Mucosal Immunity of the Adolescent Female Genital Tract

doi:10.1016/S1054-139X(02)00536-0

Journal of Adolescent Health

Volume 32, Issue 3, March 2003, Pages 183-186

https://doi.org/10.1016/S1054-139X(02)00536-0 Get rights and content

Abstract

This study sought to characterize mucosal immunity of the adolescent genital tract during the cycle and determine if adolescents have more suppressed immunoglobulin levels in the follicular phase than adults. Daily from cycle day 9 until ovulation, then every other day until menses, cervical secretions for IgA, IgG, and cytokines were collected via Weck-Cel sponge and serum for luteinizing hormone (LH), estradiol, and progesterone was obtained from three adolescent girls (mean age 16.8 years). Immunoglobulin and cytokine levels varied during the menstrual cycle, reaching their nadir around ovulation. Compared with 13 adults, adolescents had a greater drop in IgG in the follicular phase (mean β−953 vs. −269 μg/mL/day, p = .045), but a similar rate of rise in IgG in the luteal phase (mean β +118 vs. +100 μg/mL/day, p = .252). Rates of change in IgA did not differ between adolescents and adults for either phase. Although limited by the small sample size, these findings suggest that adolescents may be more sensitive to unopposed estrogen and warrant further investigation.

Section snippets

Methods

Female patients aged 15 to 17 years attending the Adolescent/Young Adult Clinic, Children’s Hospital Boston were eligible if they were at least 2 years past menarche, had regular menstrual cycles, had initiated sexual intercourse but would abstain during the study, and had a normal Papanicolaou smear within the previous 6 months. Exclusion criteria included pregnancy, current tobacco use, autoimmune disease or other immunodeficiency, an abnormal gastrointestinal tract, use of immunosuppressive

Results

Three adolescents (16.8 ± 0.8 years old) were each followed through one menstrual cycle; one participant was followed during an additional cycle owing to missed study visits around the time of ovulation. Participants were 4.2 ± 0.9 years postmenarche and sexually active for 2.5 ± 0.4 years.

IgA concentrations (Table 1) varied throughout the menstrual cycle, with levels lower at ovulation and higher in the follicular and luteal phases. IL-6 and IL-8 concentrations differed similarly across the

Discussion

Our findings indicate that, similar to adults, ovulatory adolescents experience changes in concentrations of IgA, IgG, and cytokines in cervical secretions throughout the menstrual cycle. Cervical immune barriers fall around ovulation presumably to provide a receptive environment for spermatozoa [7]. Unlike a previous cross-sectional study of adolescents [3], this longitudinal analysis demonstrated that IgA levels decreased during the follicular phase, reached a low at ovulation, and increased

References (19)

J. McGrath et al.
Secretory IgA in cervical mucus
J Adolesc Health
(1994)
J. Ellen et al.
Cervical secretory immunoglobulin A in adolescent girls
J Adolesc Health
(1999)
R. Edwards et al.
Immunoglobulin and interleukin-6 (IL-6) concentrations in cervical mucus are suppressed at ovulation
J Soc Gynecol
(1995)
A. Hildesheim et al.
Cytokine and immunoglobulin concentrations in cervical secretionsReproducibility of the Weck-Cel collection instrument and correlates of immune measures
J Immunol Methods
(1999)
K. Rosenthal et al.
Challenges for vaccination against sexually transmitted diseasesInduction and long-term maintenance of mucosal immune responses in the female genital tract
Semin Immunol
(1997)
Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance, 2000. Atlanta, GA: U.S....
P. Crowley-Nowick et al.
Cytokine profile in genital tract secretions from female adolescentsImpact of human immunodeficiency virus, human papillomavirus, and other sexually transmitted pathogens
J Infect Dis
(2000)
R. Sweet et al.
Chlamydial salpingitis tends to occur early in the menstrual cycle
JAMA
(1986)
S. Nowicki et al.
Susceptibility to gonococcal infection during the menstrual cycle
JAMA
(2000)

There are more references available in the full text version of this article.

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Women may be more susceptible to infections in the luteal phase, supposedly as a consequence of the hormone progesterone and its immunosuppressive action. While immunosuppression may be important for successful oocyte implantation and pregnancy, it makes women more vulnerable to pathogens. According to theory, to compensate for reduced immunocompetence, women in the luteal phase exhibit proactive behavioral responses, such as disgust and avoidance of disease-associated stimuli, to minimize contagion risk. However, previous studies yielded inconsistent results, and did not account for accompanying proactive immune responses, like the increase of secretory immunoglobin A (sIgA). Here, we assessed the proactive immune response and feelings of disgust associated with disease cues in the comparison of 61 woman with a natural menstrual cycle (31 in the follicular and 30 in the luteal phase) and 20 women taking hormonal contraception (HC). Women rated disease vulnerability and disgust propensity, watched a video displaying people with respiratory symptoms, which was evaluated for its disgust-evoking potential and contagiousness, and provided saliva samples for hormone and sIgA analysis. Women with HC reported a heightened vulnerability to disease compared to naturally cycling women, whereas both the feeling of disgust and the sIgA increase elicited by the disease video were similar across groups, regardless of progesterone. We found a u-shaped relationship between progesterone and baseline sIgA in naturally cycling women, with its nadir during ovulation. Overall, our data do not support a compensatory relationship between the proposed progesterone-induced immunosuppression and heightened disgust or a proactive sIgA response.
Mucosal immunology of the female reproductive tract and its regulation by female sex hormones
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This chapter describes fundamental knowledge regarding mucosal immune responses in the female reproductive tract (FRT). It starts by discussing the physical composition of the FRT including division of the organ into two distinct compartments. It then thoroughly outlines the innate and adaptive immune responses which take place in the FRT during homeostasis. Finally, it describes how these responses are modulated by the presence of female sex hormones.
Deciphering sex differences in the immune system and depression
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Certain mood disorders and autoimmune diseases are predominately female diseases but we do not know why. Here, we explore the relationship between depression and the immune system from a sex-based perspective. This review characterizes sex differences in the immune system in health and disease. We explore the contribution of gonadal and stress hormones to immune function at the cellular and molecular level in the brain and body. We propose hormonal and genetic sex specific immune mechanisms that may contribute to the etiology of mood disorders.
A randomized clinical trial on the effects of progestin contraception in the genital tract of HIV-infected and uninfected women in Lilongwe, Malawi: Addressing evolving research priorities
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The knowledge/understanding of the mechanism by which hormonal contraception may modify sexually transmitted infection (STI) and HIV risk is incomplete. Hormonal contraception may work systemically or locally within the genital tract to alter HIV susceptibility and transmissibility [14–32]. The physiology, cell composition, and immunology of the genital tract, a critical portal for HIV entry and source of transmission to partners and to newborns during childbirth, can be altered by changes in endogenous hormones and hormonal contraception.
Hormonal contraception is central in the prevention of unintended pregnancy; however there are concerns that certain methods may increase the risk of HIV acquisition and transmission. Hormonal contraceptives may modify the genital mucosa in several ways, however the mechanisms are incompletely understood. Few studies have examined genital HIV shedding prospectively before and after initiation of hormonal contraception. The effects of hormonal contraception on genital HIV shedding in the setting of antiretroviral therapy (ART) are also unknown.
We designed a pilot clinical trial in which HIV-infected and uninfected women were randomized to either depot medroxyprogesterone acetate (DMPA) injectable or levonorgestrel (LNG) implant in Lilongwe, Malawi. The objectives were to: 1) assess the effect and compare the impact of type of progestin contraception (injectable versus implant) on HIV genital shedding among HIV-infected women, 2) assess the effect and compare the impact of type of progestin contraception on inflammatory/immune markers in the genital tract of both HIV-infected and uninfected women, and 3) assess the interaction of progestin contraception and ART by examining contraceptive efficacy and ART efficacy. An additional study aim was to determine the feasibility and need for a larger study of determinants of HIV transmissibility and acquisition.
As injectable contraception is widely used in many parts of the world with high HIV prevalence, this study will provide important information in determining the need for and feasibility of a larger study to address these questions that can impact the lives of millions of women living with or at risk for HIV.
Characterization of cytological changes, IgA, IgG and IL-8 levels and pH value in the vagina of prepubertal and sexually mature Ellegaard Göttingen minipigs during an estrous cycle
2016, Developmental and Comparative Immunology
Citation Excerpt :
In women, the function of both the innate and the adaptive genital immune systems fluctuate during a menstrual cycle due to their strict regulation by sex hormones (Hickey et al., 2011; Weissenbacher, 2014). Within the innate immune system e.g. the level of IL-8 fluctuates through the reproductive cycle (Keller et al., 2007; Shrier et al., 2003) and within the adaptive immune system the genital antibody levels fluctuate. In terms of antibodies, both the levels of total IgG and IgA and the levels of antigen specific IgG and IgA antibodies decrease significantly around ovulation (Keller et al., 2007; Kutteh et al., 1996; Nardelli-Haefliger et al., 2003; Usala et al., 1989; Wright, 2011).
The pig is increasingly used as an advanced animal model of the genital tract in women and knowledge on the genital immune system is therefore needed.
In this study, evaluation of vaginal smears revealed that almost no neutrophils or other leukocytes were present in the vaginal mucosa of prepubertal minipigs (n = 10). In sexually mature minipigs (n = 10), evaluated through an estrous cycle, there was an increase in number of mucosal neutrophils and other leukocytes during estrus. The level of total IgA on the vaginal mucosa increased during diestrus. The level of total IgG showed no significant changes through the cycle. The vaginal IgA level in the prepubertal minipigs was similar to the low estrus level in sexually mature minipigs, and the IgG level in prepubertal was similar to the stable level in the sexually mature minipigs.
Medroxyprogesterone acetate differentially regulates interleukin (IL)-12 and IL-10 in a human ectocervical epithelial cell line in a glucocorticoid receptor (GR)-dependent manner
2014, Journal of Biological Chemistry
Citation Excerpt :
However, evidence for the effects of these ligands on IL-10 gene expression is contradictory. Some studies show no effect (79, 82, 83), whereas others are in agreement with the classical mechanism showing an increase in IL-10 mRNA and protein expression (67, 79, 84–86), and some deviate from the classical mechanism by showing a decrease in IL-10 mRNA and protein levels (79, 87–90). Clearly, our results in the ectocervical epithelial cell line showing pro-inflammatory GR-mediated effects by P4, MPA, and cortisol via a unique tethering mechanism deviate from the classically accepted GR mechanism.
Medroxyprogesterone acetate (MPA), designed to mimic the actions of the endogenous hormone progesterone (P₄), is extensively used by women as a contraceptive and in hormone replacement therapy. However, little is known about the steroid receptor-mediated molecular mechanisms of action of MPA in the female genital tract. In this study, we investigated the regulation of the pro-inflammatory cytokine, interleukin (IL)-12, and the anti-inflammatory cytokine IL-10, by MPA versus P₄, in an in vitro cell culture model of the female ectocervical environment. This study shows that P₄ and MPA significantly increase the expression of the IL-12p40 and IL-12p35 genes, whereas IL-10 gene expression is suppressed in a dose-dependent manner. Moreover, these effects were abrogated when reducing the glucocorticoid receptor (GR) levels with siRNA. Using a combination of chromatin immunoprecipitation (ChIP), siRNA, and re-ChIP assays, we show that recruitment of the P₄- and MPA-bound GR to the IL-12p40 promoter requires CCAAT enhancer-binding protein (C/EBP)-β and nuclear factor κB (NFκB), although recruitment to the IL-10 promoter requires signal transducer and activator of transcription (STAT)-3. These results suggest that both P₄ and MPA may modulate inflammation in the ectocervix via this genomic mechanism.

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^☆: This research was supported in part by 5 K23 MH01845 Mentored Patient-Oriented Research Career Development Award (L.A.S.) from the National Institute of Mental Health and R29 HD33210 (P.A.C.-N.) from the National Institute of Child Health and Development, National Institutes of Health, Bethesda, MD.

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Adolescent health briefMucosal Immunity of the Adolescent Female Genital Tract☆

Abstract

Section snippets

Methods

Results

Discussion

J Adolesc Health

J Adolesc Health

J Soc Gynecol

J Immunol Methods

Semin Immunol

Cytokine profile in genital tract secretions from female adolescentsImpact of human immunodeficiency virus, human papillomavirus, and other sexually transmitted pathogens

J Infect Dis

Chlamydial salpingitis tends to occur early in the menstrual cycle

JAMA

Susceptibility to gonococcal infection during the menstrual cycle

JAMA

Adolescent health brief
Mucosal Immunity of the Adolescent Female Genital Tract☆