Vaginal Innate Immunity

Alteration During Pregnancy and its Impact on Pregnancy Outcomes

Hector Mendez-Figueroa; Brenna Anderson

Disclosures

Expert Rev of Obstet Gynecol. 2011;6(6):629-641. 

In This Article

Abstract and Introduction

Abstract

The vaginal innate immune system represents the first line of defense against foreign organisms and pathogenic microbes. Through its major components, a natural balance is maintained and disease is averted. Many recent advances have furthered our knowledge of this intricate equilibrium and the contribution of each element to the final homeostasis. Various adverse obstetric and gynecologic conditions have been traced to abnormalities in the vaginal environment. This article highlights the importance of this subject in future interventions and opens the venue for future research.

Introduction

The female genital tract is a unique immunologic environment acting as the first line of defense against pathogenic organisms. The innate immune system – the nonspecific portion of the immune response – is well represented within this environment. An intricate interaction between the normal vaginal flora, different immune cells and various peptides create conditions that protect the host and thus avoid infection. Each component contributes in such a way that homeostasis prevails; any alteration in these components has been associated with disease processes. As an example, the absence of Lactobacillus, a principal component of the normal vaginal flora, has been associated with an increased incidence in sexually transmitted diseases[1] and with an overgrowth of pathogenic bacteria.[2] Bacterial vaginosis (BV) has been defined as a condition characterized by a decrease in the number of lactobacilli, increased vaginal pH and overgrowth of several anaerobic or facultative bacteria (Mobiluncus species, Prevotella species, Gardnerella vaginalis, and genital Mycoplasmas: Mycoplasma hominis, Ureaplasma urealyticum and Atopobium vaginae, etc.), which is not typically considered to be associated with inflammation. This pathologic condition has been associated with an increase of greater than twofold in the relative risk of developing preterm birth (PTB)[3] and a 1.61 relative risk for HIV acquisition.[4] Changes in vaginal flora that allow the growth of gastrointestinal bacteria have also been associated with an increased risk of PTB with an adjusted odds ratio of 2.99 (95% CI: 1.37–6.53).[5]

The vaginal innate immune system plays a critical role in defense against all sexually transmitted diseases including HIV. With the associated compromise of fecundity seen with lower genital tract infections along with the high mortality associated with HIV infection, improved understanding of this protective environment becomes much more important. The economic burden imposed on society by the management and treatment of all lower genital tract infections exposes the need for an adequate grasp and comprehension of the body's natural defense against invading organisms.

The evaluation of the vaginal innate immune system is facilitated when every component is analyzed and understood individually. The components of this defense mechanism can be divided into normal vaginal flora, antimicrobial peptides, cytokines and immune cells. All these components interact in order to maintain homeostasis. But, unfortunately, our current understanding of this complex interaction is quite limited; so limited in fact that it has become the focus of much recent research. New antimicrobial peptides have been isolated and we are just beginning to understand their role in protection as well as their variations during normal pregnancy. New techniques involving DNA analysis have also expanded understanding of the complex vaginal flora and its intricate role in local immunity. This article focuses on the various components that make up the innate vaginal immunologic system, the relationship present among all the elements and the impact that normal pregnancy can have on this milieu.

Normal Vaginal Flora

A number of bacterial species can be found within the lower genital tract. Throughout the years, it has been noted that their presence was not only associated with lack of disease, but it was also determined that these bacteria actually serve as a protective barrier against other truly pathogenic organisms. As knowledge expanded, it was discovered that any alteration to this normal bacterial colonization could lead to disruption in the genital tract immunity and subsequently the development of a diseased state. Normal vaginal flora contains a rich network of organisms, predominated by hydrogen peroxide-producing lactobacilli.[6,7] These bacteria maintain a slightly acidic pH within the vagina that makes it inhospitable for pathogenic organisms. Disruption of this flora by anaerobic bacteria, termed BV, leads to an increase in the vaginal pH and has been associated with various adverse health outcomes in both pregnant and nonpregnant women. The absence of normal lactobacilli in the vagina has been shown to be a strong indicator of the presence of sexually transmitted diseases such as trichomoniasis, Chlamydia trachomatis, Neisseria gonorrhoeae and syphilis.[1] BV has been repeatedly shown to be related to risk of HIV acquisition.[8,9] A meta-analysis of over 20 published studies has concluded that the presence of BV is associated with a increase in the incidence of HIV infection; when HIV-negative women are followed prospectively, the risk of acquiring the infection is increased by almost 60% (95% CI: 21–113%).[4] When studies evaluate the prevalence of HIV infection by assessing both the status of BV and HIV at a specific time, almost every study evaluated shows a higher HIV seroprevalance in BV-positive women, with an adjusted odds ratio of 1.69 (95% CI: 1.36–2.10).[4] One of the possible mechanisms attributed to this increased risk in HIV infection is the alteration of vaginal pH; more basic vaginal pH has been linked with increased CD4+ vaginal lymphocyte activation[10] and increase in adherence and survival of the HIV virus.[8] The disturbance of lactobacilli has also been associated with an overgrowth of enterococci, group B steptococci and Escherichia coli.[11] The associated adverse pregnancy outcomes attributed to disturbances in the vaginal flora and BV will be discussed later in this article.

The definition of 'normal flora' has been the subject of much debate recently. Various authors have tried to identify and categorize the bacteria contained in this bionetwork. When evaluating these studies, the variety in sampling methods, patient characteristics at enrollment as well as the techniques used to identify the microorganisms make comparison and generalization of results quite challenging. New molecular methodologies are beginning to be applied in this field with the hope of advancing our knowledge. Recently, Fredricks et al. evaluated samples of vaginal fluid from 73 women divided into two groups: patients with confirmed BV and patients without. Using broad-range PCR of 16S rDNA, bacterium-specific PCR and FISH, the authors discovered that women with BV had a greater bacterial diversity than women without the disease.[12] They also discovered several bacteria not previously described including three species in the Clostridia order that were highly specific for BV. Newer techniques may help identify the truly high-risk patient for developing BV-associated PTB that our current methodologies (use of Nugent or Amsel criteria) fail to recognize; this could then allow for a more targeted therapy.

Recent work has revealed that some inflammatory states in the lower genital tract can be the result of the overgrowth of aerobic bacteria, in comparison to the general anaerobic overgrowth seen in BV. Donders et al. recently introduced the term 'aerobic vaginitis,' which they defined as an inflammatory state characterized by the overgrowth of aerobic microorganisms such as E. coli and group B streptococci.[13] This entity differs from BV in that vaginal lactate levels are severely depressed but there is no associated production of vaginal succinate.[13] This pathogenic state is also associated with higher production of IL-6, IL-1β and leukemia inhibitory factor.[13] This demonstrates our limited knowledge on what constitutes normal versus abnormal flora in the vaginal milieu.

Along with the normal microbial flora present in the vagina, other mechanical components contribute to maintaining homeostasis and preventing disease. In the vagina, there is a barrier that protects the epithelium from disruption. This barrier, termed 'the protective surface layer', consists of compounds that coats the epithelium and prevent disruption of the epithelial layer as well as access to the cellular components of the genital tract. Figure 1 illustrates all the major components of the vaginal immune system.

Figure 1.

Representation of the overall immune components in the vaginal immune system. Major components involved in vaginal innate immunity. Represented here are the mechanical (normal flora), chemical (cytokines/chemokines and antimicrobial peptides) and cellular components (epithelial cells). GM-CSF: Granulocyte–macrophage colony-stimulating factor; LIF: Leukemia inhibitory factor; SLPI: Secretory leukocyte protease inhibitor.

Recently, the use of probiotics in an attempt to restore normal vaginal flora and thus avoid disease, has come into practice. This has been proposed by certain authors as a more directed treatment option.[14] Although theoretically sound, all the evidence to date implicating its value in both treatment and prevention of genital tract infections has been anecdotal. Small trials have shown that oral ingestion of live lactobacillus has been associated with colonization of the bacteria in the urogenital tract,[15] thus eliminating the need for vaginal application, which is a potential barrier for its use. The application of this strategy in the prevention of urinary tract infections (UTIs) has been better evaluated. Since the majority of pathogens causing UTIs originate from the GI tract, in women with recurrent UTIs, restoring normal vaginal with an intravaginal probiotic suppository was associated with a reduction in recurrent UTIs.[16]

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