Role of inflammation in benign gynecologic disorders: from pathogenesis to novel therapies†.

Emerging evidence supports the notion that inflammation fosters the development of common benign gynecologic disorders, including uterine leiomyoma, endometriosis, and adenomyosis. Numerous cytokines, chemokines, and growth and transcription factors have indisputable roles in the establishment and maintenance of benign gynecologic disorders by initiating complex cascades that promote proliferation, angiogenesis, and lesion progression. The interaction between inflammation and benign gynecologic disorders is orchestrated by a plethora of factors, including sex steroids, genetics, epigenetics, extracellular matrix, stem cells, cardiometabolic risk factors, diet, vitamin D, and the immune system. The role of inflammation in these disorders is not limited to local pathobiology but also extends to involve clinical sequelae that range from those confined to the reproductive tract, such as infertility and gynecologic malignancies, to systemic complications such as cardiovascular disease. Enhanced understanding of the intricate mechanisms of this association will introduce us to unvisited pathophysiological perspectives and guide future diagnostic and therapeutic implications aimed at reducing the burden of these disorders. Utilization of inflammatory markers, microRNA, and molecular imaging as diagnostic adjuncts may be valuable, noninvasive techniques for prompt detection of benign gynecologic disorders. Further, use of novel as well as previously established therapeutics, such as immunomodulators, hormonal treatments, cardiometabolic medications, and cyclooxygenase-2 and NF-κB inhibitors, can target inflammatory pathways involved in their pathogenesis. In this comprehensive review, we aim to dissect the existing literature on the role of inflammation in benign gynecologic disorders, including the proposed underlying mechanisms and complex interactions, its contribution to clinical sequelae, and the clinical implications this role entails.

Clinical Applications of Interleukin-37: A Key Player in the Immunopathogenesis of Immune Disorders.

Recently, the era of medicine has been encountered with the exponential growth of special seroimmunobiomarkers in clinical trials. Lately, Interleukin-37 (IL-37) has attracted a wide range of basic medical scientists' attention due to its controversial functions in physiologic or pathologic microenvironments. In this research, an updated overview of immunobiological functions and clinical applications of IL-37 in a wide range of diseases, are discussed in order to highlight the role of recent laboratory-based results of IL-37. Data of this systematic review article were collected from initial 237 articles in Google Scholar search engine, Science Direct, PubMed, Scopus, and Embase databases. Eventually, 134 total articles were considered from March 2000 to June 2019 time interval, by using 5 keywords. Relevant English articles, abstracts and conference papers all were included. No restrictions of methods and type of the article were imposed. As one of the newly immunotherapeutic based approaches, clinical applications of cytokines are promisingly taken into account for diagnosis and treatment of multiple diseases. Various evidence suggests that IL-37 has notable roles in the regulation of acute and chronic inflammatory responses. Also, IL-37 has been studied in pregnancy, obesity, infectious, cardiovascular, neurologic, autoimmune, and metabolic diseases. Also, the protective functions of IL-37 against multiple cancers, are disputably related to the type and stage of cancer as well as the IL-37 variant. The broad spectrum of IL-37 and its receptors in diseases, seem to be a potential candidate with pivotal effects for immunomodulation and immune gene therapy of various pathologic states.

The interplay between immune system and microbiota in gynecological diseases: a narrative review.

OBJECTIVE: The vaginal microbiome is a dynamic environment, depending on the results of a complex interplay between microbiota and the host. In physiological conditions, Lactobacillus species are the most represented, regulating glycogen metabolism in order to maintain normal pH. Vaginal flora has been divided into five subtypes. Pattern recognition receptors are present on both squamous epithelial cells lining the vagina and columnar cells lining the upper female genital tract. They respond directly to bacterial product expressed by vaginal microbiome. The vagina contains different immune related cells and receptors which can recognize and react with the microbial environment. Altered microbiota and altered interplay between microbiota and immune system underlie several gynecologic diseases. MATERIALS AND METHODS: In this review, literature data related to vaginal microbiota, vaginal inflammation, immune system and menopause, preterm labor and miscarriage, were summarized. Relevant publications were retrieved from: PubMed, Medline, Scopus and Web of Science. RESULTS: The vaginal microbiome and the relationship with immune system has been analyzed in different gynecologic conditions. Menopause is associated to estrogen loss which causes vaginal atrophy, reduced abundance of Lactobacilli and increased amount of other bacterial species. Estrogens influence vaginal immunity through known and unknown mechanisms. In bacterial vaginosis (BV), due to many bacterial species, there has been found an inhibition of the chemotaxis and cytokine secretion. A decreased concentration of Lactobacilli seems to be playing a role in preterm labor as well as the increased levels of pro-inflammatory cytokines. Finally, the disequilibrium in the Th1/Th2 immune adaptive response, with a shift from Th2 to Th1, appears to be playing a role in miscarriage. CONCLUSIONS: The interplay between microbiota and the host closely involves the immune system. In particular, the vaginal microbiota is classically characterized by Lactobacilli even if vaginal microbiome of asymptomatic woman of reproductive age includes multiple aerobic and facultative or obligate anaerobic species. The role of microbiota and immune system in determining gynecological and obstetric events has been studied throughout recent years reaching new advancements. Therefore, additional studies are needed to better comprehend the complexity of the issue.

Myeloid-derived suppressor cells in obstetrical and gynecological diseases.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid-origin cells which have immunosuppressive activities in several conditions, such as cancer and inflammation. Recent research has also associated MDSCs with numerous obstetrical and gynecological diseases. During pregnancy, MDSCs accumulate to ensure maternal-fetal immune tolerance, whereas they are decreased in patients who suffer from early miscarriage or pre-eclampsia. While the etiology of endometriosis is still unknown, abnormal accumulation of MDSCs in the peripheral blood and peritoneal fluid, alongside an increased level of reactive oxygen species (ROS), has been observed in these patients, which is central to the cellular immune regulations by MDSCs. Additionally, the regulation of MDSCs observed in tumours is also applicable to gynecologic neoplasms, including ovarian cancer and cervical cancer. More recently, emerging evidence has shown that there are high levels of MDSCs in premature ovarian failure (POF) and in vitro fertilization (IVF), but the underlying mechanisms are unknown. In this review, the generation and mechanisms of MDSCs are summarized. In particular, the modulation of these cells in immune-related obstetrical and gynecological diseases is discussed, including potential treatment options targeting MDSCs.

Bivalent Vaccine Effectiveness Against Anal Human Papillomavirus Positivity Among Female Sexually Transmitted Infection Clinic Visitors in the Netherlands.

Human papillomavirus (HPV) vaccines are indicated for anal cancer prevention, but evidence for vaccine effectiveness (VE) against anal HPV infections among women is limited. We estimated the VE (≥1 dose) against anal HPV positivity of the bivalent vaccine, whose target types HPV-16/18 are associated with approximately 90% of HPV-related anal cancers. Among 548 female STI clinic visitors 16-24 years old who provided an anal swab sample as part of a repeated cross-sectional survey, VE against HPV-16/18 was 89.9% (95% confidence interval, 63.0%-97.2%). Type-specific VE correlated well with VE against cervicovaginal HPV (Spearman ρ = 0.76), suggesting comparable effectiveness of HPV-16/18 vaccination against genital and anal infections.

Evaluation of Patch Test Findings in Patients With Anogenital Dermatitis.

Importance: Contact dermatitis in the anogenital area is associated with sleep disturbance and dyspareunia and can profoundly affect quality of life. The literature on anogenital contact dermatitis and culprit allergens is limited. The last large-scale study on common, relevant allergens in patients with anogenital dermatitis was published in 2008. Objectives: To characterize patients with anogenital dermatitis referred for patch testing by the North American Contact Dermatitis Group, to identify common allergens, and to explore sex-associated differences between anogenital dermatitis and allergens. Design, Setting, and Participants: A retrospective, cross-sectional analysis was conducted of the North American Contact Dermatitis Group database among 28 481 patients who underwent patch testing from January 1, 2005, to December 31, 2016, at outpatient referral clinics in the United States and Canada. Exposure: Patch testing for allergens. Main Outcomes and Measures: Currently relevant allergic patch test reactions in patients with anogenital dermatitis. Results: Of 28 481 patients tested during the study period, 832 patients (336 men and 496 women; mean [SD] age, 50.1 [26.5] years) had anogenital involvement and 449 patients (177 men and 272 women; mean [SD] age, 49.6 [17.4] years) had anogenital dermatitis only. Compared with those without anogenital involvement, there were significantly more male patients in the group with anogenital dermatitis (177 [39.4%] vs 8857 of 27 649 [32.0%]; relative risk, 1.37; 95% CI, 1.14-1.66; P < .001). In the group with anogenital involvement, female patients were significantly less likely than male patients to have allergic contact dermatitis as a final diagnosis (130 [47.8%] vs 107 [60.5%]; relative risk, 0.78; 95% CI, 0.64-0.94; P = .01), whereas a final diagnosis of other dermatoses (eg, lichen planus, lichen sclerosus, or lichen simplex chronicus) was more frequent for female patients than for male patients (67 [24.6%] vs 28 [15.8%]; relative risk, 1.54; 95% CI, 1.02-2.31; P = .03). Of the 449 patients in the group with anogenital involvement only, 227 (50.6%) had 1 or more relevant reaction with patch testing. Allergens that were statistically significantly more common in patients with anogenital involvement compared with those without anogenital involvement included medicaments such as dibucaine (10 of 250 patients tested [4.0%] vs 32 of 17 494 patients tested [0.2%]; relative risk, 22.74; 95% CI, 11.05-46.78; P < .001) and preservatives such as methylchloroisothiazolinone and methylisothiazolinone (30 of 449 patients tested [6.7%] vs 1143 of 27 599 patients tested [4.1%]; relative risk, 1.61; 95% CI, 1.14-2.41; P = .008). A total of 152 patients met the definition for anogenital allergic contact dermatitis, which is defined as anogenital involvement only, allergic contact dermatitis as the only diagnosis, and 1 or more positive reaction of current clinical relevance. Conclusions and Relevance: For patients with anogenital involvement only who were referred for patch testing, male patients were more likely to have allergic contact dermatitis, whereas female patients were more likely to have other dermatoses. Common allergens or sources consisted of those likely to contact the anogenital area. For individuals with anogenital involvement suspected of having allergic contact dermatitis, reactions to preservatives, fragrances, medications (particularly topical anesthetics), and topical corticosteroids should be tested.

Natural history, dynamics, and ecology of human papillomaviruses in genital infections of young women: protocol of the PAPCLEAR cohort study.

INTRODUCTION: Human papillomaviruses (HPVs) are responsible for one-third of all cancers caused by infections. Most HPV studies focus on chronic infections and cancers, and we know little about the early stages of the infection. Our main objective is to better understand the course and natural history of cervical HPV infections in healthy, unvaccinated and vaccinated, young women, by characterising the dynamics of various infection-related populations (virus, epithelial cells, vaginal microbiota and immune effectors). Another objective is to analyse HPV diversity within hosts, and in the study population, in relation to co-factors (lifestyle characteristics, vaccination status, vaginal microbiota, human genetics). METHODS AND ANALYSIS: The PAPCLEAR study is a single center longitudinal study following 150 women, aged 18-25 years, for up to 2 years. Visits occur every 2 or 4 months (depending on HPV status) during which several variables are measured, such as behaviours (via questionnaires), vaginal pH, HPV presence and viral load (via qPCR), local concentrations of cytokines (via MesoScale Discovery technology) and immune cells (via flow cytometry). Additional analyses are outsourced, such as titration of circulating anti-HPV antibodies, vaginal microbiota sequencing (16S and ITS1 loci) and human genotyping. To increase the statistical power of the epidemiological arm of the study, an additional 150 women are screened cross-sectionally. Finally, to maximise the resolution of the time series, participants are asked to perform weekly self-samples at home. Statistical analyses will involve classical tools in epidemiology, genomics and virus kinetics, and will be performed or coordinated by the Centre National de la Recherche Scientifique (CNRS) in Montpellier. ETHICS AND DISSEMINATION: This study has been approved by the Comité de Protection des Personnes Sud Méditerranée I (reference number 2016-A00712-49); by the Comité Consultatif sur le Traitement de l'Information en matière de Recherche dans le domaine de la Santé (reference number 16.504); by the Commission Nationale Informatique et Libertés (reference number MMS/ABD/AR1612278, decision number DR-2016-488) and by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (reference 20160072000007). Results will be published in preprint servers, peer-reviewed journals and disseminated through conferences. TRIAL REGISTRATION NUMBER: NCT02946346; Pre-results.

Levels of different cytokines in women and men with asymptomatic genital infection caused by Chlamydia.

INTRODUCTION: Immune response to genital Chlamydia trachomatis infection is involved in both immunity and pathology. The cytokine profile during infection has been implicated in the disease outcome, either resolution or severe sequelae. METHODOLOGY: In total, 3900 patients were analyzed for presence of genital infections caused by Chlamydia using molecular assays. Interleukins (IL) IL-10, IL-17, IL-6, IL-2 and chemokine IP-10 were estimated by ELISA in urine, cervical swabs and semen samples. Statistical analysis was performed using the T student test. RESULTS: A total of 47 out of 3900 samples (1.2%) were found to be positive for Chlamydia trachomatis based on the Real Time (RT) PCR results. Statistical analysis revealed that the differences between Chlamydia trachomatis positive and negative samples regarding levels of cytokines were not significant. CONCLUSIONS: Our results demonstrated that no significant difference in cytokine concentrations exists in Chlamydia trachomatis infected patients when compared to healthy controls. In further study, we aim to test on a greater number of positive samples a greater number of cytokines involved in the immune response to Chlamydia trachomatis infections.

Type I IFNs in the female reproductive tract: The first line of defense in an ever-changing battleground.

The primary function of the female reproductive tract (FRT) is to enable successful reproduction, yet the biologic mechanisms required to accomplish this, which include fluctuating sex hormones and tolerance of semen and a semi-allogeneic fetus, can leave this unique mucosal environment susceptible to pathogenic challenge. Consequently, the FRT has evolved specialized innate and adaptive immune responses tailored to protecting itself from infection without compromising reproductive success. A family of innate immune cytokines that has emerged as important regulators of these immune responses is the type I IFNs. Type I IFNs are typically rapidly produced in response to pathogenic stimulation and are capable of sculpting pleotropic biologic effects, including immunomodulation, antiproliferative effects, and inducing antiviral and bactericidal molecules. Here, we review what is currently known about type I IFN-mediated immunity in the FRT in human, primate, and murine models and explore their importance with respect to three highly relevant FRT infections: HIV, Zika, and Chlamydia.

Neutrophils Are Central to Antibody-Mediated Protection against Genital Chlamydia.

Determining the effector populations involved in humoral protection against genital chlamydia infection is crucial to development of an effective chlamydial vaccine. Antibody has been implicated in protection studies in multiple animal models, and we previously showed that the passive transfer of immune serum alone does not confer immunity in the mouse. Using the Chlamydia muridarum model of genital infection, we demonstrate a protective role for both Chlamydia-specific immunoglobulin G (IgG) and polymorphonuclear neutrophils and show the importance of an antibody/effector cell interaction in mediating humoral immunity. While neutrophils were found to contribute significantly to antibody-mediated protection in vivo, natural killer (NK) cells were dispensable for protective immunity. Furthermore, gamma interferon (IFN-γ)-stimulated primary peritoneal neutrophils (PPNs) killed chlamydiae in vitro in an antibody-dependent manner. The results from this study support the view that an IFN-γ-activated effector cell population cooperates with antibody to protect against genital chlamydia and establish neutrophils as a key effector cell in this response.

Multitype Infections With Human Papillomavirus: Impact of Human Immunodeficiency Virus Coinfection.

BACKGROUND: Human immunodeficiency virus (HIV) infection predisposes women to genital coinfection with human papillomaviruses (HPVs). Concurrent infection with multiple HPV types has been documented, but its frequency, correlates, and impact on development of precancer are poorly defined in HIV-seropositive women. METHODS: Human immunodeficiency virus-seropositive women and -seronegative comparison women were enrolled in a cohort study and followed every 6 months from 1994 to 2006. Cervicovaginal lavage samples were tested for HPV types using polymerase chain reaction amplification with MY09/MY11 consensus primers followed by hybridization with consensus and HPV type-specific probes. Analyses were performed using generalized estimating equations. RESULTS: Multitype HPV infections were found in 594 (23%) of 2543 HIV-seropositive women and 49 (5%) of 895 HIV-seronegative women (P < 0.0001). Compared with HPV uninfected women, those with multiple concurrent HPV infections were more likely to be younger, nonwhite, and current smokers, with lower CD4 counts and HIV RNA levels. The average proportion of women with multitype HPV infections across visits was 21% in HIV-seropositive women and 3% in HIV-seronegative women (P <0.0001). Compared with infection with 1 oncogenic HPV type, multitype concurrent infection with at least 1 other HPV type at baseline did not measurably increase the risk of ever having cervical intraepithelial neoplasia 3+ detected during follow-up (odds ratio, 0.80; 95% confidence interval, 0.32-2.03, P = 0.65). CONCLUSIONS: Concurrent multitype HPV infection is common in HIV-seropositive women and frequency rises as CD4 count declines, but multitype infection does not increase precancer risk.

A vaccine formulated with the major outer membrane protein can protect C3H/HeN, a highly susceptible strain of mice, from a Chlamydia muridarum genital challenge.

C3H/HeN female mice were vaccinated with native Chlamydia muridarum major outer membrane protein (MOMP), using Montanide+CpG or Alum+CpG as adjuvants. Negative control groups were immunized with ovalbumin (OVA) and the same adjuvants. As positive control, mice were inoculated intranasally with live Chlamydia. Mice were challenged in the ovarian bursa with 10(5) C. muridarum inclusion forming units. Six weeks after the genital challenge the animals were caged with male mice and monitored for pregnancy. Mice vaccinated with MOMP+Montanide+CpG developed high levels of C. muridarum-specific antibodies, with a high IgG2a/IgG1 ratio and neutralizing titres. Animals immunized using Alum+CpG had low antibody levels. Cellular immune responses were significantly higher in mice vaccinated with MOMP and Montanide+CpG, but not with Alum+CpG, when compared with negative controls. Following the genital challenge, only 20% (4/20) of mice vaccinated with MOMP+CpG+Montanide had positive vaginal cultures whereas 100% (9/9) of mice immunized with MOMP+CpG+Alum had positive cultures. Of the positive control animals inoculated with live Chlamydia only 15% (3/20) had positive vaginal cultures. In contrast, 100% (20/20) of mice immunized with OVA+CpG+Montanide, or minimal essential medium, had positive cultures. Following mating, 80% (16/20) of mice vaccinated with MOMP+CpG+Montanide, and 85% (17/20) of animals inoculated intranasally with live C. muridarum carried embryos in both uterine horns. No protection against infertility was observed in mice immunized with MOMP and CpG+Alum or OVA. In conclusion, this is the first time that a subunit vaccine has been shown to elicit a protective immune response in the highly susceptible C3H/HeN strain of mice against an upper genital challenge.

The perinatal origins of major reproductive disorders in the adolescent: Research avenues.

The fetal endometrium becomes responsive to steroid hormones around the fourth month of pregnancy starting with an oestrogenic phase, which is followed late in pregnancy by a secretory phase. Based on post-mortem studies, the endometrium at birth is secretory in only one-third of neonates and proliferative in the remaining cases. Decidual or menstrual changes are rare in fetal endometrium despite high circulating steroid hormone levels, which drop rapidly after birth. Hence, acquisition of progesterone responsiveness appears to be dependent on endometrial maturation and relative immaturity may persist in a majority of girls until the menarche and early adolescence. Two major reproductive disorders have been linked with either advanced or delayed endometrial maturation. First, early-onset endometriosis may be caused by menstruation-like bleeding in the neonate, leading to tubal reflux and ectopic implantation of endometrial stem/progenitor cells. Second, persistence of partial progesterone resistance in adolescent girls may compromise deep placentation and account for the increased risk of major obstetrical syndromes, including preeclampsia, fetal growth retardation and preterm birth. The concept of neonatal origins of common reproductive disorders poses important research challenges but also subsumes potential new preventative strategies.

Female genital tract chronic graft-versus-host disease: review of the literature.

BACKGROUND: Chronic graft-versus-host disease (cGVHD) is the most common late complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although the involvement of skin, oral cavity, eyes, liver and gut is well-described, gynaecological manifestations are rare, often undiagnosed and untreated. MATERIALS AND METHODS: A selective literature search of articles in English language, published from 1982 to 2014 (indexed in PubMed) was performed. DISCUSSION: Genital cGVHD is characterised by polymorphic clinical manifestations with sclerotic changes of the vulva and vagina. Introital stenosis or complete vaginal closure were reported in severe cases. Thus, cGVHD can seriously affect female sexual function and the overall quality of life. A prompt diagnosis and an appropriate therapy may prevent the development of severe forms and the need for surgery. Thus, a systematic specialized gynaecological consultation should be performed early in every allo-HSCT recipient as part of the routine post-transplantation management, even in asymptomatic women.

Subpopulations of macrophages within eutopic endometrium of endometriosis patients.

PROBLEM: Endometriosis is recognized as a chronic inflammatory disease and is related to immune response. There have been reports that revealed the different distribution of macrophage within the eutopic endometrium of women with endometriosis. Macrophages are functionally polarized into M1 and M2 cell lineages. We studied a difference in the subpopulations of M1 and M2 macrophages within the eutopic endometrium in patients with or without endometriosis to investigate how the eutopic endometrium is stimulated immunologically. METHOD OF STUDY: Thirty-six patients with endometriosis (endometriosis group) and 37 without endometriosis (non-endometriosis group) were analyzed. Paraffin-embedded endometrial specimens were used for the study. Consecutive sections were used for immunostaining of CD68 (pan-macrophage marker) and CD163 (M2 macrophage marker). Cells positive for each marker were quantified, and the ratio of M2 macrophages in pan-macrophages was calculated. RESULT: The endometriosis group had a significantly higher number of pan-macrophages than the control group in all phases (P < 0.05). The ratios of M2 macrophages in pan-macrophages were significantly lower in all phases in the endometriosis group (P < 0.05). CONCLUSION: The macrophage population slants toward M1 in the endometrium of endometriosis patients. The endometrium appeared to be stimulated by some organelles and/or substances that induce M1 in endometriosis patients.

The role of dendritic cells in driving genital tract inflammation and HIV transmission risk: are there opportunities to intervene?

Effective prevention of new HIV infections will require an understanding of the mechanisms involved in HIV acquisition. HIV transmission across the female genital tract is the major mode of new HIV infections in sub-Saharan Africa and involves complex processes, including cell activation, inflammation and recruitment of HIV target cells. Activated CD4(+) T-cells, dendritic cells (DC) and macrophages have been described as targets for HIV at the genital mucosa. Activation of these cells may occur in the presence of sexually-transmitted infections, disturbances of commensal flora and other inflammatory processes. In this review, we discuss causes and consequences of inflammation in the female genital tract, with a focus on DC. We describe the central role these cells may play in facilitating or preventing HIV transmission across the genital mucosa, and in the initial recognition of HIV and other pathogens, allowing activation of an adaptive immune response to infection. We discuss studies that investigate interventions to limit DC activation, inflammation and HIV transmission. This knowledge is essential in the development of novel strategies for effective HIV control, including microbicides and pre-exposure prophylaxis.

Effect of female genital schistosomiasis and anti-schistosomal treatment on monocytes, CD4+ T-cells and CCR5 expression in the female genital tract.

BACKGROUND: Schistosoma haematobium is a waterborne parasite that may cause female genital schistosomiasis (FGS), characterized by genital mucosal lesions. There is clinical and epidemiological evidence for a relationship between FGS and HIV. We investigated the impact of FGS on HIV target cell density and expression of the HIV co-receptor CCR5 in blood and cervical cytobrush samples. Furthermore we evaluated the effect of anti-schistosomal treatment on these cell populations. DESIGN: The study followed a case-control design with post treatment follow-up, nested in an on-going field study on FGS. METHODS: Blood and cervical cytobrush samples were collected from FGS negative and positive women for flow cytometry analyses. Urine samples were investigated for schistosome ova by microscopy and polymerase chain reaction (PCR). RESULTS: FGS was associated with a higher frequency of CD14+ cells (monocytes) in blood (11.5% in FGS+ vs. 2.2% in FGS-, p = 0.042). Frequencies of CD4+ cells expressing CCR5 were higher in blood samples from FGS+ than from FGS- women (4.7% vs. 1.5%, p = 0.018). The CD14+ cell population decreased significantly in both compartments after anti-schistosomal treatment (p = 0.043). Although the frequency of CD4+ cells did not change after treatment, frequencies of CCR5 expression by CD4+ cells decreased significantly in both compartments (from 3.4% to 0.5% in blood, p = 0.036; and from 42.4% to 5.6% in genital samples, p = 0.025). CONCLUSIONS: The results support the hypothesis that FGS may increase the risk of HIV acquisition, not only through damage of the mucosal epithelial barrier, but also by affecting HIV target cell populations, and that anti-schistosomal treatment can modify this.

Innate immunity and inflammation of the bovine female reproductive tract in health and disease.

Mammalian reproductive physiology and the development of viviparity co-evolved with inflammation and immunity over millennia. Many inflammatory mediators contribute to paracrine and endocrine signalling, and the maintenance of tissue homeostasis in the female reproductive tract. However, inflammation is also a feature of microbial infections of the reproductive tract. Bacteria and viruses commonly cause endometritis, perturb ovarian follicle development and suppress the endocrine activity of the hypothalamus and pituitary in cattle. Innate immunity is an evolutionary ancient system that orchestrates host cell inflammatory responses aimed at eliminating pathogens and repairing damaged tissue. Pattern recognition receptors on host cells bind pathogen-associated molecular patterns and damage-associated molecular patterns, leading to the activation of intracellular MAPK and NFκB signalling pathways and the release of inflammatory mediators. Inflammatory mediators typically include the interleukin cytokines IL1ß and IL6, chemokines such as IL8, interferons and prostaglandins. This review outlines the mechanisms of inflammation and innate immunity in the bovine female reproductive tract during health and disease condition.

Influence of common mucosal co-factors on HIV infection in the female genital tract.

Women constitute almost half of HIV-infected population globally, and the female genital tract (FGT) accounts for approximately 40% of all new HIV infections worldwide. The FGT is composed of upper and lower parts, distinct in their morphological and functional characteristics. Co-factors in the genital microenvironment, such as presence of hormones, semen, and other sexually transmitted infections, can facilitate or deter HIV infection and play a critical role in determining susceptibility to HIV. In this review, we examine some of these co-factors and their potential influence. Presence of physical and chemical barriers such as epithelial tight junctions, mucus, and anti-microbial peptides can actively block and inhibit viral replication, presenting a significant deterrent to HIV. Upon exposure, HIV and other pathogens first encounter the genital epithelium: cells that express a wide repertoire of pattern recognition receptors that can recognize and directly initiate innate immune responses. These and other interactions in the genital tract can lead to direct and indirect inflammation and enhance the number of local target cells, immune activation, and microbial translocation, all of which promote HIV infection and replication. Better understanding of the dynamics of HIV transmission in the female genital tract would be invaluable for improving the design of prophylactic strategies against HIV.

Genital chronic graft-versus-host disease in females: a cross-sectional study.

Using the National Institutes of Health (NIH) consensus criteria for chronic graft-versus-host disease (cGVHD), we assessed the prevalence, symptoms, and clinical signs of female genital cGVHD in a cross-sectional population-based study. Forty-two women were evaluated at a median of 80 months (range, 13 to 148 months) after undergoing hematopoietic stem cell transplantation (HSCT). Medical history, ongoing medications, and genital signs and symptoms were recorded. Gynecologic examination for the diagnosis and clinical scoring of genital cGVHD was combined with clinical scoring of extragenital cGVHD for the estimation of each patient's global cGVHD score. Biopsy specimens from the genital mucosa were obtained from 38 patients. Genital cGVHD was diagnosed in 22 of 42 patients (52%). Its presence was associated with systemic corticoid steroid treatment of extragenital cGVHD (P = .001), older age (P = .07), and HSCT from a sibling donor (P = .002). Five patients had isolated genital cGVHD. Dryness, pain, smarting pain (P < .05 for all), and dyspareunia (P = .001) were observed more frequently in the women with genital cGVHD. Twelve patients had advanced genital cGVHD (clinical score 3), which was the main factor explaining the high rate (15 of 42) of severe global cGVHD. The rate of genital cGVHD was similar (P = .37) in patients with a follow-up of ≥80 months (10 of 22) and those with a follow-up of <80 months (12 of 20). We found no convincing relationship between clinical diagnosis and histopathological assessment of mucosal biopsy specimens. In our group of women with a long follow-up after HSCT, genital cGVHD was common and in many cases incorrectly diagnosed. Genital cGVHD causes genital symptoms and affects sexual life, and may present without any other cGVHD, warranting early and continuous gynecologic surveillance in all women after HSCT.