Immune Pathogenesis of Asymptomatic Chlamydia trachomatis Infections in the Female Genital Tract

Chlamydia trachomatis (CT) infections of the female genital tract, although frequently asymptomatic, are a major cause of fallopian-tube occlusion and infertility. Early stage pregnancy loss may also be due to an unsuspected and undetected CT infection. In vitro and in vivo studies have demonstrated that this organism can persist in the female genital tract in a form undetectable by culture. The mechanism of tubal damage as well as the rejection of an embryo may involve an initial immune sensitization to the CT 60 kD heat shock protein (HSP), followed by a reactivation of HSP-sensitized lymphocytes in response to the human HSP and the subsequent release of inflammatory cytokines. The periodic induction of human HSP expression by various microorganisms or by noninfectious mechanisms in the fallopian tubes of women sensitized to the CT HSP may eventually result in tubal scarring and occlusion. Similarly, an immune response to human HSP expression during the early stages of pregnancy may interfere with the immune regulatory mechanisms required for the maintenance of a semiallogeneic embryo

Detection of Ureaplasma urealyticum in Second-Trimester Amniotic Fluid by Polymerase Chain Reaction Correlates with Subsequent Preterm Labor and Delivery

Ureaplasma urealyticum is the microorganism most frequently isolated from the amniotic fluid of women in preterm labor. The relationship between intra-amniotic U. urealyticum in healthy second-trimester pregnant women and subsequent pregnancy outcome was investigated. Transabdominal amniotic fluid obtained from 254 asymptomatic women at 15-17 weeks' gestation were tested by polymerase chain reaction (PCR). U. urealyticum was identified in 29 subjects (11.4%). A subsequent preterm labor occurred in 17 U. urealyticum-positive women (58.6%), compared with 10 (4.4%) U. urealyticum-negative women (P<.0001). Preterm birth was documented in 7 (24.1%) U. urealyticum-positive women compared with only 1 U. urealyticum-negative woman (0.4%) (P<.0001). U. urealyticum-positive women also had a higher prevalence of preterm labor in a prior pregnancy (20.7%) than did the negative women (2.7%; P=.0008). PCR testing of second-trimester amniotic fluid for U. urealyticum can identify women at risk for subsequent preterm labor and deliver

Pregnancy Outcome Following Pelvic Infection

To determine whether a previous pelvic infection has an effect on the outcome of a subsequent pregnancy, we identified women with a diagnosis of pelvic inflammatory disease (PID), amnionitis, and postpartum or postabortal endometritis-salpingitis by a retrospective chart review of all patients admitted to the Department of Obstetrics and Gynecology at The New York Hospital-Cornell Medical Center between 1975 and 1977 and between 1985 and 1988. Antimicrobial regimens effective against Chlamydia trachomatis were initiated in 1985. Controls were randomly selected patients presenting during the same time period for routine examinations who had normal Pap smears and no infections. Both groups were comparable for age, race, gravity, and parity. Differences were evaluated by chi square analysis, using the Yates correction factor. We identified 183 women with a history of the above infections who subsequently conceived, and 82 controls. There were no differences in outcome between the two index groups. Term vaginal deliveries occurred in 14.2% of the women with a prior pelvic infection and in 56% of the controls (P < 0.001). Among the 97 women who had had PID, 21 (21.6%) had a spontaneous abortion in the subsequent pregnancy, as opposed to 6 (7.3%) of the controls (P = 0.013). In addition, eight of the women with PID (but no controls) went into preterm labor (P = 0.021). An increased incidence of preterm labor (P = 0.001) was also observed in women with a history of amnionitis. A history of endometritis was not associated with an increased prevalence of abnormal outcome in subsequent pregnancies. PID and amnionitis may adversely affect the outcome of subsequent pregnancies

Immune Recognition of the 60kD Heat Shock Protein: Implications for Subsequent Fertility

The 60kD heat shock protein (hsp60) is a highly conserved protein and a dominant antigen of most pathogenic bacteria. In some women, chronic or repeated upper genital tract infections with Chlamydia trachomatis, and possibly with other microorganisms, induces immune sensitization to epitopes of hsp60 that are present in both the microbial and human hsp60. Once a woman becomes sensitized to these conserved epitpes, any subsequent induction of human or bacterial hsp60 expression will reactivate hsp60-sensitized lymphocytes and initiate a pro-inflammatory immune response. Hsp60 is expressed during the early stages of pregnancy, by both the embryo and the maternal decidua. We examined, therefore, whether women who were sensitized to hsp60 experienced less successful pregnancy outcomes compared to women who were not sensitized to this antigen. In women undergoing in vitro fertilization (IVF), the presence of cervical IgA antibodies reactive with the C. trachomatis hsp60 correlated with implantation failure after embryo transfer. Further analysis revealed that an immunodominant epitope for these IgA antibodies was an hsp60 epitope shared between C. trachomatis and man. In subsequent studies of women not undergoing IVF, cervical IgA antibodies to the human hsp60 were identified in 13 of 91 reproductive age women. This antibody was most prevalent in those women with a history of primary infertility (p = 0.003). In addition, cervical anti-hsp60 IgA correlated with the detection of the pro-inflammatory cytokines interferon-γ (p = 0.001) and tumor necrosis factor-α (p = 0.02) in the cervix. Conversely, women with proven fertility had the highest prevalence of the anti-inflammatory cytokine, interleukin 10, in their cervices (p = 0.001). In an analysis of serum samples in a third study, women with a history of two or more consecutive first trimester spontaneous abortions had a higher prevalence (p = 0.01) of IgG antibodies to the human hsp60 (36.8%) than did age matched fertile women (11.1%) or women with primary infertility (11.8%). Immune sensitization to epitopes expressed by the human hsp60 may reduce the probability of a successful pregnancy outcome due to reactivation of hsp60-reactive lymphocytes, induction of a pro-inflammatory cytokine response and interference with early embryo development and/or implantation

Immune Regulation in the Male Genital Tract

Spermatozoa are not produced until puberty, long after the establishment of tolerance to self-antigens. Therefore, sperm-specific antigens are immunogenic in men. Most men, however, do not produce antibodies to their own gametes. Development of mechanisms to prevent or limit autoimmune responses to spermatozoa were essential for preservation of reproductive capacity. Tight junctions between adjacent Sertoli cells, as part of the blood-testis barrier, prevent sperm-immune cell contact. In some portions of the genital tract this barrier is thin or incomplete. Immune mechanisms have evolved to actively suppress the autoimmune response to spermatozoa within the genital tract. Unlike in the circulation where CD4+ helper T lymphocytes predominate, CD8+ suppressor/cytotoxic T lymphocytes are the most prominant T cells in the epididymis and vas deferens. In addition, spermatozoa suppress pro-inflammatory lymphocyte immune responses, possibly by inducing production of anti-inflammatory cytokines. Antisperm antibody production is induced in the male genital tract when a local infection or disruption in the genital tract physical barrier leads to an influx of CD4+ T cells. In response to induction of a productive immune response, two additional mechanisms downregulate humoral immunity within the genital tract. T lymphocytes possessing the γσ form of the antigen receptor (γσ T cells) are concentrated in the male genital tract and in semen. These cells become activated and proliferate in men with evidence of sperm autoimmunity. Activated γσ T cells inhibit production of antibodies by activated B lymphocytes, thereby limiting antisperm antibody production. Heat shock proteins (hsps) are also present in semen in association with infection and antisperm antibody formation. Hsp gene transcription leads to inhibition of transcription of the genes coding for pro-inflammatory cytokines and, conversely, to activation of γσ T cells. Activated γσ T cells also promote hsp synthesis. The mechanisms to inhibit immunity to sperm may hinder effective immune elimination of microoganisms in the male genital tract

Vulvar Vestibulitis—A Complex Clinical Entity

Objective: This study aims to determine the pathophysiology of vulvar vestibulitis and to evaluate currently used treatment options

Relation between recurrent vulvovaginal candidiasis, vaginal concentrations of mannose-binding lectin, and a mannose-binding lectin gene polymorphism in latvian women

Funding Information: Financial support: FIGO/Schering Research Foundation Fellowship (O.B.).Vaginal concentrations of mannose-binding lectin (MBL) and possession of a polymorphism in codon 54 of the MBL gene were determined in 42 women with recurrent vulvovaginal candidiasis (RVVC) and 43 control subjects. Reduced vaginal MBL levels and an increased occurrence of the polymorphism were present in women with RVVC.Peer reviewe

Frequency of interleukin-4 (IL-4) -589 gene polymorphism and vaginal concentrations of IL-4, nitric oxide, and mannose-binding lectin in women with recurrent vulvovaginal candidiasis

Background. A C→T substitution at position -589 in the interleukin-4 (IL-4) gene is associated with increased production of IL-4. Associations between this polymorphism and recurrent vulvovaginal candidiasis (RVVC), as well as vaginal concentrations of IL-4 and the anticandidal compounds nitric oxide (NO) and mannose binding lectin (MBL), were evaluated. Methods. Vaginal samples obtained by lavage from 42 women with RVVC during the acute stage of the disease and 43 control samples were assayed by enzyme-linked immunosorbent assay for IL-4 and NO metabolites. The -589 IL-4 gene polymorphism was detected by polymerase chain reaction and endonuclease digestion. Data were analyzed by Fisher's exact test, the nonparametric Mann-Whitney and Kruskal-Wallis tests, and Spearman rank correlation. P < .05 was considered significant. Results. Candida albicans was identified in 38 patients with RVVC; 3 others had infection due to Candida tropicalis, and 1 had infection due to Candida krusei. The IL-4 T,T genotype was detected in 59.5% of patients with RVVC and in 7.0% of control subjects (P < .0001). The frequency of IL-4*T was 76.2% in patients with RVVC and 23.3% in control subjects (P < .0001). The median concentration of vaginal IL-4 was elevated in patients with RVVC, compared with control subjects (P < .0001). Conversely, vaginal concentrations of NO metabolites (P = .02) and MBL (P < .0001) were reduced in patients with RVVC. There was a positive association between IL-4*T homozygosity and vaginal IL-4 levels (P < .0001) and negative associations between this genotype and vaginal NO (P = .01) and MBL (P < .0001) concentrations. Conclusions. Reduced vaginal levels of anticandidal factors in IL-4*T homozygotes may increase susceptibility to RVVC.Peer reviewe