Effects of female bone marrow transplantation on male reproductive organs.

Graft-versus-host disease (GVHD), an adverse effect after bone marrow transplantation (BMT), may affect male reproductive function. It is hypothesized that a sex-mismatched BMT induces GVHD in male reproductive organs because female immune cells are not immunologically tolerant to specific antigens of the male organs. However, this hypothesis has not been experimentally verified using male (M) recipient animals following BMT from the female (F) donors. Therefore, the aim of the present study is to examine whether the female BMT to males (F→M group) induces some GVHD reactions in the testis and the other male reproductive organs. The results showed that no inflammation was found in recipients of the male BMT to males (M→M group), whereas significant inflammatory cell responses lasting for at least 4 months were induced in testis, epididymis, prostate and preputial gland in some mice of F→M group. The most severe lesion was found in the preputial gland, in which lymphocytic inflammation was accompanied by loss of glandular acini, thickening of the interstitum and increased cytokines such as TNF-α and IFN-γ. Western blot analyses revealed that sera from the F→M group reacted with various antigens of the male reproductive organs. These results indicate that transplanted female immune cells may recognize the male reproductive organs as immunologically foreign ones and induce chronic GVHD, which may affect male reproductive function.

Tissue-resident immunity in the female and male reproductive tract.

The conception of how the immune system is organized has been significantly challenged over the last years. It became evident that not all lymphocytes are mobile and recirculate through secondary lymphoid organs. Instead, subsets of immune cells continuously reside in tissues until being reactivated, e.g., by a recurring pathogen or other stimuli. Consequently, the concept of tissue-resident immunity has emerged, and substantial evidence is now available to support its pivotal function in maintaining tissue homeostasis, sensing challenges and providing antimicrobial protection. Surprisingly, insights on tissue-resident immunity in the barrier tissues of the female reproductive tract are sparse and only slowly emerging. The need for protection from vaginal and amniotic infections, the uniqueness of periodic tissue shedding and renewal of the endometrial barrier tissue, and the demand for a tailored decidual immune adaptation during pregnancy highlight that tissue-resident immunity may play a crucial role in distinct compartments of the female reproductive tract. This review accentuates the characteristics of tissue-resident immune cells in the vagina, endometrium, and the decidua during pregnancy and discusses their functional role in modulating the risk for infertility, pregnancy complications, infections, or cancer. We here also review data published to date on tissue-resident immunity in the male reproductive organs, which is still a largely uncharted territory.

Relationship between COVID-19 and the male reproductive system.

OBJECTIVE: The objective of this review is to provide currently available information on the potential effects of coronavirus disease 2019 (COVID-19) on male fertility. MATERIALS AND METHODS: This is a mini-review. Due to the similarity between the COVID-19 and severe acute respiratory syndrome (SARS) virus, we searched for the following keywords: "SARS-CoV, male reproductive system, infertility, COVID-19, SARS-CoV-2, and orchitis". By reviewing and analyzing the literature, we analyzed the influence of temperature on sperm, the expression of angiotensin-converting enzyme 2 (ACE2) in the testes, and the impact of SARS-CoV-2 on the male reproductive system. RESULTS: SARS-CoV-2 enters the body through the ACE2 receptor. The high expression of ACE2 on the surface of spermatogonia and supporting cells in the testes, as well as the immune response caused by COVID-19, can lead to testicular spermatogenesis dysfunction and reduced sperm count. CONCLUSIONS: COVID-19 infection can affect male reproductive function, and standard treatment strategies should be established in time to help male patients infected with COVID-19.

Bacterial infection of the male reproductive system causing infertility.

Bacterial infections play a disruptive and hidden role in male reproductive failure. Different kinds of bacteria are often able to interfere with reproductive function in both sexes and lead to infertility. In this study, to further evaluate the role of bacterial infections in male reproduction we provided an extensive overview of so far researches investigating the effects of bacterial infections on male fertility. We searched Medline, PubMed, Scopus and Google scholar databases to identify the potentially relevant studies on bacterial infections and their implications in male infertility. All the bacteria included in this article have negative effects on the male reproductive function; however, there is ample evidence to blame bacteria such as Escherichia coli, Chlamydia trachomatis, Ureaplasma, Mycoplasma and Staphylococcus aureus for reduced fertility and deterioration of sperm parameters. More studies are needed to clarify the molecular mechanisms by which different bacteria exert their detrimental effects on male reproductive system. Getting more insight into probable mechanisms, would significantly facilitate the production of new, advanced, and effective remedies in the future. In view of all evidence, we strongly suggest increasing awareness among people and considering screening programs for patients seeking fertility both to avoid transmission and to improve fertility outcomes among them.

Natural killer and NKT cells in the male reproductive tract.

Natural killer (NK) cells are important effector lymphocytes that play a pivotal role in the innate and adaptive immune responses to tumors and viral infection. NKT cells are a heterogeneous group of T cells that share properties with both T cells and NK cells. They display immunoregulatory properties as they facilitate the cell-mediated immune response to tumors and infectious diseases, and inhibit cell-mediated immunity associated with autoimmune diseases and allograft rejection. However, the roles of NK and NKT cells in the male reproductive tract remain largely unexplored, in particular, NKT cells, tissue distribution, and state of health or disease. Infection and inflammation of the male genital tract are thought to be the primary etiological factors of male infertility. In this review, we considered this complex and rapidly growing field. We summarize the recent findings and the characterization and roles of NK and NKT cells in the male reproductive tract, including the testis, epididymis, prostate, seminal vesicle, and semen, to enhance our understanding of the immunological mechanisms of male infertility and for the design effective vaccines for male reproductive health in the future.

Obesity and metabolic syndrome associated with systemic inflammation and the impact on the male reproductive system.

Obesity and metabolic syndrome (MetS) are global epidemics, driven by an obesogenic environment. This is mediated by complex underlying pathophysiology, in which chronic inflammation is an important aetiological and mechanistic phenomenon. A shift towards a subclinical TH 1-lymphocyte mediated innate and chronic inflammatory response is well defined in obesity and MetS, demonstrated in multiple systems including visceral adiposity, brain (hypothalamus), muscles, vasculature, liver, pancreas, testes, epididymis, prostate and seminal fluid. Inflammatory cytokines disrupt the hypothalamic-pituitary-testes axis and steroidogenesis cascades (hypogonadotropic hypogonadism), spermatogenesis (poor semen parameters, including DNA fragmentation and detrimental epigenetic modification) and results in subclinical prostatitis and prostate hyperplasia. This review aims to highlight the role of chronic inflammation in obesity and MetS, cytokines in male reproductive physiology and pathophysiology, the impact on steroidogenesis and spermatogenesis, prostate pathology and erectile dysfunction. Currently, it is recommended that clinical assessment of male infertility and reproductive dysfunction in obese and MetS patients includes inflammation assessment (highly sensitive C-reactive protein), and appropriate advice and therapeutic options are incorporated in the management options. However, the mechanisms and therapeutic options remain poorly understood and require significant interdisciplinary research to identify potential novel therapeutic strategies.

Impact of Immune System Activation and Vascular Impairment on Male and Female Sexual Dysfunction.

INTRODUCTION: Male and female sexual dysfunction (SD) is considered a multifactorial condition. Numerous studies have shown the involvement of inflammatory processes in this pathological condition. Sexual intercourse requires healthy and functioning vessels to supply the pelvic region in both males and females, generating penile erection and clitoral and vaginal lubrication, respectively. Cardiovascular diseases and associated risk factors may contribute negatively to pelvic blood flow, possibly through immune system activation. AIM: The study aimed to address the correlation between vascular inflammation driven by immune system activation and SD in males and females. METHODS: A literature review was performed to identify articles addressing male and female SD and vascular inflammation. Key words included "male and female sexual dysfunction," "vascular inflammation," "iliac and pudendal arteries dysfunction," "genitourinary tract," and "blood flow." MAIN OUTCOME MEASURES: Management of systemic and local inflammation may be a useful alternative to improve SD and reduce the risk of cardiovascular diseases in the future. RESULTS: Increased levels of cytokines and chemokines have been detected in humans and animals with hypertension, obesity, and diabetic conditions. Chronic activation of the innate immune system, especially by pathogen- or damage-associated molecular patterns, and metabolic-related disorders may act as triggers further contributing to an increased inflammatory condition. Due to the reduced size of vessels, SD and retinal vascular impairments have been shown to be predictive factors for cardiovascular diseases. Therefore, considering that blood flow to the genitalia is essential for sexual function, endothelial dysfunction and vascular remodeling, secondary to chronic immune system activation, may be implicated in male and female vasculogenic SD. CONCLUSIONS: Several conditions appear to play a role in SD. In the present review, we have identified a role for the immune system in generating vascular and tissue impairments contributing to erectile dysfunction and female SD. Calmasini FB, Klee N, Webb RC, et al. Impact of Immune System Activation and Vascular Impairment on Male and Female Sexual Dysfunction. Sex Med Rev 2019;7:604-613.

Equine arteritis virus long-term persistence is orchestrated by CD8+ T lymphocyte transcription factors, inhibitory receptors, and the CXCL16/CXCR6 axis.

Equine arteritis virus (EAV) has the unique ability to establish long-term persistent infection in the reproductive tract of stallions and be sexually transmitted. Previous studies showed that long-term persistent infection is associated with a specific allele of the CXCL16 gene (CXCL16S) and that persistence is maintained despite the presence of local inflammatory and humoral and mucosal antibody responses. Here, we performed transcriptomic analysis of the ampullae, the primary site of EAV persistence in long-term EAV carrier stallions, to understand the molecular signatures of viral persistence. We demonstrated that the local CD8+ T lymphocyte response is predominantly orchestrated by the transcription factors eomesodermin (EOMES) and nuclear factor of activated T-cells cytoplasmic 2 (NFATC2), which is likely modulated by the upregulation of inhibitory receptors. Most importantly, EAV persistence is associated with an enhanced expression of CXCL16 and CXCR6 by infiltrating lymphocytes, providing evidence of the implication of this chemokine axis in the pathogenesis of persistent EAV infection in the stallion reproductive tract. Furthermore, we have established a link between the CXCL16 genotype and the gene expression profile in the ampullae of the stallion reproductive tract. Specifically, CXCL16 acts as a "hub" gene likely driving a specific transcriptional network. The findings herein are novel and strongly suggest that RNA viruses such as EAV could exploit the CXCL16/CXCR6 axis in order to modulate local inflammatory and immune responses in the male reproductive tract by inducing a dysfunctional CD8+ T lymphocyte response and unique lymphocyte homing in the reproductive tract.

Development of disease and immunity at the genital epithelium following intrarectal inoculation of male guinea pigs with herpes simplex virus type 2.

Most analyses of genital immunity to herpes simplex virus type 2 (HSV-2) have been performed in females, consequently immune protection of the male genital epithelium is incompletely understood. We developed a model of male genital HSV-2 infection resulting from intrarectal inoculation of guinea pigs. Vesicular lesions developed transiently on the perineum and foreskin concurrent with acute virus shedding. Virus shedding and recurrent genital lesions were also detected after establishment of a latent infection. Analysis of perineum and foreskin RNA detected transcripts for IFNγ, proinflammatory and regulatory cytokines, and for genes involved in migration and regulation of leukocytes. HSV-specific T cells were detected in lymphoid and genital tissues after resolution of the primary infection whereas virus-specific antibody secreting cells were detected only in lymphoid tissue. Taken together, the ability to quantify pathogenesis and local immunity in this guinea pig model represent an important advance towards understanding immunity to HSV-2 in males.

Cutting Edge: Evidence for Nonvascular Route of Visceral Organ Immunosurveillance by T Cells.

Lymphocytes enter tissues from blood vessels through a well-characterized three-step process of extravasation. To our knowledge, nonvascular routes of lymphocyte entry have not been described. In this article, we report that Ag-experienced CD8 T cells in mice recirculate from blood through the peritoneal cavity. In the event of infection, Ag-experienced CD8 T cell subsets adhered to visceral organs, indicating potential transcapsular immunosurveillance. Focusing on the male genital tract (MGT), we observed Ag-experienced CD8 T cell migration from the peritoneal cavity directly to the infected MGT across the capsule, which was dependent on the extracellular matrix receptor CD44. We also observed that, following clearance of infection, the MGT retained functional resident memory CD8 T cells. These data suggest that recirculation through body cavities may provide T cells with opportunities for broad immunosurveillance and potential nonvascular mechanisms of entry.

Ageing and inflammation in the male reproductive tract.

Ageing is usually characterised by a mild chronic proinflammatory state. Despite the tight association between both processes, the phenomenon has recently been termed inflammageing. Inflammation in the male reproductive tract is frequently linked with bacterial or virus infections but also with a broad range of noninfectious processes. Prostatitis, epididymitis and orchitis, among others, can lead to infertility. However, in spite of the inflammation theory of disease, chronic inflammation in male urogenital system does not always cause symptoms. With advancing age, inflammatory processes are commonly observed in the male reproductive tract. Nevertheless, the incidence of inflammation in reproductive organs and ducts varies greatly among elderly men. Inflammageing is considered a predictor of pathogenesis and the development of age-related diseases. This article briefly summarises the current state of knowledge on inflammageing in the male reproductive tract. Yet, the precise aetiology of inflammageing in the male urogenital system, and its potential contribution not only to infertility but most importantly to adverse health outcomes remains almost unknown. Thus, further investigations are required to elucidate the precise cross-links between inflammation and male reproductive senescence, and to establish the impact of anti-inflammatory drug treatments on elder men's general health status.

Immunoendocrine abnormalities in the male reproductive system during experimental pulmonary tuberculosis.

INTRODUCTION: Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) that mainly affects the lungs. Along the course of pulmonary TB there are remarkable changes in the production of cytokines that cause endocrine changes. So far, it is not known the physiological and histological changes in the male reproductive system during pulmonary TB. OBJECTIVE: To investigate whether pulmonary TB produces histological alterations of the BALB/c mice reproductive organs, as well as abnormalities in spermatogenesis, serum testosterone concentrations and expression of testicular cytokines. METHODS: BALB/c mice were infected intratracheally with high dose Mtb strain H37Rv. Groups of six non infected and infected animals were euthanized on days 1, 3, 7, 14, 21, 28, 60, 90 and 120 post-infection. Bacillary loads were determined by counting colony forming units (CFUs) in lungs, testes, prostate and seminal vesicles. Histological sections were obtained from the same organs. Spermatozoids number and quality were assessed by spermatobioscopy. Serum testosterone concentrations were determined by radioimmunoanalysis (RIA) in control and infected mice in each time of sacrifice. RESULTS: Mtb only grew in lung tissue. Serum androgens showed a trend to decrease in the infected mice compared to the healthy animals, the difference turn into statistically significance at post infection day 120. The weight of the testis was not modified throughout the study, and no histopathological changes were found. However, we detected a significant decrease in the weight of the seminal vesicles and prostate starting at 28 days post-infection. Atrophy of the seminal vesicles and prostate epithelia were significant, beginning after 60 days of infection. Spermatobioscopy revealed hypospermia in the later stages of the disease. We have observed in the testes a local significant disbalance on the cytokine profile (increase of IL-6 and decrease of IL-10 and TGF-b levels) together with a very significant reduction of the body weight during late pulmonary TB. CONCLUSION: Pulmonary TB affects the histophysiology of the male reproductive system due to hormonal changes, an imbalance of pro-inflammatory cytokine profile, and a wasting syndrome during late disease.

Male genital tract immune response against Chlamydia trachomatis infection.

Chlamydia trachomatis is the most commonly reported agent of sexually transmitted bacterial infections worldwide. This pathogen frequently leads to persistent, long-term, subclinical infections, which in turn may cause severe pathology in susceptible hosts. This is in part due to the strategies that Chlamydia trachomatis uses to survive within epithelial cells and to evade the host immune response, such as subverting intracellular trafficking, interfering signaling pathways and preventing apoptosis. Innate immune receptors such as toll-like receptors expressed on epithelial and immune cells in the genital tract mediate the recognition of chlamydial molecular patterns. After bacterial recognition, a subset of pro-inflammatory cytokines and chemokines are continuously released by epithelial cells. The innate immune response is followed by the initiation of the adaptive response against Chlamydia trachomatis, which in turn may result in T helper 1-mediated protection or in T helper 2-mediated immunopathology. Understanding the molecular mechanisms developed by Chlamydia trachomatis to avoid killing and host immune response would be crucial for designing new therapeutic approaches and developing protective vaccines. In this review, we focus on chlamydial survival strategies and the elicited immune responses in male genital tract infections.

Detection of invariant natural killer T cells in ejaculates from infertile patients with chronic inflammation of genital tract.

Chronic inflammation of genital tract is thought to play a major role in male fertility disorder. Natural killer (NK) T cells are a heterogeneous group of T cells that share properties of both T cells and NK cells which display immunoregulatory properties. However, little is known regarding the presence and function of NK T cells in ejaculates from patients with chronic inflammation of genital tract. Invariant NK T (iNK T) cells were detected by invariant (Vα24-JαQ) TCR chain in ejaculates from patients suffering from chronic inflammation of genital tract (CIGT) using flow cytometry and immunofluorescence of double staining (n=40). Inflammatory cytokines interleukin (IL)-6, IL-17, and IFN-γ were detected in cell-free seminal plasma using an enzyme-linked immunosorbent assay (ELISA). The correlation between the percentage of iNK T cells and spermatozoa count, motility, vitality, seminal IL-6, IL-17, and IFN-γ was investigated. Significant percentages of iNK T cells above 10% were detected in 50% (CIGT-NKT+ group). A negative correlation was detected between the percentage of iNK T cells and spermatozoa count (r=-.5957, P=.0056), motility (r=-.6163, P=.0038), and vitality (r=-.8032, P=.0019) in CIGT-NKT+ group (n=20). Interestingly, a significant correlation of iNK T cells to seminal IL-6 (r=.7083, P=.0005), IFN-γ (r=.9578, P<.0001) was detected whereas lack of correlation between iNK T cells and IL-17 (r=-.1557, P=.5122) in CIGT-NKT+ group. The proliferative response of iNK T cells could accompany an inflammatory response to spermatozoa and consequently influence sperm quality through secretion of IFN-γ but not IL-17 under chronic inflammatory condition.

Humoral responses against HIV in male genital tract: role in sexual transmission and perspectives for preventive strategies.

: Most new HIV infections occur via sexual routes. The induction of protective anti-HIV antibodies in genital mucosa is an important step toward reducing HIV transmission. Mucosal anti-HIV antibodies may play a dual role by either protecting against HIV transmission or facilitating it. Protective properties against HIV of mucosal IgGs and IgAs exhibiting neutralizing or antibody-dependent cell-mediated cytotoxicity activities have been described in highly exposed seronegative individuals. Conversely, some IgGs may facilitate the crossing of HIV free-particles through epithelial barriers by transcytosis. Hence knowledge of the mechanisms underlying anti-HIV antibody production in the genital tract and their exact role in sexual transmission may help to develop appropriate preventive strategies based on passive immunization or mucosal vaccination approaches. Our review focuses on the characteristics of the humoral immune responses against HIV in the male genital tract and related prevention strategies.

Parasitism and inflammation in ear skin and in genital tissues of symptomatic and asymptomatic male dogs with visceral leishmaniasis.

Canine visceral leishmaniasis (CVL) is transmitted through vector, although venereal transmission has been suggested. This study aimed to compare the parasitic loads and inflammatory processes in genital tissues with ear skin from seropositive male dogs. Forty-five seropositive dogs were separated into groups containing symptomatic (n = 23) and asymptomatic (n = 22) animals. The control group (n = 2) healthy animals with seronegative and negative results in direct parasitological test. Samples of ear tip skin, prepuce, glans penis, testis, epididymis, and prostate were collected for evaluation of parasitic load and inflammatory infiltrate. Although ear tip skin was the most intensely parasitized, prepuce and epididymis revealed no difference in parasitism when compared with ear tip skin (P > 0.05). Parasitic loads in testis and prostate were lower than other tissues (P < 0.05). Parasitism in glans penis was high, similar to prepuce and epididymis, but lower than ear tip skin. High parasitism was more frequent in symptomatic dogs than asymptomatic animals. Severe inflammatory processes were more frequent within the symptomatic animals compared with asymptomatic and more predominant in prepuce and epididymis. Ear tip skin and genital tissues presented signs of chronic inflammation. There were weak and moderate positive correlations between parasitic loads and inflammatory processes. Our results demonstrate that, likewise with the ear tip skin, the genital of seropositive dogs can carry a large number of Leishmania infantum amastigotes and this process are more intense in symptomatic animals. These data have important implications for understanding the possibility of venereal transmission of CVL.

The role of dendritic cells in male reproductive tract.

Dendritic cells (DCs) are the most potent professional antigen-presenting cells. The central role of various DC subsets as bridges between innate and adaptive immunity has become more and more evident. However, the role of DC subsets in male reproductive tract remains largely unexplored, in particular distinct DC subsets (including myeloid and plasmacytoid DCs), their maturation stage, and tissue distribution, as well as state of health or disease. Furthermore, infection and inflammation of male genital tract are thought to be a primary etiological factor of male infertility. This review sheds some light on this complex and rapidly growing field. It summarized the recent findings and deals with the characterization and role of DCs in male reproductive tract, that is, testis, epididymis, prostate, seminal vesicle, semen, and foreskin, which might help to understand the immunopathological mechanisms of male infertility and design effective vaccines for male reproductive health.

Mathematical Modeling Predicts that Increased HSV-2 Shedding in HIV-1 Infected Persons Is Due to Poor Immunologic Control in Ganglia and Genital Mucosa.

A signature feature of HIV infection is poor control of herpes virus infections, which reactivate from latency and cause opportunistic infections. While the general mechanism underlying this observation is deficient CD4+T-cell function, it is unknown whether increased severity of herpes virus infections is due primarily to poor immune control in latent or lytic sites of infection, or whether CD4+ immunodeficiency leads to more critical downstream deficits in humoral or cell-mediated immunologic responses. Here we compare genital shedding patterns of herpes simplex virus-2 (HSV-2) in 98 HIV infected and 98 HIV uninfected men matched on length of infection, HSV-1 serostatus and nationality. We demonstrate that high copy HSV-2 shedding is more frequent in HIV positive men, particularly in participants with CD4+ T-cell count <200/µL. Genital shedding is more frequent due to higher rate of shedding episodes, as well as a higher proportion of prolonged shedding episodes. Peak episode viral load was not found to differ between HIV infected and uninfected participants regardless of CD4+ T-cell count. We simulate a mathematical model which recapitulates these findings and identifies that rate of HSV-2 release from neural tissue increases, duration of mucosal cytolytic immune protection decreases, and cell-free viral lifespan increases in HIV infected participants. These results suggest that increased HSV-2 shedding in HIV infected persons may be caused by impaired immune function in both latent and lytic tissue compartments, with deficits in clearance of HSV-2 infected cells and extracellular virus.