Female and male reproductive tracts are of interest sites to study of immune system because they encounter specific infections such as those are sexually transmitted.Furthermore, female reproductive tract is in close contact with allogenic sperms and transmitted microorganisms during intercourse and semi allogenic fetus during pregnancy. In mammals, there are two types of immune responses, the innate and the acquired immune responses. While acquired immune responses act later in an infection and are highly specific for the pathogen that induces them, the innate immune responses react immediately after exposure to pathogens and serve as the first line of host defense. The innate immune system depends on the pattern recognizing receptors (PRRs) including the toll-like receptor (TLR) family that detect the pathogen-associated molecular patterns (PAMPs) and activate subsequent immune cell responses.TLRs can recognize a variety of PAMPs including lipoprotein, lipopolysaccharide (LPS), peptidoglycan, zymosan, bacterial flagella, CpG DNA, single and double strand RNAs. To date, ten human TLRs and thirteen mouse TLRs have been identified. Several groups have reported the expression of TLRs in different tissues. Nevertheless, relatively little has been done to identify TLRs in the human female reproductive tract (FRT). Furthermore, some findings are controversial. In our recent works, we showed that TLR1-10 genes were expressed in human fallopian tube and endometrial tissue. The mean relative expression of some TLR genes was significantly higher during the secretory phase of the menstrual cycle in endometrium.Although these findings were in consist with previous works but some differences were shown as we found TLR10 gene expression in the endometrium. We also investigated TLR expression and function in three human endometrial epithelial cell lines, including hTERT-EEC, HEC-1B and Ishikawa cells and showed that TLR expression in these cell lines is comparable to published literature on TLR expression in primary human endometrial tissue. We also found that hTERT-EEC cells were responsive to TLR5 ligand and HEC-1B cells respond to TLR3 and TLR5 ligands. In contrast, Ishikawa cells respond only to PMA/I, which was used as a positive control for IL-8 production. We also showed that the endometrial cell lines have a tendency for increased TLR5 expression in response to flagellin stimulation, which was significant in hTERT-EEC cells.On the other hand, determination and characterization of TLRs have been studied limited in the human male reproductive tract. Therefore, we investigated the expression of TLRs in different regions of male reproductive tract in our last research. In this research, RT–PCR was used to show the existence of all TLR genes exception TLR8 in the male reproductive tract, Q-PCR analysis used to investigate the relative expression of TLR2, 3 and 4 genes and immunoblot analysis was used for detect TLR2-4 on spermatozoa. The results showed that most intended TLRs except TLR4, 6, 7 and 10 in vasa deferens, TLR3 in Prepuce and TLR7 in Testis, are expressed in different parts of the human male reproductive tract. Existence of TLR2, 3 and 4 in spermatozoa has been shown by using western blot technique. However, related to TLRs that have not been expressed, additional experiments are needed. TLRs function and expression were also investigated in certain tissues associated with pregnancy such as placenta and amnion. Different researches showed that normal term placental tissue expresses TLR1–10. In addition, it was shown that first trimester syncytiotrophoblast do not express TLR2 and TLR4 in contrast to first-trimester placental tissues. Other researches in this regard showed that human first-trimester trophoblast secretion of chemokines is significantly increased following the ligation of TLR3 by poly (I: C) or TLR4 by bacterial LPS. However, anti-viral factors, such as interferon-b and secretory leukocyte protease inhibitor seem to be produced by these cells following stimulation with poly I: C (TLR3- specific ligand), but not TLR4 ligand (LPS). In addition, it was shown that although TLR3 and TLR4 ligation promote cytokine production in first-trimester trophoblast cells, it seems ligation of TLR2 in these cells induces apoptosis. This TLR2-mediated trophoblast apoptosis may provide a novel mechanism of pathogenesis by which certain intra-uterine infections may contribute to conditions such as preterm labour, intra uterine growth restriction (IUGR), spontaneous abortion and preeclampsia.Expression of all ten TLRs is shown in first trimester and term deciduas. For amnion, it was reported that both TLR2 and TLR4 are expressed by amniotic epithelial cells. Also the soluble form of TLR2 was demonstrated in amniotic fluid. As implantation is one of key steps in reproduction, we recently used two cell lines (hTERT-EECs and JAr cells) and provided an in vitro model for studying human implantation.We showed that treatment of endometrial cells with TLR5 ligand (flagellin) suppresses the attachment of JAr spheres to the endometrial cells while usage of TLR5 function blocking antibody restores the attachment of JAr spheres to endometrium. Consequently, further studies are needed to explore other mechanisms by which the presence of intrauterine infections may result in implantation failure. Studying the function of TLRs in the female reproductive tract presents an exciting opportunity to further understand the regulation of innate immune system in the female reproductive tract. It seems sex hormones regulate the function and expression of TLRs in the female reproductive tract and therefore influence/regulate innate and adaptive immune function in this tract to protect against potential pathogens while providing an environment that supports an allogeneic fetus. How TLR function and expression is exactly regulated in reproductive tract by sex hormones would be a challenging but fruitful area of future research.

Autism Spectrum Disorder (ASD) is a multifaceted neurodevelopmental condition characterized by diverse behavioral and cognitive challenges. Despite its rising prevalence, the underlying mechanisms remain inadequately understood. toll-like receptors (TLRs), as critical components of the innate immune system, are implicated in neuroinflammatory processes that may contribute to the pathogenesis of ASD. This narrative review delves into the relationship between TLRs and ASD. Notably, studies reveal an upregulation of TLR4 and TLR2 expression in B cells and placental tissues of individuals with ASD, correlating with increased levels of pro-inflammatory cytokines such as IL-6 and TNF-alpha. Maternal immune activation (MIA), particularly due to infections during pregnancy, has been shown to trigger TLR-mediated inflammatory responses that adversely affect fetal brain development. For instance, maternal cytomegalovirus (CMV) infection leads to heightened expression of TLR4/2 in the placenta, resulting in significant placental inflammation and altered neurodevelopmental trajectories in offspring. Furthermore, evidence indicates that individuals with ASD exhibit impaired immune responses characterized by dysfunctional natural killer (NK) cells and monocytes, which produce excessive pro-inflammatory cytokines upon TLR4 stimulation but show diminished responses to TLR9 ligands. This immune dysregulation is associated with a shift towards a TH2 cytokine profile, complicating the understanding of immune phenotype correlations with ASD symptom severity. Additionally, TLR3 activation by viral RNA has been linked to behavioral changes in murine models, underscoring the potential for maternal infections to influence neurodevelopment through TLR signaling pathways. These findings illuminate the role of TLRs in ASD pathophysiology and suggest that targeting TLR pathways may offer novel therapeutic avenues for intervention in this complex disorder.

Background: Endometriosis is a complex disease that profoundly affects the quality of life in many women. This disease affects roughly one in ten women of reproductive age. Endometriosis induces a variable amount of inflammatory reaction in pelvic environment. An active immune system needs to recognize these inflammatory agents. Rapid innate immune system defenses against infections involve the recognition of invading viral and bacterial pathogens, by the family of toll like receptors (TLRs). Among TLRs family only TLR3, 7, 8 and 9 that expressed in the intracellular endosomal compartments, which can detect viral infections.TLR3 distinguishes double strand RNA viral motifs. TLR 7/8 are specific for single strand RNA. While TLR9 recognizes unmethylated CPG DNA of viruses. The objective of this study is to clarify the expression of intracellular TLRs in the woman with endometriosis.Materials and Methods: In this study three groups were examined. Ectopic biopsies were obtained with laparoscopic procedure from patient with endometriosis. Eutopic and control biopsies were gained with piplle from endometrium of women with and without endometriosis.Reverse transcriptase polymerase chain reaction (RTPCR) and quantitative-PCR (Q-PCR) for 5 samples of each groups used to show the existence of TLR3, 7, 8 and 9 genes.Results: TLR3, 7, 8 and 9 mRNA were expressed in the each groups but in ectopic and eutopic samples we showed variable expression.Conclusion: Our finding suggested that TLRs is involved in endometriosis pathophysiology. It is shown that some products of TLRs signaling such as TNf-a and IL-1 were increased in endometriosis.

Female and male reproductive tracts are of interest sites to study of immune system because they encounter specific infections such as those are sexually transmitted. Furthermore, female reproductive tract is in close contact with allogenic sperms and transmitted microorganisms during intercourse and semi allogenic fetus during pregnancy.In mammals, there are two types of immune responses, the innate and the acquired immune responses. While acquired immune responses act later in an infection and are highly specific for the pathogen that induces them, the innate immune responses react immediately after exposure to pathogens and serve as the first line of host defense. The innate immune system depends on the pattern recognizing receptors (PRRs) including the toll-like receptor (TLR) family that detect the pathogen-associated molecular patterns (PAMPs) and activate subsequent immune cell responses. TLRs can recognize a variety of PAMPs including lipoprotein, lipopolysaccharide (LPS), peptidoglycan, zymosan, bacterial flagella, CpG DNA, single and double strand RNAs. To date, ten human TLRs and thirteen mouse TLRs have been identified.Several groups have reported the expression of TLRs in different tissues. Nevertheless, relatively little has been done to identify TLRs in the human female reproductive tract (FRT). Furthermore, some findings are controversial. In our recent works, we showed that TLR1-10 genes were expressed in human fallopian tube and endometrial tissue. The mean relative expression of some TLR genes was significantly higher during the secretory phase of the menstrual cycle in endometrium. Although these findings were in consist with previous works but some differences were shown as we found TLR10 gene expression in the endometrium. We also investigated TLR expression and function in three human endometrial epithelial cell lines, including hTERT-EEC, HEC-1B and Ishikawa cells and showed that TLR expression in these cell lines is comparable to published literature on TLR expression in primary human endometrial tissue. We also found that hTERT-EEC cells were responsive to TLR5 ligand and HEC-1B cells respond to TLR3 and TLR5 ligands. In contrast, Ishikawa cells respond only to PMA/I which was used as a positive control for IL-8 production. We also showed that the endometrial cell lines have a tendency for increased TLR5 expression in response to flagellin stimulation which was significant in hTERT-EEC cells.On the other hand, determination and characterization of TLRs have been studied limited in the human male reproductive tract. Therefore, we investigated the expression of TLRs in different regions of male reproductive tract in our last research. In this research, RT-PCR was used to show the existence of all TLR genes exception TLR8 in the male reproductive tract, Q-PCR analysis used to investigate the relative expression of TLR2, 3 and 4 genes and immunoblot analysis was used for detect TLR2-4 on spermatozoa. The results showed that most intended TLRs except TLR4, 6,7and 10 in vasa deferens, TLR3 in Prepuce and TLR7 in Testis, are expressed in different parts of the human male reproductive tract. Existence of TLR2, 3 and 4 in spermatozoa has been shown by using western blot technique. However, related to TLRs that have not been expressed, additional experiments are needed.TLRs function and expression were also investigated in certain tissues associated with pregnancy such as placenta and amnion. Different researches showed that normal term placental tissue expresses TLR1-10. Also it was shown that first trimester syncytiotrophoblast do not expressTLR2 and TLR4 in contrast to first-trimester placental tissues. Other researches in this regard showed that human first-trimester trophoblast secretion of chemokines is significantly increased following the ligation of TLR3 by poly (I:C) or TLR4 by bacterial LPS. However, anti-viral factors, such as interferon-b and secretory leukocyte protease inhibitor seem to be produced by these cells following stimulation with poly I:C (TLR3- specific ligand), but not TLR4 ligand (LPS). In addition, it was shown that although TLR3 and TLR4 ligation promote cytokine production in first-trimester trophoblast cells, it seems ligation of TLR2 in these cells induces apoptosis. This TLR2-mediated trophoblast apoptosis may provide a novel mechanism of pathogenesis by which certain intra-uterine infections may contribute to conditions such as preterm labour, intra uterine growth restriction (IUGR), spontaneous abortion and preeclampsia. Expression of all ten TLRs is shown in first trimester and term deciduas. For amnion, it was reported that both TLR2 and TLR4 are expressed by amniotic epithelial cells. Also the soluble form of TLR2 was demonstrated in amniotic fluid.As implantation is one of key steps in reproduction, we recently used two cell lines (hTERT-EECs and JAr cells) and provided an in vitro model for studying human implantation. We showed that treatment of endometrial cells with TLR5 ligand (flagellin) suppresses the attachment of JAr spheres to the endometrial cells while usage of TLR5 function blocking antibody restores the attachment of JAr spheres to endometrium. Consequently, further studies are needed to explore other mechanisms by which the presence of intrauterine infections may result in implantation failure.Studying the function of TLRs in the female reproductive tract presents an exciting opportunity to further understand the regulation of innate immune system in the female reproductive tract. It seems sex hormones regulate the function and expression of TLRs in the female reproductive tract and therefore influence/regulate innate and adaptive immune function in this tract to protect against potential pathogens while providing an environment that supports an allogeneic fetus. How TLR function and expression is exactly regulated in reproductive tract by sex hormones would be a challenging but fruitful area of future research.

Background: One-third of the world’ s population is infected with Mycobacterium tuberculosis. Investigation of toll-like receptors (TLRs) has revealed new information regarding the immunopathogenesis of this disease. toll-like receptors can recognize various ligands with a lipoprotein structure in the bacilli. toll-like receptor 2 and TLR-4 have been identified in association with tuberculosis infection. Objectives: The aim of our study was to investigate the relationship between TLR polymorphism and infection progress. Methods: Twenty-nine patients with a radiologically, microbiologically, and clinically proven active tuberculosis diagnosis were included in this 25-month study. toll-like receptor 2 and TLR-4 polymorphisms and allele distributions were compared between these 29 patients and 100 healthy control subjects. Peripheral blood samples were taken from all patients. Genotyping of TLR-2, TLR-4, and macrophage migration inhibitory factor was performed. The extraction step was completed with a Qiagen mini blood purification system kit (Qiagen, Ontario, Canada) using a peripheral blood sample. The genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism. Results: In total, 19 of the 29 patients with tuberculosis infection had a TLR-2 polymorphism, and 20 of the 100 healthy subjects had a TLR-2 polymorphism (P < 0. 001). The TLR-4 polymorphism and interferon- allele distributions were not statistically correlated. Conclusions: toll-like receptor 2 polymorphism is a risk factor for tuberculosis infection. The limiting factor in this study was the lack of investigation of the interferon- and tumor necrosis factor- levels, which are important in the development of infection. Detection of lower levels of these cytokines in bronchoalveolar lavage specimens, especially among patients with TLR-2 defects, will provide new data that may support the results of this study.