Mucosal immunity of the female genital tract 

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Seminal fluid

Seminal fluid (SF), also cited as seminal plasma, represents a part of the semen containing a range of organic/inorganic substances (e.g. neutral α-glucosidase, hyaluronidase, carnitine, glycerolphosphocholin, fructose, prostaglandins, citrate, zinc, selenium) that are necessary for the physiological metabolism of sperm. The seminal complex mixture of secretions originates in the testis, epididymis and accessory glands including the prostate, seminal vesicles and Cowper‟s gland. It also acts as a nutritive, transport and buffering medium of pH 7.35 – 7.5 that defines the main SF functions: sperm protection from the acidic environment of the vagina, metabolic support and competence, liquefaction and clot formation. SF composition is similar to blood plasma. However, it differs in saccharide content (Kumar et al., 2009; Rodriguez-Martinez et al., 2011; Brazdova et al., 2012a).
Semen liquefaction is caused by the fibrinolytic activity of some proteinases and peptidases present in prostatic SF. The key role of seminal enzymes (kallikrein-like protease 3, prostate-specific antigen) consists of a clot digestion formed immediately after ejaculation. It is said that SF containes hundreds of proteins of molecular or catalytic activity including additional proteins classified as their regulators (Yousef and Diamandis, 2001; Pilch and Mann, 2006).
In general, seminal proteins can be divided into three different groups. The first group contains the extracellular and intracellular proteins supporting basic SF function. The second group, originating in proteasomes and membrane-enclosed structures, is mainly involved in oocyte-sperm fusion. The third group is known as the potential biomarkers of testis/prostate cancer and male infertility as they represent the abraded epithelial cells from tissue surface (Pilch and Mann, 2006).
SF is in routine examined to evaluate pathological spermiogram and to monitor the progression of either testis or prostate cancer. In particular, prostate cancer is diagnosed by the seminal level of prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), prostate stem-cell antigen or glutamate carboxypeptidase II that is a prostate-specific membrane antigen (Jones, 1991; Ostrowski and Kuciel, 1994; Cao et al., 2003). Prostate cancer can be diagnosed by the serum PSA level. The serum concentration of 4 ng/ml means a 20-30% risk of prostate cancer. The risk increases approximately to 60% with a PSA level higher than 10 ng/ml (Fung et al., 2004). An early elevated level of serum zinc alpha-2-glycoproteins (ZAG), originally secreted by the prostate, indicates tumor growth as well. PSA, PAP and prostate-specific protein-94 (PSP-94) belong to the prostate secretion that accounts for about 30% of the total SF volume. This SF fraction is in direct contact with sperm and is the first to confront the cervical tissues. PSA ( -seminoprotein, seminin, kallikrein-3, P30 antigen, semenogelase) is a 33 kDa member of the glandular kallikrein subfamily of serine proteases. In particular, it is a member of the kallikrein subgroup of the (chymo)-trypsin serine protease family. It differs from the prototype member of this subgroup, tissue kallikrein, by possessing specificity more similar to that of chymotrypsin than trypsin. PSA is known as a zinc-binder and the most common protease in human semen. It is mainly released in proteasomes. It hydrolyzes semenogelin-1, thus leading to the liquefaction of the seminal coagulum. Its activity is strongly inhibited by zinc ions. This inhibition is relieved by exposure to semenogelins, which are avid zinc binders (Espana et al., 1991; Utleg et al., 2003; Pilch and Mann, 2006). PAP belongs to histidine acid phosphatase family, is stored in lysosomes and has an acid pH optimum below 7.0. It is a non-specific tyrosine phosphatase that dephosphorylates macromolecules and inactivates lysophosphatidic acid in SF. Its isoform 2 acts as a tumor suppressor of prostate cancer through the deactivation of mitogen-activated protein kinases. Decreased PAP level exhibits poor liquefaction (Autiero et al., 1991; Tanaka et al., 2004).
It contains the membrane-enveloped secretory vesicles. The fructose level is a marker of seminal vesicle function. High concentration of fructose is essential for sperm survival in the female reproductive tract. Fructose and other sugars are a source of energy for mitochondria-rich sperm. A decreased fructose level means a lower intensity of fructose oxidation. It leads to a lactate accumulation, which results in reduced sperm motility (Anderson et al., 2004). SF is rich in proteins secreted by seminal vesicles. Semenogelin I and II, fibronectin and fibronectin-related derivates belong to the gel-forming proteins. They are active after the cleavage by kallikrein-like protease and then have a role in entrapping sperm into a viscous gel immediately after ejaculation. They are also involved in sperm capacitation and sperm-oocyte interaction. Another SF element is lactoferrin, thanks to which SF may have an antimicrobial activity. SF content also involves albumin, serum and testis derived, that is a predominant protein participating in cholesterol removal from the sperm membrane during capacitation. The decreased seminal level of albumin and the increased seminal level of cholesterol are found in oligozoospermic men (Lilja et al., 1987; Autiero et al., 1991; Kosanovic and Jankovic, 2010).
Seminal components that bind to the acrosomal sperm head region protect sperm and are then carried together with it into the higher female genital tract. SF plays an important role in moving the sperm into the female reproductive tract due to its high content of transforming growth factor beta (TGF ) and prostaglandin E (PGE), both of which inhibit the function of natural killer (NK) cells and neutrophils that are recruited into the superficial epithelial layers of the cervical tissues. SF is rich in PGE of 19-hydroxy form that promotes an expression of chemotactic interleukin 8 (IL-8). TGF is synthesized in the prostate and is testosterone-dependent. This glycoprotein belongs to cell-secreted molecules and occurs in 75% in the latent form in SF. It is further activated in the female reproductive tract by either the enzymes of male/female origin, acidic vaginal pH or through conformational change after
an interaction with epithelial cells. The remaining proportion of TGF , β5%, exists in an active form (Denison et al., 1999; Robertson et al., 2002). TGF acting may result in the immune tolerance of seminal antigens, for which TGF I is, most likely, responsible. It is a cytokine of TGF family. A divergent member of this family is growth/differentiation factor 15 (GDF 15), which is highly abundant in SF. Surprisingly, its level is not related to semen quality but its expression serves as a cancer marker, often in combination with PSA. However, GDF 15 has antitumorigenic activity. In contrast, the high level of GDF 15 in female serum corresponds to spontaneous abortion as it is expressed in placenta as well. It has been suggested that thanks to the presence of seminal antigens on a conceptus, TGF facilitates the female immune tolerance to a fetus (Robertson, 2005; Soucek et al., 2010).
SF includes a repertoire of signaling molecules interacting with epithelium in the female reproductive tract. SF may modulate the chemotactic and phagocytic response of the female reproductive tract. Phagocytes serve to filter out the morphologically abnormal sperm. Sperm selection is based on morphological or antigenic structures. Mainly, the immune modulating properties are mediated by the prostaglandins of the E series, complement inhibitors, cytokines and proteins capable to bind IgG antibodies (Tomlinson et al., 1992; Kelly and Critchley, 1997). Local reactions may lead to an inflammation (Robertson, 2005).
However, SF has a built-in mechanism preventing an immunological sensitization of the female against sperm as well as seminal structures. This protective system exists due to the presence of immune inhibitors originating in the male sex accessory glands (Prakash, 1981). SF has been suggested to be the modulator of sperm-induced inflammation that leads to sperm elimination from the female genital tract (Troedsson et al., 2005).
SF elicits endometrial changes by inducing pro-inflammatory cytokines and cyclooxygenase-2. Their presence leads to macrophage and dendritic cell recruitment into the female reproductive tract. Seminal components activate the income of neutrophils into the endometrial stroma (Robertson, 2005; Bronson, 2011; Morrell et al., 2012). However, it has been proved that the influx of neutrophils is higher and faster when the washed sperm inseminated (Rozeboom et al., 1999). This fact proves the protective and signaling activity of SF. The immuno-suppressive activity prevents the iso-immunization of the female reproductive tract and suppresses the cell-mediated cytotoxicity (Lord et al., 1977). Seminal prostaglandin D2 is known for its immuno-suppressive effect, by which the anti-sperm antibody formation is avoided in the female genital tract. The immuno-modulating properties are mediated by prostaglandin E, complement inhibitors, cytokines and proteins capable of binding the Fc region of IgG. These IgG-binding proteins are Fc receptor-like proteins. In general, seminal antibody-binding proteins contribute to sperm protection against immune-mediated damage by enabling successful sperm passage in the female reproductive tract and by blocking an interaction with immune effectors. For instance, prolactin-inducible protein (PIP), which is a secretory glycoprotein located in seminal vesicles, binds to immunoglobulin G via its Fc fragment, it may therefore be involved in immune regulation by trapping anti-sperm antibodies (ASA) and neutralizing them (Chiu and Chamley, 2002; Chiu and Chamley, 2003).
SF has been considered to be linked to the IgE-mediated rare reaction to semen (Weidinger et al., 2006). This rare phenomenon was firstly reported by James (1945). Human seminal plasma allergy (HSPA) or the so-called hypersensitivity to semen is defined by localized and/or systemic symptoms after exposure to seminal fluid. The symptoms occur immediately after contact with semen or even within several hours after intercourse. The local symptoms include vulvar/vaginal itching, burning, redness and swelling. Local reaction can appear on any semen contact site. Local symptoms can be misdiagnosed as chronic vulvo-vaginitis caused by bacteria, yeasts, viruses and other parasites. Systemic features include generalized urticaria, angioedema (face, tongue, lips, throat), dyspnea, wheezing, cough, chest tightness, rhinorrhea, nausea, vomiting, diarrhea. Generalized malaise may result in an anaphylactic shock, which is a life-threatening reaction. The symptoms can manifest after the first time intercourse in up to 50% of cases. Response mediated by IgE antibodies is then the most common mechanism. It has been suggested (Basagana et al., 2008) that female patients experiencing any allergic symptoms after/during the first time intercourse might be sensitive to other antigens/allergens that cross-react with SF. Basagana et al. (2008) has already proved the IgE cross-reactivity among proteins from dog epithelium and PSA. Patients diagnosed with HSPA have difficulties conceiving but infertility has not been demonstrated, so far (Shah and Panjabi, 2004; Weidinger et al., 2006; Bernstein, 2011).

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Spermatozoa

Mature male gamete is commonly known and cited as sperm but specifically called as spermatozoa. It was firstly described in 1677 by Anthony van Leeuwenhoek. Sperm is a male reproductive cell of approximately 55-65 µm, containing genetic information and participating in the fertilization of an ovum (150-300 µm). Sperm consists of a head, middle section (mid-piece) and tail (Fig. 2). It is characterized by a minimum of cytoplasm. The head contains a nucleus, its shape is flat and oval in order to attach and easily penetrate an oocyte. An anterior peak of sperm head carries a cap-like structure called acrosome. It is designed, thanks to its hydrolytic enzymes, to help the sperm to penetrate the oocyte. The middle section consists of mitochondrial spiral, outer dense fibers and core microtubular structures. The mitochondrial formation contains the enzymes of oxidative phosphorylation. The mid-piece is, therefore, composed of substances that propel the tail. The tail enables the sperm to be motile by rotating in a circular motion, not from side to side like a whip (Collins discovery encyclopedia, 2005). The speed of sperm in ejaculate ranges from 10 to 60 µm/s. Its movement is based on the enzymatic and microtubule components, and is calcium and magnesium dependent. The tail is able to move ten times per second. Twenty thousand movements are estimated to be needed to reach the oocyte. In vitro, the speed is positively influenced by methylxanthins, lower temperature, and negatively by proteolytic enzymes, hydrogen peroxide and human saliva as it contains amylase and lysozyme enzymes (Ulcova-Gallova, 2006).
Normal sperm is characterized by an oval head with a long tail. Abnormal sperm has the defects of any body part (Fig. 3). Defects occurring on the head cause different shapes: large (giant), small (micro), elongated, irregular, amorphous, and then involve the acrosome deficiency and the so-called bicephalic head. The defective mid-piece is asymmetric, bent, thin, thick, irregular or with cytoplasmic droplets. The defective tail is coiled, shortened, hairpined, broken, duplicated or with terminal droplets. Any defects may impair the ability of the sperm to reach and fertilize the oocyte. In general, sperm morphological abnormalities are related to congenital background, varicocele, high fever, infection or drug use (Gilbert, 2000).

Spermatogenesis

Spermatogenesis (Fig. 4) is a complex process creating functional sperm, starting at puberty and ending with death. It occurs in the testis, progresses to the epididymis and takes approximately 64 days for completion. Effective maturation is conditioned by temperature, 2 °C lower than body temperature. This explains its location in external genitals. Sperm cells are then stored in the epididymides. The entire process is regulated by hormones (follicle stimulating hormone, luteinizing hormone, testosterone). It consists of three major steps:
(1) the multiplication of spermatogonia by mitosis, (2) meiosis to reduce the chromosome number from diploid to haploid, (3) the successful transformation of the round spermatid into the so-called spermatozoa. The spermatogonial population is created from the germ cells in the testis. The population then fuses with the Sertoli cells by creating seminiferous cords. After multiplication, several types of spermatogonia are distinguished: type A and B. The subsequent meiosis reduces the chromosome number from a diploid to a haploid form of type B spermatogonia. Type A diploid spermatogonium divides into two diploid cells called primary spermatocytes. The newly developed cells migrate into seminiferous tubules to undergo the meiosis by creating the secondary spermatocytes. The secondary spermatocytes are haploid. The next step reflects the forming of rounded spermatids. The differentiated spermatids mature in the epididymis into functional spermatozoa. There is an evidence of post-translational modifications that are considered to be essential for efficient spermatozoa. Some of them can activate capacitation directly in the epididymis or post-ejaculatory in the female reproductive tract. The cascade of modifications includes phosphorylation, glycosylation, proteolytic cleavage and methylation. A healthy man is usually able to produce up to 100 million of sperm/day. However, the concentration of 20 million/ml reflects, nowadays, the mean amount (Ulcova-Gallova, 2006; Warwick, 2006; Vacek, 2006; du Plessis et al., 2011).

Table of contents :

1 INTRODUCTION 
2 MALE FACTOR IN REPRODUCTION 
2.1 Seminal fluid
2.2 Spermatozoa
2.2.1 Spermatogenesis
2.2.2 Capacitation
2.2.3 Acrosome reaction
2.2.4 Fertilization
3 FEMALE FACTOR IN REPRODUCTION 
3.1 Oocyte
3.1.1 Oogenesis
3.2 Embryo development
4 INFERTILITY 
4.1 Unexplained infertility
4.2 Immune infertility
4.2.1 Anti-sperm antibodies
4.2.2 Association of seminal components with female sensitization
4.2.3 Auto-immune aspects in infertility
4.3 Mucosal immunity of the female genital tract
4.3.1 Cervical Mucus
4.4 Treatment of female infertility
4.4.1 Fertility drugs
4.4.2 Reproductive assistance
4.4.3 Intravenous immunoglobulins
4.4.3.1 IVIg and infertility related disorders
5 RESULTS 
5.1 Publications
5.1.1 Anti-sperm antibodies
5.1.2 Disintegration of human sperm and characterization of its antigen
5.1.3 IgG, IgA and IgE reactivities to sperm antigens in infertile women
5.1.4 Female serum immunoglobulins G, A, E and their immunological reactions to seminal fluid antigens
5.1.5 Immunodominant semen proteins I: New patterns of sperm proteins related to female immune infertility
5.1.6 Immunodominant semen proteins II: Contribution of seminal proteins to female immune infertility
5.1.7 Immunodominant semen proteins III: IgG1 and IgG4 linkage in female immune infertility
5.1.8 Pre-eclampsia: a life-threatening pregnancy syndrome
6 FUTURE ASPECTS 
6.1 Design of a miniaturized diagnostic tool
6.2 Immuno-Intervention in female immune infertility
7 DISCUSSION 
7.1 Antibody recognition
7.2 Protein markers
7.3 Immunoassay to screen female semen sensitivity
7.4 Immuno-Intervention strategies
8 CONCLUSION 
9 PERSPECTIVES 
10 REFERENCES

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