Immunity in the Cervix: Interphase between Immune and Cervical Epithelial Cells

Abstract

The cervix is divided into two morphologically and immunologically distinct regions, namely, (1) the microbe-laden ectocervix, which is proximal to the vagina, and (2) the "sterile" endocervix, which is distal to the uterus. The two cervical regions are bordered by the cervical transformation zone (CTZ), an area of changing cells, and are predominantly composed of cervical epithelial cells. Epithelial cells are known to play a crucial role in the initiation, maintenance, and regulation of innate and adaptive response in collaboration with immune cells in several tissue types, including the cervix, and their dysfunction can lead to a spectrum of clinical syndromes. For instance, epithelial cells block progression and neutralize or kill microorganisms through multiple ways. These (ways) include mounting physical (intercellular junctions, secretion of mucus) and immune barriers (pathogen-recognition receptor-mediated pathways), which collectively and ultimately lead to the release of specific chemokines and or cytokines. The cytokines subsequently recruit subsets of immune cells appropriate to a particular immune context and response, such as dendritic cells (DCs), T, B, and natural killer (NK) cells. The immune response, as most biological processes in the female reproductive tract (FRT), is mainly regulated by estrogen and progesterone and their (immune cells) responses vary during different physiological phases of reproduction, such as menstrual cycle, pregnancy, and post menopause. The purpose of the present review is to compare the immunological profile of the mucosae and immune cells in the ecto- and endocervix and their interphase during the different phases of female reproduction.

Figure 1

Histology of the female reproductive tract (FRT). This figure illustrates the two immunologically distinct regions of FRT (see left side), i.e., the pathogen-laden lower FRT, shown by the yellow arrow, and the “sterile” upper FRT (see blue arrow) and their respective histological sections (see images in the middle and right side). Image credit of histological section: Human Protein Atlas, available from http://v18.1.proteinatlas.org.

Figure 2

Microscopic illustration of the cervix. The cervix is divided into the two main compartments, namely, the microbe-laden ectocervix and “sterile” endocervix, which are bordered by the cervical transformation zone (CTZ) and their associated immune cells. The ectocervix (and vagina, not shown) has squamous stratified epithelia, while endocervix (and uterus, not shown) has simple columnar epithelia.

Figure 3

Profile of intercellular junctions in the cervix. This figure shows the profile and intercellular localization of interepithelial adhesion molecules in the ecto- and endocervix. The most “potent” junctions in the stratified squamous epithelium of the ectocervix (and vagina), namely, adherens junctions (AJ), are located in the parabasal layer, just above the basal layer. As epithelial cells transition toward the apical surface, the junctions get “more loose.” In contrast, endocervical epithelia contain tight junctions (TJ) located close to the apical surface and AJ just below the TJ. Desmosomes are the most basal junctions.

Figure 4

Profile and distribution of cervical mucus. This figure shows the main ingredients of cervical mucus and common and distinct distribution of mucin in the ecto- and endocervix. Mucus provides a physical and chemical barrier against pathogens.

Figure 5

Antimicrobial peptide (AMP) profile and distribution in the ecto- and endocervix. Full names of abbreviations: human β-defensins (hBDs), secretory leukocyte protease inhibitor (SLPI), lysozyme, macrophage inflammatory protein-3 (MIP3α/CCL20), surfactant A, and elafin (also known as peptidase inhibitor 3).

Figure 6

Cytokine profile, distribution, and expression pattern in the ecto- and endocervix. Full names of abbreviations: interleukin (1β, 6, 10, 12, 15, 18), vascular endothelial growth factor (VEGF).

Figure 7

Chemokine profile and distribution in the ecto- and endocervix. Chemokine profile. Full names of abbreviations: interleukin (1, 6, 10, 12, 15, 18), vascular endothelial growth factor (VEGF), macrophage migration inhibitory factor (MIF) and dickkopf homolog 1 (DKK1), pathogen-associated molecular patterns (PAMPs), and pattern recognition receptor (PRR).

Figure 8

Comprehensive profile of immunity in the three compartments of the cervix. This figure shows the overall innate and adaptive immunity of the pathogen-laden ectocervix and “sterile” CTZ and endocervix, as well as their associated cells and molecules. Full names of abbreviations: interleukin (1, 6, 10, 15, 18), interferon gamma (IFN-γ), vascular endothelial growth factor (VEGF), macrophage migration inhibitory factor (MIF) and dickkopf homolog 1 (DKK1), pathogen-associated molecular patterns (PAMPs), pattern recognition receptor (PRR), and cervical transformation zone (CTZ). The illustration on the distribution of leukocytes is a modification from the following manuscripts: Givan et al. [57]; Trifonova et al. [58]; and Zhou et al. [10].