Ovarian Steroid Hormones: effects of estradiol and progesterone on innate and adaptive immune responses and on Chlamydia trachomatis infection of the Female Genital Tract

Abstract

A critical function of the unique mucosal immune system of the female genital tract (FGT) is to identify and eliminate pathogenic viral and bacterial agents particularly those such as Chlamydia trachomatis causing sexually transmitted infections (STIs) and associated disease sequelae including tubal infertility(1)(2)(3). The FGT comprises several immune compartments found in the lower genital tract (LGT) (ectocervix, endocervix and vagina) lined with squamous epithelium and the upper genital tract (UGT) (ovaries, Fallopian tubes and endometrium) lined with columnar epithelium (reviewed in (4). Commensal flora is found in the LGT whilst documented relative sterility in the uterus and fallopian tubes is under hormonal influences (5).

Host protection of the FGT is afforded by two arms of defense comprising innate and acquired immunity. The more gradual acquired response is mediated through antibodies and/or T cells and is a very specific recognition and response to foreign antigens. The cellular components of this specific immunity are T lymphocytes expressing αβ- and γδ-T cell receptors (TCR) and immunoglobulin (Ig) producing B lymphocytes (6).The more rapid innate responses to infection recognise and respond to structures specific for microbes. Effector cells of this non-specific response are epithelial cells, monocytes, macrophages, granulocytes (neutrophils, eosinophils and basophils), dendritic cells (DCs) and Natural Killer (NK) cells conferring protection through chemokines and cytokines. Cells of both the innate and adaptive immune mechanisms are found in the FGT in Fallopian tubes, uterus, cervix and vagina (7). Localisation of T lymphocyte populations in the female upper (UGT) and lower (LGT) genital tracts over the menstrual cycle is summarised (Table 1).

Innate host defense particularly at the LGT is provided by vaginal microbiota maintained in a healthy equilibrium (reviewed in (32) as well as the myriad of antimicrobial peptides (AMPs) and protease inhibitors of cervicovaginal fluid (33) and reviewed in (32, 34). The AMPs and pathogen recognition receptors (PRR) toll-like receptors (TLRs) are key intermediaries of innate immunity in the FGT (34-37).

Female sex hormones estrogens, progestins and androgens are produced by ovarian cells with levels of estradiol (E2 or 17β-estradiol) and progesterone or P4 (pregn-4-ene3,20-dione) varying in accordance with fluctuations in the menstrual cycle (6). In the menstrual/ovarian cycle of humans the endometrium develops and follicles grow until ovulation in the Proliferative/Follicular phase. The Secretory/Luteal phase is characterised by high levels of progesterone from the corpus luteum to maintain the endometrium. Finally, corpus luteum regression and menstruation occurs during the menstrual phase. At menstruation, E2 levels measure typically <50pg/ml. Gradually increasing amounts of E2 are found in the follicular (proliferative) phase of the adult female menstrual cycle with serum levels at a pre-ovulatory stage (day 14) ranging from 110-410 pg/ml and dropping briefly at ovulation. High levels of E2 (20-160pg/mol) and P4(>5ng/ml) are present during the luteal (secretory) phase from days 14-28 of the menstrual cycle typically peaking at day 21 of the cycle. At the end of the secretory phase E2 levels return to their menstrual levels.
The sex hormones E2 and P4 are key contributors to susceptibility and innate and acquired immune responses to bacterial and viral infections of the FGT (38) reviewed in (6); 39, 40). It is also known that these hormones contribute to the sex-based differences both in innate and in acquired immunity and infectious diseases with estrogens affecting levels of chemokine receptors by T cells and the higher CD4+ T-cell populations in women undergoing significant changes during the ovarian cycle [reviewed in (41)]. Differences in E2 levels between male and female mice have also been reported as impacting on the expression of inducible nitric oxide synthase (iNOS)(42) and hence the production of nitric oxide (NO) a gas that modulates production of pro-inflammatory cytokines such as interleukin-6 ( IL-6) and tumour necrosis factor δ (TNF-δ)(43)

Innate and adaptive mucosal immunity in the FGT are regulated by the female sex hormones E2 and P4 have been reviewed (6);(44). Hormones regulate the transport of immunoglobulins, the levels of cytokines, the expression of TLR genes (45, 46) and the distribution of immune cells and antigen presentation in the genital tissues during the reproductive cycle (7, 35).
The afferent and efferent arms of uterine, cervical and vaginal immune responses are separately regulated, and control by sex hormones is distinct and species-specific in vaginal immune compartments (39). In the human uterus/cervix cellularity and CTL activity is menstrual cycle dependent with abundant IgA-secreting cells and secretory component (SC) expression in the endocervix. In the vaginal immune compartment cellularity and CTL activity is not menstrual cycle dependent, CD8+ T cells dominate and these are vital in a response to chlamydial infection (see review 47) , there is only a minor population of IgA plasma cells and low levels of SC expression, and IgG dominates with peri-ovulatory antibody peaks (39).
This review summarises our current knowledge of the effects of the sex hormones E2 and P4 in the female genital tract on innate immunity, antigen presentation, specific immune responses, antibody secretion, genital tract infections caused by sexually transmitted pathogens (particularly Chlamydia trachomatis) and vaccine-induced immunity.