**1. Introduction**

244 Endometriosis - Basic Concepts and Current Research Trends

Zhou, H.E. & Nothnick, W.B. The relevancy of the matrix metalloproteinase system to the

No.1, (January 2005), pp.569-575, ISSN 1945-0494

pathophysiology of endometriosis. *Frontiers in Bioscience (Elite Edition),*Vol*.* 10,

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 involved in the pathogenesis of endometriosis.

#### **1.1 Immunology and inflammation in endometriosis**

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 important features will be presented in this section.

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

Virus Infection and Type I Interferon in Endometriosis 247

Fig. 1. The role of the immune system in the development and maintenance of

Expressed and Secreted; TGF, Transforming Growth Factor; MMP, Matrix

al., 2003).

Haider & Knöfler, 2009).

endometriosis. Following retrograde menstruation, multiple altered actions of the immune system influence step-wise disease progression. PF, peritoneal fluid; NK cells, natural killer cells; ICAM, Intercellular Adhesion Molecule; TNF, Tumour Necrosis Factor; IL, interleukin; MCP, Monocyte Chemotactic protein; RANTES, Regulated upon Activation, Normal T-cell

Metalloproteinase; TIMPs, Tissue Inhibitor of Matrix Metalloproteinases; VEGF, Vascular Endothelial Growth Factor; DC, dendritic cells. Simplified overview inspired by (Kyama et

TNFα also stimulates the growth of both endometrial and endometriotic stromal cells from women with endometriosis, whereas it inhibits the growth of endometrial cells from healthy women (Haider & Knöfler, 2009). The peritoneal fluid level of TNFα is correlated with disease severity. In addition, anti-TNFα therapy effectively reduces endometriosis lesions in rats and baboons (Zulfikaroglu et al., 2010) revealing a potential future medical treatment for endometriosis. However, a placebo-controlled clinical trial of anti-TNFα treatment failed to demonstrate a significant decrease of pain associated with deep endometriosis (see

peritoneal cavity should be cleared by the immune system, and a number of mechanisms contribute to the failure of this in endometriosis. These mechanisms are summarized in figure 1 and will be addressed here in the order of disease progression.
