Givan et al. estimated that leukocytes represent 6 to 20% of the total number of cells in fallopian tubes, endometrium, cervix and vaginal mucosa with greater cell numbers in the upper tract (459). B cells are present in low but measurable numbers but T cells accounted for about 50% of all leukocytes, with CD8+ T cells predominating over CD4+ T cells.
This was confirmed some years later in a study by Johansson and colleagues who also showed a characteristical distribution of immune cells (626). They found that both CD4+ and CD8+ T cells were concentrated in a band beneath the epithelium and dispersed in epithelium and lamina propria. They also found several lymphoid aggregates consisting of T cells and B cells in one cervical sample.
Also another study detected aggregates consisting of an inner core of B cells surrounded by mainly CD8+ T cells and an outer halo of macrophages in the human endometrium (1560). Size was found to vary with the stage of menstrual cycle with larger size during secretory stage than those at proliferative stage. The absence of these aggregates in uteri of postmenopausal women provided further evidence that these aggregates are under hormonal control (1560). These aggregates had multiple features of inductive lymphoid tissue, for example aggregated lymphocytes in follicle-like structures, lymphocyte invasion of overlying epithelium and the presence of HEV. This suggests that these structures represent an organization of immune cells that are not dependent on the presence of infection or malignancy.
White et al. used hysterectomy specimens cocultured with IL-2 that contained CD3+CD8+ T cells to demonstrate cytolytic activity in the genital tract (1497). Cytolysis by CD3+ CD8+ T cells was found throughout the reproductive tract and appeared to be hormonally regulated, since in the uterine endometrium, the capacity for CD3+ T cell cytolytic activity was present during the proliferative phase of the menstrual cycle and absent during the subsequent secretory phase. In contrast, in postmenopausal women the entire reproductive tract, including the uterus, retains the capacity for strong CD3+ T cell cytolytic activity (1497).
A study by Pudney et al. showed that in women without inflammation, T cells and APCs were most prevalent in the cervical transformation zone and surrounding tissue (1146). Intraepithelial lymphocytes were predominantly CD8+ T cells; most CD8+ cells in the transformation zone and endocervix, and a proportion of cells in the ectocervix, expressed T-cell internal antigen-1, a marker of cytotoxic potential. In contrast, the normal vaginal mucosa contained few T cells and APCs. Cervicitis and vaginitis cases had increased numbers of intraepithelial CD8+ and CD4+lymphocytes and APCs. The menstrual cycle and menopause had no apparent effect on cellular localization or abundance in any of the lower genital tract tissues. These data indicated that the cervix, especially the transformation zone, is the major inductive and effector site for cell-mediated immunity in the lower female genital tract (1146).
Other data demonstrated that changes in circulating levels of estrogen can regulate the recruitment of bone marrow-derived cells to the uterine endometrium. In a study by DeLoia et al., the total uterine leukocyte population increased significantly when the women received oral estrogen, which resulted in higher serum estrogen levels (318). This rise in leukocytes was due to a significant increase in both the uterine NK cells and the macrophage populations whereas T-cell numbers did not change relative to circulating estrogen levels.
While further studies will be required to determine the effects of sex hormones on T cell function, receptors for estradiol have been demonstrated on both CD8+ and CD4+ T cell populations whereas the presence of progesterone receptors on T lymphocytes remains controversial (91).
To conclude, the human systemic and mucosal compartments of the immune system, especially the female genital tract, display a remarkable degree of independence. In contrast to other mucosal systems, the genital tract mucosal system is characterized by a significant contribution of the systemic compartment with respect to Ig isotype distribution, unique distribution and phenotypes of B and T cells, strong hormonal dependency and lack of typical lymphoepithelial inductive sites (Table 15).
Humoral immunity Cellular immunity Ig- producing cells J chain pIgR T cells CD4 - CD8 NK cells MA DC N Myometrium – – – – – – – – – Fallopian tube + + + ++ ++ + + + +++ Ovary – – – + + – +/– +/– + Endometrium +/– +/– ++ ++ ++ ++ + – ++ Endocervix +++ ++ +++ ++ ++ + + ++ ++ Ectocervix ++ + + +++ +++ + + ++ ++ Vagina + + – +++ +++ + + ++ ++ Table 15: Components of humoral and cellular immunity at different sites of the female reproductive tract; MA=macrophages, N=neutrophils, adapted from Kutteh et al. (763)
4.
Immunization studies
Based on the concept of a common mucosal immune system through which a fraction of lymphocytes activated at one mucosal site can disseminate immunity not only at this specific site, but also to other mucosal tissues, there has been much interest in the possibility of developing vaccines against mucosal infections in the genital tract (287).
Although the concept of the common mucosal immune system has been the dominant paradigm in mucosal immunology for more than two decades, it has become increasingly clear that there is a substantial degree of subcompartmentalization with the human reproductive tracts representing a component of this system with unique features, as discussed in the last chapters in detail. Indirect evidence suggests that female genital tract tissues may be preferentially supplied by cells from inductive sites located in intestine, rectum and nasal cavity.
It has been well established that the dissemination of cells from the inductive to the effector site is regulated by characteristic homing receptor-ligand interactions operational in mucosal tissue. In order to recruit leukocytes to mucosal tissue, the endothelium of the vessels expresses adhesion molecules, or addressins, that serve as ligands for homing receptors on the cells. Johansson et al. described the expression of intercellular adhesion molecule-1 (ICAM-1), VCAM-1, vascular
adhesion protein-1 (VAP-1) and P-/E-selectins in cervical and vaginal tissue (626). However, none of the samples expressed mucosal addressin cell adhesion molecule- 1 (MAdCAM-1). MAdCAM-1 has been shown in the gut-associated lymphoid tissue and is the only known vascular adhesion molecule that specifically directs lymphocytes to mucosal tissue via binding to the lymphocyte integrin α4β7 (1364). Immunization that produces secretory immunity in the female reproductive tract against STDs could have important practical applications. Investigators have attempted to elicit secretory immunity in the genital tract by using different routes of immunization. These local, remote and parenteral routes should be briefly outlined here.