial antigens are not effectively recognised and ectopic endometrium continues to grow.

Role of immune cells and cytokines in endometriosis

VI. Role of cytokines in endometriosis

       Cytokines are the main mediators and communicators of the immune system. The normal immune response to abnormal cell or pathogen involves a delicate balance of inflammatory and anti-inflammatory cytokines. The cytokine dysregulation is an important aspect of the pathogenesis of endometriosis. Peritoneal fluid of women with endometriosis contains higher concentration of pro-inflammatory and angiogenic cytokines.

1. Inflammatory Cytokines.

The important inflammatory cytokines that are raised in PF of with endometriosis are IL-1, TNFα and IL-6.

IL- 1 is an acute phase inflammatory cytokine produced by mononuclear cells and found in high levels in PF and endometriotic implant. TNF α is produced by activated macrophages and high levels are found in mild or early stages of the disease. IL-6 levels positively correlate with the size and number of the implants. IL-1/IL-33 signaling plays an important role in the development of the disease.

2. Anti-inflammatory cytokines

IL-10, an anti-inflammatory cytokine, is found in high concentration in PF in endometriosis. The increased concentration of IL-10 leads to the decreased cytotoxicity of NK cells, observed in endometriosis.

3. Angiogenic Cytokines

IL- 8 is a potent neutrophil chemotactic factor and has angiogenic effect. Higher levels of IL-8 are found in early stages of endometriosis.

4. Chemokines

Of all the chemokines found in PF in endometriosis, Monocyte Chemo-attractant protein- (MCP-1), an inflammatory chemokine, is the most significant. The levels of MCP-1 have been seen to increase with the increase in severity of the disease.

VII. Endometriosis and autoimmunity

       Several studies have proposed that women suffering from endometriosis have an immune-associated disorder and there is an association between endometriosis and autoimmune disease. There is evidence of increased levels of a range of autoantibodies in women with endometriosis. A recent series of Cochrane reviews on blood biomarkers and urinary biomarkers for endometriosis found that only anti-endometrial antibodies are significant and can be useful for detecting endometriosis. However, whether these antibodies are the cause or effect of the disease is still not very clear.

        Association between auto-immunity related genes and endometriosis has been evaluated. Gene associated with rheumatoid arthritis (PTPN22) has been shown to be associated with endometriosis. HLA alleles commonly associated with autoimmune disease have been seen in endometriosis. Endometriosis fulfils most of the criteria commonly used for definition of autoimmune diseases – abnormal function of T and B lymphocytes, elevated apoptosis and multiorgan involvement. However, it is still unclear whether endometriosis is a risk factor or a consequence of autoimmune disease or these two disorders share pathological mechanism and pathways.

VIII. Clinical implications of immune basis of endometriosis

  1. The understanding of immune mechanisms underlying the pathogenesis of endometriosis can help to plan diagnostic and therapeutic approaches in endometriosis.
  2. Estimation of anti-endometrial antibodies and IL-6 can be used as biomarkers for detecting endometriosis but their accuracy still cannot replace the standard surgical diagnosis.
  3. In endometriosis, lower NK cells Cytotoxicity and higher expression of NK cells inhibitory receptors (NKp46), leads to progression of the disease. This can be altered by Dinogest and oral contraceptive pills (OCP).
  4. IL-1/IL-33 Signaling plays an important role in the onset and development of endometriosis. In the absence of IL-33 OR IL-1R1, endometriotic lesions are reduced. This can be achieved by administration of inhibitor against IL-1R associated kinase4 (IRAK4) orally. IRAK4 inhibitor helps to prevent onset and progression of endometriosis and can provide a novel non-hormonal treatment for endometriosis. This beneficial effect can be augmented by use of anti-IL-33 antibody.
  5. Endometrial CD57 Cells: Estimation of CD57+ cells in the endometrium can be done, using immunohistochemistry, by doing a luteal phase endometrial biopsy in patients with associated infertility. These patients can be effectively treated by immunomodulatory treatment, including Lymphocyte Immunization Therapy (LIT).

Role of NK cells inhibitory receptors (NKp46)

IX. Conclusion

           Endometriosis is an inflammatory disease with a strong immunological basis. It is associated with abnormalities of immune system involving immune cells. (Macrophages, DCs, NK cells), cytokines (IL-1, IL-10, IL-6, IL-8) and chemokines. The endometrial tissue grows at ectopic sites due to the phenomenon – “Escape of immune-surveillance”. Endometriosis shares many features of an autoimmune disease but it is still unclear whether endometrium is the cause or effect of autoimmune disorders. By understanding the immune mechanisms involved in the pathogenesis of endometriosis, novel non-hormonal therapeutic options (IRAC4 inhibitors) have been identified for endometriosis.

X. References

  1. Riccio, L. da G. C., Santulli, P., Marcellin, L., Abrão, M. S., Batteux, F., & Chapron, C. (2018). Immunology of endometriosis. Best Practice & Research Clinical Obstetrics & Gynaecology, 50, 39–49. doi:10.1016/j.bpobgyn.2018.01.010
  2. Soo Hyun Ahn, Stephany P. Monsanto, Caragh Miller, Sukhbir S. Singh, Richard Thomas, Chandrakant Tayade Pathophysiology and Immune Dysfunction in Endometriosis. BioMed Research International, Volume 2015; Article ID 795976
  3. Fukui, A., Mai, C., Saeki, S., Yamamoto, M., Takeyama, R., Kato, T., … Shibahara, H. (2020). Pelvic endometriosis and natural killer cell immunity. American Journal of Reproductive Immunology. doi:10.1111/aji.13342
  4. Crispim, P. C. A., Jammal, M. P., Murta, E. F. C., & Nomelini, R. S. (2020). Endometriosis: What is the Influence of Immune Cells? Immunological Investigations, 1–17. doi:10.1080/08820139.2020.1764577
  5. Lebovic DI, Mueller MD, Taylor RN. Immunobiology of endometriosis. Fertil Steril. 2001 Jan;75(1):1-10. doi: 10.1016/s0015-0282(00)01630-7. PMID: 11163805.
  6. Ishii KJ, Hirota S, Yoshimoto T and Shibahara H (2019) Interleukin-1/-33 Signaling Pathways as Therapeutic Targets for Endometriosis. Front. Immunol. 10:2021. doi: 10.3389/fimmu.2019.02021
  7. Shigesi N, Kvaskoff M, Kirtley S, Feng Q, Fang H, Knight JC, Missmer SA, Rahmioglu N, Zondervan KT, Becker CM. The association between endometriosis and autoimmune diseases: a systematic review and meta-analysis. Hum Reprod Update. 2019 Jul 1;25(4):486-503. doi: 10.1093/humupd/dmz014. PMID: 31260048; PMCID: PMC6601386.

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