Innate immune defences in the human endometrium
© King et al; licensee BioMed Central Ltd. 2003
Received: 13 June 2003
Accepted: 28 November 2003
Published: 28 November 2003
The human endometrium is an important site of innate immune defence, giving protection against uterine infection. Such protection is critical to successful implantation and pregnancy. Infection is a major cause of preterm birth and can also cause infertility and ectopic pregnancy. Natural anti-microbial peptides are key mediators of the innate immune system. These peptides, between them, have anti-bacterial, anti-fungal and anti-viral activity and are expressed at epithelial surfaces throughout the female genital tract. Two families of natural anti-microbials, the defensins and the whey acidic protein (WAP) motif proteins, appear to be prominent in endometrium. The human endometrial epithelium expresses beta-defensins 1–4 and the WAP motif protein, secretory leukocyte protease inhibitor. Each beta-defensin has a different expression profile in relation to the stage of the menstrual cycle, providing potential protection throughout the cycle. Secretory leukocyte protease inhibitor is expressed during the secretory phase of the cycle and has a range of possible roles including anti-protease and anti-microbial activity as well as having effects on epithelial cell growth. The leukocyte populations in the endometrium are also a source of anti-microbial production. Neutrophils are a particularly rich source of alpha-defensins, lactoferrin, lysozyme and the WAP motif protein, elafin. The presence of neutrophils during menstruation will enhance anti-microbial protection at a time when the epithelial barrier is disrupted. Several other anti-microbials including the natural killer cell product, granulysin, are likely to have a role in endometrium. The sequential production of natural anti-microbial peptides by the endometrium throughout the menstrual cycle and at other sites in the female genital tract will offer protection from many pathogens, including those that are sexually transmitted.
The key role of the human endometrium is to orchestrate the events that lead to fertilization, implantation and pregnancy. The prevention of uterine infection is crucial to successful human reproduction and although the endometrium must function as an efficient mucosal barrier the passage of spermatozoa has to be accommodated. The innate immune system in endometrium, as elsewhere, must protect against infection while also signalling the presence of a pathogen to the acquired immune system in the event that infection does occur. Natural anti-microbials are gene-encoded peptides that are key mediators of the innate immune system and the primary focus of this review is to describe their expression in the human endometrium
The menstrual cycle
The human endometrium undergoes characteristic cyclical changes in response to the steroid hormones, oestradiol and progesterone. These have been described in detail by Noyes et al . In the first half of the menstrual cycle (proliferative phase, days 4–13), when oestradiol concentrations are increasing due to the development of a follicle, the endometrium undergoes proliferation. Ovulation occurs on day 14 of the cycle, the corpus luteum forms and progesterone concentrations increase thereafter. Under the influence of progesterone endometrial growth ceases and differentiation occurs in preparation for implantation and pregnancy. The secretory function of the endometrial glands increases with maximal secretion in the mid secretory phase (days 19–23) around day 20. In the late secretory phase (days 24–28) spiral arteriole differentiation occurs and the stromal cells in immediate proximity to these vessels differentiate (decidualize). The nuclei of these cells become enlarged and the cytoplasmic volume increases. These changes also occur in the stromal cells below the surface epithelium and, if pregnancy occurs, the entire endometrium decidualizes. In the absence of implantation menstruation occurs resulting in tissue breakdown and repair allowing regeneration of the endometrium for the subsequent cycle. There are also cyclical changes to the leukocyte populations present in endometrium and these are described below.
The two major families of natural anti-microbials that will be discussed in relation to endometrium are (i). defensins and (ii). whey acidic protein (WAP) motif containing proteins. Studies in other mucosal systems such as the respiratory tract  strongly suggest that other anti-microbials will also be active within the uterus.
Defensins are a family of small cationic proteins that have been shown to confer the host with anti-bacterial, anti-fungal and anti-viral protection. Defensins have six cysteine residues that form three disulphide bonds and they are divided into two main groups on the basis of the position of these bonds: α-defensins are found in neutrophils (human neutrophil peptides (HNP)1-4) and at epithelial sites (human defensin (HD) 5 and 6) while the β-defensins (human β defensins (HBD)) are found mainly at epithelial surfaces e.g. gut, lung [3, 4]. It has recently been reported that there are 28 defensin-like sequences in the human genome  but currently only HBD1-6 have been characterized [6–11]. The β-defensins further subdivide into those that are constitutively expressed (e.g. HBD1) and those that are induced upon challenge with inflammatory or pathogen-derived stimuli [9, 10, 12–14]. In addition to their role as anti-microbials, the β-defensins are chemoattractants allowing an interaction between the innate and the acquired immune systems [8, 9, 15]. The expression, regulation and role of the β-defensins at non-reproductive sites has been reviewed elsewhere [16–18].
WAP motif containing proteins
Proteins containing the WAP motif have a 50 amino acid domain, which forms a tight core containing four disulphide bonds . This family includes secretory leukocyte protease inhibitor (SLPI), elafin, eppin and HE4 . SLPI and elafin are the most widely studied WAP proteins. These two molecules share 40% homology, with eight identical cysteines and five identical prolines, and both are expressed at mucosal surfaces where they have anti-protease and anti-microbial actions [21–26]. Both proteins inhibit serine proteases with SLPI inhibiting several proteases including neutrophil elastase and cathepsin G  while elafin regulates only neutrophil elastase and proteinase 3 [28–30]. These actions combined with their anti-microbial activity allow SLPI and elafin to protect epithelial surfaces during infection and inflammation. The similarity between SLPI, elafin and other proteins containing the WAP motif suggests that they may also have anti-protease and anti-microbial actions at epithelial surfaces .
Natural anti-microbial expression by the human endometrium
There are two main sites of natural anti-microbial expression in the endometrium: the epithelium and the leukocyte populations that are an important component of the cell types constituting the endometrium.
Natural anti-microbial expression by the endometrial epithelium
It is likely that the endometrial epithelium will also express additional natural anti-microbials. For example, the iron-binding protein lactoferrin is expressed by the endometrial epithelium . Lactoferrin has anti-microbial actions  and has been shown to be oestrogen regulated with maximal expression in the proliferative phase . Lactoferrin has been shown to act in synergy with SLPI  and it is likely that interactions between natural anti-microbials in endometrium will also be important.
Natural anti-microbial expression by endometrial leukocytes
Leukocyte populations are an important component of the endometrium, constituting 8.2% of the stroma during the proliferative phase with this figure increasing to 31.7% in first trimester decidua . The presence of several leukocyte populations in human endometrium is cycle dependent. The populations of neutrophils, uterine NK cells (uNK), macrophages and mast cells are relevant to endometrial anti-microbial expression. uNK cells are present in endometrium in the mid-late secretory phase of the menstrual cycle and are the major leukocyte population in first trimester decidua accounting for 70% of the leukocytes present at this time . They are believed to have a role in implantation, decidualization and placentation . uNK cells differ from the main population of NK cells in peripheral blood as they are CD56bright . The presence of these cells in endometrium is dependent on progesterone although this may be an indirect action, as uNK cells do not express the nuclear progesterone receptor . These cells express receptors for the glucocorticoid receptor and oestrogen receptor β suggesting that they do respond to these steroid hormones . Macrophages are present throughout the cycle with a small increase in number premenstrually [50, 54]. There are also increased numbers present in early pregnancy with a high concentration found at the implantation site . Immediately prior to menstruation there is an influx of neutrophils into the endometrium . Leukoctyes are involved in the tissue breakdown and repair that occurs at this time . Infiltration of endometrium with both neutrophils and macrophages around the time of menstruation is coincident with falling progesterone concentrations. The effects of progesterone withdrawal on these leukocyte populations is believed to be mediated by increased expression of inflammatory mediators such as interleukin-8 and monocyte chemoattractant protein-1 in the endometrium premenstrually [58–60]. Mast cells are also present throughout the menstrual cycle, although in smaller numbers, and are activated at menstruation .
Granulysin is an anti-microbial molecule that is stored in the granules of cytolytic T cells and peripheral blood NK cells . Granulysin mRNA has been found to be maximally expressed in endometrium from the late secretory phase suggesting that the uNK cell is also a source of this anti-microbial . Expression of granulysin during the late secretory phase may provide additional protection around the time of implantation or in its absence, menstruation.
It is also likely that endometrial macrophages and mast cells will express natural anti-microbial peptides. There are reports that HBD1 and 2 are expressed by blood monocytes and alveolar macrophages  and that hCAP-18 is expressed by human skin mast cells . However, localization of these peptides to endometrial leukocytes has not yet been described.
Importance of natural anti-microbial expression to reproductive health
Natural anti-microbial expression in the female reproductive tract.
Site of expression
First trimester decidua
HNP1 or 3
The combined oral contraceptive pill (COCP) can alter the susceptibility of users to pelvic infection. For example, the prevalence of infection of the cervix with Chlamydia is increased  while symptomatic Chlamydial infection of the upper genital tract is decreased in COCP users compared to non-users . Oral contraceptive users are also at higher risk of gonococcal infections . These differences are likely to be due to several factors including changes to the viscosity of cervical mucus, alterations to cell mediated immunity and decreased menstrual blood flow [37, 74]. Changes to innate immune factors are also likely to be important. Expression of the β-defensins, HBD1-4, is suppressed in COCP users compared to peak expression of these defensins in non-users suggesting that innate immune defences are altered [35, 36]. This may have important consequences and it is clear that future contraceptive design should ascertain the effects on anti-microbial molecules. New contraceptives should not have a deleterious effect on the innate immune system and ideally, might enhance its actions.
Uterine infection is a major contributory factor in preterm births . There are studies that suggest that the expression of anti-microbial molecules is upregulated in response to this situation. Concentrations of lactoferrin increase in amniotic fluid in patients with intra-amniotic infections, whether in preterm or term labour . In addition, levels of the α-defensins, HNP1-3, are increased 4–24 fold in patients in preterm labour suffering from infection . It is not yet clear whether or not any defects in expression of anti-microbial molecules exist that may increase susceptibility to uterine infections during pregnancy. The role of anti-microbials in the acquisition of sexually transmitted infections has also not been fully established although one study reports a decrease in SLPI concentrations in vaginal fluid from women suffering from lower genital tract infections . In contrast, there are reports to suggest that high concentrations of SLPI may be beneficial in the limitation of spread of HIV. SLPI has been shown to be the active component of saliva that inhibits infection of monocytes with HIV  and there is evidence to suggest that high concentrations of SLPI in vaginal fluid reduce the likelihood that an infant will be infected with HIV during vaginal delivery . Similarly, high concentrations of SLPI in infant saliva are reported to offer protection against HIV transmission during breast-feeding .
The human endometrium, in common with other mucosal surfaces, produces a wide array of natural anti-microbial peptides with the appearance of these peptides appearing to be governed by the stage of the menstrual cycle. These are expressed by both epithelial cells and endometrial leukocytes and have the potential to provide protection throughout the menstrual cycle and in pregnancy. The actions of these molecules may limit the spread of sexually transmitted infections and prevent against the uterine infections that cause preterm birth.
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