Citation Olovsson M. Immunological Aspects of Endometriosis: An Update. Am J Reprod Immunol 2011; 66 (Suppl. 1): 101–104
Endometriosis is a very complex disease that profoundly affects the quality of life of many women.
Method of study
A review of the relationships between the female immune system and the occurrence and development of endometriosis.
Function and dysfunction of the female immune system plays important roles in the initiation and progression of the disease and its relation to infertility and cancer.
Owing to obvious associations between endometriosis and the immune system, future treatment strategies might be based on immunological concepts and methods.
Endometriosis means the growth of endometrial-like tissue outside the uterine cavity.1 These lesions can be found at most sites in the body but most commonly affected are the pelvic peritoneum and organs such as the ovaries, rectum, and urine bladder.2 The disease affects roughly one in ten women of reproductive age. The cost of illness is not known in detail but annual health-care costs and costs of productivity loss associated with endometriosis have been estimated to $2801 and $1023 per patient in the USA.3 This means that the disease costs huge amounts of money for societies worldwide. Endometriosis may give a wide array of symptoms but is mainly associated with pain including dysmenorrhea and deep dyspareunia as well as problems with fertility. There are several treatment options including hormonal and surgical treatment4 but none of them are curative. At menopause, the lesions usually disappear and pain vanishes. This paper reviews various aspects of endometriosis, particularly in relation to the immune system and its eventual significance for future treatment of the pathology.
Pathogenesis of Endometriosis
It is not fully understood why some women develop endometriosis. Sampson’s hypothesis that endometrial fragments entering the abdominal cavity owing to retrograde menstruation in some cases have the capacity to attach to the peritoneal surface and later establish lesions is still valid.5 There is, however, a missing link because the majority of women do have retrograde menstruation but only about one in ten women have endometriosis.
Endometriosis and the Immune System
The missing link probably is the immune status that has been suggested to play an important role in both initiation and progression of the disease.6–8 In particular, immune cells like T and B lymphocytes and natural killer cells seem to play essential roles in determining either accept or reject survival, implantation, and proliferation of endometrial and endometriotic cells.9,10 Several studies have shown a reduced activity of cytotoxic T cells and NK cells, cytokine secretion by helper T cells, and autoantibody production by B lymphocytes in women with endometriosis.9–11 NF-κB transcriptional activity modulates inflammatory key cell processes contributing to the initiation and progression of endometriosis.12 It has also been shown that immune–endocrine interactions are likely to be involved in the pathogenesis of endometriosis.13
Endometriosis and Inflammatory Activity
It has since long been observed that endometriosis is associated with an increased inflammatory activity, as signaled by elevated serum levels inflammatory markers such as CA-12514 and C-reactive protein.15 Changes in the peritoneal fluid inflammatory markers have also been observed in women with endometriosis.16 The generalized inflammatory activity may lead to more generalized clinical effects where some women with endometriosis suffer from fever and a general feeling of malaise, especially in periods with more pain. Pain and other symptoms associated with the inflammatory markers are often relieved by use of non-steroidal anti-inflammatory drugs.
Genetics of Endometriosis
Changes seen in the immune system at least partly depend on genetic variations seen in women with endometriosis, and there are several attempts performed to identify gene pathways contributing to disease using the latest genome-wide strategies.17,18 A recent genome-wide association study identified a locus at 7p15.2 associated with endometriosis,19 and it has been shown that women with endometriosis diverge in their expression of several genes including heat-shock protein, S100, fibronectin, and neutrophil elastase, which might be involved in the process of Toll-like receptor-dependent sterile inflammation.20 Recent data reveal an association between Toll-like receptor-4 A896G (D299G) polymorphism and endometriosis.21 This polymorphism is functional, resulting in peritoneal inflammation that is favorable for the endometrial cells in the initiation of endometriosis.
Endometriosis and Autoimmune Disease
An increased co-occurrence of autoimmune diseases in women with endometriosis has been proposed,22,23 which could be associated with the genetic deviations found in diseased women. In a recent publication, it was, however, not possible to show any co-occurrence of endometriosis with multiple sclerosis, systemic lupus erythematosus, and Sjögren syndrome.24 The prevalence of autoimmune thyroid disease does not seem to be increased in women with endometriosis.25 There are, however, diverging data in the literature regarding whether there is an association between endometriosis and autoimmune disease or not.
Endometriosis, Infertility, and the Immune System
It is believed that there is an association between the immune system and endometriosis-associated subfertility and infertility.26–28 One recent finding is serum anti-endometrial antibodies in infertile women that might constitute a potential risk factor for implantation failure.29 The inflammatory environment occurring in ectopic endometrium results in high tissue factor (TF) expression causing further inflammatory cytokine or chemokine production, process that probably causes a reduced fertility.30 A recent study shows that antilaminin-111 autoantibodies may have a major pathogenic role on endometriosis-associated infertility.31
Endometriosis, Cancer, and the Immune System
Several studies indicate that women with endometriosis are more prone to develop epithelial and clear cell ovarian cancer32 and certain other types of cancer such as endocrine tumours, non-Hodgkin’s lymphoma, and brain tumours.33 The precise mechanism for the development of endometriosis-associated ovarian cancer remains poorly understood but micro-environmental factors, including oxidative stress and inflammation, may play an important role in this process.34 Recent data show that the molecular events involved in the early transformation of endometriosis to ovarian clear cell and endometrioid carcinomas seem to involve a mutation of ARID1A, a tumour-suppressor gene frequently disrupted in ovarian clear cell and endometrioid carcinomas.35 Why women with endometriosis are at higher risk of developing other types of cancer than ovarian cancer is not known but it is believed that it is caused by changes in the immune system.
Endometriosis, New Treatment Strategies, and the Immune System
There is an urgent need for new approaches to the medical treatment of endometriosis.36 An increased understanding of the immune aspects in endometriosis would be beneficial in the search for novel treatment strategies. Inhibiting NF-κB might be a promising strategy for future therapies targeting endometriosis,37 and recent in vitro data using pyrrolidine dithiocarbamate, a potent NF-κB inhibitor, support the hypothesis.38 Nuclear factor-kappa-B p50 subunit is a member of the NF-kappa-B family, which seems to be involved in the development of endometriosis and according to experiments on mice may be a promising therapeutic target.39 Antitumor necrosis factor-alpha (anti-TNF-alpha) inhibitors have also been evaluated for the treatment of endometriosis,40 but according to a recent Cochrane review, there is not enough evidence to support the use of anti-TNF-alpha drugs in the management of women with endometriosis for the relief of pelvic pain.41 Another approach is an immunoconjugate binding with high affinity and specificity to aberrant endothelial TF with subsequent destruction of endometriotic implants by vascular disruption.42 These and several other promising approaches are currently under investigation.
Endometriosis is a very complex disease with a great impact on many women’s quality of life. It is also very costly for societies around the world. There are obvious associations between endometriosis and the immune system, and future strategies to treat endometriosis might be based on immunological concepts and methods.