Mucosal immunity in the female Reproductive tract: Correlation of Immunoglobulins, cytokines, and reproductive hormones in human cervical mucous around the time of ovulation
Mucosal surfaces serve as the portal of entry for many viral, bacterial, and parasitic infections. Understanding the immunity at mucosal membranes is essential to enhancing protection and decreasing infections. To evaluate the humoral and cellular immunity in the female reproductive tract, 15 reproductive-age women with a history of regular, cyclic monthly menses were recruited for this study. The presence of immunoglobulins and cytokines in cervical mucus was correlated with the production of reproductive hormones in sera. Cervical mucus specimens were collected at each daily visit beginning on cycle day 8 and continuing for 5 days postovulation. Volunteers were monitored by daily urinary LH testing coupled with transvaginal ultrasonography to ascertain follicular collapse. The cervix was washed in sterile saline before aspirating the cervical mucus from the cervical canal. Collection volumes ranged between 50 and 800 microl and were considered to represent the total mucus produced. Estradiol displayed the characteristic biphasic pattern with a peak before ovulation and in the luteal phase. Both IgG (30 mg/dl) and IgA (15 mg/dl) had a biphasic pattern with peak immunoglobulin levels detected 1 day before the estradiol peak and increasing again just after ovulation. Peak interleukin 10 (40 pg/ml) levels corresponded precisely with estradiol peak levels just before ovulation. Peak interleukin 1beta (1.3 ng/ml) levels occurred approximately 1 day before the estradiol peak. No apparent pattern in interleukin 6 (150 pg/ml) could be ascertained. Our data suggest a correlation between the IgG and IgA immunoglobulin levels, interleukin 1beta and interleukin 10, in the female reproductive tract and estradiol levels in the circulation. The increase in immunoglobulins and cytokines occurs approximately 1 day before the peak estradiol production before ovulation. These data suggest a role for cytokines and hormones in the regulation of reproductive tract immunity.
Available from: Florian Hladik
- "Moreover, sample collection and storage methods, in addition to the conservative, two-tiered definition of antibody positivity, may have contributed to the relatively low frequency of HPTN 035 women with positive HIV-1-specific vaginal IgA. Additionally the hormonal cycle can influence both IgG and IgA antibody levels , . One limitation of our study with HPTN 035 samples was that due to study size and inclusion criteria (∼3099 female participants with some contraceptive use) the sample collections were not synchronized around the participant’s menstrual cycle. "
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Many participants in microbicide trials remain uninfected despite ongoing exposure to HIV-1. Determining the emergence and nature of mucosal HIV-specific immune responses in such women is important, since these responses may contribute to protection and could provide insight for the rational design of HIV-1 vaccines.
Methods and Findings
We first conducted a pilot study to compare three sampling devices (Dacron swabs, flocked nylon swabs and Merocel sponges) for detection of HIV-1-specific IgG and IgA antibodies in vaginal secretions. IgG antibodies from HIV-1-positive women reacted broadly across the full panel of eight HIV-1 envelope (Env) antigens tested, whereas IgA antibodies only reacted to the gp41 subunit. No Env-reactive antibodies were detected in the HIV-negative women. The three sampling devices yielded equal HIV-1-specific antibody titers, as well as total IgG and IgA concentrations. We then tested vaginal Dacron swabs archived from 57 HIV seronegative women who participated in a microbicide efficacy trial in Southern Africa (HPTN 035). We detected vaginal IgA antibodies directed at HIV-1 Env gp120/gp140 in six of these women, and at gp41 in another three women, but did not detect Env-specific IgG antibodies in any women.
Vaginal secretions of HIV-1 infected women contained IgG reactivity to a broad range of Env antigens and IgA reactivity to gp41. In contrast, Env-binding antibodies in the vaginal secretions of HIV-1 uninfected women participating in the microbicide trial were restricted to the IgA subtype and were mostly directed at HIV-1 gp120/gp140.
Available from: Daniel J Stieh
- "The remaining three samples had low or very minimal detectable IgA above background controls (Figure 4, representative sample in bottom row). The variability in detection of IgA could be due to differences in native flora of the patients or differences in menstrual cycle as to when the samples were collected . The detection of IgG and IgA at the surface of the endocervical epithelium supports evidence for cells within the endocervix as a source of Ig secretion; and it allows for Igs to interact with mucus being secreted from the same location. "
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ABSTRACT: Cells of the endocervix are responsible for the secretion of mucins, which provide an additional layer of protection to the female reproductive tract (FRT). This barrier is likely fortified with IgA as has previously been shown in the gastrointestinal tract and lungs of mice. Mucus associated IgA can facilitate clearance of bacteria. While a similar function for IgG has been proposed, an association with mucus has not yet been demonstrated. Here we find that IgA and IgG are differentially associated with the different types of mucus of the FRT. We observed that while both IgA and IgG are stably associated with cervical mucus, only IgG is associated with cervicovaginal mucus. These findings reveal that antibodies can bind tightly to mucus, where they can play a significant role in the fortification of the mucus barriers of the FRT. It may be possible to harness this interaction in the development of vaccines designed to protect the FRT mucosal barriers from sexually transmitted diseases such as HIV.
Available from: umich.edu
- "Ashcroft et al., 1997; Angele and Faist, 2000; Klein, 2000b; Johansson et al., 2001). Evidence also comes from healthy women, by the use of correlational studies over women's menstrual cycles (e.g. with IgG, IgA, interleukin 10 and 1b: Kutteh et al., 1998) and studies of synthetic E 2 administration via hormonal contraceptives. However, most research on immunity and T is conducted with males, and most research on immunity and E 2 is conducted with females. "
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ABSTRACT: Empirical evidence from clinical, nonhuman animal, and in vitro studies point to links between immune function and gonadal steroids, including potential androgenic immunosuppression and estrogenic immunoenhancement. This study was designed to test links between steroids and one marker of mucosal humoral immunity-immunoglobulin A (IgA) in healthy individuals, to facilitate comparisons with other species and clinical populations, as there are few existing studies with healthy humans that also allow gender/sex investigations. Participants (86 women, 91 men) provided a saliva sample for measurement of testosterone (T), estradiol (E(2)), and IgA. Results showed that E(2) was significantly and positively correlated with IgA in women, and group analyses by E(2) quartile showed that this association was linear. No significant correlations or nonlinear associations were seen between T and IgA in men or women, or E(2) and IgA in men. Evidence from this study indicates that IgA and E(2) are significantly associated in healthy premenopausal women.
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