Association between postmenopausal vulvovaginal discomfort, vaginal microbiota, and mucosal inflammation.

BACKGROUND: Half of all postmenopausal women report symptoms of vulvar, vaginal, or urinary discomfort with substantial impact on sexual function and quality of life; underlying mechanisms leading to symptoms are poorly understood. OBJECTIVE: To examine the possibility that the vaginal microbiota and/or mucosal immune response contributes to the severity of bothersome vaginal symptoms, we conducted a substudy of samples from a randomized trial of vaginal treatment for genitourinary syndrome of menopause to compare these features between women whose symptoms improved and women whose symptoms did not improve. STUDY DESIGN: This is a secondary analysis of samples collected in a 12-week randomized trial of treatment with vaginal estradiol or moisturizer vs placebo for moderate-severe postmenopausal symptoms of vaginal discomfort. We randomly selected 20 women in each arm with ≥2-point decrease in most bothersome symptom severity (responders) and 20 matched controls with ≤1-point decrease (nonresponders). At 0, 4, and 12 weeks, we characterized vaginal microbiota (16S ribosomal RNA gene sequencing), vaginal fluid metabolites (broad-based metabolomic profiling), vaginal fluid-soluble immune markers (Meso Scale Discovery), pH, and vaginal maturation index. We compared responders with nonresponders at baseline and across all visits using linear mixed models to evaluate associations with microbiota, metabolites, and immune markers, incorporating visit and participant-specific random effects while controlling for treatment arm. RESULTS: Here, the mean age of women was 61 years (n=120), and most women (92%) were White. At enrollment, no significant differences were observed between responders and nonresponders in age, most bothersome symptom type or severity, microbiota composition or diversity, Lactobacillus dominance, metabolome, or immune markers. There was a significant decrease in diversity of the vaginal microbiota in both responders and nonresponders (P<.001) over 12 weeks. Although this change did not differ by responder status, diversity was associated with treatment arm: more women in the estradiol arm (63%) had Lactobacillus-dominant, lower diversity bacterial communities than women in the moisturizer (35%) or dual placebo (23%) arms (P=.001) at 12 weeks. The metabolome, vaginal maturation index, and measured immune markers were not associated with responder status over the 12 weeks but varied by treatment arm. CONCLUSION: Postmenopausal vaginal symptom severity was not significantly associated with vaginal microbiota or mucosal inflammatory markers in this small study. Women receiving vaginal estradiol experienced greater abundance of lactobacilli and lower vaginal pH at end of treatment.

Immunoglobulin G4-related Disease of the Genitourinary System: Spectrum of Imaging Findings and Clinical-Pathologic Features.

Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibroinflammatory disease characterized by focal or diffuse organ infiltration of IgG4-bearing plasma cells. The diagnosis of IgG4-RD is based on a combination of clinical, serologic, radiologic, and histopathologic findings. IgG4-RD has been reported to affect almost all organ systems. The kidney is the most frequently involved of the genitourinary organs. The most common renal manifestation of IgG4-RD is IgG4-RD tubulointerstitial nephritis, followed by membranous glomerulonephropathy and, less frequently, obstructive nephropathy involving the renal pelvis, ureter, or retroperitoneum. Renal parenchymal lesions may appear as multiple nodular lesions, diffuse patchy infiltrative lesions, or a single nodular lesion. Multiple small nodular cortical lesions are the most common imaging findings of IgG4-RD involving the kidney. Renal pelvic, sinus, or perinephric lesions can also occur. IgG4-RD involvement of other genitourinary organs including the ureter, bladder, urethra, and male and female reproductive organs is rare compared with kidney involvement but may show variable imaging findings such as a localized mass within or surrounding the involved organ or diffuse enlargement of the involved organ. Imaging findings of IgG4-RD involving the genitourinary system are nonspecific but should be differentiated from inflammatory and neoplastic lesions that mimic IgG4-RD. The online slide presentation from the RSNA Annual Meeting is available for this article. ©RSNA, 2020.

Immunotolerant indoleamine-2,3-dioxygenase is increased in condyloma acuminata.

BACKGROUND: The tryptophan-depleting enzyme indoleamine-2,3-dioxygenase (IDO) is critical for the regulation of immunotolerance and plays an important role in immune-associated skin diseases. OBJECTIVES: To analyse the level of IDO in condyloma acuminata (CA) and its role in this condition. METHODS: IDO expression was assessed in the skin and peripheral blood of healthy controls and patients with CA. To assess the role of skin IDO in immunity, the ability of isolated epidermal cells to metabolize tryptophan and the influence on polyclonal T-cell mitogen (PHA)-stimulated T-cell proliferation were explored. RESULTS: IDO median fluorescence intensities in peripheral blood mononuclear cells from patients with CA were similar to those from healthy controls. Immunohistochemistry showed that IDO+ cells were rare in normal skin and the control skin of patients with CA, but were greatly accumulated in wart tissue. Most fluorescence signals of IDO+ cells did not overlap with those of CD1a+ Langerhans cells. Human papillomavirus (HPV) DNA probe in situ hybridization showed a large number of IDO+ cells in the HPV- site. Keratinocytes in the skin of healthy controls and the circumcised skin of patients with CA could minimally transform tryptophan into kynurenine, but IDO-competent epidermal cells from warts could transform tryptophan. In addition, these IDO-competent epidermal cells could inhibit PHA-stimulated T-cell proliferation. The addition of an IDO inhibitor, 1-methyl-d-tryptophan, restored the inhibited T-cell proliferation. CONCLUSIONS: Abnormally localized high IDO expression might be involved in the formation of a local immunotolerant microenvironment.

Evolution of hosts paying manifold costs of defence.

Hosts are expected to incur several physiological costs in defending against parasites. These include constitutive energetic (or other resource) costs of a defence system, facultative resource costs of deploying defences when parasites strike, and immunopathological costs of collateral damage. Here, we investigate the evolution of host recovery rates, varying the source and magnitude of immune costs. In line with previous work, we find that hosts paying facultative resource costs evolve faster recovery rates than hosts paying constitutive costs. However, recovery rate is more sensitive to changes in facultative costs, potentially explaining why constitutive costs are hard to detect empirically. Moreover, we find that immunopathology costs which increase with recovery rate can erode the benefits of defence, promoting chronicity of infection. Immunopathology can also lead to hosts evolving low recovery rate in response to virulent parasites. Furthermore, when immunopathology reduces fecundity as recovery rate increases (e.g. as for T-cell responses to urogenital chlamydiosis), then recovery and reproductive rates do not covary as predicted in eco-immunology. These results suggest that immunopathological and resource costs have qualitatively different effects on host evolution and that embracing the complexity of immune costs may be essential for explaining variability in immune defence in nature.

[SPECIES COMPOSITION OF INFECTIOUS FACTORS THAT CAUSE THE REACTIVE ARTHRITIS DEVELOPMENT AND THEIR EFFECT ON ARGINASE-NO-SYNTHASE REGULATORY SYSTEM OF PERIPHERAL BLOOD LYMPHOCYTES].

The own observations results of urogenital, gastrointestinal and nasopharyngeal infectious factors that cause the development of reactive arthritis (PeA) are being presented. The greatest contribution to the development of this disease make Chlamidia trachomatis (36%), Streptococcus haemolyticus (pyogenes) (19%) and hepatitis viruses B and C (10%). As a result of the research a number of kinetic parameters of arginase and NO-synthase reactions in peripheral blood lymphocytes of patients with reactive arthritis was identified. The authentic increase of arginase activity in 3.3 times and eNO-synthase activity decrease by 1,9 times in peripheral blood lymphocytes of patients with PeA, compared to practically healthy donors were determined. Increased activity of arginase and iNO-synthase of lymphocytes indicates changes in immune cells functional activity, which may be due to impaired metabolic and regulatory processes in these cells caused by a bacterial or viral infection.

Immunity in urogenital protozoa.

Innate and adaptive immunity play a significant role in urogenital infections. Innate immunity is provided by the epithelial cells and mucus lining along with acidic pH, which forms a strong physical barrier against the pathogens in female reproductive tract. Cells of innate immune system, antimicrobial peptides, cytokines, chemokines and adaptive immunity in the reproductive tract are evolved during infection, and a pro-inflammatory response is generated to fight against the invading pathogen Trichomonas vaginalis, a primary urogenital protozoa, the etiological agent of human trichomoniasis, a curable sexually transmitted infection. The involvement of the urogenital tract by other protozoal infections such as P. falciparum, Trypanosoma, Leishmania, Toxoplasma, Entamoeba histolytica and Acanthamoeba infection is rarely reported. Trichomonas induce pro-inflammatory and immunosuppressive responses in infected subjects. Multifactorial pathogenic mechanisms including parasite adherence, cysteine proteases, lipophosphoglycan, free radical, cytokine generation and Toll-like receptors appear to interplay with the induction of local and systemic immune responses that ultimately determine the outcome of the infection. However, the involvement of urogenital pathogen-specific immune mechanisms and effect of normal local resident flora on the outcome (symptomatic vs. asymptomatic) of infection are poorly understood. Moreover, immune interactions in trichomoniasis subjects co-infected with bacterial and viral pathogens need to be elucidated.

Imaging features of immune-mediated genitourinary disease.

PURPOSE: Imaging features of immune-mediated genitourinary diseases often overlap, and the same disease may manifest in different ways, so understanding imaging findings in the context of the patient's entire clinical picture is important in providing the correct diagnosis. METHODS: In this article, diseases mediated by the immune system which affect the genitourinary system are reviewed. Examples of immune-mediated genitourinary disease including IgG4-related disease, post-transplant lymphoproliferative disorder, immunodeficiency-associated lymphoproliferative disorder due to immunosuppressive and immunomodulatory medications, lymphoma, leukemia, myeloma, amyloidosis, and histiocytosis. RESULTS: Clinical and imaging features will be presented which may help narrow the differential diagnosis for each disease. CONCLUSION: Recognition of immune-related genitourinary disease is important for appropriate medical management as they may mimic other diseases both by imaging and clinical presentation.

[Role of Toll-like receptors and defensins in antimicrobial protection of urogenital tract in females].

Levels of expression of hBD-1 gene (beta-defensin 1) and Toll-like receptors (TLR1, TLR2, TLR6) in cells of cervical mucosa in healthy nonpregnant and healthy pregnant women as well as in pregnant women with urogenital infection was measured by developed RT-PCR systems. During normal pregnancy compared with nonpregnant women, increase of TLRs genes expression which was correlated with increase of hBD-1 gene expression was observed. During urogenital infection in pregnant women compared with healthy pregnant, 10- fold and 50-fold increase of TLR1 and TLR2 genes expression respectively was associated with 2.5-fold decrease of hBD-1 gene expression in cervical mucosa. In group of women with untrauterine infection more marked increase of TLRs genes expression was observed. Thus significant changes (TLRs, antimicrobial peptides, cytokines etc.) in cells of cervical mucosa can be used as prognostic criteria for development of intrauterine infection.

Outcome of urogenital infection with Chlamydia muridarum in CD14 gene knockout mice.

BACKGROUND: CD14 has been postulated to play a role in chlamydial immunity and immunopathology. There is evidence to support this role in human infections but its function in a mouse model has not been investigated. METHODS: Female CD14 gene knockout and C57BL/6J wild type mice were infected intravaginally with Chlamydia muridarum. The infection course was monitored by detection of viable chlamydiae from serially collected cervical-vaginal swabs. The sequela of tubal factor infertility was assessed using hydrosalpinx formation as a surrogate marker. RESULTS: A significantly abbreviated infection course was observed in the CD14 gene knockout mice but hydrosalpinx formation occurred at similar rates between the two groups. CONCLUSION: Involvement of CD14 during chlamydial infection impedes infection resolution but this does not affect the sequela of infertility as assessed by hydrosalpinx formation.

[The anti-infective resistance system in women with chronic urogenital inflammatory diseases of chlamydia ethiology].

A complex clinico-instrumental and immuno-microbiological examination of 433 reproductive age women was performed. The results show that a lingering and relapsing chlamydian infection in women with an exacerbation of a chronic inflammatory urogenital disease develops against the background of disturbances in the anti-infective resistance system (AIRS), and is characterized by combination of chlamydian infection with other sexually transmitted infections and the presence of dysbiosis. The immunological aspects of this process consist in almost a total absence of neutrophiles' ability to digest a bacterial antigen, and incompleteness of phagocytosis, in general. These changes may be connected with a low immunogenicity and intracellular parasitizing of chlamydiae, on the one hand, and with primary incompetence of the subjects' AIRS, on the other. From a microbiological point of view, this is manifested by complete combined urogenital and colon dysbiosis.

[Impaired immunological status due to the urogenital chlamydiosis in women of reproductive age and its correction].

The aim of our research was to assess clinical-immunological properties of disease course and efficiency of complex etiotropic, enzyme-immunomodification therapy in women with urogenital chlamydiosis. Out of examined 818 women chlamydia was found in 276. The diagnoses of chlamydiosis in all women was assessed using the following methods: immuno-enzymatic, immunofluorescent and DNA-hybridization. Immune responses were studied in regard of forms and severity of the disease and its dynamics, as well as the regimens of treatments and their results. Vilkoxon-Mann-Witney non-parametric criterion U was used for statistical evaluation of the results. For measuring of identity of the various forms of treatment Spirman's coefficient r was used. Urogenital chlamydiosis is characterised by expressed misbalance of immune response of depressive character, the intensity of which depends upon the severity of genital pathology and obstetric anamnesis as well. Oral form of plaferon--LB enhances the immune-competent ability of the organism. The most expressive clinical effect was received using the combination of the antibiotic, enzymes and immuno-correction (95%).

Exploiting ovine immunology to improve the relevance of biomedical models.

Animal models of human disease are important tools in many areas of biomedicine; for example, in infectious disease research and in the development of novel drugs and medical devices. Most studies involving animals use rodents, in particular congenic mice, due to the availability of a wide number of strains and the ease with which they can be genetically manipulated. The use of mouse models has led to major advances in many fields of research, in particular in immunology but despite these advances, no animal model can exactly reproduce all the features of human disease. It is increasingly becoming recognised that in many circumstances mice do not provide the best model and that alternative species may be more appropriate. Here, we describe the relative merits of sheep as biomedical models for human physiology and disease in comparison to mice, with a particular focus on reproductive and respiratory pathogens.

Manifestations of Chlamydia induced arthritis in patients with silent versus symptomatic urogenital chlamydial infection.

OBJECTIVES: To evaluate whether Chlamydia-infected patients with and without urogenital symptoms have similar rheumatological manifestations or whether they belong to distinct clinical groups. METHODS: In a university-based study, we examined patients with unexplained arthritis in whom other rheumatic diseases had been excluded for urogenital chlamydial infection, and we investigated the clinical and radiological manifestations of the Chlamydia-positive patients. RESULTS: Sixty of 283 patients (21%) with unexplained arthritis had urogenital chlamydial infection. The infection was asymptomatic in 30%. There was no difference in the pattern of arthritis or immunological and serological characteristics in the patients with and without symptoms of urogenital infection, respectively. CONCLUSION: The pattern of Chlamydia-induced arthritis is similar in patients with or without symptoms of urogenital chlamydial infection. To recognize CIA, it may be helpful to examine patients with unexplained arthritis for Chlamydia even though they do not have symptoms of urogenital infection.

Limitations of serodiagnosis in chlamydial genital tract infections.

Infection with Chlamydia trachomatis results in the formation of a variety of antibodies with group, species, subspecies and serovarspecificity. Sera from patients with genital tract infections often show broad reactivity in serological tests. This may be due to the presence of cross-reacting antibodies, repeated infections by different serotypes or concurrent genital and respiratory infections by different chlamydial species. Other factors contributing to difficulties in interpretation include how antibody titres in acute mucosal infections, the occurrence of latent infections and reactivations, and the persistence of IgG which does not allow the differentiation of past from current infections. For these reasons, serology alone is inadequate for the diagnosis of uncomplicated lower genital tract infections. In upper genital tract infections, however, because of difficulties with sampling from the infected site, a positive serology may be the only indications of chlamydial involvement. This paper discusses the principles of chlamydial antibody assays, difficulties with their interpretation and their role in the diagnosis of upper and lower genital tract infections.

[Analysis of the monomeric IgA to polymeric IgA ratio in specific IgA antibodies for Chlamydia trachomatis--clinical studies in chlamydial urogenital infections].

Antibody titers of monomeric and polymeric types of serum specific IgA for Chlamydia trachomatis were measured by indirect immunoperoxidase assay (Savyon kit) in male and female cases with various chlamydial urogenital infections. From these results, the ratio of monomeric to polymeric IgA (m/p ratio) was determined. All cases were positive for specific IgA and IgG antibodies for C. trachomatis, and the antigen was also detected in all of cases except for those with prostatitis. 1. Study in males: The m/p ratio (mean +/- S.E.) was 2.6 +/- 1.0 in acute chlamydial urethritis and 8.0 +/- 2.2 in chronic non-bacterial prostatitis. The result indicated monomeric IgA-predominance in the chronic stage. 2. Study in females: The m/p ratio was 5.0 +/- 1.9 in subacute chlamydial cervicitis, while it was 8.5 +/- 2.9 in pregnant women considered to have chronic chlamydial infection. The rate was 31.5 +/- 16.8 in prostitutes considered to have repeated chlamydial infections. The result suggested that monomeric IgA was predominant in patients with chronic and repeated infections. 3. As for sequential changes of IgA antibody titer, polymeric IgA alone decreased after treatment of acute chlamydial urethritis. However monomeric IgA decreased in chronic infection such as prostatitis, and a similar change was shown in IgG antibody. 4. These results suggest that polymeric IgA is predominant in the acute stage of chlamydial infections, while monomeric IgA predominates in the chronic stage.

[The clinical significance of specific IgA antibodies in local secretions in cases with chlamydial urogenital infections--comparison with serum antibodies and analysis of antigen specificity by immunoblotting assay].

IgA antibody titers to C. trachomatis in local secretions were measured by immunoperoxidase assay (Savyon kit) in male and female cases with various urogenital infections, and the clinical significance of IgA antibody in the local secretion was discussed. In addition, the antigen specificity of the IgA for C. trachomatis in the local secretions was analyzed by immunoblotting assay. 1) In female cases with cervicitis and male cases with urethritis, the positive rate of IgA antibody in their secretions was higher in cases with C. trachomatis antigen than in those without it. In addition, the IgA antibody titers in their secretions tended to be higher than in serum, suggesting that the result reflected a local immune response at the site of infection. 2) In cases with chronic prostatitis, a condition in which detection of antigen at the site of infection was difficult, the positive rate of IgA antibody in prostatic secretion was 23.6%. We confirmed that most of the IgA antibodies in prostatic secretions were of the secretory type. 3) IgA antibodies in secretions reacted to the major outer membrane protein (MOMP) and 60-Kd polypeptides of the outer membrane of C. trachomatis by immunoblotting assay, proving that they were the secretory IgA antibodies specific for C. trachomatis. These results described above confirmed that measurement of IgA antibody titers in local secretions by immunoperoxidase assay and immunoblotting assay was useful for the diagnosis of chlamydial urogenital infections such as chronic prostatitis, which the antigen detection was usually difficult. Examination of IgA antibody in local secretions was considered to be useful for making a correct diagnosis even in cases who were suspected to have C. trachomatis infection but showed negative antigen.

[Immunologic response against spermatozoa in the human genital tract]. / Odpowiedz immunologiczna przeciw plemnikom w ukladzie rozrodczym czlowieka.

Spermatozoa are immunogenic and may induce an immune response in reproductive compartments. There have been controversies concerning the effect of naturally existing antisperm antibodies on fertility of males and females. It is known, that men or women suffering from unexplained infertility have often antisperm antibodies in their urogenital secretions and/or serum. Systemic and local immune responses to sperm antigens differ between each other and they may differently affect the fertilisation process. Physiologically, females are protected from an immune response against "foreign", spermatozoal antigens. Nevertheless under local pathological conditions antisperm antibodies can be induced and may interfere with fertilisation.

[Probable prognostic markers of immune status in patients with chronic infectious diseases]. / Vozmozhnye prognosticheskie markery immunnogo statusa bol'nykh khronicheskimi infektsionnymi zabolevaniiami.

The comparative study of the main characteristics of immune status in patients with urogenital chlamydiosis, furunculosis, urogenital herpes (38 patients) and in the members of the control group (21 subjects) was made. The analysis of the results obtained in this study revealed the numerical values of immunological characteristics, capable of being used as markers indicating transition into the chronic form. Thus, it showed a decrease in the population of cells with phenotype CD72+ in chlamydiosis; a fourfold increase in the population of cells with phenotype CD16+ in furunculosis; an increase in the population of cells with phenotype CD8+, a decrease in the immunoregulatory index and the population of cells with phenotype CD72+ in herpes. The data thus obtained may be used in prescribing immunocorrective therapy.

[The immunocorrective properties of bacterial preparations (lactobacterin, bifidumbacterin) and bemitil in pregnant women with a urogenital infection]. / Izuchenie immunokorrigiruiushchikh svoistv bakterial'nykh preparatov (laktobakterina, bifidumbakterina) i bemitila u beremennykh s urogenital'noi infektsiei.

The results of the analysis of the cell-mediated and humoral factors of the peripheral blood and cervical mucus in pregnant women with urogenital infections (pyelonephritis, colpitis, cervicitis, endocervicitis) and in healthy pregnant women are presented. These results indicate that considerable changes in the systemic immunity of the body and in the local antiinfectious protection of the reproductive tract develop in pregnant women with urogenital infections. The prescription of bifidumbacterin and lactobacterin to the patients during pregnancy (intravaginally) and bemitil after parturition (orally) completely restores the functional validity of their immune system and decreases the number of postnatal complications.