bims-reprim 2021-03-07 papers

Issue of 2021–03–07
five papers selected by
Iva Filipovic, Karolinska Institutet

Am J Reprod Immunol. 2021 Feb 28. e13412

Impact of the menstrual cycle and ethinyl estradiol/etonogestrel contraceptive vaginal ring on granulysin and other mucosal immune mediators.

Sean M Hughes, Urvashi Pandey, Christine Johnston, Jeanne Marrazzo, Florian Hladik, Elizabeth Micks.

PROBLEM: Changes in sex hormones during the menstrual cycle and contraceptive vaginal ring (CVR) use influence immunity within the female genital tract, but the magnitude of these effects and their anatomical location are unclear.
METHOD OF STUDY: In a prospective study, 29 women were assessed at three time points: follicular phase, luteal phase, and one month after initiation of the ethinyl estradiol/etonogestrel CVR (NuvaRing®, Merck). We performed microarrays on endocervical cytobrushes and measured immune mediators in cervicovaginal fluid, adjusting for bacterial vaginosis and presence of blood. We compared these results to public gene expression data from the fallopian tubes, endometrium, endo- and ectocervix, and vagina.
RESULTS: Immune-related gene expression in the endocervix and immune mediators in cervicovaginal fluid increased during CVR use versus both menstrual phases, and in the follicular versus luteal phase. The antimicrobial protein granulysin was high during CVR use, intermediate in the follicular phase, and nearly absent from the luteal phase. Re-analysis of public gene expression data confirmed increased immune-related gene expression in the endocervix during the follicular phase. However, in the fallopian tube, endometrium and vagina, the follicular phase showed immunosuppression.
CONCLUSIONS: Immune-related genes in the cervicovaginal tract were highest during CVR use, intermediate in the follicular phase, and lowest in the luteal phase. Granulysin is a potential biomarker of menstrual phase: frequently detected in follicular samples, but rare in luteal. Lastly, immunological differences between the follicular and luteal phases vary throughout the female genital tract.

Keywords: Bacterial vaginosis; Cervix; Endometrium; Fallopian tubes; Follicular phase; Granulysin; Granzyme B; Herpes simplex 2; Hormonal contraception; Luteal phase; Progesterone; Vagina

DOI: https://doi.org/10.1111/aji.13412

J Clin Med. 2021 Feb 20. pii: 869. [Epub ahead of print]10(4):

Immunological Risk Factors in Recurrent Pregnancy Loss: Guidelines Versus Current State of the Art.

Kilian Vomstein, Katharina Feil, Laura Strobel, Anna Aulitzky, Susanne Hofer-Tollinger, Ruben-Jeremias Kuon, Bettina Toth.

Around 1-5% of all couples experience recurrent pregnancy loss (RPL). Established risk factors include anatomical, genetic, endocrine, and hemostatic alterations. With around 50% of idiopathic cases, immunological risk factors are getting into the scientific focus, however international guidelines hardly take them into account. Within this review, the current state of immunological risk factors in RPL in international guidelines of the European Society of Reproduction and Embryology (ESHRE), American Society of Reproductive Medicine (ASRM), German/Austrian/Swiss Society of Obstetrics and Gynecology (DGGG/OEGGG/SGGG) and the Royal College of Obstetricians and Gynecologists (RCOG) are evaluated. Special attention was drawn to recommendations in the guidelines regarding diagnostic factors such as autoantibodies, natural killer cells, regulatory T cells, dendritic cells, plasma cells, and human leukocyte antigen system (HLA)-sharing as well as treatment options such as corticosteroids, intralipids, intravenous immunoglobulins, aspirin and heparin in RPL. Finally, the current state of the art focusing on both diagnostic and therapeutic options was summarized.

Keywords: NK cells; recurrent miscarriage; regulatory T cells; reproductive immunology

DOI: https://doi.org/10.3390/jcm10040869

Front Cell Infect Microbiol. 2020 ;10 596917

Lactobacillus-Depleted Vaginal Microbiota in Pregnant Women Living With HIV-1 Infection Are Associated With Increased Local Inflammation and Preterm Birth.

Charlotte-Eve S Short, Richard G Brown, Rachael Quinlan, Yun S Lee, Ann Smith, Julian R Marchesi, Robin Shattock, Phillip R Bennett, Graham P Taylor, David A MacIntyre.

Background: Pregnant women living with HIV-1 infection (PWLWH) have an elevated risk of preterm birth (PTB) of unknown aetiology, which remains after successful suppression of HIV. Women at high risk for HIV have a common bacterial profile which has been associated with poor birth outcomes. We set out to explore factors associated with gestational age at delivery of PWLWH in a UK population.
Methods: Prospective study of PWLWH (n = 53) in whom the vaginal microbiota and cervicovaginal cytokine milieu were assessed using metataxonomics and multiplexed immunoassays, respectively. Cross-sectional characterisation of vaginal microbiota in PWLWH were compared with 22 HIV uninfected pregnant women (HUPW) at a similar second trimester timepoint. Within PWLWH the relationships between bacterial composition, inflammatory response, and gestational age at delivery were explored.
Findings: There was a high rate of PTB among PWLWH (12%). In the second trimester the vaginal microbiota was more diverse in PWLWH than in HUPW (Inverse Simpson Index, p = 0.0004 and Species Observed, p = 0.009). PWLWH had a lower prevalence of L. crispatus dominant vaginal microbiota group (VMB I, 15 vs 54%) than HUPW and higher prevalence of L. iners dominant (VMB III, 36 vs 9% and VMB IIIB, 15 vs 5%) and mixed anaerobes (VMB IV, 21 vs 0%). Across the second and third trimesters in PWLWH, VMB III/IIIB and IV were associated with PTB and with increased local inflammation [cervicovaginal fluid (CVF) cytokine concentrations in upper quartile]. High bacterial diversity and anaerobic bacterial abundance were also associated with CVF pro-inflammatory cytokines, most notably IL-1β.
Interpretation: There is an association between local inflammation, vaginal dysbiosis and PTB in PWLWH. Understanding the potential of antiretroviral therapies to influence this cascade will be important to improve birth outcomes in this population.

Keywords: HIV; Lactobacillus sp. Gardnerella spp.; bacterial diversity; cytokines; inflammation; microbiome; preterm

DOI: https://doi.org/10.3389/fcimb.2020.596917

Lancet. 2021 Feb 27. pii: S0140-6736(21)00389-5. [Epub ahead of print]397(10276): 839-852

Endometriosis is a chronic systemic disease: clinical challenges and novel innovations.

Hugh S Taylor, Alexander M Kotlyar, Valerie A Flores.

Endometriosis is a common disease affecting 5-10% of women of reproductive age globally. However, despite its prevalence, diagnosis is typically delayed by years, misdiagnosis is common, and delivery of effective therapy is prolonged. Identification and prompt treatment of endometriosis are essential and facilitated by accurate clinical diagnosis. Endometriosis is classically defined as a chronic, gynaecological disease characterised by endometrial-like tissue present outside of the uterus and is thought to arise by retrograde menstruation. However, this description is outdated and no longer reflects the true scope and manifestations of the disease. The clinical presentation is varied, the presence of pelvic lesions is heterogeneous, and the manifestations of the disease outside of the female reproductive tract remain poorly understood. Endometriosis is now considered a systemic disease rather than a disease predominantly affecting the pelvis. Endometriosis affects metabolism in liver and adipose tissue, leads to systemic inflammation, and alters gene expression in the brain that causes pain sensitisation and mood disorders. The full effect of the disease is not fully recognised and goes far beyond the pelvis. Recognition of the full scope of the disease will facilitate clinical diagnosis and allow for more comprehensive treatment than currently available. Progestins and low-dose oral contraceptives are unsuccessful in a third of symptomatic women globally, probably as a result of progesterone resistance. Oral gonadotropin-releasing hormone (GnRH) antagonists constitute an effective and tolerable therapeutic alternative when first-line medications do not work. The development of GnRH antagonists has resulted in oral drugs that have fewer side-effects than other therapies and has allowed for rapid movement between treatments to optimise and personalise endometriosis care. In this Review, we discuss the latest understanding of endometriosis as a systemic disease with multiple manifestations outside the parameters of classic gynaecological disease.

DOI: https://doi.org/10.1016/S0140-6736(21)00389-5

Sci Immunol. 2021 Mar 05. pii: eabh3186. [Epub ahead of print]6(57):

Immunological yin-yang after pregnancy.

Jonathan S Maltzman.

Pregnancy induces both humoral sensitization and T cell tolerance to paternal tissues.

DOI: https://doi.org/10.1126/sciimmunol.abh3186