Kikuchi-Fujimoto disease during early pregnancy.

Kikuchi-Fujimoto disease (KFD) is rare during pregnancy. It is characterized by necrotizing lymphadenitis and often occurs in young Asian women. We report a case of KFD during pregnancy, which was difficult to diagnose. A 37-year-old pregnant female (gestational week [GW] 7+5) was admitted to our hospital because of hyperemesis gravidarum. On the eighth day of hospitalization (GW 8+6), she suddenly developed a fever (38.0°C) with skin rash and posterior pharynx redness. Blood tests showed pancytopenia and abnormal liver function. The patient was misdiagnosed with severe Epstein-Barr virus infection and administered with prednisolone. Subsequently, cervical lymphadenopathy was observed, and biopsy results led to the diagnosis of KFD. Thereafter, her symptoms improved, and she was discharged at GW 13+4. KFD must be included as a differential diagnosis for patients with fever, abnormal liver function, and pancytopenia during pregnancy.

Placenta-specific lncRNA 1600012P17Rik is expressed in spongiotrophoblast and glycogen trophoblast cells of mouse placenta.

A few long noncoding RNAs (long ncRNAs, lncRNAs) exhibit trophoblast cell type-specific expression patterns and functional roles in mouse placenta. However, the cell- and stage-specific expression patterns and functions of most placenta-derived lncRNAs remain unclear. In this study, we explored mouse placenta-associated lncRNAs using a combined bioinformatic and experimental approach. We used the FANTOM5 database to survey lncRNA expression in mouse placenta and found that 1600012P17Rik (MGI: 1919275, designated P17Rik), a long intergenic ncRNA, was the most highly expressed lncRNA at gestational day 17. Polymerase chain reaction analysis confirmed that P17Rik was exclusively expressed in placenta and not in any of the adult organs examined in this study. In situ hybridization analysis revealed that it was highly expressed in spongiotrophoblast cells and to a lesser extent in glycogen trophoblast cells, including migratory glycogen trophoblast cells invading the decidua. Moreover, we found that it is a polyadenylated lncRNA localized mainly to the cytoplasm of these trophoblast cells. As these trophoblast cells also expressed the neighboring protein-coding gene, pappalysin 2 (Pappa2), we investigated the effects of P17Rik on Pappa2 expression using Pappa2-expressing MC3T3-E1 cells and found that P17Rik transfection increased the messenger RNA (mRNA) and protein levels of Pappa2. These results indicate that mouse placenta-specific lncRNA P17Rik modulates the expression of the neighboring protein-coding gene Pappa2 in spongiotrophoblast and glycogen trophoblast cells of mouse placenta during late gestation.

Upregulated serum granulysin levels in women with antiphospholipid antibody-associated recurrent miscarriage are downregulated by heparin treatment.

Purpose: Granulysin is a cytotoxic protein that simultaneously activates innate and cellular immunity. The authors aimed to evaluate whether granulysin is associated with the antiphospholipid antibody syndrome and whether heparin changes the granulysin levels. Methods: A cohort study was performed with women with antiphospholipid antibody-positive recurrent pregnancy loss (RPL). The authors examined granulysin levels under RPL and evaluated the changes in serum granulysin levels before and 1 week after the commencement of heparin treatment. Results: Serum granulysin levels before heparin treatment were significantly higher in women who tested positive for one or more types of antiphospholipid antibodies (2.75 ± 1.03 vs. 2.44 ± 0.69, p = 0.0341 by Welch's t test), particularly anti-phosphatidylethanolamine antibodies (IgG: 2.98 ± 1.09 vs. 2.51 ± 0.86, p = 0.0013; IgM: 2.85 ± 1.09 vs. 2.47 ± 0.77, p = 0.0024 by Welch's t test). After heparin treatment for 1 week, serum granulysin levels were significantly reduced (p = 0.0017 by the paired t test). The miscarriage rate was significantly higher in women whose serum granulysin levels were not reduced by heparin treatment (p = 0.0086 by Fisher's exact probability test). Conclusion: The results suggest that heparin may reduce the incidence of miscarriage by suppressing serum granulysin levels.

Miscarriage induced by adoptive transfer of dendritic cells and invariant natural killer T cells into mice.

Unexpected fetal loss is one of the common complications of pregnancy; however, the pathogenesis of many miscarriages, particularly those not associated with infections, is unknown. We previously found that activated DEC-205+ dendritic cells (DCs) and NK1.1+ invariant natural killer T (iNKT) cells are recruited into the myometrium of mice when miscarriage is induced by the intraperitoneal administration of α-galactosylceramide (α-GalCer). Here we demonstrate that the adoptive transfer of DEC-205+ bone marrow-derived DCs cocultured with α-GalCer (DEC-205+ BMDCs-c/w-α-GalCer) directly induced marked fetal loss by syngeneic pregnant C57BL/6 (B6) mice and allogeneic mice (B6 (♀) × BALB/c (♂)), which was accompanied by the accumulation of activated iNKT cells in the myometrium. Further, the adoptive transfer of NK1.1+ iNKT cells obtained from B6 mice injected with α-GalCer facilitated miscarriages in syngeneic Jα18(-/-) (iNKT cell-deficient) mice. These results suggest that DEC-205+ DCs and NK1.1+ iNKT cells play crucial roles required for the initiation of fetal loss associated with stimulation by glycolipid antigens and sterile inflammation.

Induction of tumor-specific CD8+ cytotoxic T lymphocytes from naïve human T cells by using Mycobacterium-derived mycolic acid and lipoarabinomannan-stimulated dendritic cells.

The main effectors in tumor control are the class I MHC molecule-restricted CD8+ cytotoxic T lymphocytes (CTLs). Tumor-specific CTL induction can be regulated by dendritic cells (DCs) expressing both tumor-derived epitopes and co-stimulatory molecules. Immunosuppressive tolerogenic DCs, having down-regulated co-stimulatory molecules, are seen within the tumor mass and can suppress tumor-specific CTL induction. The tolerogenic DCs expressing down-regulated XCR1+CD141+ appear to be induced by tumor-derived soluble factors or dexamethasone, while the immunogenic DCs usually express XCR1+CD141+ molecules with a cross-presentation function in humans. Thus, if tolerogenic DCs can be reactivated into immunogenic DCs with sufficient co-stimulatory molecules, tumor-specific CD8+ CTLs can be primed and activated in vivo. In the present study, we converted human tolerogenic CD141+ DCs with enhanced co-stimulatory molecule expression of CD40, CD80, and CD86 through stimulation with non-toxic mycobacterial lipids such as mycolic acid (MA) and lipoarabinomannan (LAM), which synergistically enhanced both co-stimulatory molecule expression and interleukin (IL)-12 secretion by XCR1+CD141+ DCs. Moreover, MA and LAM-stimulated DCs captured tumor antigens and presented tumor epitope(s) in association with class I MHCs and sufficient upregulated co-stimulatory molecules to prime naïve CD3+ T cells to become CD8+ tumor-specific CTLs. Repeat CD141+ DC stimulation with MA and LAM augmented the secretion of IL-12. These findings provide us a new method for altering the tumor environment by converting tolerogenic DCs to immunogenic DCs with MA and LAM from Mycobacterium tuberculosis.

Innate immune cells in reproduction.

Fetomaternal immune tolerance is required to prevent fetal rejection during pregnancy; simultaneously, the maternal immune system must also protect the fetus from harmful endogenous and exogenous antigens, including those associated with viral and bacterial infections. Therefore, a delicate immune balance is critical for the maintenance of a successful pregnancy, while disruption of this balance can induce complications such as implantation failure, miscarriage, preterm birth/labor, preeclampsia and fetal growth restriction. While the adaptive immune system is critical for the development of tolerance, this review summarizes evidence that modulation of the innate immunity is also essential for achieving this delicate balance between tolerance and protection. Canonical cells of the innate immune system, including dendritic cells, macrophages, natural killer cells and invariant natural killer T cells, contribute to the modulation of the immune balance at the fetomaternal interface. The newly identified myeloid-derived suppressor cells and innate lymphoid cells also appear important for successful reproduction. Moreover, it is possible that sterile inflammation facilitates complications of pregnancy via the innate immune system. In this review, the characteristic features and functions of innate immune cells in fetomaternal immunity and their contributions to pregnancy complications related to sterile inflammation are discussed. These insights on innate immune system function in reproduction may provide new perspectives for understanding the mechanisms of fetomaternal tolerance and the etiology of pregnancy complications.

Suppression of murine tumour growth through CD8+ cytotoxic T lymphocytes via activated DEC-205+ dendritic cells by sequential administration of α-galactosylceramide in vivo.

Cancer immunity is mediated through the effective priming and activation of tumour-specific class I MHC molecule-restricted CD8+ cytotoxic T lymphocytes (CTLs). DEC-205+ dendritic cells (DCs) can cross-present the epitope(s) of captured tumour antigens associated with class I MHC molecules alongside co-stimulatory molecules to prime and activate tumour-specific CD8+ CTLs. Immunosuppressive tolerogenic DCs with reduced co-stimulatory molecules may be a cause of impaired CTL induction. Hepa1-6-1 cells were established from the mouse hepatoma cell line Hepa1-6; these cells grow continuously after subcutaneous implantation into syngeneic C57BL/6 (B6) mice and do not prime CD8+ CTLs. In this study, we show that the growth of ongoing tumours was suppressed by activated CD8+ CTLs with tumour-specific cytotoxicity through the administration of the glycolipid α-galactosylceramide (α-GalCer), which is a compound known to stimulate invariant natural killer T (iNKT) cells and selectively activate DEC-205+ DCs. Moreover, we demonstrated that sequential repetitive intraperitoneal inoculation with α-GalCer every 48 hr appeared to convert tolerogenic DEC-205+ DCs into immunogenic DCs with a higher expression of co-stimulatory molecules and a stronger cross-presentation capacity, which primed CTL precursors and induced tumour-specific CD8+ CTLs within the tumour environment without activating iNKT cells. These findings provide a new basis for cancer immunotherapy to convert tolerogenic DEC-205+ DCs within tumours into immunogenic DCs through the sequential administration of an immuno-potent lipid/glycolipid, and then activated immunogenic DCs with sufficient expression of co-stimulatory molecules prime and activate tumour-specific CD8+ CTLs within the tumour to control tumour growth.

α-Galactosylceramide-activated murine NK1.1(+) invariant-NKT cells in the myometrium induce miscarriages in mice.

Innate immunity, which is unable to discriminate self from allo-antigens, is thought to be important players in the induction of miscarriages. Here, we show that the administration of IL-12 to syngeneic-mated C57BL/6 mice on gestation day 7.5 (Gd 7.5), drives significant miscarriages in pregnant females. Furthermore, the administration on Gd 7.5 of α-galactosylceramide (α-GalCer), which is known to activate invariant natural killer T (iNKT) cells, induced miscarriages in both syngeneic-mated C57BL/6 mice and allogeneic-mated mice (C57BL/6 (♀) × BALB/c (♂)). Surprisingly, the percentages of both DEC-205(+) DCs and CD1d-restricted NK1.1(+) iNKT cells were higher in the myometrium of pregnant mice treated i.p. with α-GalCer than in the decidua. IL-12 secreted from α-GalCer-activated DEC-205(+) DCs stimulated the secretion of cytokines, including IL-2, IL-4, IFN-γ, TNF-α, perforin, and granzyme B, from the NK1.1(+) iNKT cells in the myometrium, leading to fetal loss in pregnant mice. Finally, the i.p. administration of IL-12 and/or α-GalCer in iNKT-deficient Jα18(-/-) (Jα18 KO) mice did not induce miscarriages. This study provides a new perspective on the importance of the myometrium, rather than the decidua, in regulating pregnancy and a mechanism of miscarriage mediated by activated DEC-205(+) DCs and NK1.1(+) iNKT cells in the myometrium of pregnant mice.

Effects of Dendritic Cell Subset Manipulation on Airway Allergy in a Mouse Model.

BACKGROUND: Two major distinct subsets of dendritic cells (DCs) are arranged to regulate immune responses: DEC-205+ DCs drive Th1 polarization and 33D1+ DCs establish Th2 dominancy. Th1 polarization can be achieved either by depletion of 33D1+ DCs with a 33D1-specific monoclonal antibody (mAb) or by activation of DEC-205+ DCs via intraperitoneal injection of α-galactosylceramide (α-GalCer). We studied the effect of 33D1+ DC depletion or DEC-205+ DC activation in vivo using an established mouse model of allergic rhinitis (AR). METHODS: Mice were injected intraperitoneally with OVA plus alum and challenged 4 times with daily intranasal administration of OVA. Immediately after the last challenge, allergic symptoms such as sneezing and nasal rubbing as well as the number of cells in the bronchoalveolar lavage fluid (BALF) and nasal lavage fluid (NALF) were counted. The levels of serum OVA-specific IgG1, IgG2a, and IgE were also determined by ELISA. RESULTS: The allergic symptom scores were significantly decreased in 33D1+ DC-depleted or DEC-205+ DC-activated AR mice. The levels of OVA-specific IgG1, IgG2a, and IgE, and the number of NALF cells, but not BALF cells, were reduced in 33D1+ DC-depleted but not in DEC-205+ DC-activated AR mice. Moreover, the activated DEC-205+ DCs suppressed histamine release from IgE-sensitized mast cells, probably through IL-12 secretion. CONCLUSIONS: The manipulation of innate DC subsets may provide a new therapeutic strategy for controlling various allergic diseases by reducing histamine release from IgE-sensitized mast cells by driving the immune response towards Th1 dominancy via activation of DEC-205+ DCs in vivo.

Associations of Nutrients and Dietary Preferences with Recurrent Pregnancy Loss and Infertility.

This review examines associations of nutrients and dietary preferences with recurrent pregnancy loss (RPL), miscarriage, and infertility. Research articles, reviews, and meta-analyses of RPL and infertility that focused on nutrition, meals, and lifestyle were reviewed, and associations of nutrients and dietary preferences with pregnancy are discussed in relation to recent research findings. Studies related to RPL were given the highest priority, followed by those dealing with miscarriage and infertility. Multivitamin supplements-even when lacking folic acid or vitamin A-reduced total fetal loss. High-dose folic acid supplementation before conception reduced the risk of miscarriage and stillbirth. A meta-analysis revealed a strong association of vitamin D deficiency/insufficiency with miscarriage. Another meta-analysis revealed that seafood and dairy products reduced the risk of miscarriage, whereas a caffeine intake of 300 mg/day or more was associated with miscarriage. A balanced diet that included nutrients with antioxidant properties helped prevent miscarriage, whereas a diet that included processed foods and nutrients with proinflammatory effects increased the risk of miscarriage. Associations of nutrients with RPL warrant further research.

Downregulation of pattern recognition receptors on macrophages involved in aggravation of endometriosis.

PROBLEM: In women of reproductive age, endometriosis may contribute to dysmenorrhea, chronic pelvic pain, dyspareunia, infertility, adenomyosis, and endometrial ovarian cyst (EOC). Recent studies have shown that chronic inflammation occurs in the pelvis of endometriosis patients and that this inflammation is exacerbated by immunosuppression, leading to survival endometrial debris. However, the detailed immunological mechanisms underlying the aggravation of inflammation and immunosuppression in endometriosis patients remain unclear. METHOD OF STUDY: We investigate the alarmins (high-mobility group box-1, IL-33, IL-1α, and S100B protein), proinflammatory cytokines (IL-6 and IL-1ß), and immune cells (CD8+ T cells, CD4+ T cells, natural killer cells, natural killer T cells, dendritic cells, and macrophages) in peritoneal fluid of patients with EOC using enzyme-linked immunosorbent assay, electrochemiluminescence, and flow cytometry. Then, we analyzed the correlation between these factors and the aggravating indicators of endometriosis, tumor size and revised American Society for Reproductive Medicine (r-ASRM) score. RESULTS: Unexpectedly, there was no correlation between each alarmin level and aggravating indicators. However, the expression of pattern recognition receptors, toll-like receptor 4, and receptor of advanced glycation end-products on macrophages was inversely correlated with aggravating indicators. CONCLUSIONS: The aggravation of endometriosis is associated with a decrease in alarmin receptors but not alarmin levels. Investigation of innate immune systems, such as alarmins and their receptors, may help elucidate new mechanisms of endometriosis.

Cytoplasmic and nuclear DROSHA in human villous trophoblasts.

In villous trophoblasts, DROSHA is a key ribonuclease III enzyme that processes pri-microRNAs (pri-miRNAs) into pre-miRNAs at the placenta-specific, chromosome 19 miRNA cluster (C19MC) locus. However, little is known of its other functions. We performed formaldehyde crosslinking, immunoprecipitation, and sequencing (fCLIP-seq) analysis of terminal chorionic villi to identify DROSHA-binding RNAs in villous trophoblasts. In villous trophoblasts, DROSHA predominantly generated placenta-specific C19MC pre-miRNAs, including antiviral C19MC pre-miRNAs. The fCLIP-seq analysis also identified non-miRNA transcripts with hairpin structures potentially capable of binding to DROSHA (e.g., SNORD100 and VTRNA1-1). Moreover, in vivo immunohistochemical analysis revealed DROSHA in the cytoplasm of villous trophoblasts. DROSHA was abundant in the cytoplasm of villous trophoblasts, particularly in the apical region of syncytiotrophoblast, in the full-term placenta. Furthermore, in BeWo trophoblasts infected with Sindbis virus (SINV), DROSHA translocated to the cytoplasm and recognized the genomic RNA of SINV. Therefore, in trophoblasts, DROSHA not only regulates RNA metabolism, including the biogenesis of placenta-specific miRNAs, but also recognizes viral RNAs. After SINV infection, BeWo DROSHA-binding VTRNA1-1 was significantly upregulated, and cellular VTRNA1-1 was significantly downregulated, suggesting that DROSHA soaks up VTRNA1-1 in response to viral infection. These results suggest that the DROSHA-mediated recognition of RNAs defends against viral infection in villous trophoblasts. Our data provide insight into the antiviral functions of DROSHA in villous trophoblasts of the human placenta.

Oxidative Stress and Antioxidant Capacity in Patients with Endometrioma.

BACKGROUND: Endometriosis has several clinical features, including dysmenorrhea, infertility, and endometrioma (EMO). Although oxidative stress status is closely related to endometriosis, it is unclear how the balance between oxidative stress capacity and antioxidant capacity correlates with treatment of or factors that worsen endometriosis. In this study, we used peritoneal fluid from patients with EMO to investigate the role of oxidative stress capacity and antioxidant capacity. MATERIALS AND METHODS: Participants with EMO (n = 30) and without EMO (uterine myoma, n = 13) were enrolled. All peritoneal fluid samples were collected at the beginning of surgery. We evaluated oxidative stress capacity and antioxidant capacity in peritoneal fluid samples by using the diacron-reactive oxygen metabolites (d-ROM) and biological antioxidant potential (BAP) tests, respectively. The d-ROM and BAP values and the d-ROM/BAP ratio were measured, and their correlations with the CA125 level, revised American Society for Reproductive Medicine (r-ASRM) score, and tumor size were analyzed. RESULTS: The d-ROM/BAP ratio was significantly higher in patients with EMO than in those without EMO. In addition, the d-ROM/BAP ratio was positively correlated with CA125 level and r-ASRM scores in patients with EMO. CONCLUSIONS: Oxidative stress is correlated with factors that worsen EMO. The d-ROM/BAP test may be useful for assessing disease status in patients with EMO.

Sustained sterile inflammation is related to pulmonary morbidities in premature infants.

OBJECTIVE: Sterile inflammation, initiated by endogenous molecules such as high-mobility group box-1 (HMGB1), has come to be recognized as a critical mechanism in a variety of chronic diseases. To elucidate the involvement of sterile inflammation in neonatal disease, the association between serum HMGB1 levels and the development of bronchopulmonary dysplasia (BPD) was evaluated. STUDY DESIGN: Serum HMGB1 levels were measured in 25 premature infants born before 33 weeks of gestation, excluding any infection cases. Samples were collected at birth, two, and four weeks of age and compared according to BPD status. RESULTS: The serum HMGB1 levels in infants with BPD were maintained up to 4 weeks of age, while those without BPD declined with time. Postnatal cardiopulmonary and nutritional transition was delayed in infants with BPD. CONCLUSION: Sustained elevation of serum HMGB1 levels was associated with the development of BPD, suggesting that prolonged sterile inflammation may contribute to lung injury.

Inflammation in preterm birth: Novel mechanism of preterm birth associated with innate and acquired immunity.

Preterm birth (PB) is the most-frequent complication occurring during pregnancy, with a significant impact on neonatal morbidity and mortality. Chorioamnionitis (CAM), the neutrophil infiltration into chorioamniotic membranes, is a major cause of PB. However, several cases of PB have also been reported without apparent pathogenic infection or CAM. Such cases are now attributed to "sterile inflammation." The concept of sterile inflammation has already attracted attention in various diseases, like cardiovascular diseases, diabetes, and autoimmune diseases; recently been discussed for obstetric complications such as miscarriage, PB, gestational hypertension, and gestational diabetes. Sterile inflammation is induced by alarmins, such as high-mobility group box 1 (HMGB1), interleukins (IL-33 and IL-1α), and S100 proteins, that are released by cellular damage without apparent pathogenic infection. These antigens are recognized by pattern-recognition receptors, expressed mainly on antigen-presenting cells of decidua, placenta, amnion, and myometrium, which consequently trigger inflammation. In reproduction, these alarmins are associated with the development of various pregnancy complications, including PB. In this review, we have summarized the development of PB related to acute CAM, chronic CAM, and sterile inflammation as well as proposed a new mechanism for PB that involves innate immunity, acquired immunity, and sterile inflammation.

Harmful and beneficial effects of inflammatory response on reproduction: sterile and pathogen-associated inflammation.

In reproduction, inflammatory processes play important roles in the development of many pregnancy complications such as preterm labor/birth, recurrent pregnancy loss, recurrent implantation failure, and preeclampsia. Inflammation can be initiated by both microbial and non-microbial causes. Bacterial infection in the feto-maternal interface and uterus can provoke preterm labor/birth, miscarriage, and chronic endometritis. By contrast, inflammation without infection, or 'sterile inflammation,' can also lead to many kinds of complications, such as preterm labor/birth, miscarriage, or preeclampsia. Aberrant inflammation is facilitated by immune cells such as macrophages, dendritic cells, natural killer cells, and invariant natural killer T cells. In addition, cytokines, chemokines, and several kinds of inflammatory mediators are involved. On the other hand, appropriate inflammation is required for a successful offspring during the progression of the entire pregnancy. Herein, we discuss the relation between pregnancy and inflammation with immunological alterations. Understanding the role of inflammation in complications during pregnancy may establish new perspectives of the progress of normal pregnancy as well as treatments during pregnancy complications.

Inflammation related to high-mobility group box-1 in endometrial ovarian cyst.

Endometriosis is a chronic inflammatory disease often associated with dysmenorrhea, infertility, adenomyosis, and endometrial ovarian cyst (EOC). In particular, EOC can sometimes become malignant in a longitudinal follow-up. This study aimed to investigate the involvement of high-mobility group box-1 (HMGB1) in an inflammatory milieu and the characteristics of immune cells in EOC. The samples were obtained from patients who underwent ovarian cystectomy for benign ovarian cyst. The participants were divided into two groups: patients with EOC (EOC group) and those without EOC (nEOC group). We divided a part of the removed ovary into small sections and isolated the tissue cells. Thereafter, the cytoplasmic HMGB1 levels in DCs, macrophages, and non-immune cells were analyzed by flow cytometry. We also evaluated the proportions of immune, T, NK, iNKT, NK, and regulatory T (Treg) cells. Results showed that the DCs, macrophages, and non-immune cells of EOC had significantly higher cytoplasmic HMGB1 levels than those of nEOC. The expression of CD69 and CD107a on CD8+ T and CD4+ T cells of EOC was also more enhanced than that of nEOC. Furthermore, the M2 macrophages and Tregs highly accumulated in EOC. These results indicate that HMGB1 may aggravate chronic inflammation related to T-cell activation and simultaneously facilitate development of the immunosuppressive milieu in EOCs.

Inappropriate activation of invariant natural killer T cells and antigen-presenting cells with the elevation of HMGB1 in preterm births without acute chorioamnionitis.

PROBLEM: Acute chorioamnionitis (aCAM) associated with microbial infection is a primary cause of preterm birth (PB). However, recent studies have demonstrated that innate immunity and sterile inflammation are causes of PB in the absence of aCAM. Therefore, we analyzed immune cells in the decidua of early to moderate PB without aCAM. METHOD OF STUDY: Deciduas were obtained from patients with PB at a gestational age of 24+0 to 33+6  weeks without aCAM in pathological diagnosis. The patients were divided into two groups as follows: patients with labor and/or rupture of membrane (ROM) (no aCAM with labor and/or ROM: nCAM-w-LR), and patients without labor and/or ROM (no aCAM without labor and/or ROM: nCAM-w/o-LR). The immune cells and high mobility group box 1 (HMGB1) levels in the decidua were analyzed using flow cytometry. Co-culture of CD56+ cells with dendritic cells (DCs) and macrophages obtained from the decidua was also performed in the presence of HMGB1. RESULTS: The nCAM-w-LR group demonstrated an accumulation of iNKT cells, and increased expression of HMGB1, TLR4, receptors for advanced glycation end products, and CD1d on DCs and macrophages. HMGB1 facilitated the proliferation of iNKT cells co-cultured with DCs and macrophages, which was found to be inhibited by heparin. CONCLUSIONS: Inappropriate activation of innate immune cells and increased HMGB1 expression may represent parturition signs in human pregnancy. Therefore, control of these cells and HMGB1 antigenicity may be represent a potential therapeutic target for the prevention of PB.

Alcohol consumption induces murine osteoporosis by downregulation of natural killer T-like cell activity.

INTRODUCTION: Chronic alcohol consumption (CAC) can induce several deleterious effects on the body, including the promotion of osteoporosis; however, the immunological mechanism underlying alcohol-induced osteoporosis is still unclear. METHODS: We administered alcohol to mice for 4 weeks as the experimental CAC model and analyzed the bone and immune cells that are located in the vicinity of a bone. RESULTS: IL-4 is known to be a suppressive factor for osteoclastogenesis, and we found that natural killer T (NKT)-like cells, which showed NK1.1-positive, CD3-positive, and α-galactosylceramide-loaded CD1d tetramer-negative, produced IL-4 more effectively than CD4+ T and natural killer (NK) cells. The alcohol consumption facilitated a significant decrease of bone mineral density with the upregulation of nuclear factor of activated T cells 1 and receptor activator of NF-κB ligand expression. Meanwhile, we confirmed that alcohol consumption suppressed the activity of antigen-presenting cells (APCs) and NKT-like cells, leading to decreased IL-4 secretion. Moreover, these harmful effects of alcohol consumption were reduced by simultaneous treatment with a glycolipid antigen OCH. CONCLUSIONS: Our results indicate that the inactivation of innate immune cells, APCs, and NKT-like cells are likely to be crucial for alcohol-induced osteoporosis and provide a new therapeutic approach for preventing osteoporosis.

Distribution of dendritic cells in the septate uterus: An immunological perspective.

PROBLEM: Septate uterus is associated with spontaneous abortion. Surgical intervention of the uterine septa (US) is frequently performed following spontaneous abortion; however, immunological mechanisms for spontaneous abortion in patients with septate uterus remain completely unknown. METHOD OF STUDY: A total of 12 women with septate uterus who underwent hysteroscopic metroplasty and 10 women with uterine leiomyoma who underwent total hysterectomy were enrolled as the experimental and control groups, respectively. Immune cells, dendritic cells (DCs), macrophages, T cells, natural killer cells, invariant natural killer cells, and chemokine receptors in US and uterine myometrium tissue (UMT) were analyzed using flow cytometry and immunohistochemical staining. Additionally, the chemokine production of macrophage inflammatory protein 1 alpha (MIP-1α), regulated upon activation normal T-cell express sequence (RANTES), and macrophage inflammatory protein 3 beta (MIP-3ß) from the viable cells obtained from the US and UMT samples was evaluated in an ex vivo study. RESULTS: The percentage of CD141+ DCs in US was significantly lower than that in UMT. Both US and UMT showed CCR1 and CCR5 expression on CD141+ DCs; however, the production of chemokines, MIP-1α, RANTES, and MIP-3ß was abundant in UMT-obtained viable cells. CONCLUSION: The accumulation of CD141+ DCs was lower in US than that in UMT. This phenomenon may be caused by low chemokine productions in US. Our findings support the benefit of surgical intervention for septate uterus-that is, the elimination of inappropriate implantation sites.