William H. Kutteh

Characterization of immunoglobulins and cytokines in human cervical mucus: influence of exogenous and endogenous hormones.

Mucosal immunity in the female reproductive tract is influenced by immunoglobulins (Igs), cytokines, and reproductive hormones. Previous studies of reproductive-aged women demonstrated that IgA and IgG increases in cervical mucus corresponded to elevated levels of IL-1beta which occurred 1 day before the peak of endogenous estradiol production prior to ovulation. We sought to determine the effect of exogenous hormones on reproductive tract immunity in women on oral contraceptive pills (OCPs) and to compare the results with respect to naturally cycling women. Twelve women of reproductive age who had negative cervical cultures, a normal pap smear, and agreed to abstain from sexual intercourse during the study initiated OCPs. Cervical mucus and vaginal washes were collected at six intervals (2-3 days apart) throughout the treatment cycle. Fifteen naturally cycling women had similar samples collected prior to, during, and subsequent to ovulation. Cervical mucus samples were assayed for IgA, IgG, IL-1beta, IL-6, and IL-10 by enzyme-linked immunosorbent assay (ELISA). IgA, IgG and IL-1beta levels in women on OCPs paralleled increasing levels of norethindrone. Mean values of IgA increased from a low of 14.4+/-3.1 to 41.1+/-9.4 mg/dl and decreased significantly after the cessation of the pills (P < 0.001). In naturally cycling women, the largest quantities of Igs were detected prior to ovulation. By comparison, mean values of IgA in the cervical mucus of women on OCPs (24.4 mg/dl) exceeded peak levels of IgA in the cervical mucus of naturally cycling women (14.6 mg/dl). IgA was the predominant Ig detected in cervical mucus of women on OCPs. Both immunoglobulins in each group exhibited changes relative to their hormonal status. The increased levels of IgA in the cervical mucus of women on OCPs may explain the clinical observation of a lower incidence of sexually transmitted diseases.

Antiphospholipid antibodies and reproduction: The antiphospholipid antibody syndrome

In women who have a diagnosis of APS (both clinical and laboratory criteria) the chance for successful pregnancy is reduced. In these cases, treatment appears to be a clear option, particularly in the case of prior thromboembolic events. The current preference of treatment for women with RPL and aPL antibodies is subcutaneous heparin and aspirin. This treatment should begin with a positive pregnancy test and continue postpartum. It is unclear, at this time, what treatment, if any, is required for women who do not meet all the criteria for diagnosis of APS, but who are known to have aPL antibodies. In some cases, these women were tested because of a prior false-positive test for syphilis, with subsequent identification of aPL antibodies. More recently, women undergoing IVF were tested and found to have an increased incidence of aPL antibodies. It was suggested that aPL antibodies are associated with infertility and failure to implant. However, a summary of published reports indicate that positive aPL antibodies in patients undergoing IVF do not influence ongoing pregnancy rates. This subject, however, remains an area of active investigation because aPL antibodies were shown to interact with the syncytiotrophoblast and cytotrophoblast layers and could, theoretically, after implantation.

Multivariant Analysis of Men from Infertile Couples With and Without Antisperm Antibodies

PROBLEM: Research studies in animal and human systems have demonstrated conclusively that antisperm antibodies can interfere with fertilization. In the male, autoantibodies to sperm can be detected both in the sera and seminal plasma.

Induction of specific immune responses in the genital tract of women after oral or rectal immunization and rectal boosting with Salmonella typhi Ty 21a vaccine

The purpose of this study was to determine the efficacy of intestinal tract immunization in the induction of specific antibodies in human female genital tract secretions. Live attenuated typhoid vaccine Ty 21a was administered to three groups of healthy female volunteers, who were not using hormonal contraceptives. Group 1 included 15 women vaccinated orally. Group 2 included seven of the same women, who were vaccinated rectally 6 months later. Group 3 included 11 volunteers, who were vaccinated rectally. Salmonella-specific antibodies of IgG and IgA were measured in vaginal lavage and cervical mucus after oral or rectal primary vaccination. Salmonella-specific antibodies measured 1 month after rectal booster vaccination demonstrated significant increases in vaginal fluids and cervical mucus and were dominated by IgA. These results indicate that specific antibodies in the human female genital tract induced by primary vaccination can be enhanced by subsequent rectal administration of vaccines.

Preimplantation Genetic Screening: A Practical Guide

The past several decades have seen tremendous advances in the field of medical genetics. The application of genetic technologies to the field of reproductive medicine has ushered in a new era of medicine that is likely to greatly expand in the coming years. Concurrent with an in vitro fertilization (IVF) cycle, it is now possible to obtain a cellular biopsy from a developing embryo and genetically evaluate this sample with increasing sophistication and detail. Preimplantation genetic screening (PGS) is the practice of determining the presence of aneuploidy (either too many or too few chromosomes) in a developing embryo. However, how and in whom PGS should be offered is a topic of much debate.

Report from the Society for Gynecologic Investigation, Atlanta, Georgia, March 11–14, 1998

The 45th annual meeting of the Society for Gynecologic Investigation (SGI)included three sessions specifically devoted to immunology. A concurrent slidesession on Thursday, March 12th moderated by Ware Branch (Salt Lake City)and Deborah Anderson (Boston) included six oral presentations. There weretwo poster sessions, Thursday and Friday, entitled ‘Infertility: AutoimmuneDisorders and IVF’ with eight poster presentations and ‘Immunology’ with10 presentations. Two breakfast sessions also highlighted immunologic topics.On Friday morning a discussion of ‘Immunotherapies of HPV InducedDiseases’ was held by Dr Ellen Sheets and Peggy Crowley-Nowick (Crowley-Nowick et al., 1998), (Boston). On Saturday morning ‘Controversies in theManagement of Recurrent Pregnancy Loss’ were discussed by ProfessorLesley Regan (London) and Dr Ware Branch (Salt Lake City). There wereseveral other immunological presentations in other sessions. Overall, six of66 (9%) of oral presentations, 25 of 576 (4.2%) of poster presentations andtwo of 20 (10%) of the breakfast sessions were devoted to immunologic topics.It was also commendable for reproductive immunologists that Dr DeborahAnderson (Boston) was awarded the Distinguished President’s Young Inves-tigator prize at this meeting for her research.

Thyroid Function and Reproduction

Thyroid hormones play a vital role in fetal development and they influence metabolic processes in almost all tissues throughout life. The thyroid gland is the only significant source of thyroxin (T4) while most of the biologically more active triiodothyronine (T3) is produced extra-thyroidally. Disorders of the thyroid gland can be categorized into those associated with underproduction of thyroid hormones (hypothyroidism, such as Hashimotos thyroiditis) and those associated with an overproduction of thyroid hormones (hyperthyroidism, such as Graves disease). Recent studies have associated thyroid dysfunction with reproductive disorders including infertility and pregnancy loss.

Task force report on “non-criteria” antiphospholipid antibody tests

A Task Force of experts in the Antiphospholipid Syndrome (APS) field met prior to the 13th International Congress on Antiphospholipid Antibodies and addressed a number of critical questions regarding the antiphospholipid antibody (aPL) tests included in current international consensus criteria for the classification of APS (anticardiolipin antibodies (aCL), anti-β2glycoprotein I antibodies (aβ2GPI), and lupus anticoagulant (LA) test, namely, the “criteria” aPL tests). The Task Force was divided into the following three subgroups: (1) aCL and aβ2GPI tests, (2) LA test, and (3) the role of aPL as thrombotic risk factors. Subgroup 1 reviewed and critiqued the current state of aCL/aβ2GPI testing and recommended developing international consensus guidelines for performance of these assays and establishing universal units of measurement for anti-β2GPI. Subgroup 2 reviewed recent guidelines for LA testing published by the International Society of Thrombosis and Haemostasis Standardization Subcommittee (ISTH-SSC) on Lupus Anticoagulants and Phospholipid-dependent Antibodies; the subgroup recommended continued close collaboration with ISTH-SSC to address remaining issues, including the role of TCT and PT in LA testing and the validity of integrated test systems that lack mixing studies. Subgroup 3 emphasized the need for more data on the risks associated with aPL and recommended collaborative studies using existing large, population-based, prospective cohorts with available data on thrombosis and/or pregnancy outcomes. Such studies should include a comprehensive panel of current and newer aPL assays, assess the effect of antibody titer, analyze the risks associated with combinations of aPL, and use state-of-the-art statistical approaches for assessment of risk factors.