Peritoneal natural killer cell chemotaxis is decreased in women with pelvic endometriosis.

PROBLEM: NK cell and macrophage function are decreased in endometriosis, and the disease may involve reduced immune surveillance in the peritoneal cavity. NK cell cytotoxicity and migration ability (chemotaxis) are considered important; the former has been investigated, but the latter has not. METHOD OF STUDY: We compared chemotaxis of immunocompetent cells (NK cells, macrophages, T cells) in peritoneal fluid obtained during laparoscopy in 27 women with and 13 without endometriosis. Peripheral blood NK cells were also obtained by the peripheral blood antibody beads method. Micro-cultured cells were examined by time-lapse photography, and the mean migration speed per cell was calculated as the chemotaxis. We investigated the relationship between chemotaxis and endometriosis. RESULTS: NK cell chemotaxis was significantly lower in the endometriosis group. Macrophages and lymphocytes were not significantly different between the groups. During menstruation, NK cell chemotaxis decreased in both groups. Postmenstrual chemotaxis was increased significantly in women without endometriosis but remained low in women with endometriosis. The Revised-American Society for Reproductive Medicine score was not correlated with chemotaxis; in women with endometriosis, chemotaxis was decreased even at early stages. Peripheral blood NK cells showed no significant differences. CONCLUSIONS: In women with endometriosis, not only cytotoxicity but also chemotaxis by NK cells in peritoneal cavity is significantly decreased, and particularly chemotaxis is decreased throughout the menstrual cycle. Therefore, antigens in retrograde menstrual blood that enters the peritoneal cavity might be left unprocessed. Repetition of this immune process in the peritoneal cavity may lead to the onset and subsequent progression of endometriosis.

Role of NK cells and HLA-G in endometriosis.

Impaired natural killer (NK) activity in women with endometriosis is thought to promote implantation and progression of endometrial tissue, in accord with Sampson's hypothesis. However, the mechanisms responsible for decreased NK cell activity and the antigens recognized by NK cells are not clear.We focused on human leukocyte antigen (HLA)-G, a ligand of NK receptors, expression and its menstrual cycle changes by eutopic endometrium. Interestingly, HLA-G expression was identified on eutopic endometrium only in the menstrual phase but not in the proliferative or secretory phases. Furthermore, HLA-G expressing cells were also detected in peritoneal fluid during the menstrual period. During retrograde menstruation, HLA-G expressing endometrial tissue may enter the peritoneal cavity, and may be reduced by immunosurveillance system. Although peritoneal NK cells play an important role in this system, impairment of NK cytotoxicity via HLA-G may allow peritoneal endometrial cell survival and implantation. In this review, we discuss the pathogenesis of endometriosis from the viewpoint of intraperitoneal immune interaction between NK cell receptors and HLA-G that can enter into peritoneal cavity from eutopic endometrium through retrograde menstruation.

Human leukocyte antigen-G, a ligand for the natural killer receptor KIR2DL4, is expressed by eutopic endometrium only in the menstrual phase.

OBJECTIVE: To investigate menstrual cycle changes in expression by eutopic endometrium of a nonclassic human leukocyte antigen, HLA-G, which binds to the killer immunoglobulin-like receptor (KIR) 2DL4 (CD158d) on natural killer (NK) cells. Such antigens have been linked to endometriosis. DESIGN: Case-control study. SETTING: University hospital. PATIENT(S): We examined 20 Japanese women undergoing hysterectomy for endometriosis and 17 undergoing hysterectomy for myoma. INTERVENTION(S): Immunohistochemical HLA-G staining of eutopic endometrium and peritoneal fluid (PF) cells from women with and without endometriosis. Flow cytometric analysis of PF NK cells from women with and without endometriosis. MAIN OUTCOME MEASURE(S): HLA-G staining in eutopic endometrium was quantified by image analysis. The KIR2DL4-expressing NK cells in PF were investigated by flow cytometry. RESULT(S): The HLA-G was expressed by eutopic endometrium only in the menstrual phase and not in the late proliferative or secretory endometrium. Intensity of HLA-G staining did not differ significantly between women with and without endometriosis. The HLA-G- expressing cells were detected in PF during the menstrual period. These cells are morphologically and flow cytometrically different from mesothelial cells and NK cells. CONCLUSION(S): The HLA-G expression is observed in eutopic endometrium only during the menstrual phase, and no differences were observed between women with and without endometriosis. Epithelial cells bearing HLA-G may enter the peritoneal cavity during retrograde menstruation, allowing the antigen to react locally with KIR2DL4.

Decreased human leukocyte antigen-DR expression in the lipid raft by peritoneal macrophages from women with endometriosis.

OBJECTIVE: To investigate the macrophage response in endometriosis by determining the expression and localization of human leukocyte antigen (HLA)-ABC and HLA-DR by the peritoneal fluid (PF) macrophages and PF concentrations of interferon (IFN)-gamma that regulate HLA expression. DESIGN: Case-control study. SETTING: University hospital. PATIENT(S): 64 Japanese endometriosis patients, and 65 women with other laparoscopic diagnoses. INTERVENTION(S): Venipuncture and laparoscopic peritoneal fluid collection. MAIN OUTCOME MEASURE(S): Expression and localization of HLA-ABC and HLA-DR in PF macrophages were determined by flow cytometry and confocal microscopy. The concentration of IFN-gamma in PF was determined by enzyme-linked immunosorbent assay. RESULT(S): In women with endometriosis, expression of HLA-ABC and HLA-DR by PF macrophages, and the IFN-gamma concentrations in PF were statistically significantly lower than in controls. Women with endometriosis showed a statistically significant positive correlation between HLA expression and IFN-gamma concentration. By confocal microscopy, HLA-ABC was distributed homogenously on the macrophage surface whereas HLA-DR expression on these cells corresponded to the lipid raft. CONCLUSION(S): In women with endometriosis, low HLA expression and particularly reduced HLA-DR in the lipid raft may be influenced by low IFN-gamma and may compromise antigen presentation, limiting the immune response to peritoneal cavity antigens such as implanted or metaplastic endometrial tissue.

Killer immunoglobulin-like receptor and human leukocyte antigen expression as immunodiagnostic parameters for pelvic endometriosis.

PROBLEM: We investigated host immunologic responses to endometriosis by comparing immune cell surface antigens in peripheral blood (PB) and peritoneal fluid (PF) from women with endometriosis with those in PB and PF from other patients. METHOD OF STUDY: Japanese women with endometriosis (n = 56) were compared with controls with other laparoscopic diagnoses (n = 68). PB and PF were collected at the time of laparoscopy for flow cytometry. RESULTS: No significant difference in phenotypic parameters of T cells (CD3, CD4, and CD8), B cells (CD19), natural killer (NK) cells (CD56), or monocytes/macrophages (CD14) was seen between women with and without endometriosis. However, increased killer immunoglobulin-like receptor (CD158a) expression by NK cells and decreased human leukocyte antigen (HLA)-ABC and -DR expression by macrophages, all suggesting decreased functional activation were found in endometriosis. These markers showed significant association with endometriosis by odds ratio, logistic regression, and decision tree analyses. CONCLUSIONS: Increased CD158a(+) NK cells in PB and PF indicated decreased NK cell cytotoxicity in endometriosis, while decreased HLA expression on PF macrophages suggested impaired antigen presentation. Thus, aberrant immune responses by NK cells and macrophages may represent risk factors for endometriosis.

Human leukocyte antigen expression by peritoneal macrophages from women with pelvic endometriosis is depressed but coordinated with costimulatory molecule expression.

OBJECTIVE: To investigate the macrophage response in endometriosis, we determined expression of human leukocyte antigen (HLA)-ABC, HLA-DR, and their costimulatory molecules by peritoneal fluid (PF) macrophages. DESIGN: Case-control study of immunologic markers. SETTING: University hospital. PATIENT(S): We compared 38 Japanese women with endometriosis with 59 control subjects who were given other laparoscopic diagnoses. INTERVENTION(S): Venipuncture and laparoscopic peritoneal fluid collection. MAIN OUTCOME MEASURE(S): Expression of HLA-ABC, HLA-DR, CD54, CD40, CD58, CD80, and CD86 by peripheral blood (PB) monocytes and PF macrophages was quantitated as mean fluorescence intensities by flow cytometry. Expression of each marker on PF macrophages was divided by that on PB monocytes as an index of macrophage activation (macrophage activation ratio). RESULT(S): In women with endometriosis, PF macrophages showed significant positive correlations between expression of HLA-ABC and other costimulatory molecules and also between HLA-DR and their costimulatory molecules. However, expression of HLA-ABC and DR by PF macrophages, and also their activation ratios, were significantly lower than in controls. CONCLUSION(S): Coordination with costimulatory molecules but relatively low expression of HLA-ABC and HLA-DR indicates a positive but limited immune response (antigen presentation) to events in the peritoneal cavity in women with endometriosis. This may induce immune tolerance to implanted or metaplastic endometrial tissue.

Expression of inhibitory-motif killer immunoglobulin-like receptor, KIR2DL1, is increased in natural killer cells from women with pelvic endometriosis.

PROBLEM: We investigated inhibitory and activation motif expression of killer immunoglobulin-like receptor (KIR) by natural killer (NK) cells, which may be pathogenetically involved in endometriosis. METHOD OF STUDY: We compared cells from 24 Japanese women laparoscopically diagnosed with endometriosis, to cells from 25 women with other laparoscopic diagnoses. KIR expression by NK cells was assessed in peripheral blood (PB) and peritoneal fluid (PF) by flow cytometry. Intracellular immunoreceptor tyrosine-based (IT) inhibitory and activation motifs (ITIM and ITAM) of KIR in PB was assessed by Western blotting. RESULTS: ITIM-KIR expression by PB NK cells was significantly and similarly greater than ITAM-KIR expression in women with and without endometriosis. Percentages of CD56(+) NK cells in PB and PF did not differ significantly between women with and without endometriosis; however, the percentage of CD158a(+) cells among CD56(+) NK cells in PB and PF was significantly higher in women with than without endometriosis. CONCLUSIONS: ITIM-KIR expressing NK cells might confer tolerance to peritoneal endometriotic implants.

MRI of endocervical glandular disorders: three cases of a deep nabothian cyst and three cases of a minimal-deviation adenocarcinoma.

The incidence of cervical adenocarcinoma is increasing. Nabothian cysts are a common gynecologic condition; if multiple and/or large cysts are present, it is difficult to differentiate them from a minimal-deviation adenocarcinoma (MDA), which is classified as a special type of cervical adenocarcinoma. We report three cases of deep nabothian cysts and three cases of MDAs. Magnetic resonance imaging (MRI) findings, signs, and symptoms of these cases are described. The absence of a watery discharge and an MR image displaying a round or oval cyst without enhancement after intravenous gadolinium are helpful in the diagnosis of a deep nabothian cyst.

Killer inhibitory receptor CD158a overexpression among natural killer cells in women with endometriosis is undiminished by laparoscopic surgery and gonadotropin releasing hormone agonist treatment.

PROBLEM: Natural killer (NK) dysfunction is considered to contribute to the pathogenesis of endometriosis. In this study, we investigated the host immune response to endometriosis in terms of killer inhibitory receptor (KIR) expression by NK cells. METHOD OF STUDY: We compared cells from Japanese women laparoscopically diagnosed with endometriosis and treated with laparoscopic surgery (n = 98), 1 month after laparoscopic surgery (n = 36), and 12 weeks after gonadotropin releasing hormone agonist (GnRHa) treatment (n = 18) to cells from 104 women with other laparoscopic diagnoses. KIR expression by NK cells was assessed in peripheral blood and peritoneal fluid samples by flow cytometry. RESULTS: In women with endometriosis, the percentage of CD158a-expressing cells among CD16-expressing NK (CD158a(+)NK) cells in both peritoneal fluid and peripheral blood was significantly higher than in control subjects. No significant differences in proportion of CD158a(+)NK cells were identified between peripheral blood NK cells sampled before and 1 month after laparoscopic surgery, or 12 weeks after initiating GnRHa treatment. CONCLUSIONS: Increased percentage of CD158a(+)NK cells in peripheral blood from women with endometriosis was undiminished by laparoscopic surgery and GnRHa treatment; the persistence of CD158a(+)NK cell excess is probably related to NK cell suppression in endometriosis. This overexpression may represent a risk factor for development of endometriosis and its recurrence after treatments.

Coordinated but depressed expression of human leukocyte antigen-DR, intercellular adhesion molecule-1, and CD14 on peritoneal macrophages in women with pelvic endometriosis.

OBJECTIVE: To investigate the macrophage response in endometriosis, we determined the expression of human leukocyte antigen (HLA)-DR, intercellular adhesion molecule (ICAM)-1, and CD14 on peritoneal macrophages. DESIGN: Case-control study of immunologic markers. SETTING: University hospital. PATIENT(S): Forty-five Japanese women with endometriosis were compared with 48 control subjects with other laparoscopic diagnoses. INTERVENTION(S): Venipuncture and laparoscopic peritoneal fluid (PF) collection. MAIN OUTCOME MEASURE(S): Expression of HLA-DR, ICAM-1, and CD14 on peripheral blood (PB) monocytes and PF macrophages were quantitated as mean fluorescence intensities by flow cytometry. Expression of each marker on PF macrophages was divided by that on PB monocytes, as an index of macrophage activation (macrophage activation ratio). RESULT(S): In women with endometriosis, PF macrophages showed significant positive correlations between expression of HLA-DR and ICAM-1, HLA-DR and CD14, and ICAM-1 and CD14. However, expression of individual markers on PF macrophages and their activation ratios were significantly lower than in control. CONCLUSION(S): Coordinated but relatively low expression of HLA-DR, ICAM-1, and CD14 on PF macrophages indicates a positive but limited immune response to events in the peritoneal cavity in women with endometriosis, which may induce immune tolerance to implanted or metaplastic endometrial tissue.

Aberrant expression of intercellular adhesion molecule-1 and killer inhibitory receptors induces immune tolerance in women with pelvic endometriosis.

OBJECTIVE: To investigate host immunologic response to endometriosis in terms of intercellular adhesion molecule (ICAM)-1 expression by macrophages and killer cell inhibitory receptor (KIR) expression by natural killer (NK) cells. DESIGN: Case-control study of immunologic markers. SETTING: University hospital. PATIENT(S): Twenty-eight Japanese women with endometriosis. Control subjects were 26 women without endometriosis. Diagnoses were made at laparoscopy. INTERVENTION(S): Venipuncture and laparoscopic peritoneal fluid collection. MAIN OUTCOME MEASURE(S): ICAM-1 expression by macrophages and KIR expression by NK cells, measured by flow cytometry. RESULT(S): In women with endometriosis, expression of ICAM-1 by peritoneal macrophages was significantly lower and expression of KIR by NK cells in peritoneal fluid and peripheral blood was significantly higher than in control subjects. CONCLUSION(S): Properties of macrophages and NK cells in women with endometriosis promote immunotolerance to implanted tissue in the peritoneal environment. Increased KIR(+)NK cells in peripheral blood may represent a risk factor for endometriosis.

Increased killer inhibitory receptor KIR2DL1 expression among natural killer cells in women with pelvic endometriosis.

OBJECTIVE: To investigate the host immunologic response to endometriosis in terms of killer inhibitory receptor (KIR) expression by natural killer (NK) cells. DESIGN: Case-control study of immunologic markers. SETTING: University hospital. PATIENT(S): We compared cells from Japanese women with laparoscopically diagnosed endometriosis to cells from 40 women with other laparoscopic diagnoses. INTERVENTION(S): Peripheral venous blood sampling and laparoscopic peritoneal fluid collection. MAIN OUTCOME MEASURE(S): Flow cytometry was used to assess expression of KIR by NK cells in the cell samples. RESULT(S): The percentage of cells that expressed KIR2DL1 among NK (KIR2DL1(+)NK) cells in peritoneal fluid and peripheral blood was significantly higher in women with endometriosis than in controls. The proportion of KIR2DL1(+)NK cells in peripheral blood NK cells before and 1 month after laparoscopic surgery did not differ significantly. CONCLUSION(S): The proportion of KIR2DL1(+)NK cells was increased in peritoneal fluid and peripheral blood in women with endometriosis; this difference is probably related to NK cell suppression in endometriosis. This increase in KIR2DL1 expression by NK cells may represent a risk factor in the pathogenesis of endometriosis.