Tadahiro Yasuo

Potential Selectin L Ligands Involved in Selective Recruitment of Peripheral Blood CD16(–) Natural Killer Cells into Human Endometrium

Abstract Unique CD16(–) natural killer (NK) cells appear in the human cycling endometrium and acutely increase in number after ovulation. Selective recruitment from peripheral blood (PB) CD16(–) NK cells is a potential mechanism for the postovulatory increase of these NK cells. The interaction between selectin L, an adhesion molecule playing a critical role in leukocyte extravasation, and its ligands may be involved in this phenomenon. We investigated the menstrual cycle-dependent fluctuation of selectin L expression on PB CD16(–) NK cells and selectin L ligand expression in the human endometrial endothelium. The expression of selectin L on PB CD16(–) NK cells was constantly high throughout the menstrual cycle compared with other PB CD16(+) NK cells and non-NK lymphocytes. Among eight selectin L ligands examined, podocalyxin-like, mucosal addressin cell adhesion molecule-1 (MADCAM1) and chondroitin sulfate proteoglycan 2 (CSPG2) were localized in the endometrial endothelium. Semiquantitative score of immunostaining intensity in the endometrial endothelium for MADCAM1 was highest in the late secretory phase, whereas that for CSPG2 peaked throughout the secretory phase. There was a strong positive correlation between the number of endometrial NK cells and the semiquantitative score for CSPG2. Three active isoforms of CSPG2 mRNA were detected in the human endometrium. These findings support the idea that the interaction between selectin L and selectin L ligands functions in the postovulatory selective recruitment of PB CD16(–) NK cells into the human endometrium.

Immunohistochemistrical and Clinicopathological Characterization of Chronic Endometritis

Citation Kitaya K, Yasuo T. Immunohistochemistrical and clinicopathological characterization of chronic endometritis. Am J Reprod Immunol 2011; 66: 410–415

Aberrant expression of selectin E, CXCL1, and CXCL13 in chronic endometritis

Chronic endometritis is often identified in the patients with unexplained infertility, and is histopathologically characterized by infiltration of plasmacytes within the endometrial stroma. In parallel with stromal plasmacyte infiltration, the endometrial functional layer in chronic endometritis is invaded by B cells, which are a rare leukocyte subset residing within the basal layer in the nonpathological endometrium. In this study, we investigated the molecular expression underlying this unusual increase of B cells in chronic endometritis. Twenty-two out of 76 infertile patients were diagnosed with chronic endometritis from the stromal plasmacyte infiltration, and the endometrium contained numerous stromal B-cell aggregates and glandular single B cells. However, the other major leukocyte subsets, including T cells, natural killer cells, macrophages, and neutrophils were comparable in densities in chronic endometritis and nonpathological endometrium. The microvascular endothelium showed immunoreactivity to adhesion molecule selectin E and chemokine CXCL13 along with immunoreactivity to CXCL1 in the glandular epithelium in chronic endometritis, but not in the nonpathological endometrium. Lipopolysaccharide significantly induced surface selectin E expression and CXCL13 secretion in uterine microvascular endothelial cells, and CXCL1 secretion in endometrial epithelial cells in vitro. These findings indicated that the aberrant local microenvironment triggered possibly by bacterial infection has a role in selective extravasation of circulating B cells in chronic endometritis.

Dermatan sulfate proteoglycan biglycan as a potential selectin L/CD44 ligand involved in selective recruitment of peripheral blood CD16(−) natural killer cells into human endometrium

Unique CD16(−) NK cells acutely increase in the human uterine endometrium after ovulation. The origin of these NK cells remains unknown, but they may be recruited selectively from the circulation. Proteoglycans and their glycosaminoglycan side‐chains expressed on endometrial microvascular endothelial cells play a key role in lymphocyte tethering/rolling, the initial step of lymphocyte extravasation. In this study, we sought for the potential proteoglycans involved in tethering/rolling of peripheral blood CD16(−) NK cells on endometrial microvascular endothelial cells. As compared with CD16(+) NK cells and non‐NK cells, enriched peripheral blood CD16(−) NK cells bound preferably to immobilized glycosaminoglycans except for keratan sulfate. CD16(−) NK cells bound maximally to dermatan sulfate (DS), which was diminished by enzymatic pretreatment with dermatanase and chondroitinase ABC, but not with chondroitinase ACII. The binding capacity of CD16(−) NK cells to DS was attenuated by blocking antibodies against selectin L and CD44 or pretreatment of CD16(−) NK cells with IL‐15. Of three known DS proteoglycans, biglycan and decorin but not epiphycan were expressed in the human cycling endometrium. In the endometrial microvessels, the immunoreactivity for biglycan was greater in the secretory phase than in the proliferative phase, and there was little, if any, immunoreactivity for decorin throughout the menstrual cycle. The ovarian steroid progesterone enhanced biglycan expression in cultured human uterine microvascular endothelial cells. These findings demonstrated that DS proteoglycan biglycan is a potential selectin L/CD44 ligand involved in tethering/rolling of peripheral blood CD16(−) NK cells on endometrial microvascular endothelial cells.

Chronic Endometritis: Potential Cause of Infertility and Obstetric and Neonatal Complications.

Chronic endometritis (CE) is a local inflammatory disease characterized by unusual plasmacyte infiltration in the endometrial stromal areas. CE has been neglected in gynecologic practice, as it is a less symptomatic benign disease that requires demanding and time‐consuming histopathologic examinations for the definite diagnosis. Recent studies, however, suggest the association of CE with infertility and obstetric and neonatal complications. In this review article, we aimed to update the knowledge on epidemiology, etiology, and pathogenesis of CE as well as discuss its clinical management from diagnosis to treatment.

Leukocyte density and composition in human cycling endometrium with uterine fibroids

In this study, we evaluated the leukocyte density and composition in the human cycling endometrium with uterine fibroids (UF). The endometrium with neighboring nodule (NN group, n = 62), autologous endometrium without NN (non-NN group, n = 62), and allogeneic endometrium without UF (non-UF group, n = 24) were immunostained for the leukocyte common and subset-specific antigens. The immunoreactive cells in the unit areas were enumerated under a light microscope. The stromal pan-leukocyte density in the proliferative phase was significantly higher in the endometrium in the NN group than in the non-NN group. The macrophage density was higher in the NN group than in the non-NN group throughout the menstrual cycle. The NK cell density in the mid-to-late secretory phase was lower in the NN group than in the non-NN group. The T cell density in the midsecretory phase was higher in the non-NN group than in the non-UF group. The neutrophil density in the proliferative phase was higher in the non-NN group than in the non-UF group. The leukocyte density and composition in the endometrium with UF are different from those without UF, suggesting their local effects on endometrial leukocyte population.

Effect of ovarian steroids on gene expression profile in human uterine microvascular endothelial cells

OBJECTIVE To examine the effect of the ovarian steroids on the gene expression profile in human uterine microvascular endothelial cells. DESIGN An experimental study. SETTING University hospital and research laboratory. PATIENT(S) Eighteen premenopausal women with proven fertility undergoing hysterectomy for cervical carcinoma in situ or cervical dysplasia. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) The effect of E(2) and P on gene expression profile in pooled human uterine microvascular endothelial cells was examined with cDNA microarray analysis and confirmed with quantitative real-time reverse transcriptase polymerase chain reaction. In vivo endometrial endothelial expression of the proteins encoded by the genes significantly regulated by E(2) and/or P was examined with Western blotting analysis and immunohistochemistry. RESULT(S) The genes steadily up-regulated by E(2) and/or P included angiogenic factors, water transporters, immunomodulators, binding proteins, electron transporters, amino acid transporter, signal transduction proteins, and blood pressure regulation factors. The proteins encoded by IL1RL1, WAS, and NPPA were detected in endometrial microvascular endothelial cells. CONCLUSION(S) Progesterone (alone or in combination with E(2)) can induce the genes involved in angiogenesis, edematous change, and leukocyte recruitment in human uterine microvascular endothelial cells. Ovarian steroids may contribute to endometrial differentiation via the action on local microvessels.

Inter-observer and intra-observer variability in immunohistochemical detection of endometrial stromal plasmacytes in chronic endometritis

Chronic endometritis (CE) is an unusual endometrial inflammation characterized by stromal plasmacyte infiltration. CE is easily missed due to its subtle symptoms and demanding histopathological examinations. Although the immunohistochemistry for the plasmacyte marker CD138 has facilitated the detection of endometrial stromal plasmacytes, the accuracy and biases of this method for CE diagnosis remain poorly understood. The aim of this study was to investigate the inter- and intra-observer variability in the immunohistochemical detection of stromal plasmacytes in the human endometrium. A total of 80 CE and 20 non-pathological archival hematoxylin-stained endometrial preparations with or without immunostaining for CD138 were evaluated independently by two experienced observers and two inexperienced observers. Endometrial stromal plasmacytes in unit areas were counted in the hematoxylin-stained and CD138-immunostained preparations. Each preparation was subdivided into 11 categories by every five plasmacyte counts. The second evaluation was performed four weeks after the first evaluation. The immunohistochemical detection method was superior to conventional histopathological evaluation in both the inter- and intra-observer agreement, irrespective of the experience level of the observers. The linear weighted κ coefficient for intra-observer agreement was higher in the experienced observers than in the inexperienced observers. The inter-observer agreement among the four observers by the immunohistochemical detection method was similarly good between the first and second evaluation. There was no significant inter- or intra-observer variability in the paired comparison of the individual samples. These findings validate the use of immunohistochemistry for CD138 as an accurate and less biased diagnostic tool for CE.

Premature delivery due to intrauterine Candida infection that caused neonatal congenital cutaneous candidiasis: A case report

Congenital cutaneous candidiasis is a very rare disease with less than 100 cases published in the medical literature. Neonates having this disease present with systemic skin lesions caused by intrauterine Candida infections. We present a case of threatened premature delivery due to Candida chorioamnionitis, which caused both maternal postpartum endometritis and neonatal congenital cutaneous candidiasis. A 34‐year‐old woman who was admitted for fetal membrane bulging at 20 weeks of gestation underwent McDonald cervical cerclage. We diagnosed threatened premature delivery due to intrauterine infection; therefore, we terminated the gestation by cesarean section at 24 weeks of gestation. Fungi‐like yeast was detected in infantile gastric juice. Histopathological findings of the placenta revealed that Candida albicans mycelium invaded the placenta, chorioamniotic membrane and umbilical cord.

Unusual inflammation in gynecologic pathology associated with defective endometrial receptivity.

Human cycling endometrium displays a series of periodic transitions unique to this mucosal tissue, which includes rapid proliferation, secretory transformation, physiological angiogenesis, interstitial edema, and menstrual shedding. Among these properties of the endometrium are the inflammatory changes that occur dynamically across the menstrual cycle. Immunocompetent cell composition and inflammatory gene expression pattern in the human endometrium drastically fluctuate from the proliferative phase to the secretory phase, particularly at the time of ovulation. These local immune responses are fine-tuned by the direct or indirect action of two representative ovarian steroids, estradiol and progesterone, and are essential for successful blastocyst implantation. Meanwhile, studies have been accumulating the evidence that such physiological endometrial inflammatory status is altered in the presence of certain gynecologic pathologies. Given that blastocysts are semi-allografts for maternal tissue, even subtle alterations in endometrial immunity potentially have a negative impact on implantation process. In this article, we aimed to review and discuss the physiological and pathological mucosal inflammatory conditions that can affect endometrial receptivity.