Immunological Aspects of Infertility-The Role of KIR Receptors and HLA-C Antigen.

The mechanisms of immune tolerance of a mother against an antigenically foreign fetus without a concomitant loss of defense capabilities against pathogens are the factors underlying the success of a pregnancy. A significant role in human defense is played by killer immunoglobulin-like receptor (KIR) receptors, which regulate the function of the natural killer (NK) cells capable of destroying antigenically foreign cells, virus-infected cells, or tumor-lesioned cells. A special subpopulation of NK cells called uterine NK cells (uNK) is found in the uterus. Disruption of the tolerance process or overactivity of immune-competent cells can lead to immune infertility, a situation in which a woman's immune system attacks her own reproductive cells, making it impossible to conceive or maintain a pregnancy. Since the prominent role of the inflammatory response in infertility, including KIR receptors and NK cells, has been postulated, the process of antigen presentation involving major histocompatibility complex (MHC) molecules (HLA) appears to be crucial for a successful pregnancy. Proper interactions between KIR receptors on female uNK cells and HLA class I molecules, with a predominant role for HLA-C, found on the surface of germ cells, are strategically important during embryo implantation. In addition, maintaining a functional balance between activating and inhibitory KIR receptors is essential for proper placenta formation and embryo implantation in the uterus. A disruption of this balance can lead to complications during pregnancy. The discovery of links between KIR and HLA-C has provided valuable information about the complexity of maternal-fetal immune interactions that determine the success of a pregnancy. The great diversity of maternal KIR and fetal HLA-C ligands is associated with the occurrence of KIR/HLA-C combinations that are more or less favorable for reproductive success.

IL-22 regulates endometrial regeneration by enhancing tight junctions and orchestrating extracellular matrix.

The uterine endometrium uniquely regenerates after menses, postpartum, or after breaks in the uterine layer integrity throughout women's lives. Direct cell-cell contacts ensured by tight and adherens junctions play an important role in endometrial integrity. Any changes in these junctions can alter the endometrial permeability of the uterus and have an impact on the regeneration of uterine layers. Interleukin 22 (IL-22) is a cytokine that is recognized for its role in epithelial regeneration. Moreover, it is crucial in controlling the inflammatory response in mucosal tissues. Here, we studied the role of IL-22 in endometrial recovery after inflammation-triggered abortion. Fecundity of mice was studied in consecutive matings of the same animals after lipopolysaccharide (LPS) (10 µg per mouse)-triggered abortion. The fecundity rate after the second mating was substantially different between IL-22 knockout (IL-22-/-) (9.1%) and wild-type (WT) (71.4%) mice (p < 0.05), while there was no difference between the groups in the initial mating, suggesting that IL-22 deficiency might be associated with secondary infertility. A considerable difference was observed between IL-22-/- and WT mice in the uterine clearance following LPS-triggered abortion. Gross examination of the uteri of IL-22-/- mice revealed non-viable fetuses retained inside the horns (delayed clearance). In contrast, all WT mice had completed abortion with total clearance after LPS exposure. We also discovered that IL-22 deficiency is associated with a decreased expression of tight junctions (claudin-2 and claudin-10) and cell surface pathogen protectors (mucin-1). Moreover, IL-22 has a role in the remodeling of the uterine tissue in the inflammatory environment by regulating epithelial-mesenchymal transition markers called E- and N-cadherin. Therefore, IL-22 contributes to the proper regeneration of endometrial layers after inflammation-triggered abortion. Thus, it might have a practical significance to be utilized as a treatment option postpartum (enhanced regeneration function) and in secondary infertility caused by inflammation (enhanced barrier/protector function).

Immune Responses to Neisseria gonorrhoeae: Challenges and Opportunities With Respect to Pelvic Inflammatory Disease.

Pelvic inflammatory disease and infertility frequently develop after female genital tract infection with Neisseria gonorrhoeae, but determining their etiology from among various possibilities presents difficulties. Exploitation of serology to identify the causative agent is complicated by numerous factors, and no immunological test currently exists to determine unequivocally whether an individual currently is, or has been, infected with N. gonorrhoeae. The extensive antigenic variability of N. gonorrhoeae and its expression of antigens shared with other Neisseria species commonly carried in humans render problematic an assay that is specific for all gonococcal strains. However, novel conserved gonococcal antigens identified for potential vaccines may find additional application in diagnostic assays. N. gonorrhoeae also interferes with the adaptive immune response, and antibody responses to uncomplicated infection are usually weak. Elucidating the mechanisms whereby N. gonorrhoeae manipulates the human immune system may lead to improved understanding of the pathogenesis of pelvic inflammatory disease and infertility.

Immune checkpoints and reproductive immunology: Pioneers in the future therapy of infertility related Disorders?

As co-stimulatory receptors, immune checkpoint molecules are found on the surface of various immune cells and transduce inhibitory signals following ligand binding. The most studied members in this regard include PD-1, TIM-3, and CTLA-4. The physiological part immune checkpoints possess is the prevention of dangerous immune attacks towards self-antigens throughout an immune response, which takes place through the negative regulation of the effector immune cells, through the induction of T-cell exhaustion, for instance. It has recently been suggested that each checkpoint reduces immunoactivation via distinct intracellular mechanisms of signaling. Regulators of immune checkpoints are supposed to participate actively in immune defense mechanisms against infections, preventing autoimmunity, transplantation, and tumor immune evasion. In pregnancy, as an active immunotolerance mechanism which is also natural, the maternal immune system encounters two simultaneous challenges; in addition to accepting the semi-allogeneic fetus, the maternal immune system should also prevent infections. In this regard, the part immune checkpoint molecules possess is particularly interesting. Herein, the current understanding of such part in reproductive immunology is described.

The association between subclinical hypothyroidism and TPOAb positivity with infertility in a population-based study: Tehran thyroid study (TTS).

BACKGROUND: Thyroid autoimmunity(TAI) is the most prevalent autoimmune condition in women of fertile age. There are increasing data regarding the association of thyroid dysfunction and thyroid autoimmunity with adverse pregnancy outcomes but there is no consensus regarding infertility and TPOAb positivity; thus we aimed to evaluate the association between thyroid TPOAb positivity and infertility in females and males in a population-based study (TTS). METHODS: Cross-sectional study of 3197 female and male participants in Tehran Thyroid Study (TTS) at the framework of the Tehran Lipid and Glucose Study (TLGS). Data included biochemical measurements and a self-administered questionnaire. RESULTS: A total of 12,823 cases in phase 4, 3719 cases (2108 female and 1611 male) were analyzed. The mean TSH of the infertile female and male was 2.52 ± 2.68 µIU/ml and 3.24 ± 10.26 µIU/ml respectively. The TPO median(IQR) of women with and without a history of infertility were 6.05 (3.30-13.96)and 6.04 (3.17-11.15);(P = 0.613), they were 5.08 (3.20-125.68) and 5.31 (3.93-125.68);(P = 0.490) in male participants, respectively. Results of crude and adjusted logistic regression analysis of the development of infertility by thyroid function and TPOAb, except for fT4 in male subjects, depicted no association between infertility and other variables in both crude and adjusted models. CONCLUSION: Based on the result, thyroid autoimmunity was not associated with infertility in both females and males.

Functional Ambivalence of Dendritic Cells: Tolerogenicity and Immunogenicity.

Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs) and inducers of T cell-mediated immunity. Although DCs play a central role in promoting adaptive immune responses against growing tumors, they also establish and maintain peripheral tolerance. DC activity depends on the method of induction and/or the presence of immunosuppressive agents. Tolerogenic dendritic cells (tDCs) induce immune tolerance by activating CD4+CD25+Foxp3+ regulatory T (Treg) cells and/or by producing cytokines that inhibit T cell activation. These findings suggest that tDCs may be an effective treatment for autoimmune diseases, inflammatory diseases, and infertility.

CLTA-4 Expression is Associated with the Maintenance of Chronic Inflammation in Endometriosis and Infertility.

Altered immune mechanisms are implicated in the pathogenesis of endometriosis. CTLA-4 is a membrane receptor that favors the anergic state of lymphocytes, which may disrupt the immune system response in the endometriotic environment. In this study, we examined the expression of CTLA-4 on T and B cells by flow cytometry and its levels in blood serum and peritoneal fluid by ELISA. Levels of CTLA-4+ T cells were significantly higher in patients with more advanced endometriosis than in those with less advanced disease. Additionally, the negative correlation of CTLA-4+ T lymphocytes and the percentage of NK and NKT-like cells in women with endometriosis and infertility may indicate a different etiopathogenesis of endometriosis accompanying infertility. Our findings shed light on the potential of CTLA-4 in developing new diagnostic and therapeutic approaches in endometriosis management.

The Role of AIRE Deficiency in Infertility and Its Potential Pathogenesis.

The increasing number of patients with infertility is recognized as an emerging problem worldwide. However, little is known about the cause of infertility. At present, it is believed that infertility may be related to genetic or abnormal immune responses. It has long been indicated that autoimmune regulator (AIRE), a transcription factor, participates in immune tolerance by regulating the expression of thousands of promiscuous tissue-specific antigens in medullary thymic epithelial cells (mTECs), which play a pivotal role in preventing autoimmune diseases. AIRE is also expressed in germ cell progenitors. Importantly, the deletion of AIRE leads to severe oophoritis and age-dependent depletion of follicular reserves and causes altered embryonic development in female mice. AIRE-deficient male mice exhibit altered apoptosis during spermatogenesis and have a significantly decreased breeding capacity. These reports suggest that AIRE deficiency may be responsible for infertility. The causes may be related to the production of autoantibodies against sperm, poor development of germ cells, and abnormal ovarian function, which eventually lead to infertility. Here, we focus on the potential associations of AIRE deficiency with infertility as well as the possible pathogenesis, providing insight into the significance of AIRE in the development of infertility.

Immunoendocrine Markers of Stress in Seminal Plasma at IVF/ICSI Failure: a Preliminary Study.

We have previously shown that high level of seminal interleukin (IL)-18 is positively associated with a greater risk of pregnancy failure in women exposed to their partners' seminal plasma (SP) during the in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycle. Since IL-18 and IL-1ß considered to be the key immune markers of stress, here we ask whether their increase in SP may be due to the stress experienced by men engaged in the IVF programs. Therefore, we correlated seminal IL-18 with IL-1ß and both cytokines with the seminal steroids, whose increase indicates the activation of neuroendocrine stress response systems. Retrospective analysis of stored seminal samples was performed. Based on previously identified cutoff level for content of IL-18 per ejaculate, samples with high IL-18 content from IVF failure group (n = 9), as well as samples with low IL-18 content from IVF success group (n = 7), were included in the study. Seminal cytokines were evaluated using FlowCytomix™ technology. A set of 16 biologically active steroids in SP was quantified by liquid chromatography coupled with mass spectrometry. Concentrations and total amounts per ejaculate of cytokines and steroids were determined. A positive significant correlation was found between the levels of IL-18 and IL-1ß. There was also a positive correlation between IL-18 or IL-1ß and 17-α-hydroxypregnenolone, 17-α-hydroxyprogesterone, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), androstenedione, testosterone, dihydrotestosterone, progesterone, corticosterone, 11-deoxycorticosterone, and the ratio of DHEAS/cortisol. We suggested that stress-related overexpression of immune and hormonal factors in SP may be the key link between male stress and embryo implantation failure.

Effects of treatment with hydroxychloroquine on the modulation of Th17/Treg ratio and pregnancy outcomes in women with recurrent implantation failure: clinical trial.

AIM: The imbalance of Th17/Treg cells has been recently suggested as a new risk factors for recurrent implantation failure (RIF). Furthermore Th17/Treg cells are involved in immune regulation in peripheral blood and endometrial tissue of patients with RIF. In this research, we investigated the effects of Hydroxychloroquine (HCQ) on the level and function of Th17 and Treg cells in women with RIF. It may be possible to improve pregnancy outcomes by modulating high cytokine levels. METHODS: Women with RIF received oral HCQ (n = 60) on day 4 of the menstrual cycle and continued until day 20 of the menstrual cycle and 2 days before embryo transfer and continued until the day of the pregnancy test, for a total of 16 days in another cycle. The serum levels of IL-17 and IL-10, the expression of transcription factors related to Th17 and Treg cells and the immune-reactivity of IL-17, IL-21 as Th17 related cytokines and IL-10, TGF- ß as Treg related cytokines in endometrial tissues were evaluated by ELISA, real-time PCR, and fluorescent immunohistochemistry respectively.Results: Treatment with HCQ down-regulated Th17 related cytokines and function and up-regulated Treg related cytokines and function significantly (p < .001). RORγt, the Th17 transcription factor, expression was down-regulated and FOXP-3, the T-reg transcription factor, expression was up-regulated. The biochemical pregnancy rate was not significantly different in RIF patients before and after treatment. CONCLUSION: Our results demonstrated that the administration of HCQ in RIF women with immune cell disorders during pregnancy could affect the Th17/Treg ratio and enhance Treg and diminish Th17 responses which may be associated with successful pregnancy outcomes. However, significant difference in pregnancy outcomes was not observed in the present study.

Examining extended human leukocyte antigen-G and HLA-F haplotypes: the HLA-G UTR-4 haplotype is associated with shorter time to pregnancy in an infertility treatment setting when both female and male partners are carriers.

OBJECTIVE: To study the impact of extended human leukocyte antigen (HLA)-G and HLA-F haplotypes on time to pregnancy as measured by the number of treatment cycles in a cohort of couples in infertility treatment. DESIGN: Prospective cohort study of couples undergoing infertility treatment. SETTING: University hospital. PATIENT(S): A cohort of 127 couples and four single women in infertility treatment. INTERVENTION(S): Next-generation sequencing of the HLA-G gene and genotyping of three HLA-F locus single-nucleotide polymorphisms (SNPs). MAIN OUTCOME MEASURE(S): Extended HLA-F.HLA-G haplotypes, HLA-G promoter haplotypes and HLA-G 3'UTR haplotypes and their association with time to pregnancy as measured by number of treatment cycles until achievement of pregnancy with a live birth. Linkage disequilibrium between HLA-G variations and three HLA-F locus SNPs that impact time to pregnancy. RESULT(S): The effect of the HLA-G 3'UTR haplotype, UTR-4, was significantly increased, or modified, if the partner was a carrier compared to being a noncarrier. Extended HLA-F.HLA-G haplotypes, HLA-G promoter haplotypes, and the HLA-G 14 bp indel of the female partners were not associated with time to pregnancy. However, a trend for an association of the HLA-G 14bp insertion allele with a higher frequency of miscarriage than the 14bp deletion allele was observed. Certain HLA-G variations are in linkage disequilibrium with three HLA-F locus SNPs that influence time to pregnancy. CONCLUSION(S): HLA-G UTR-4 is significantly associated with time to pregnancy in couples undergoing infertility treatment. The findings could imply that both male and female HLA class Ib genetics have clinical relevance in reproduction.

On use of animal models.

Human pregnancy, critical for our species survival, is inefficient and prone to complications such as infertility, spontaneous miscarriages and preeclampsia (PE). Immunological factors may be important as the embryo is 50% paternal and foreign to the mother. Mouse pregnancy models, and in particular the murine CBA/J x DBA/2 mating combination, has been widely used to investigate mechanisms causing and preventing partner-specific recurrent miscarriages (RM) and PE. Occult losses can represent T cell-mediated rejection, and antigen-specific regulatory T cells (Tregs) with classical αß T cell receptors (TcR) activated by semen antigens at the time of mating are protective. If there is no occult loss, an inadequate Treg response can also predispose to RM. In RM, proinflammatory cytokines from natural killer (NK)-type cells and macrophages of the innate immune system are responsible and cells with γδ TcR protect via release of TGF-ß-type molecules. Immunization of abortion-prone female CBA/J mice or administration of cell-associated or soluble CD200, an immune check point inhibitor, can prevent abortions by augmenting uterine decidual suppressor cell activity. Human studies suggest that is also true in couples with RM. Environmental activators of the innate immune system, such as bacterial LPS and stress, can cause abortions as well as occult losses. The endogenous level of Tregs and activation of Tregs specific for the male H-Y antigen may determine success rates and alter the male:female birth ratio. Intralipid alters LPS clearance, prevents abortions in the CBAxDBA/2 model, and is effective in increasing live birth rates in couples undergoing IVF treatment.

Two of a kind? Immunological and clinical risk factors differ between recurrent implantation failure and recurrent miscarriage.

Recurrent miscarriage (RM) and recurrent implantation failure (RIF) are unsolved challenges in reproductive medicine. Whether RIF patients share the same risk factors as RM patients is a matter of debate. Besides clinical factors, immune alterations are discussed in both conditions. The scope of this study was to compare the prevalence of clinical and immunological risk factors in a large cohort of RM and RIF patients. Between 11/2011 and 02/2019, 613 RM and 185 RIF patients were included. A screening for anatomical malformations, endocrine, autoimmune, prothrombotic and parental chromosomal disorders was performed. The immune status was assessed using flow cytometry analysis of peripheral lymphocyte subpopulations and uterine natural killer cells (uNK cells) using immunohistochemistry. RM patients showed a higher rate of intrauterine adhesions and elevated antinuclear antibodies ≥ 1:160 (p < 0.05). A higher prevalence of submucous fibroids and increased factor VIII levels were observed in RIF patients (p < 0.05). The prevalence of an antiphospholipid syndrome (APLS) was low and did not differ between the two groups. RIF patients had higher numbers of peripheral regulatory T-cells (p < 0.05). Significant more RIF patients were diagnosed with elevated uNK cells (p < 0.05). Differences in clinical and immunological risk factors of RM and RIF patients reflect different entities. Lower Tregs in RM and higher uNK cells in RIF patients might be related to the previous exposure of the immune system to fetal cells. The low prevalence of an APLS indicates a potential overestimation of this factor in the pathophysiology of RM and RIF.

SARS-CoV-2 testing in infertile patients: different recommendations in Europe and America.

The incorporation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing into patient care algorithms has been proposed to mitigate risk. However, the two main professional societies for human reproduction (ESHRE and ASRM) appear divergent on their clinical utility and whether they should be adopted. In this opinion paper, we review the currently available tests and discuss the strengths and weaknesses of the proposed clinical care pathways. Nucleic acid amplification tests are the cornerstone of SARS-CoV-2 testing but test results are largely influenced by viral load, sample site, specimen collection method, and specimen shipment technique, such that a negative result in a symptomatic patient cannot be relied upon. Serological assays for SARS-CoV-2 antibodies exhibit a temporal increase in sensitivity and specificity after symptom onset irrespective of the assay used, with sensitivity estimates ranging from 0 to 50% with the first 3 days of symptoms, to 83 to 88% at 10 days, increasing to almost 100% at ≥ 14 days. These inherent constraints in diagnostics would suggest that at present there is inadequate evidence to utilize SARS-CoV-2 testing to stratify fertility patients and reliably inform clinical decision-making. The failure to appreciate the characteristics and limitations of the diagnostic tests may lead to disastrous consequences for the patient and the multidisciplinary team looking after them.

Functional significance of lymphocytes in pregnancy and lymphocyte immunotherapy in infertility: A comprehensive review and update.

During pregnancy, the fetal-maternal interface underlies several dynamic alterations to permit the fetus to be cultivated and developed in the uterus, in spite of being identifies by the maternal immune system. A large variety of decidual leukocyte populations, including natural killer cells, NKT cells, innate lymphoid cells, dendritic cells, B cells, T cells, subpopulations of helper T cells play a vital role in controlling the trophoblast invasion, angiogenesis as well as vascular remodeling. In contrast, several regulatory immunosuppressive mechanisms, including regulatory T cells, regulatory B cells, several cytokines and mediators are involved in maintain the homeostasis of immune system in the fetal-maternal interface. Nonetheless, aberrant alterations in the balance of immune inflammatory or immunosuppressive arms have been associated with various pregnancy losses and infertilities. As a result, numerous strategies have been developed to revers dysregulated balance of immune players to increase the chance of successful pregnancy. Lymphocyte immunotherapy has been developed through utilization of peripheral white blood cells of the husband or others and administered into the mother to confer an immune tolerance for embryo's antigens. However, the results have not always been promising, implying to further investigations to improve the approach. This review attempts to clarify the involvement of lymphocytes in contributing to the pregnancy outcome and the potential of lymphocyte immunotherapy in treatment of infertilities with dysregulated immune system basis.

The Prevalence of Thyroid Dysfunction and Autoimmunity in Women With History of Miscarriage or Subfertility.

OBJECTIVE: To describe the prevalence of and factors associated with different thyroid dysfunction phenotypes in women who are asymptomatic preconception. DESIGN: Observational cohort study. SETTING: A total of 49 hospitals across the United Kingdom between 2011 and 2016. PARTICIPANTS: Women aged 16 to 41years with history of miscarriage or subfertility trying for a pregnancy. METHODS: Prevalences and 95% confidence intervals (CIs) were estimated using the binomial exact method. Multivariate logistic regression analyses were conducted to identify risk factors for thyroid disease. INTERVENTION: None. MAIN OUTCOME MEASURE: Rates of thyroid dysfunction. RESULTS: Thyroid function and thyroid peroxidase antibody (TPOAb) data were available for 19213 and 19237 women, respectively. The prevalence of abnormal thyroid function was 4.8% (95% CI, 4.5-5.1); euthyroidism was defined as levels of thyroid-stimulating hormone (TSH) of 0.44 to 4.50 mIU/L and free thyroxine (fT4) of 10 to 21 pmol/L. Overt hypothyroidism (TSH > 4.50 mIU/L, fT4 < 10 pmol/L) was present in 0.2% of women (95% CI, 0.1-0.3) and overt hyperthyroidism (TSH < 0.44 mIU/L, fT4 > 21 pmol/L) was present in 0.3% (95% CI, 0.2-0.3). The prevalence of subclinical hypothyroidism (SCH) using an upper TSH concentration of 4.50 mIU/L was 2.4% (95% CI, 2.1-2.6). Lowering the upper TSH to 2.50 mIU/L resulted in higher rates of SCH, 19.9% (95% CI, 19.3-20.5). Multiple regression analyses showed increased odds of SCH (TSH > 4.50 mIU/L) with body mass index (BMI) ≥ 35.0 kg/m2 (adjusted odds ratio [aOR] 1.71; 95% CI, 1.13-2.57; P = 0.01) and Asian ethnicity (aOR 1.76; 95% CI, 1.31-2.37; P < 0.001), and increased odds of SCH (TSH ≥ 2.50 mIU/L) with subfertility (aOR 1.16; 95% CI, 1.04-1.29; P = 0.008). TPOAb positivity was prevalent in 9.5% of women (95% CI, 9.1-9.9). CONCLUSIONS: The prevalence of undiagnosed overt thyroid disease is low. SCH and TPOAb are common, particularly in women with higher BMI or of Asian ethnicity. A TSH cutoff of 2.50 mIU/L to define SCH results in a significant proportion of women potentially requiring levothyroxine treatment.

Potential impact of maternal vitamin D status on peripheral blood and endometrium cellular immunity in women with recurrent implantation failure.

PROBLEM: This study aims to evaluate the modulatory effects of vitamin D on peripheral blood and endometrial cellular immunity in women with recurrent implantation failure (RIF). METHOD OF STUDY: One hundred and fifty-four women with RIF were identified at a fertility center from January 2018 and March 2019. Blood and endometrium samples were collected during the mid-luteal phase before IVF treatment or pregnancy. The serum vitamin D status, NK cell cytotoxicity, Th1 cytokine production, and endometrial immune cells were detected before and after vitamin D supplementation. RESULTS: The NK cell cytotoxicity at an effector:target (E:T) ratio of 50:1 or 25:1 was significantly higher in vitamin D insufficiency group (VDI) than those in vitamin D normal group (VDN) (P < .05 each). The percentage of IFN-γ- or TNF-α-producing Th cells was significantly increased in VDI or vitamin D deficiency group (VDD) when compared with VDN (P < .05 each). The percentage of CD68+ macrophages on all endometrial cells in VDI and VDD was significantly higher than in VDN (P < .05 each), while no significant differences in the percentage of other endometrial immune cells among the three groups were observed. This dysregulation was significantly reduced with vitamin D supplementation. CONCLUSION: Our findings highlighted that vitamin D may have an important role in the regulation of not only systemic but also local immune response for optimization of maternal tolerance for implantation in women with RIF. Pre-conception optimization of vitamin D status should be considered in women with RIF.

Immunophenotypic Profiles in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) a long-known endocrinopathy and one of the most common endocrine-reproductive-metabolic disorders in women, which can lead to infertility. Although the precise etiology remains unclear, PCOS is considered as a complex genetic trait, with a high degree of heterogeneity. Besides, hormones and immune cells, including both innate and adaptive immune cells, are reportedly a cross talk in PCOS. Chronic low-grade inflammation increases autoimmune disease risk. This proinflammatory condition may, in turn, affect vital physiological processes that ultimately cause infertility, such as ovulation failure and embryo implantation. Here, we review the accumulating evidence linking PCOS with inflammatory status providing an overview of the underlying hormone-mediated dysregulation of immune cells. We mainly focus on the correlational evidence of associations between immune status in women and the increased prevalence of PCOS, along with the specific changes in immune responses. Further recognition and exploration of these interactions may help elucidate PCOS pathophysiology and highlight targets for its treatment and prevention.

The Inflammasome in Reproductive Biology: A Promising Target for Novel Therapies.

The inflammasome is a key regulator of innate immunity involved in the inflammatory response to infections as well as disease through the activation of caspase-1 and the processing of the inflammatory cytokines interleukin (IL)-1ß and IL-18. Even though the inflammasome was first described in the context of infections, most research in recent years has focused on targeting the inflammasome as a therapeutic option in sterile inflammatory events. Recent evidence indicates a clear involvement of the inflammasome in Reproductive Biology such as infertility and preeclampsia. In this mini-review, I summarize the current findings on the inflammasome that have been described in the field of Reproductive Biology and highlight the potential that the inflammasome has as a novel therapeutic option in this field. The topics covered in this review as it pertains to the inflammasome field cover the literature published on male and female infertility, endometriosis, preeclampsia, placental inflammation, and reproductive senescence.