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Thyroid hormones(THs) are essential for the proper functioning of the ovaries, and multiple studies have shown that thyroid abnormalities, especially during adolescence and reproductive age, can lead to lifelong ovarian dysfunction. Autoimmune thyroid disease (AITD), one of the most common organ specific autoimmune diseases, is mainly mediated by cellular autoimmune reactions, and has strong inflammatory infiltration and immune active cells, including chemokines and cytokines, which are important components of ovarian aging. This suggests that autoimmune and inflammatory molecular processes may play a role in the emergence of ovarian dysfunction. The purpose of this review is to summarize recent in vivo and in vitro evidence of a complex relationship between AITD and ovarian dysfunction. AITD is closely related to the decline of ovarian function from the perspective of antibody, cytokine, oxidative stress, and genetic factors. Finally, some of the currently known treatments for AITD and hypo ovarian disease are summarized., (© 2024. The Author(s).)

Endometriosis is an estrogen-dependent disease defined by the presence and growth of functional endometrial-like tissue, glands and stroma, outside the uterine cavity. Macrophages are broadly classified into pro-inflammatory M1 macrophages, and M2 macrophages, which have selective anti-inflammatory and pro-fibrotic activities and are able to induce immunotolerance and angiogenesis. Based on these elements, the aim of our study was to evaluate CD14 + CD68 + CD197 + CD80 + M1 and CD14 + CD68 + CD163 + CD206 + M2 macrophages in tissue samples from ovarian endometriomas of women affected by endometriosis at different stages of the disease. For each patient, we collected a biological sample of the cyst (ovarian endometriomas for cases and ovarian functional cyst for controls) during laparoscopy. We found that the number of both M1 and M2 macrophages was significantly higher in endometriosis group than controls, regardless of stage ( p  < .0001 for each stage versus controls). Moreover, our data analysis shows a trend in progressive decrease of M1 macrophages from stage I to stage IV; on the contrary, M2 macrophages show a specular trend compared to M1 macrophages, with a progressive increase from stage I to stage IV. This may contribute to the pro-inflammatory microenvironment in the early stages of the disease, and to the pro-fibrotic activity of the advanced stages.

Background: Ovarian endometrioma (EM) lesions not only have overwhelmed the amount of infiltrating immune cells but also display immunosuppressive phenotype. The close relationship between neutrophils and the pathogenesis of endometriosis has been demonstrated. The present study aims to elucidate whether or not neutrophils are involved in the regulation of immunosuppressive microenvironment in ovarian endometrioma., Methods: Immunochemistry (IHC) and flow cytometry analysis (FACS) were conducted to measure CD66b expression in ovarian endometrioma samples from EM patients. The correlation between percentage of CD66b and PD1 + CD8+, TIM3 + CD8+, CTLA4 + CD8+, IFN-γ + CD8+ of CD45+ cells were analyzed. Neutrophil survival and PD-L1 expression were determined under the stimulations of ovarian endometrioma conditional supernatants (OECS). Finally, CD8+ T cell's proliferation and IFN-γ expression were detected under co-cultured with OECS cultured neutrophils stimulated with the α-CD3/α-CD28 antibody., Results: IHC and FACS results revealed correlation between the counts of neutrophils and the severity of ovarian endometrioma. The percentage of CD66b + cells was positively correlated with PD1 + CD8+, TIM3 + CD8+ and CTLA4 + CD8+ of CD45+ cells in ovarian endometrioma. OECS promoted neutrophils' survival and enhanced PD-L1 expression. OECS cultured neutrophils inhibited proliferation and activity of autologous T cells., Conclusions: Neutrophils play a crucial role in the progression of ovarian endometrioma by orchestrated the immunosuppressive microenvironment under the PD-1/PD-L1 axis.

Follicular development is a highly coordinated process that in humans takes more than 6 months. Pituitary gonadotropins and a variety of locally produced growth factors and cytokines are involved in determining a precise sequence of changes in cell metabolism, proliferation, vascularization, and matrix remodeling in order to obtain a follicle with full ovulatory and steroidogenic capability. A low-grade inflammation can alter such processes leading to premature arrest of follicular growth and female reproductive failure. On the other hand, factors that are involved in inflammatory response as well as in innate immunity are physiologically upregulated in the follicle at the final stage of maturation and play an essential role in ovulation and fertilization. The generation of pentraxin 3 (PTX3) deficient mice provided the first evidence that this humoral pattern recognition molecule of the innate immunity has a non-redundant role in female fertility. The expression, localization, and molecular interactions of PTX3 in the periovulatory follicle have been extensively studied in the last 10 years. In this review, we summarize findings demonstrating that PTX3 is synthesized before ovulation by cells surrounding the oocyte and actively participates in the organization of the hyaluronan-rich provisional matrix required for successful fertilization. Data in humans tend to confirm these findings, indicating PTX3 as a biomarker of oocyte quality. Moreover, we discuss the emerging evidence that in humans altered PTX3 systemic levels, determined by genetic variations and/or low-grade chronic inflammation, can also impact the growth and development of the follicle and affect the incidence of ovarian disorders.

The aim of the study was to ascertain the influence of AІТ on the formation of autoimmune damage to ovaries by determining the connections between the levels of AOAB, ATPO, gonadotropic and sex hormone levels, and the functional state of the ovaries and thyroid gland. 198 girls age 10-18 were studied: 166 with AIT (AIT+ Group), и 32- without AIT (the AIT- Group). A defined difference between TTH. and ATPO, was revealed, which is explained by the presence of thyroid pathology in the AIT+ Group. Prolactin levels and ovarian volume were notably higher, while Progesterone levels were lower in the AIT+ Group. No discernable differences among levels of AOAB, sex hormones, Estrogen, Testosterone or antral follicules were observed. A direct correlation was revealed between AOAB levels and the girls' age both in the AIT+ and AIT- groups. AOAB data was divided into three tertials in order to study links with various hormonal homeostasis. Analysis of data obtained showed numerous correlative links between ATPO, AOAB, gonadotropins, sex hormones, TTH and ovarian volume in all tertials of both the AIT+ and AIT- groups; correlative links were found, too, between AOAB and ATPO in the III tertial groups AIT+ and AIT-. In adolescents with AIT disbalance occurs at all levels of hormonal homeostasis as well as in ovarian structure. Such changes and the presence of ATPO and AOAB may be associated with emerging autoimmune ovary damage.

Problem: To evaluate the role of regulatory T (Treg) cells in autoimmune ovarian disease (AOD)., Method of Study: AOD model was set up by thymectomy of BALB/C mice on day 3 (d3tx). The variation of T lymphocyte subsets, especially the Treg cells were analyzed in the peripheral blood, spleen, para-aortic, and inguinal lymph nodes in d3tx mice. The effect of Treg cells on AOD was further evaluated by adoptive transfer of Treg cells into d3tx mice (d3tx+Treg)., Results: In d3tx mice, the ratio of Treg/CD4 + was significantly increased rapidly from 1st to 2nd week, rapidly declined in 3rd week, then decreased slowly until the 9th week. The CD3 + /T lymphocytes and the ratio of CD4 + /CD3 + were significantly decreased in the para-aortic and inguinal lymph nodes of d3tx mice, but the ratio of Treg/CD4 + and CD8 + /CD3 + were increased simultaneously. In d3tx mice with adoptive transfer of Treg cells (0.5×10 4 ~5×10 5 ), there was a significant increase in the Treg/CD4 + ratios in the spleen and peripheral blood. AOD score, especially adoptive transferred treg cells from the ovarian lymph nodes was significantly decreased. Oocytes were successfully obtained from d3tx+Treg mice, which could fertilize and develop to embryos normally., Conclusion: Treg cells involved in the pathogenesis of AOD. Sufficient numbers of Treg cells can modify AOD in the early phase in d3tx mice., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Endometriosis is a chronic inflammatory condition characterised by the growth of endometrial epithelial and stromal cells outside the uterine cavity. In addition to Sampson's theory of retrograde menstruation, endometriosis pathogenesis is facilitated by a privileged inflammatory microenvironment, with T regulatory FoxP3+ expressing T cells (Tregs) being a significant factor. PreImplantation Factor (PIF) is a peptide essential for pregnancy recognition and development. An immune modulatory function of the synthetic PIF analog (sPIF) has been successfully confirmed in multiple animal models. We report that PIF is expressed in the epithelial ectopic cells in close proximity to FoxP3+ stromal cells. We provide evidence that PIF interacts with FoxP3+ cells and modulates cell viability, dependent on cell source and presence of inflammatory mediators. Our finding represent a novel PIF-based mechanism in endometriosis that has potential for novel therapeutics.

Gynceological involvement in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides is rare. We describe a case of ANCA-associated vasculitis in an elderly woman presenting with fevers, cough and a rash. Further investigations revealed vasculitic involvement of the ovaries, fallopian tubes, uterus and omentum with an eosinophil-rich infiltrate., (© 2016 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objective: To identify and characterize endometriosis-associated immune cell infiltrates (EMaICI). Furthermore, to define occurrence and size of EMaICI in various types of endometriosis., Methods: Immune cells were characterized in samples of 60 premenopausal women with histological proven endometriosis. Therefore, immunohistochemical staining with monoclonal antibodies for CD3, CD4, CD8, CD45RO, CD25, CD56, CD68, and CD20 on sections of paraffin-embedded endometriotic tissue was performed., Results: EMaICI were observed in all the types of endometriosis, and characterized as T lymphocytes (CD3+), helper T lymphocytes (CD4+), cytotoxic T lymphocytes (CD8+), antigen-experienced T lymphocytes"memory cells" (CD45RO+), macrophages (CD68+), and B lymphocytes (CD20+). The maximum frequency of EMaICI and their distribution per endometriotic lesion (EML) was observed in peritoneal endometriosis (pEM) and in ovarian endometriosis (Ov. EM). In myometrium from adenomyosis (M/AM), EMaICI occurrence was lower and smaller in size in comparison with EMaICI seen in other forms of endometriosis. EMaICI were negative for regulatory T cells (CD25+ high, FoxP3+) and natural killer cells (NK cells, CD56+)., Conclusion: Numerous and brisk EMaICI comprising several types of immune cells in all endometriosis forms suggest acute immunological reactions within the microenvironment of endometriosis lesions.

The ovary is not an immunologically privileged organ, but a breakdown in tolerogenic mechanisms for ovary-specific antigens has disastrous consequences on fertility in women, and this is replicated in murine models of autoimmune disease. Isolated ovarian autoimmune disease is rare in women, likely due to the severity of the disease and the inability to transmit genetic information conferring the ovarian disease across generations. Nonetheless, autoimmune oophoritis is often observed in association with other autoimmune diseases, particularly autoimmune adrenal disease, and takes a toll on both society and individual health. Studies in mice have revealed at least two mechanisms that protect the ovary from autoimmune attack. These mechanisms include control of autoreactive T cells by thymus-derived regulatory T cells, as well as a role for the autoimmune regulator (AIRE), a transcriptional regulator that induces expression of tissue-restricted antigens in medullary thymic epithelial cells during development of T cells. Although the latter mechanism is incompletely defined, it is well established that failure of either results in autoimmune-mediated targeting and depletion of ovarian follicles. In this review, we will address the clinical features and consequences of autoimmune-mediated ovarian infertility in women, as well as the possible mechanisms of disease as revealed by animal models.

Objective: To examine the expression of CD147 in 60 human endometriosis lesions and how CD147 regulates migration and apoptosis in human uterine epithelial (HESs) cells., Design: Experimental clinical study and laboratory-based investigation., Setting: Hospital and academic research center., Patient(s): Sixty women with chocolate cysts and 16 control women without endometriosis., Intervention(s): Human uterine epithelial cells were treated with anti-CD147 antibody., Main Outcome Measure(s): Real-time polymerase chain reaction for detecting CD147 expression in 60 human endometriosis lesions; migration assay and CellTiter 96 AQueous One Solution Cell Proliferation Assay (MTS) assay for cell functional investigation; Western blot for detecting protein levels; gelatin zymography for evaluating the activity of matrix metalloproteinase-2 (MMP-2) in cultured cells., Result(s): Expression of CD147 was significantly higher in ectopic endometrial tissues from patients with endometriosis than in normal endometrial tissues. Interference with CD147 function led to decreased migration and cell viability in HESs cells. Surprisingly, MMP-2 expression and activity were not changed after treating HESs cells with anti-CD147 antibody. Further examination revealed that immunodepletion of CD147 induced apoptosis in HESs cells, leading to the activation of caspase 3 and poly(ADP-ribose) polymerase., Conclusion(s): The results of the present study suggest that abnormally high expression of CD147 in ovarian endometriosis lesions with enhanced cell survival (reduced apoptosis) and migration, in an MMP-2-independent manner, may underlie the progression of endometriosis in humans., (Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

It has reported that human endometrial stromal cells (ESCs) express thymic stromal lymphopoietin (TSLP), and TSLP concentrations in the serum and peritoneal fluid were higher in women with endometriosis. Endometriosis is an estrogen-dependent disease. The present study aimed to elucidate whether and how estrogen regulates the growth of ESCs through TSLP. The ESCs behaviors in vitro were verified by SRB assay and Ki67 level detection, respectively. In addition, the effects of estrogen on TSLP and TSLP on the correspondent functional molecules were investigated by ELISA and flow cytometry. Here we found that estrogen stimulated the secretion of TSLP in a dosage-dependent manner. Recombinant human TSLP stimulates the secretion of MCP-1 and IL-8, and markedly promotes the viability and proliferation relative gene Ki-67 expression of ESCs. These effects could be abolished by the inhibitor for JNK or NF-κB signal, respectively. Moreover, not only anti-TSLP neutralizing antibody, but also blocking JNK or NF-κB signal by inhibitor abrogated the stimulatory role in the production of MCP-1 and IL-8, and the growth of ESCs induced by estrogen. Our current study has demonstrated that TSLP is involved in the regulation of estrogen on the secretion of MCP-1 and IL-8, and the growth of ESCs through JNK and NF-κB signal pathways, which suggests that the abnormal high expression of TSLP induced by estrogen may play an important role in ESCs growth and finally contribute to the origin and development of endometriosis.

Aim: Endometriosis is a chronic inflammatory disease. Sirtuin 1 (SIRT1) plays a role in regulation of inflammation. The role of SIRT1 in endometriosis remains unknown. We here addressed the anti-inflammatory effects of SIRT1 on endometriosis., Methods: The expression of SIRT1 in human ovarian endometriomas and eutopic endometria were examined using immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). Endometriotic stromal cells (ESC) obtained from endometriomas were exposed to either resveratrol or sirtinol, an activator or inhibitor of sirtuins, respectively, and tumor necrosis factor (TNF)-α-induced interleukin (IL)-8 release from the ESC was assessed at mRNA and protein levels., Results: Both immunochemistry and RT-PCR demonstrated that SIRT1 was expressed in ESC and normal endometrial stromal cells. Resveratrol suppressed TNF-α-induced IL-8 release from the ESC in a dose-dependent manner while sirtinol increased IL-8 release., Conclusion: These opposing effects of SIRT1-related agents suggest that IL-8 release from the ESC is modulated through the SIRT1 pathway. Resveratrol may have the potential to ameliorate local inflammation in endometriomas., (© 2013 The Authors. Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology.)

Problem: Earlier studies from our group have established that about 47% cases of autoimmune ovarian failure are due to presence of autoantibodies to Heat Shock Protein 90 (HSP90). However, there are no reports correlating pathological effects of HSP90 autoantibodies leading to ovarian failure., Method of Study: Antibodies to HSP90 in female mouse model were generated by active immunization with an immunodominant peptide of HSP90, followed by detailed analysis of several reproductive parameters., Result: Estrous cyclicity remains unchanged; however, there was a significant drop in the fertility index due to an increase in pre- and post-implantation loss, associated with an increased incidence of degenerated eggs and embryos. The ovaries showed an increase in the number of empty and degenerated follicles and extensive granulosa cell deaths, which was reflected by the decrease in the levels of Nobox and Gja1 gene expression., Conclusion: This study underlines a critical role played by HSP90 in ovarian folliculogenesis and highlights the implications of the presence of anti-HSP90 antibodies in infertile women., (© 2013 John Wiley & Sons Ltd.)

NK cells are critical in immune responses against pathogens. However, their role in autoimmunity is still controversial. In this study, we demonstrate that neonatal NK cells render newborns more susceptible to neonatal autoimmunity induced by maternal autoantibodies (neonatal autoimmune ovarian disease); thus, neonatal but not adult NK cells are pathogenic after transfer into NK cell-deficient pups. The inhibitory receptors Ly49C/I are expressed in ∼5% of neonatal and ∼50% of adult NK cells. In this study, we show that the presence of Ly49C/I⁺ adult NK cells inhibits neonatal autoimmune ovarian disease induction. Thus, the ontogenetic regulation of Ly49C/I expression determines the propensity to autoantibody-induced autoimmunity. In summary, this study provides definitive evidence of a pathogenic role of NK cells in neonatal autoimmunity and also elucidates a novel mechanism by which neonatal NK cells render newborns more susceptible to autoantibody-induced autoimmunity.

Objective: To test the adjuvant use of the combination of N-palmitoylethanolamine and transpolydatin in the medical treatment of endometriotic pain., Study Design: We enrolled 47 patients admitted to the Outpatient Endometriosis Care Unit of Ferrara University from January 2011 to December 2011. They were divided into two groups according to the endometriosis site (group A: recto-vaginal septum; group B: ovary). One tablet, containing 400 mg of micronized N-palmitoylethanolamine plus 40 mg transpolydatin, was administered twice daily on a full stomach for 90 days. Each patient was requested to grade the severity of dysmenorrhea, chronic pelvic pain, dyspareunia and dyschezia using a 0-10 cm visual analogic scale prior to beginning treatment (T0), after 30 days (T1), 60 days (T2) and 90 days (T3). The continuous and categorical variables were compared, respectively, using Student's t-test and the chi-square test. Analysis of variance for repeated measures was used to verify the reduction of endometriotic pain., Results: The intensity of endometriotic pain decreased significantly for both groups (p<0.0001). The efficacy of drug treatment was significant after 30 days. Pain intensity decreased equally in the two groups except for dysmenorrhea, which was reduced more rapidly in group B., Conclusions: The combination of N-palmitoylethanolamine and transpolydatin reduced pain related to endometriosis irrespective of lesion site. It had a marked effect on chronic pelvic pain determined by deep endometriosis and on dysmenorrhea correlated to ovarian endometriosis., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Study Question: Is the occurrence of pelvic pain in women with ovarian endometrioma associated with coexisting peritoneal lesions (PLs)?, Summary Answer: Pelvic pain in women with ovarian endometrioma is usually associated with coexisting PLs. An increased tissue inflammatory reaction with elevated prostaglandin (PG) production may be responsible for the generation of pain., What Is Known Already: Severe pelvic pain in women with ovarian endometrioma is reported to be associated with deeply infiltrating endometriosis. However, information on pelvic pain in women with ovarian endometriosis with and without coexistent peritoneal superficial lesions is limited., Study Design, Size and Duration: Retrospective clinical study with case-controlled biological research using prospectively collected tissue samples derived from women with and without endometriosis and their retrospective evaluation., Participants/materials, Setting, Methods: We performed a retrospective cohort study conducted in 2988 cases who had laparoscopic surgery for indications of ectopic pregnancy, tubal infertility and other benign gynecologic diseases. We analyzed the occurrence of pelvic pain in the cases with ovarian endometrioma according to the distribution of coexisting PLs and pattern of intrapelvic adhesions. Inflammatory reaction of eutopic and ectopic endometria was measured by immunoreaction to macrophage marker, CD68. The tissue expression of cyclooxygenase (COX) 2 was examined by immunohistochemistry and tissue concentrations of PG F2α were measured by ELISA., Main Results and the Role of Chance: Among the 2988 surgical cases, 350 (11.7%) were found to have ovarian endometrioma at laparoscopy. Coexisting PLs were present in 269 of these women and in this group 85.4% of cases experienced pelvic pain and 14.6% had no pain. In contrast, among the 81 women with ovarian endometrioma only, 38.3% cases experienced pelvic pain and 61.7% cases had no pain and the difference between the groups was statistically significant (P < 0.01). The infiltration of CD68-immunoreactive macrophages was significantly higher in the eutopic and ectopic endometria of women with peritoneal endometriosis than in ovarian endometrioma. The tissue expression of COX2 and levels of PGF2α were significantly higher in both the eutopic and ectopic endometria derived from women with peritoneal endometriosis than in similar tissues derived from women with ovarian endometrioma., Limitations, Reasons for Cautions: Lack of evaluation in the detection of general or disseminated deeply infiltrating endometriosis in the pelvic cavity could be a bias or limitation in this study. Further multicenter prospective studies are needed to strengthen our current findings., Wider Implications of the Findings: Our findings may provide some new insights to understand the physiopathology of pelvic pain in women with ovarian cystic endometriosis and may hint at proper surgical manipulation to prevent the recurrence of pelvic pain in these women., Study Funding/competing Interest(s): This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Sports, Culture, Science and Technology of Japan. There is no conflict of interest related to this study., Trial Registration Number: Not applicable.

Cytokines, and specifically interleukin 6 (IL-6) and interleukin 8 (IL-8), have been associated with the pathogenesis of endometriosis. We studied serum concentrations of IL-6 and IL-8 in patients with deep infiltrating endometriosis (DIE) or ovarian endometriomas (OE), but no other forms of associated endometriosis disease type. We carried out a case-control study including 19 patients with OE alone (OE group), 14 patients with DIE alone (DIE group) and 24 healthy patients without endometriosis (C group). Serum concentrations of IL-6 and IL-8 were measured in the three groups of patients. Serum levels of both IL-6 and IL-8 were significantly higher in the OE group. A high positive correlation was found between serum IL-6 and IL-8 levels in the OE group but not in the DIE and C groups. Serum IL-8 alone achieved the highest predictive value of the presence of OE (adjusted OR: 1.44; sensitivity: 78.2%; specificity: 76.2%). The combination of IL-6 and IL-8 levels did not significantly improve the discrimination between subjects with OE and those with DIE over that of IL-8. OE but not DIE are associated with increased serum levels of IL-6 and IL-8, and thus these may become useful tools for discriminating OE alone from DIE., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The efficacy of three commercial Mycoplasma gallisepticum (MG) immunizing agents-a bacterin, a recombinant fowlpox-MG vaccine, and a live F-strain vaccine-was compared in specific-pathogen-free hens in egg production. Three groups of 25 chickens were vaccinated with one of the vaccines at 10 wk of age and 25 birds were not vaccinated. At 25 wk of age (and approximately 50% egg production), 20 birds from each of the three vaccinated groups and 15 nonvaccinated controls were challenged with virulent R-strain via aerosol; the birds were necropsied and evaluated at 10 days post-challenge. The MG bacterin and live F-strain vaccinations were both protective and resulted in significant differences in air sac lesions, tracheal lesions, and ovarian regression compared to the nonvaccinated controls and the recombinant fowlpox-MG vaccine (P < or = 0.05). The evaluation of ovarian regression is a useful method of testing the efficacy of MG vaccines in laying hens.

Objective: To assess the relationship between endometriotic lesions with associated nerve fibers with both pain and peritoneal fluid (PF) cytokine concentrations based on lesion location., Design: An observational study., Setting: University hospital., Patient(s): Premenopausal women undergoing laparoscopy., Intervention(s): The pain experienced by patients was recorded before surgery and ectopic endometrial tissue excised and matching PF collected during laparoscopy. Immunohistochemistry was performed on endometriotic tissue sections to identify nerve fibers and PF cytokine concentrations determined., Main Outcome Measure(s): The pain experienced by women with endometriosis, the lesion locations, and the prevalence and proximity of nerve fibers to endometriotic lesions, as well as the PF concentrations of multiple cytokines., Result(s): Lesions from the rectovaginal septum were significantly more likely to be associated with a nerve fiber and report more menstrual pain than lesions from other regions. The PF glycodelin concentrations were also significantly higher in samples with an endometriotic-associated nerve. In peritoneal endometriotic lesions significantly more menstrual pain was reported when endometriotic lesions were associated with nerve fibers, although no difference was observed between the cytokine concentrations. Ovarian endometriotic lesions were rarely associated with nerve fibers., Conclusion(s): The presence of endometriosis-associated nerve fibers appear to be related to both the pain experienced by women with endometriosis and the concentration of PF cytokines; however, this association varies with the lesion location., (Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

DNA vaccines have been widely used to induce immune responses against molecular targets. In this study, we explored the possibility of using DNA vaccine combined with the immunosuppressant FK506 (tacrolimus) to antigen-specifically suppress unwanted immune responses and prevent autoimmune ovarian disease. To that end, we immunized C57BL/6 mice with a DNA vaccine encoding mouse zona pellucida 3 (ZP3) together with FK506. The immunization induced ZP3-specific CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg), which suppressed the induction of ZP3-specific delayed-type hypersensitivity in the animals. Significantly, the immunization also protected the animals from experimentally induced autoimmune ovarian disease. These results suggest that DNA vaccination in the presence of FK506 may be used to induce Treg cells and prevent AOD.

The specifics of inflammation created by infection with Chlamydia trachomatis could be favourable to the genesis of endometriosis. To investigate this hypothesis, we studied the association between Chlamydia trachomatis specific IgG and IgA antibodies in serum and the peritoneal fluid of 51 women undergoing laparoscopic surgery. There was no significant difference between women with and without endometriosis with respect to the incidence of IgG and IgA in serum or the peritoneal fluid. The results of our preliminary study did not show any significant link between past infection with Chlamydia trachomatis and the presence of endometriosis.

Objective: To evaluate the clinical value of autoantibody spectrum against ovarian cancer associated antigens combine CA(125) in detecting and monitoring ovarian cancer., Methods: Circulating IgG, IgM autoantibodies against ovarian cancer associated antigens which included TM4SF1, C1D, TIZ, OV-142, FXR1 and OV-189 were measured by indirect ELISA in serum from 126 patients with ovarian cancer (prior treatment), 42 patients with benign ovarian masses, 142 healthy women. Cut off value of IgG, IgM autoantibodies were determined by receive operating characteristic (ROC) curve. CA(125) was measured in serum by immunoradiometric assay (IRMA). We evaluated the clinical value of combining multiple autoantibodies (autoantibody spectrum), combining autoantibody spectrum with CA(125) by binary logistic regresion. The positive ratio of autoantibody spectrum in serum (prior and post treatment) of 24 synchronization patients with ovarian cancer was analyzed to evaluate the value in monitoring state of illness., Results: Our data indicated that serum contains IgG, IgM autoantibodies against ovarian cancer associated antigens. The positive ratio of IgG autoantibodies in serum from ovarian cancer patients and cancer-free patients were 34.1% - 47.6% and 13.0% - 19.0%, respectively (P < 0.05). The positive ratio of IgM autoantibodies in serum from ovarian cancer patients and cancer-free patients were 39.7% - 53.2% and 12.0% - 33.2%, respectively (P < 0.05). The positive ratio of IgG autoantibodies against FXR1 and IgM autoantibodies against TIZ, FXR1 and OV-189 in early stage (I-II) ovarian cancer (55.3%, 63.8%, 61.7% and 66.0%) were significantly higher than those in advanced (III-IV) ovarian cancer (34.2%, 39.2%, 26.6%, 45.6%; all P < 0.05). Combining five autoantibodies (TM4SF1 IgG, TM4SF1 IgM, C1D IgG, FXR1 IgG and TIZ IgM) showed significantly improved sensitivity (75.4%, P < 0.05), lower specificity (78.3%, P < 0.05) and similar accuracy (77.1%, P > 0.05) in detecting ovarian cancer compared to those of CA(125) (61.1%, 88.0%, 77.1%). But the autoantibody spectrum showed significantly improved sensitivity in classifying early stage (76.6%), compared to those of CA(125) (51.1%, P < 0.05). Combining autoantibody spectrum with CA(125) showed significantly improved sensitivity (85.7%), specificity (90.8%)and accuracy (88.7%) in detecting ovarian cancer compared to those of autoantibody spectrum alone (all P < 0.05), while CA(125) (61.1%, P < 0.05; 88.0%, P > 0.05; 77.1%, P < 0.05). The positive ratio of combine the autoantibody spectrum with CA(125) was significantly lower in 24 post-treatment serum (42%) compared to the pairing prior treatment serum (88%, P < 0.05)., Conclusion: Combining the autoantibody spectrum against ovarian cancer associated antigens with CA(125) can improve sensitivity, specificity and accuracy in detecting early ovarian cancer and may be used to monitoring state of illness.

The data about premature ovarian failure and autoimmune oophoritis are collected and analysed in the review. The data about experimental models of ovarian autoimmunity: autoimmune ovarian dysgenenesis, murine experimental autoimmune oophoritis, experimental immune ovarian failure are collected and analysed in the review of the literature.

Background: The presence of regulatory T (Treg) cells in human endometrium is crucial for maintaining immunological homeostasis within the uterus. For this study we decided to evaluate the subpopulations of Treg cells in conditions where a disturbance in the immunological equilibrium in ectopic endometrium and decidua has been observed, such as in cases of ovarian endometriosis (involving local immune cell suppression) and ectopic pregnancy (involving an increase in local immune system activity). We then compared these findings to what we observed in the normal eutopic endometrium of women during the secretory phase of the menstrual cycle (with immune cells under individual control)., Methods: The endometrium tissue samples evaluated in our study were obtained from 47 women during one of two kinds of laparoscopic procedures. 16 of the women underwent laparoscopies due to Fallopian tube pregnancies (EP), and 16 due to ovarian endometrioma, while 15 women made up a control group. The presence of regulatory T cells in these tissue samples was evaluated by FACS., Results: In our study, the percentages of FOXP3+ cells within the subpopulation of CD4+ T lymphocytes found in the decidua of the patients treated for Fallopian tube pregnancies were statistically significantly lower than both those observed in the ovarian endometriosis tissue samples and those found in the secretory eutopic endometrium samples of the control group., Conclusion: The disturbance in the immunological equilibrium observed in ectopic endometrium and decidua would seem to be related to the alteration in the Treg cell population that occurs in these ectopic tissues.

Purpose: To provide an update of putative auto-antigens identified and proposed to be involved in human ovarian autoimmunity., Methods: Review of literature pertaining to ovarian auto-antigens / proteins identified with various immunological tools using sera of infertile women as a probe for investigation., Results: An overview of autoimmune targets known till date in the study of human ovarian autoimmunity., Conclusions: Anti-ovarian antibodies (AOA) to multiple components and compartments of the ovary are present in the sera of infertile women. Researchers propose that these AOA may be responsible for ovarian failures and therefore render women to be infertile. Evaluation of AOA can be effective as a prognostic factor in the treatment of infertile patients and for the IVF-ET program.

The fragile X mental retardation 1 (FMR1) gene is primarily associated with neuro/psychiatric risks. Recent evidence suggests that the gene also exerts controlling functions on follicle recruitment and ovarian reserve (OR). We performed unrestricted Medline and PubMed searches of the medical literature independently under search terms, FMR1 gene, fragile X gene, and in association with premature ovarian aging, primary ovarian insufficiency, occult primary insufficiency, premature ovarian failure, premature menopause, ovarian reserve (OR), diminished ovarian reserve, follicle recruitment and ovarian aging. We also used web-based resources in regards to the FMR1 gene and reviewed additional citations from reviewed publications. Recently published data strongly suggest an independent function of the FMR1 gene on ovaries. This function appears distinct from the gene's neuro/psychiatric effects, associated with a different, and specific, triple nucleotide (CGG) repeat range and characterized by specific genotypes. Ovarian function in all races/ethnicities appears defined by a normal range of 26 to 34 CGG repeats (mean 30), including the reported distribution peak of 29 to 30 repeats in humans and maximal gene translation, reported at 30 repeats. Genotypes, defined by 2 normal count alleles (normal) demonstrate different OR aging patterns from women with 1 (heterozygous) or both alleles outside of range (homozygous). Heterozygous and homozygous genotypes recruit fewer follicles at younger ages, thus preserving OR into advanced age. These observations suggest a direct FMR1 effect on follicular recruitment and OR and, therefore, on women's fecundity.

Problem: The relationship between endometriosis and cancer has been widely discussed in the literature but is still not well clarified. Perhaps significantly, soluble human leukocyte antigen-G (sHLA-G) has been identified in the microenvironment of both ovarian cancer and endometrioma. The aim of this study has been to evaluate the sHLA-G levels in the blood sera of women with deep endometriosis and ovarian endometrioma over the course of the menstrual cycle and to compare to the levels of sHLA-G in the blood sera of women with ovarian cancer., Method of Study: In our study, we examined the blood sera obtained from 123 patients operated on because of ovarian cancer (65 cases), ovarian endometrioma (30 cases), and deep endometriosis (28 cases). We decided to compare the levels of sHLA-G in patients with endometriosis to those found in patients with ovarian cancer with respect to the menstrual cycle phases. The sHLA-G concentration level was measured by enzyme-linked immunosorbent assay kit., Results: The level of sHLA-G concentration in the blood serum of patients with deep endometriosis fluctuates over the course of the menstrual cycle, and during the proliferative and secretory phases, it remains at a high level comparable to that found in patients with ovarian cancer. By contrast, the level of sHLA-G concentration in the blood serum of patients with ovarian endometrioma fluctuates minimally over the course of the different menstrual cycle phases and, as in patients with ovarian cancer, it remains at high level during the proliferative phase., Conclusion: sHLA-G blood serum concentration levels would seem to provide important information regarding the degree of immune system regulation disturbance in both ectopic endometrial cells and the cancer cell suppressive microenvironment.

The postnatal maternal environment is known to increase susceptibility to a number of autoimmune diseases. Here we asked whether the postnatal maternal environment could influence autoimmune disease development to day 3 thymectomy (d3tx)-induced autoimmune ovarian disease (AOD) and experimental allergic encephalomyelitis (EAE) in cross-fostered A/J and B6 mice. A/J pups foster-nursed by B6 mothers exhibit an increase in autoimmune disease development while cross-fostering B6 pups on A/J mothers did not alter their susceptibility. The increase in AOD incidence seen in foster-nursed d3tx A/J mice correlated with a decrease in the total number of CD4(+) T cells in the lymph nodes of these animals. Analysis of the cellular composition in the milk revealed that B6 mice shed significantly more maternally derived lymphocytes into their milk compared to A/J mothers. These data suggest that there are maternally derived postnatal factors that influence the development of autoimmune disease in A/J mice.

In experiments on CBA mice, we studied the influence of an inhibitor of nuclear transcription factor kappaB activation curcumin, obtained from Curcuma longa, on the meiotic maturation of oocytes and apoptotic and necrotic death of follicular cells at immune ovary failure induced by immunization of animals with allogenic ovarian extracts. NF-kappaB plays a pivotal role in the induction of genes encoding pro-inflammatory factors (cytokines, adhesion molecules, inducible NO-synthase and cyclooxygenase) and in regulation of cell proliferation and death. It has been shown that immunization of mice increased the death of follicular cells through anapoptotic and necrotic pathways, which led to inflammatory response (according to blood leukogram and impairment the oocyte meiotic maturation at metaphase I and II). Intragastric administration of curcumin (Sigma, USA, 2 mg of the mouse weight, four times a week during the period of immunization) reduced the number of the follicular cells died through apoptotic and especially necrotic pathway. Curcumin attenuated an inflammatory response and improved the meiotic maturation of oocytes impaired under experimental immune ovarian failure in mice.

Natural CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) effectively prevent autoimmune disease development, but their role in maintaining physiological tolerance against self-Ag of internal organs is not yet defined. In this study, we quantified disease-specific Treg (DS-Treg) as Treg that preferentially suppress one autoimmune disease over another in day 3 thymectomized recipients. A striking difference was found among individual lymph nodes (LN) of normal mice; Treg from draining LN were 15-50 times more efficient than those of nondraining LN at suppressing autoimmune diseases of ovary, prostate, and lacrimal glands. The difference disappeared upon auto-Ag ablation and returned upon auto-Ag re-expression. In contrast, the CD4(+)CD25(-) effector T cells from different individual LN induced multiorgan inflammation with comparable organ distribution. We propose that peripheral tolerance for internal organs relies on the control of autoreactive effector T cells by strategic enrichment of Ag-specific Treg in the regional LN.

Problem: We previously reported that lipopolysaccharide (LPS)-promoted endometriotic stromal cell (ESC) proliferation by inducing TNFalpha production. The aim of this study was to investigate the efficacy of TNFalpha gene silencing on LPS-treated ESCs., Method of Study: Endometriotic stromal cells (ESCs) and endometrial stromal cells (ESCs) (EMSCs) were obtained from ovarian chocolate cysts and uterine myoma, respectively. Using PCR array, LPS-induced gene expression profiling after transfection of TNFalpha siRNA into ESCs was performed. Down-regulated genes by TNFalpha silencing were examined using real-time RT-PCR. Effect of TNFalpha silencing was examined using ELISA and BrdU incorporation, respectively., Results: In PCR array, TNFalpha silencing in ESCs repressed LPS-induced expression of cIAP2 and IL-8, NFkappaB pathway responsive genes. After adding LPS, the levels of cIAP2 and IL-8 expression in ESCs were higher compared with those in EMSCs. TNFalpha silencing attenuated the LPS-induced ESC proliferation., Conclusion: Tumor necrosis factor alpha may be involved in cell proliferation of endometriotic tissues.

Several ovarian disorders in women are associated with autoimmune factors. In this study it was investigated a level of cytokines--TNF-alpha and IFNs in ovarian homogenate and blood serum at ovarian autoimmune damage of mammals. Experimental immune ovarian failure was induced in CBA mice by either immunization with allogenic ovarian extracts or administration of xenogenic anti-ovarian antibodies. Both models were accompanied with abnormalities in production of immunoregulatory cytokines. These data confirm the importance of definition of proinflammatory cytokine level for disclosing immune mechanisms which lay in a pathogenesis autoimmune ovarian diseases of female reproductive organs.

Background: Autoimmune ovarian disease (AOD) caused by auto-reactive T cells is considered a major reason for human premature ovarian failure, which affects 5% of women worldwide., Methods and Results: To develop an effective treatment for AOD, we showed that the co-administration of mouse zona pellucida protein 3 (mZP3) protein and DNA vaccine encoding the mZP3 was able to meliorate AOD in an AOD murine model induced by the mZP3. We observed that established AOD in mice reverted to a normal ovarian morphology without notable T-cell infiltration in the co-administrated group; whereas mice in the control groups developed severe AOD. The amelioration appears to be antigen specific because other co-administration combinations failed to reverse AOD and correlates with significant reductions of pathogenic T-cell responses and productions of tumor necrosis factor-alpha and interferon-gamma. Furthermore, the melioration is apparently associated with the induction of mZP3 specific regulatory T cells that exhibit a phenotypic CD4(+)CD25(-)FoxP3(+)IL-10(+) in the co-administrated group, which can be transferred to reverse AOD in vivo., Conclusions: Thus, co-administration of mZP3 DNA and protein vaccines can be used to treat established AOD, and may provide a novel immunotherapy strategy to treat other autoimmune diseases.

Problem: The selective suppression phenomenon of the cytotoxic immune response may be brought about by an increase in sRCAS1 blood serum concentration. Such an increase has been observed during cancer progression and decidualization. The aim of this study has been to evaluate alterations in RCAS1 blood serum concentration in women during normal menstrual cycle (NMC) phases and to compare the levels found with those in patients with ovarian endometriosis., Method of Study: The sRCAS1 blood serum concentration level was determined for both 147 patients with ovarian endometriosis and a healthy control group., Results: Fluctuations in sRCAS1 blood serum concentration levels correlating with the NMC phases were demonstrated. The highest level of sRCAS1 was found during menstruation and the lowest during the proliferative cycle phase. However, no such fluctuations correlating with menstrual cycle phases were observed in the patients with endometriosis. The level of sRCAS1 in patients with endometriosis remained almost constant. Moreover, the sRCAS1 blood serum concentration level has been shown to increase, as ovarian endometriosis progresses., Conclusion: RCAS1 blood serum concentration may be a useful indicator of the selective suppression of the immune cytotoxic cell phenomenon associated with the development of endometriosis.

Background and Aims: Autoimmune gastritis is one of the most common autoimmune diseases and is caused by a CD4(+) T-cell response to the gastric H(+)/K(+) ATPase encoded by Atp4a and Atp4b (H(+)/K(+) ATPase). Here, we have elucidated events that result in immunological tolerance to the H(+)/K(+) ATPase and thus the prevention of autoimmune gastritis., Methods: T cells from H(+)/K(+) ATPase-deficient mice and H(+)/K(+) ATPase-specific T-cell receptor transgenic mice were purified and transferred to wild-type (WT) or H(+)/K(+) ATPase-deficient recipients to assess the impact of exposure to antigen on pathogenicity., Results: The CD4(+) T-cell population from H(+)/K(+) ATPase-deficient mice was highly effective at inducing gastritis when compared with T cells from WT mice and, as a population, was comparatively resistant to the suppressive activity of regulatory T cells. Exposing T cells from H(+)/K(+) ATPase-deficient mice to H(+)/K(+) ATPase in WT mice decreased their ability to induce gastritis and resulted in a population that could be more easily suppressed by T(reg) cells. Transfer of clonotypic antigen-inexperienced H(+)/K(+) ATPase-specific T cells into WT mice resulted in extra-thymic clonal deletion., Conclusions: Prevention of autoimmune gastritis requires the extra-thymic purging of highly autoaggressive H(+)/K(+) ATPase-specific T cells to produce a T-cell repertoire that is more susceptible to the suppressive activity of regulatory T cells. Taken together with recent published data describing the role of T-cell receptor signalling in the maintenance of regulatory T-cell populations, we propose that exposure of T cells to antigen in the periphery is able to both delete autoaggressive specificities and maintain regulatory T-cell activity, establishing a balance between pathogenicity and regulation.

Actinomycosis is an infectious disease that has been known since the late nineteenth century. In the pre-antibiotic era it was thought to be rather common but with increased use of antimicrobial agents its incidence has decreased significantly. The causative agent, most commonly Actinomyces israelii, is part of the commensal bacterial flora. It can infect any tissue, respects no tissue boundaries and can spread throughout the body. The clinical presentation of this illness can be similar to malignant disease and definite diagnosis is sometimes not apparent until after surgery and histologic examination. We report the case of a 71 year old woman who suffered from actinomycosis of the uterus and ovaries due to a forgotten intrauterine contraceptive device that had been in place for over four decades. The disease presentation was consistent with malignant disease and tumor markers, CA 125, CA 19-9 and CEA, measured in blood were elevated. She was treated successfully with total hysterectomy and bilateral salphingo-oophorectomy, as well as penicillin for six months.

Background: The coexistence of endometrial and immune cells during decidualization is preserved by the ability of endometrial cells to regulate the cytotoxic immune activity and their capability to be resistant to immune-mediated apoptosis. These phenomena enable the survival of endometrial ectopic cells. RCAS1 is responsible for regulation of cytotoxic activity. Metallothionein expression seems to protect endometrial cells against apoptosis. The aim of the present study was to evaluate RCAS1 and metallothionein expression in human ovarian and scar endometriomas in relation to the presence of immune cells and their activity., Methods: Metallothionein, RCAS1, CD25, CD69, CD56, CD16, CD68 antigen expression was assessed by immunohistochemistry in ovarian and scar endometriomas tissue samples which were obtained from 33 patients. The secretory endometrium was used as a control group (15 patients)., Results: The lowest metallothionein expression was revealed in ovarian endometriomas in comparison to scar endometriomas and to the control group. RCAS1 expression was at the highest level in the secretory endometrium and it was at comparable levels in ovarian and scar endometriomas. Similarly, the number of CD56-positive cells was lower in scar and ovarian endometriomas than in the secretory endometrium. The highest number of macrophages was found in ovarian endometriomas. RCAS1-positive macrophages were observed only in ovarian endometriomas. CD25 and CD69 antigen expression was higher in scar and ovarian endometriomas than in the control group., Conclusion: The expression of RCAS1 and metallothionein by endometrial cells may favor the persistence of these cells in ectopic localization both in scar following cesarean section and in ovarian endometriosis.

The involvement of serum anti-ovarian autoantibodies (AOA) in ovarian pathology still remains controversial. In some cases of clinically patent ovarian failure, there seems to be a causal relationship between AOA and the ovarian disease. In patients with various organ-specific or systemic autoimmune diseases, or with unexplained, repeated reproductive failure, but otherwise normal ovarian function, it is even more difficult to determine the significance of AOA for several reasons: i) AOA recognize many different antigenic targets in the ovary ii) the antiovarian response may be transient or variable with time iii) the presence of AOA does not imply their aetiopathogenic role in the disease. The present paper reviews the clinical significance of AOA based on their ovarian targets as far as they have been identified until now.

This study investigated the unresolved issue of antigen-dependency and antigen-specificity of autoimmune disease suppression by CD4+CD25+ T cells (T regs). Based on autoimmune ovarian disease (AOD) in day 3 thymectomized (d3tx) mice and polyclonal T regs expressing the Thy1.1 marker, we determined: (a) the location of recipient T cell suppression, (b) the distribution of AOD-suppressing T regs, and (c) the relative efficacy of male versus female T regs. Expansion of recipient CD4+ T cells, activation/memory marker expression, and IFN-gamma production were inhibited persistently in the ovary-draining LNs but not elsewhere. The cellular changes were reversed upon Thy1.1+ T reg depletion, with emergence of potent pathogenic T cells and severe AOD. Similar changes were detected in the regional LNs during autoimmune dacryoadenitis and autoimmune prostatitis suppression. Although the infused Thy1.1+ T regs proliferated and were disseminated in peripheral lymphoid organs, only those retrieved from ovary-draining LNs adoptively suppressed AOD at a suboptimal cell dose. By depriving d3tx recipients of ovarian antigens, we unmasked the supremacy of ovarian antigen-exposed female over male T regs in AOD suppression. Thus, disease suppression by polyclonal T regs depends on endogenous antigen stimulation; this occurs in a location where potent antigen-specific T regs accumulate and continuously negate pathogenic T cell response.

Under physiological conditions normally characterised by low tissue infiltration of eosinophils, a conspicuous number of these cells are attracted into the human and ruminant ovary. Eosinophils suddenly increase in the thecal layer of the preovulatory follicle and corpus luteum at very early development. Currently, we only have a limited understanding of the mechanism for the recruitment of the ovarian eosinophils. Eotaxin (CCL11) may be one of the chemoattractants involved in stimulating eosinophils to migrate selectively into ovary. As a prerequisite for the analysis of eotaxin expression in the bovine ovary, we determined the complete bovine eotaxin mRNA sequence since it was not available from databases. The bovine eotaxin is the first member of the monocyte chemoattractant protein (MCP)/eotaxin subfamily with two mRNA isoforms varying in length in the untranslated 3'-untranslated region. The unusual amino-acid sequence of bovine eotaxin contains structural features that are so far known to be characteristic for MCP, but not eotaxin. In our microchemotaxis assays, recombinant bovine eotaxin showed a functional pattern orthologous to known eotaxins. Thus, the chimeric structure of bovine eotaxin did not affect the favoured chemotactic activity on eosinophils. Semiquantitative RT-PCR was used to investigate the expression of eotaxin in different regions of the bovine ovary. We only detected faint eotaxin mRNA signals that did not indicate physiological significance even in stimulated granulosa cell cultures, follicle-derived macrophages or fibroblasts. Taken together, bovine eotaxin attracts eosinophils in vitro but is not responsible for eosinophilia in the ovary. Its unusual chimeric structure confirms the unity of the MCP/eotaxin subfamily of CC chemokines and distinguishes it from other CC chemokine subfamilies.

Background: The aim of this study was to evaluate the diagnostic significance of CA-125 for endometriosis without ovarian endometriomas., Methods: Preoperative serum CA-125 levels were measured in 775 consecutive women diagnosed by laparoscopy or laparotomy with endometriosis, adenomyosis, leiomyomas, or normal pelvis., Results: Receiver operating characteristic curve analysis revealed that the area under the curve for endometriosis without endometriomas was 0.788, significantly smaller than that for endometriosis with endometriomas (0.935, P < 0.05). In diagnosis of endometriosis without endometriomas, both the maximal accuracy of 78.8% and the maximal diagnostic value of 61.2% were obtained at the cutoff value of 20 U/mL. Negative predictive value was 78.0% at the cutoff value of 20 U/mL, whereas positive predictive value was 92.9% at the cutoff value of 30 U/mL. This range is clearly superior to the empirical single cutoff of 35 U/mL., Conclusions: In the diagnosis of endometriosis without endometriomas, combined use of two cutoff values for CA-125, 20 and 30 U/mL, provides improved diagnostic performance. However, the accuracy of using only CA-125 testing for diagnosis is still limited. Serum CA-125 testing can be done during initial screenings of women with possible endometriosis.

Although previous studies have emphasized the tolerogenic property of murine neonatal immune system, recent studies indicate that neonatal mice are prone to autoimmune disease. This chapter will summarize the evidence for neonatal propensity to autoimmune ovarian disease (AOD) and describe the new finding that autoantibody can trigger a T cell-dependent autoimmune disease in neonatal but not adult mice. Based on depletion or addition of the CD4+ CD25+ T cells, disease resistance of older mice is explicable by the emergence of CD4+ CD25+ regulatory T-cell function after day 5, whereas disease susceptibility is associated with resistance to regulation by CD4+ CD25+ T cells.

Background: Endometriosis is associated with inflammatory autoimmune reactions; however, aetiopathogenesis of the disease is still poorly understood. While autoimmune disorders are often associated with particular HLA alleles, the possible involvement of HLA in the aetiopathogenesis of endometriosis is still a subject of controversy. The aim of the study was to examine the distribution of HLA-DRB1 alleles in women with endometriosis. To ensure homogeneity of the studied group, only women with ovarian endometrial cysts were included., Methods: The study included 65 Polish patients of Caucasian origin in whom ovarian endometriosis had been confirmed by laparoscopic and histopathological examinations. HLA-DRB1 alleles were typed using a reverse slot blot method. A frequency of particular HLA-DRB1 alleles in patients was compared with that of a control group of 700 unrelated ethnically matched individuals as well as 193 age-matched women without endometriosis., Results: No statistically significant differences were found in the distribution of HLA-DRB1 alleles in patients with ovarian endometriosis as compared with control populations., Conclusions: The results of the present study show that ovarian endometriosis is not associated with particular HLA-DRB1 allele(s). This may suggest that aetiology of this form of endometriosis may be not primarily associated with class II HLA-mediated autoimmune reactions.

Objective: To determine the changes in cytokine levels from women with endometriomas who are treated with recombinant interleukin-2 after ultrasound-guided cyst aspiration, and to relate these changes to the clinical results observed in these patients., Design: A double-blind randomized controlled trial., Setting: University hospital., Patient(s): Twenty-four women with endometriosis-related symptoms and endometriomas., Intervention(s): Endometriomas in women receiving GnRH analogues and undergoing transvaginal ultrasound-guided cyst aspiration were injected with dextrose that did or did not contain recombinant interleukin-2 (IL-2). Serum samples were collected before and after treatment., Main Outcome Measure(s): Serum samples were analyzed by enzyme immunoassay to determine the levels of IL-1beta, IL-2, IL-6, IL-8, IL-10, IL-12, IL-13, and IL-17., Result(s): The cytokine levels after treatment with GnRH analogues and recombinant IL-2 were similar to the initial levels. The patients receiving GnRH analogues without IL-2 had higher IL-1, IL-2, IL-8, and IL-13 levels. Good clinical results were observed in 90% of the patients in the first group but in only 30% of the second one., Conclusion(s): Administration of recombinant IL-2 intracystically decreases cytokine production in women with endometriomas. These results have important implications for the design of future therapies based on immunomodulation, such as using higher or repeated doses of recombinant IL-2 in the cysts.

Discovery of the CD4+CD25+ T cells has stemmed from investigation of the AOD in the d3tx mice. Besides CD4+CD25+ T cell depletion, d3tx disease induction requires effector T cell activation prompted by lymphopenia. This is supported by other neonatal AOD models in which T cell-mediated injury has been found to be triggered by immune complex or Ag immunization. In addition, there is growing evidence that support a state of neonatal propensity to autoimmunity, which depends on concomitant endogenous antigenic stimulation, concomitant nematode infection, resistance to CD4+CD25+ T cell regulation, and participation of the neonatal innate system. The suppression of d3tx disease by polyclonal CD4+CD25+ T cells appears to be dependent on endogenous Ag and the persistence of regulatory T cells. Thus, suppression of AOD occurs in the ovarian LN, and AOD emerges upon ablation of the input regulatory T cells; and in AIP, the hormone-induced expression of prostate Ag in the CD4+CD25+ T cell donors rapidly enhances the capacity to suppress disease over Ag negative donors. Finally, genetic analysis of AOD and its component phenotypes has uncovered seven Aod loci. As the general themes that emerged, significant epistatic interactions among the loci play a role in controlling disease susceptibility, the majority of the Aod loci are linked to susceptibility loci of other autoimmune diseases, and the genetic intervals encompass candidate genes that are differentially expressed between CD4+CD25+ T cells and other T cells. The candidate genes include Pdcd1, TNFR superfamily genes, H2, Il2, Tgfb, Nalp5 or Mater, an oocyte autoAg that reacts with autoantibody in sera of d3tx mice.