**6. Conclusions**

Thus, it is very difficult to distinguish between the participation of endometrial abnormalities and immune impairments in peritoneal fluid in endometriosis pathogenesis. The frontiers between the two mechanisms are not clear-cut and evidently both mechanisms are responsible for endometriotic disease development. From one side, the development and growth of endometriosis lesions are associated with the significant changes in endometrium which are characterized by the high level of the expression of genes, stimulating invasiveness, and imbalanced production of anti- and pro-apoptotic factors in endometrial tissue. There are some differences in eutopic and ectopic endometrium in endometriosis. High level of anti-apoptotic factors XIAP synthesis is the characteristic feature of eutopic endometrium, which can provide high viability of menstrual endometrial cells in peritoneal cavity. But in endometriotic lesions the simultaneously elevated expression of both pro- and anti-apoptotic genes was seen. Likely, this phenomenon might provide the ectopic but not malignant growth of endometrium in endometriosis. The development and growth of already formed ectopic lesions but not the eutopic endometrium of women with endometriosis is under the control of proteolytic enzymes from metalloproteinases family. We found that some of these differences between eutopic and ectopic endometrium might be due to the impairment of immunosurveillance in peritoneal cavity. Both peritoneal macrophages and humoral factors of peritoneal fluid directly influenced upon apoptosis and invasiveness of endometrial cells. This action might be connected with the changes of functional activity of peritoneal macrophages and local cytokine production. The impairment of the scavenger function of peritoneal macrophages due to the decreased level of membrane expression of integrins, scavenger receptors and apoptosis-inducing molecules FasL is possibly one of the fundamental defects of immune response in peritoneal cavity, which allow endometrial cell to live, proliferate and be implanted. Altered cytokine profile of peritoneal fluid in endometriosis likely can promote the invasiveness of ectopic lesions. Though it can be said that now we don't fully understand the fine immune mechanisms providing the development of endometriosis. More studies into the macrophage functioning and cytokines production as well as clinical experiments on the animal model may improve our understanding of endometriosis pathogenesis and results in the novel therapeutic modalities for endometriosis.

#### **7. References**

236 Endometriosis - Basic Concepts and Current Research Trends

TNFα or tumor necrosis factor α initially was identified for its ability to kill certain cell lines, but now it is known that TNFα have the ability to initiate the cascade of other cytokines and factors associated with inflammatory responses. Earlier it was shown that TNFα increased the adherence of cultured endometrial stromal cells to mesothelial cells (Zang et al., 1993). This finding suggests that the presence of TNFα in peritoneal fluid may facilitate the adherence of ectopic endometrial tissue to the peritoneum and allow implants to develop. There are some experimental data, also evidenced about implication of TNFα in the pathogenesis of endometriosis (Agic et al., 2006). In baboons with laparoscopically confirmed endometriosis, TNFα blockade with p55 soluble TNFαreceptors results in inhibition of the development and growth of endometriotic implants (D'Hooghe et al., 2006). In rats with ectopically transplanted endometrial tissue, the administration of recombinant human TNFα- binding protein-1 (r-hTBP-1) resulted in defective development of implants compared with controls (D'Antonio et al., 2000). All these data and our own results let us to suggest the possible involvement of TNFα in initial mechanisms of ectopic endometrium implantation and growth. But it must be special noted that the macrophage's production and peritoneal fluid content of the majority of proinflammatory cytokines significantly elevated only at advantage stages of

Thus, we must very careful to speculate about possible involvement of cytokines in the peritoneal fluid in regulation of the behavior of endometrial cells in peritoneal cavity, because the prominent action of peritoneal fluid cytokines generally is seen only in advantage stages of endometriosis. We thought that the impairment of peritoneal macrophages function plays the decisive role in immune mechanisms participating in implantation and growth of ectopic endometrium. Incapability of peritoneal macrophages to act as effective scavengers and adequately to eliminate the misplaced endometrial cells from peritoneal cavity possibly is one of the primary immunological disorders participating in endometriosis pathogenesis. Elevation of proinflammatory cytokines production in peritoneal cavity likely depends on the presence of ectopic lesions and can be stimulated by viable endometrial cells proliferating and growing in peritoneal cavity. Invasion of already implanted ectopic endometrial cells is evidently under the control of proinflammatory

Thus, it is very difficult to distinguish between the participation of endometrial abnormalities and immune impairments in peritoneal fluid in endometriosis pathogenesis. The frontiers between the two mechanisms are not clear-cut and evidently both mechanisms are responsible for endometriotic disease development. From one side, the development and growth of endometriosis lesions are associated with the significant changes in endometrium which are characterized by the high level of the expression of genes, stimulating invasiveness, and imbalanced production of anti- and pro-apoptotic factors in endometrial tissue. There are some differences in eutopic and ectopic endometrium in endometriosis. High level of anti-apoptotic factors XIAP synthesis is the characteristic feature of eutopic endometrium, which can provide high viability of menstrual endometrial cells in peritoneal cavity. But in endometriotic lesions the simultaneously elevated expression of both pro- and

endometriosis.

cytokines of peritoneal fluid.

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**12** 

*Denmark* 

**Virus Infection and Type I** 

**Interferon in Endometriosis** 

*1Department of Molecular Biology, Aarhus University,* 

*3Department of Biomedicine, Aarhus University,* 

Pia M. Martensen1, Anna L. Vestergaard1,3 and Ulla B. Knudsen2

*2Department of Gynecology and Obstetrics, Aarhus University Hospital, Skejby,* 

Endometriosis is a chronic disease in which endometrium-like lesions are located ectopically, frequently in the pelvic cavity but also in more distant regions. It has been estimated that 5 to 10% of fertile women are suffering from the disease, and in a population of women with dysmenorrhoea (painful periods), around 50% have endometriosis (Faquhar, 2007). The symptoms include chronic pelvic pain, dysmenorrhoea, dyspareunia (pain during intercourse), and subfertility. The pathogenesis of endometriosis is unclear. Endometriosis is hormonal-dependent and therefore mainly found in women in the fertile age, although rare cases have been found in men and postmenopausal women. The risk is increased seven- to nine-fold for women who have a close relative (mother and/or sister) with endometriosis, indicating some genetic involvement (Simpson et al., 1980). Endometriosis displays malignant-like features, such as invasiveness and metastasis, and DNA viruses might play a role in endometriosis, like human papillomavirus (HPV) is part of the pathogenesis of cervix cancer (zur Hausen, 2009). Signs of inflammation are the key findings in endometriosis. From the above, some evidence points towards a possible involvement of the type I interferons (IFNs). This chapter will discuss whether DNA-viruses and the innate immune system might be

Inflammation, characterized by activated lymphocytes, neutrophils, and macrophages, is a key feature of endometriosis tissue, associated with the overproduction of prostaglandins, metalloproteinases, cytokines, and chemokines (Bulun, 2009). It is debated whether the peritoneal inflammation is a consequence or a cause of endometriosis, or both. The immune system is involved in the pathogenesis of endometriosis on multiple levels, of which

It is believed that defective immunosurveillance in women with endometriosis contributes to the attachment, persistence and progression of the endometriosis tissue (Kyama et al., 2003; Osuga et al., 2011). Following retrograde menstruation, endometrial cells in the

**1. Introduction** 

involved in the pathogenesis of endometriosis.

**1.1 Immunology and inflammation in endometriosis** 

important features will be presented in this section.

Zhou, H.E. & Nothnick, W.B. The relevancy of the matrix metalloproteinase system to the pathophysiology of endometriosis. *Frontiers in Bioscience (Elite Edition),*Vol*.* 10, No.1, (January 2005), pp.569-575, ISSN 1945-0494
