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1.
Transplantation ; 104(8): 1537-1541, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732829

RESUMO

This historical retrospective explores the study of the freemartin condition and its impact on the discovery of immunologic tolerance and the field of transplant surgery-from the ancient Romans, to early modern anatomists Valsalva, Scarpa, and Hunter, to contemporary immunologists Owen, Medawar, and Billingham, and to legendary transplant surgeon Joseph Murray. The legacy of freemartin cattle in the understanding of acquired tolerance and transplant immunology represents generations of scientific inquiry guided by careful observation and occasional serendipity, and the present-day immunologists and surgeons exploring immune transplant tolerance owe much to the history of the freemartin, several millennia in the making.


Assuntos
Rejeição de Enxerto/imunologia , Infertilidade Feminina/veterinária , Transplante de Órgãos/história , Transplante de Tecidos/história , Tolerância ao Transplante , Animais , Pesquisa Biomédica/história , Bovinos/imunologia , Feminino , Rejeição de Enxerto/prevenção & controle , História do Século XVII , História do Século XVIII , História do Século XIX , História do Século XX , História do Século XXI , História Antiga , Humanos , Infertilidade Feminina/imunologia , Transplante de Órgãos/efeitos adversos , Transplante de Tecidos/efeitos adversos
2.
Klin Lab Diagn ; 65(7): 435-438, 2020 Jun 04.
Artigo em Russo | MEDLINE | ID: mdl-32762182

RESUMO

Personalized therapy for female infertility means determining of immune mechanisms, including allergic sensitization towards sperm antigens. In order to determine antisperm serum IgE antibodies in women with infertility suffering from pelvic inflammatory diseases, the modified Anti-Spermatozoa Antibody protocol was used (ASA Serum ELISA, Demeditec Diagnostisc, Germany). The modification of the protocol is designed to detect only serum antisperm IgE antibodies carrying Fab fragments to sperm antigens. Allergen-specific IgEs to a common panel of 176 respiratory and food allergenic molecules were determined using the MeDALL scientific chip developed as a part of the European project. Forty patients suffering from infertility of inflammatory etiology and 16 practically healthy women of reproductive age were examined. Specific IgE antibodies towards sperm antigens were detected in blood serum in 7/40 (17.5%) patients with infertility. The maximum level of sIgE was 4 times higher than the maximal value of fertile women. No correlation with total IgE was detected. Women with sIgE-ASA complained of burning and itching immediately after coition. Systemic and long-term allergic reactions were not noted. Women with positive sIgE-ASA values were 2 times more likely to suffer from chronic recurrent vaginal dysbiosis. The presence of specific anti-sperm IgE antibodies is likely to have pathogenetic significance in female infertility, and they should be taken into consideration for creating personalized therapy approaches.


Assuntos
Infertilidade Feminina , Doença Inflamatória Pélvica , Antígenos , Feminino , Humanos , Imunoglobulina E/análise , Infertilidade Feminina/imunologia , Masculino , Doença Inflamatória Pélvica/imunologia , Espermatozoides/imunologia
3.
Immunol Lett ; 217: 84-90, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31756347

RESUMO

HCMV coevolved with humans for millions of years and is now one of the most widespread infections worldwide. For a long time HCMV seropositivity was considered a safe clinical condition. In recent decades both clinical observations and research results indicated that the very presence of HCMV in human organism specifically influences immune system and may affect reproduction as a process greatly dependent on immune cells function. Anti-HCMV IgG, IgG avidity, lymphocyte subsets as well as NK cytotoxicity was investigated in 470 infertile women who were eligible for IVF/ET. 419 patients were IgG anti-HCMV-positive (HCMV-seropositive) and only 51 (10.8 %) were IgG anti- HCMV-negative (HCMV-seronegative). There was not a single case of clinically significant level of low-avidity IgG. HCMV-seropositive patients had significantly increased levels of HLA-DR expression on T-lymphocytes (both on CD3CD8 and especially on CD3CD4 subsets) and HLA-DR expression on NK-lymphocytes (CD56+CD3-), increased levels of NKT-like cells (CD3+CD8+CD56+) but decreased levels of CD8 + NK lymphocytes compared to HCMV-seronegative patients. That difference was caused by significant numbers of individuals with deviated "accentuated" immune phenotypes in HCMV seropositive patients. The latter had increased (>7.5 %) levels of HLA-DR expression on T helpers in 136 cases from 419 (32.4 %) while in HCMV-seronegative group this accentuation was observed only in 3 of 51 patients (5.8 %), (OR -5.9, p < 0.0003). The number of cases with significantly increased CD56 expression on Tc lymphocytes, HLA-DR on NK and decrease of CD8-positive NK cells was more often observed in HCMV-seropositive group compared to seronegative. Thus, possibly HCMV seropositivity specifically influences immune system and results in pro-inflammatory phenotype formation in part of infected population. It was found that accentuations in immune phenotype of HCMV-seropositive women are very similar to previously described in association with reproductive failures but without HCMV serostatus taken into account.


Assuntos
Citomegalovirus/imunologia , Infertilidade Feminina/imunologia , Infertilidade Feminina/virologia , Subpopulações de Linfócitos/metabolismo , Adulto , Complexo CD3/metabolismo , Antígeno CD56/metabolismo , Antígenos CD8/metabolismo , Linfócitos T CD8-Positivos/imunologia , Citotoxicidade Imunológica , Feminino , Fertilização In Vitro , Antígenos HLA-DR/metabolismo , Humanos , Células Matadoras Naturais/imunologia , Subpopulações de Linfócitos/imunologia , Fenótipo
4.
Fertil Steril ; 113(1): 187-196.e1, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31718829

RESUMO

OBJECTIVE: To investigate whether chronic endometritis (CE) affects the immune status of peripheral blood and endometrium in patients with recurrent reproductive failure (RRF). DESIGN: Retrospective study. SETTING: Private fertility center. PATIENTS(S): A total of 524 RRF patients, including 324 women with recurrent miscarriage (RM) and 200 women with recurrent implantation failure (RIF). INTERVENTION(S): Peripheral blood and endometrium samples were collected in the midluteal phase before in vitro fertilization treatment or pregnancy. The number of peripheral T, natural killer (NK), and B cells, as well as cytotoxicity of NK cells and expression of TH1 cytokines were analyzed with the use of flow cytometry, and uterine immune cells were subjected to immunohistochemistry. MAIN OUTCOME MEASURE(S): Peripheral immune cells, cytokines, NK cytotoxicity, and endometrial immune cells were compared in RRF patients with versus without CE. RESULT(S): The proportion and function of the analyzed immune cell subsets in peripheral blood as well as the percentages of CD56+ NK cells, CD163+ M2 macrophages, and CD1a+ immature dendritic cells in the endometrium were not significantly altered between non-CE and CE patients, whereas the proportions of uterine CD68+ macrophages, CD83+ mature dendritic cells, CD8+ T cells, and Foxp3+ regulatory T cells were significantly elevated in CE patients. After antibiotic treatment, the percentage of CD68+ macrophages, CD83+ mature dendritic cells, CD8+ T cells, and Foxp3+ regulatory T cells in endometrium were significantly reduced in patients with cured CE. CONCLUSION(S): CE contributes to elevated endometrial infiltration levels of immune cells. The excessive presence of endometrial immune cells in CE patients may be involved in reduced endometrial receptivity and recurrent pregnancy failures.


Assuntos
Aborto Habitual/imunologia , Implantação do Embrião/fisiologia , Endometrite/imunologia , Endométrio/imunologia , Infertilidade Feminina/imunologia , Útero/imunologia , Aborto Habitual/sangue , Aborto Habitual/diagnóstico , Adulto , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Endometrite/sangue , Endometrite/diagnóstico , Endométrio/metabolismo , Feminino , Humanos , Infertilidade Feminina/sangue , Infertilidade Feminina/diagnóstico , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Gravidez , Estudos Retrospectivos , Útero/metabolismo
5.
Lupus ; 29(2): 105-117, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31829084

RESUMO

Antiphospholipid syndrome is a systemic autoimmune disease associated with obstetric complications along with vascular events affecting multiple organ systems in patients having positive titers of antiphospholipid antibodies. Eight to 20% of infertility cases have an unknown cause, part of which could be due to antiphospholipid syndrome. Although still debatable, many studies have addressed the relation between reproductive failure and antiphospholipid antibodies through the relation between antiphospholipid antibodies and unexplained infertility as well as the effect of antiphospholipid antibodies on the outcome of in vitro fertilization-embryo transfer. Few studies and cases have associated the presence of antiphospholipid antibodies with male infertility, describing morphofunctional penile abnormalities and testicular infarction. There are not enough data to support the routine practice of testing antiphospholipid antibodies in patients with infertility.


Assuntos
Aborto Habitual/imunologia , Anticorpos Antifosfolipídeos/imunologia , Infertilidade Feminina/imunologia , Infertilidade Masculina/imunologia , Aborto Habitual/patologia , Animais , Síndrome Antifosfolipídica/imunologia , Síndrome Antifosfolipídica/patologia , Feminino , Fertilização In Vitro , Humanos , Infertilidade Feminina/patologia , Infertilidade Masculina/patologia , Masculino , Gravidez
6.
Hum Reprod ; 34(12): 2456-2466, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31825483

RESUMO

STUDY QUESTION: Are uterine natural killer (uNK) cell numbers and their distribution relative to endometrial arterioles altered in women with recurrent implantation failure (RIF) compared to women with embryo implantation success (IS)? SUMMARY ANSWER: uNK cell numbers and their distribution relative to endometrial arterioles are not significantly different in women with RIF compared to women in whom embryo implantation occurs successfully following IVF. WHAT IS ALREADY KNOWN: uNK cells are regulators of decidual angiogenesis and spiral arteriole remodelling during early pregnancy. Although some studies have shown that uNK cell numbers may be altered in women with RIF, the methods used to measure uNK cell numbers have proven inconsistent, making reproduction of these results difficult. It is unclear, therefore, whether the results reported so far are reproducible. Moreover, it is not known how uNK cell numbers may impact IVF outcomes. Despite the lack of conclusive evidence, uNK cell numbers are often evaluated as a prognostic criterion in women undergoing assisted reproductive procedures. STUDY DESIGN, SIZE, DURATION: Endometrial pipelle biopsies were collected 6-8 days post-LH surge in natural cycles from women with RIF (n = 14), women with IS (n = 11) and women with potential RIF at the time of the study (PRIF; n = 9) from 2013 to 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: uNK cells (i.e. CD56+ and/or CD16+ phenotypes) and their distribution relative to endometrial arterioles were investigated by standard immunohistochemistry protocols and quantified using Aperio ScanScopeXT images digitized by ImageJ and deconvoluted into binary images for single cell quantification using a Gaussian Blur and Yen algorithm. MAIN RESULTS AND THE ROLE OF CHANCE: There was no significant difference in the cell density of CD56+ or CD16+ uNK cells in women with RIF compared to women with IS or PRIF. There was a higher proportion of uNK cells in the distal regions compared to the regions closest to the arterioles in all patient groups. Further, we identified a significant reduction in uNK cell density in women who had a previous pregnancy compared to those who had not, regardless of their current implantation status. LARGE SCALE DATA: Not applicable. LIMITATIONS, REASONS FOR CAUTION: Spiral arterioles could not always be accurately identified by digital image analysis; therefore, all endometrial arterioles were selected and analysed. Patient numbers for the study were low. However, as the clinical phenotypes of each patient were well defined, and endometrial dating was accurately determined by three independent pathologists, differences between patient groups with respect to the uNK numbers and distribution should have been measurable if uNK cell counts were to be useful as a prognostic marker of RIF. WIDER IMPLICATIONS OF THE FINDINGS: Our findings demonstrate that CD56+ and CD16+ uNK cell numbers are not significantly different in women with RIF in a typical cohort of women undergoing IVF. Further, prior pregnancy was associated with a significantly reduced number of uNK cells in both the RIF and IS patient groups, suggestive of a long-term pregnancy induced suppression of uNK cells. Combined, these findings do not support the clinical value of using uNK cell numbers as a prognostic indicator of implantation success with IVF treatment. STUDY FUNDING/COMPETING INTEREST(S): Funding for this work was provided by Royal Women's Hospital Foundation. P.P. was supported by an NHMRC Early Career Fellowship [TF 11/14] and W.T.T. was supported by an NHMRC Postgraduate Scholarship [1055814]. The authors do not have any competing interests with this study.


Assuntos
Implantação do Embrião/imunologia , Endométrio/imunologia , Infertilidade Feminina/imunologia , Células Matadoras Naturais , Adulto , Arteríolas/imunologia , Endométrio/irrigação sanguínea , Feminino , Humanos , Gravidez
7.
J Ovarian Res ; 12(1): 123, 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31831028

RESUMO

BACKGROUND: Endometriosis is considered to be the most intractable cause of female infertility. Administering any type of treatment for endometriosis before in vitro fertilization and embryo transfer (IVF-ET) is an important strategy for improving the IVF-ET outcomes for infertile women with endometriosis. In fact, treatment with a gonadotropin-releasing hormone (GnRH) agonist just before IVF-ET has been reported to improve the clinical outcome in endometriosis patients. However, the benefit of Dienogest (DNG), a synthetic progestin, treatment just before IVF-ET remains unclear. METHODS: Sixty-eight infertile women with Stage III or IV endometriosis (ovarian endometrial cyst < 4 cm) were recruited for this study. The subjects were divided into 2 groups: a DNG group (n = 33) and a control group (n = 35). DNG was administered orally every day for 12 weeks prior to the conventional IVF-ET cycle in the DNG group. Standard controlled ovarian hyperstimulation with the GnRH agonist long protocol was performed in the control group. The numbers of mature follicles and retrieved oocytes, fertilization rates, implantation rates, and clinical pregnancy rate were compared between the two groups. In addition, the concentrations of inflammatory cytokines, oxidative stress markers, and antioxidants in follicular fluids were also measured. RESULTS: The numbers of growing follicles, retrieved oocytes, fertilized oocytes, and blastocysts were significantly lower in the DNG group than in the control group. The fertilization and blastocyst rates were also lower in the DNG group than in the control group. Although there was no significant difference in the implantation rate between the groups, the cumulative pregnancy rate and live birth rate were lower in the DNG group than in the control group. There was no significant difference in the abortion rate. Our results failed to show that DNG reduces the inflammatory cytokine levels and oxidative stress in follicular fluids. CONCLUSIONS: Administering DNG treatment just before IVF-ET did not provide any benefits to improve the clinical outcomes for infertile women with endometriosis.


Assuntos
Transferência Embrionária , Endometriose/tratamento farmacológico , Fertilização In Vitro , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Antagonistas de Hormônios/uso terapêutico , Infertilidade Feminina/tratamento farmacológico , Nandrolona/análogos & derivados , Adulto , Citocinas/imunologia , Endometriose/imunologia , Feminino , Líquido Folicular/imunologia , Humanos , Infertilidade Feminina/imunologia , Nandrolona/uso terapêutico , Estresse Oxidativo , Resultado do Tratamento
8.
Best Pract Res Clin Endocrinol Metab ; 33(6): 101369, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31837981

RESUMO

Infertility consists by definition in" failure to achieve a clinical pregnancy after 12 months or more of regular unprotected intercourse" while the term subfertility means a delay to achieve pregnancy. Several factors can contribute to infertility or subfertility in patients with systemic autoimmune diseases. The association of systemic autoimmune conditions with endometriosis, celiac disease and thyroid autoimmunity that are well known causes of infertility and/or subfertility need to be taken in consideration when difficulties in the onset of pregnancy is reported. The majority of the used antirheumatic drugs do not interfere with fertility. However, the use of cyclophosphamide, limited to severe disease, can provoke premature ovarian failure; to preserve fertility a preventive treatment is available. Nonsteroidal anti-inflammatory drugs can cause temporary infertility and corticosteroids are associated to a prolonged time to pregnancy in some rheumatic diseases. Data on the association of antiphospholipid antibodies (aPL) with infertility are still debated but in general an increased rate of aPL is described patients undergoing medically assisted reproductive techniques. In systemic lupus erythematosus aPL and other autoantibodies (i.e. anti-oocytes) can contribute to the infertility of some patients. Subfertility, rather than infertility, is observed in patients with rheumatoid arthritis; the particular physical conditions of these women can also account for this. Physicians should not forget the patients' age, that is mandatory in order to preserve their chance to have children.


Assuntos
Doenças Autoimunes/complicações , Infertilidade Feminina/etiologia , Insuficiência Ovariana Primária/etiologia , Anticorpos Antifosfolipídeos/sangue , Autoanticorpos/efeitos adversos , Autoanticorpos/sangue , Doenças Autoimunes/terapia , Autoimunidade/fisiologia , Criança , Endometriose/complicações , Endometriose/imunologia , Endometriose/terapia , Feminino , Humanos , Recém-Nascido , Infertilidade Feminina/imunologia , Infertilidade Feminina/terapia , Gravidez , Insuficiência Ovariana Primária/imunologia , Insuficiência Ovariana Primária/terapia , Técnicas de Reprodução Assistida/tendências , Glândula Tireoide/imunologia
9.
Presse Med ; 48(11 Pt 1): e307-e315, 2019 Nov.
Artigo em Francês | MEDLINE | ID: mdl-31727487

RESUMO

INTRODUCTION: Fertility disorders in autoimmune diseases are well described. However, little is known about the presence of a humoral serum autoimmunity in case of infertility (antinuclear antibodies, ACAN or antiphospholipid, APL) without criteria of autoimmune disease. METHODS: We studied the prevalence, associated factors, and efficacy of immunomodulatory therapy in patients with unexplained infertility. Two groups were created retrospectively among patients followed in medically assisted procreation (PMA) for infertility: a group with serum autoimmunity (AI+) (ACAN, APL or anti-thyroperoxidase antibodies) and a group without serum autoimmunity (HAVE-). Clinical, biological, and therapeutic data were collected. RESULTS: The prevalence of autoimmunity was 33% among consultant patients. One hundred patients were seen in internal medicine consultation, 70 were included in the AI+ group and 30 in the AI- group. In the AI+ group, 76% had ACANs, 29% had anti-TPOs and 23% had APLs. There was a significant correlation between ACAN level and the presence of endometriosis (P=0.048). Immunomodulatory therapy was introduced for 68 of the 70 women in the AI+ group; pregnancy occurred in 28 patients (40%) during the treatment period, compared with 7 in the "AI-" group (23%), with a tendency to significance (P=0.09). In conclusion, there is an increased prevalence of serum autoimmunity in patients with fertility disorders, possibly with the efficacy of an immunomodulatory treatment to confront prospective therapeutic studies.


Assuntos
Autoanticorpos/sangue , Autoimunidade , Infertilidade Feminina/imunologia , Anticorpos Antinucleares/sangue , Anticorpos Antifosfolipídeos/sangue , Autoantígenos/imunologia , Implantação do Embrião , Endometriose/imunologia , Feminino , França , Humanos , Imunomodulação , Infertilidade Feminina/sangue , Infertilidade Feminina/terapia , Iodeto Peroxidase/imunologia , Proteínas de Ligação ao Ferro/imunologia , Gravidez , Estudos Retrospectivos
10.
J Reprod Immunol ; 136: 102617, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31604165

RESUMO

Poor ovarian response (POR1) limits the success of infertility treatment modality. In this study, we aim to investigate if POR is associated with serum 25(OH) vitamin D (VD2) levels and pro-inflammatory immune responses in infertile women with a history of in-vitro fertilization and embryo transfer failures. A retrospective cross-sectional study included 157 women with IVF failures. Study patients were divided into four groups based on serum 25(OH)VD level and ovarian responses during the most recent IVF cycle; low VD (LVD3) with POR, LVD with normal ovarian response (NOR4), normal VD (NVD5) with POR, and NVD with NOR. Serum 25(OH)VD level, cellular- and auto-immunity, and metabolic parameters, including homocysteine and plasminogen activator inhibitor-1 were investigated. Peripheral blood CD56+ NK cell levels (%) and NK cytotoxicity were significantly higher in POR-LVD when compared to the other groups (P < 0.05, respectively). CD19 + B and CD19+/5+ B-1 cell levels were significantly higher in women with POR-LVD as compared with those of NOR-LVD and POR-NVD (P < 0.05, respectively). TNF-α/IL-10 producing Th1/Th2 cell ratio of POR-LVD was significantly higher than those of POR-NVD and NOR-NVD (P < 0.05 respectively). Peripheral blood homocysteine level of POR-LVD was significantly higher than those of NOR-LVD and POR-NVD (P < 0.05 respectively). We conclude that assessment of cellular and autoimmune abnormalities and metabolic factors, such as homocysteine should be considered in women with POR and LVD. VD and folic acid supplementation may be explored further as a possible therapeutic option for POR with immune and metabolic etiologies.


Assuntos
Fertilização In Vitro , Infertilidade Feminina , Ovário , Vitamina D , Adulto , Estudos Transversais , Feminino , Humanos , Infertilidade Feminina/sangue , Infertilidade Feminina/imunologia , Infertilidade Feminina/terapia , Inflamação/sangue , Inflamação/imunologia , Interleucina-10/sangue , Interleucina-10/imunologia , Linfócitos/imunologia , Linfócitos/metabolismo , Ovário/imunologia , Ovário/metabolismo , Estudos Retrospectivos , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia , Vitamina D/sangue , Vitamina D/imunologia
11.
Clin Infect Dis ; 69(9): 1517-1525, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31504315

RESUMO

BACKGROUND: We evaluated the risk of pelvic inflammatory disease (PID), ectopic pregnancy, and infertility in women with a previous Chlamydia trachomatis (CT) diagnosis compared with women who tested negative for CT and CT untested women, considering both targeted and incidental (ie, prescribed for another indication) use of CT-effective antibiotics. METHODS: This was a retrospective study of women aged 12-25 years at start of follow-up within the Clinical Practice Research Datalink GOLD database linked to index of multiple deprivation quintiles, 2000-2013. CT test status and antibiotic use were determined in a time-dependent manner. Risk of PID, ectopic pregnancy, or female infertility were evaluated using of Cox proportional hazard models. RESULTS: We studied 857 324 women, contributing 6 457 060 person-years. Compared with women who tested CT-negative, women who tested CT-positive had an increased risk of PID (adjusted hazard ratio [aHR], 2.36; 95% confidence interval [CI], 2.01-2.79), ectopic pregnancy (aHR, 1.87; 95% CI, 1.38-2.54), and infertility (aHR, 1.85; 95% CI, 1.27-2.68). The PID risk was higher for women with 2 or more positive CT tests than those with 1 positive test. PID risk increased with the number of previous antibiotic prescriptions, regardless of CT test status. CONCLUSIONS: We showed an association between CT-positive tests and 3 adverse reproductive health outcomes. Moreover, this risk increased with repeat CT infections. CT-effective antibiotic use showed no decreased risks of subsequent PID regardless of CT history. Our results confirm the reproductive health burden of CT, which requires adequate public health interventions.


Assuntos
Chlamydia trachomatis/patogenicidade , Infertilidade Feminina/etiologia , Infertilidade Feminina/imunologia , Doença Inflamatória Pélvica/imunologia , Doença Inflamatória Pélvica/microbiologia , Adolescente , Adulto , Antibacterianos/uso terapêutico , Criança , Chlamydia trachomatis/efeitos dos fármacos , Feminino , Humanos , Gravidez , Atenção Primária à Saúde/estatística & dados numéricos , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
12.
J Clin Endocrinol Metab ; 104(12): 6155-6170, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31390009

RESUMO

CONTEXT: Polycystic ovary syndrome (PCOS) is a chronic disease affecting reproductive function and whole-body metabolism. Although the etiology is unclear, emerging evidence indicates that the epigenetics may be a contributing factor. OBJECTIVE: To determine the role of global and genome-wide epigenetic modifications in specific immune cells in PCOS compared with controls and whether these could be related to clinical features of PCOS. DESIGN: Cross-sectional study. PARTICIPANTS: Women with (n = 17) or without PCOS (n = 17). SETTING: Recruited from the general community. MAIN OUTCOME MEASURES: Isolated peripheral blood mononuclear cells were analyzed using multicolor flow cytometry methods to determine global DNA methylation levels in a cell-specific fashion. Transcriptomic and genome-wide DNA methylation analyses were performed on T helper cells using RNA sequencing and reduced representation bisulfite sequencing. RESULTS: Women with PCOS had lower global DNA methylation in monocytes (P = 0.006) and in T helper (P = 0.004), T cytotoxic (P = 0.004), and B cells (P = 0.03). Specific genome-wide DNA methylation analysis of T helper cells from women with PCOS identified 5581 differentially methylated CpG sites. Functional gene ontology enrichment analysis showed that genes located at the proximity of differentially methylated CpG sites belong to pathways related to reproductive function and immune cell function. However, these genes were not altered at the transcriptomic level. CONCLUSIONS: It was shown that PCOS is associated with global and gene-specific DNA methylation remodeling in a cell type-specific manner. Further investigation is warranted to determine whether epigenetic reprogramming of immune cells is important in determining the different phenotypes of PCOS.


Assuntos
Epigênese Genética/fisiologia , Leucócitos Mononucleares/metabolismo , Linfócitos/metabolismo , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/imunologia , Reprodução/genética , Adolescente , Adulto , Estudos de Casos e Controles , Reprogramação Celular/genética , Reprogramação Celular/imunologia , Estudos Transversais , Metilação de DNA/fisiologia , Feminino , Predisposição Genética para Doença , Humanos , Sistema Imunitário/metabolismo , Infertilidade Feminina/genética , Infertilidade Feminina/imunologia , Pessoa de Meia-Idade , Síndrome do Ovário Policístico/metabolismo , Reprodução/imunologia , Adulto Jovem
13.
J Immunol Methods ; 474: 112639, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31404551

RESUMO

Natural killer (NK) cells are the predominant innate lymphocyte subsets that mediate anti-tumor and anti-viral responses. The monitoring of NK cells function is important in various physiological and pathological conditions. Different approaches have been used to directly or indirectly evaluate NK cells activities. The purpose of this study was to investigate the correlation between the number of NK cells and cytotoxic activity of NK cells and to determine whether NKp46+NK cells reflect NK cytotoxicity status. In our study, we retrospectively analyzed laboratory data on NK cytotoxicity and NK lymphocyte levels of 4896 infertile women which underwent routine immunology investigation after IVF failures. In healthy women, NKp46 expression was assessed on NK cells (n = 214) and cytotoxicity activity was evaluated with regard to NKp46 expression. We found that despite a significant correlation coefficient (n = 4689, r = 0.447), the correlation with cytotoxicity is maintained only within the zones with a low or high NK cells frequency. NK cells frequency has no significant prognostic value for their cytotoxicity - within the medium NK frequency zone the samples may have any cytotoxicity, both reduced and elevated. However, our data demonstrate that NKp46+NK cells frequency correlates with cytotoxicity activity even more significantly than the NK cells frequency (n = 214, r = 0.67 and r = 0.62, respectively) and has significant prognostic value for the abnormal NK cytotoxicity status indications, both low and increased. Our results further support an important role of NKp46 in NK cells killing and afford grounds for using the measurement of the NKp46+NK cells frequency as an alternative method for abnormal NK cytotoxicity status indication, which is responsive, simple and reliable.


Assuntos
Citotoxicidade Imunológica , Infertilidade Feminina/imunologia , Células Matadoras Naturais/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/sangue , Adulto , Biomarcadores/sangue , Morte Celular , Técnicas de Cocultura , Feminino , Fertilização In Vitro , Citometria de Fluxo , Humanos , Infertilidade Feminina/sangue , Infertilidade Feminina/terapia , Células K562 , Contagem de Linfócitos , Fenótipo , Valor Preditivo dos Testes , Estudos Retrospectivos , Falha de Tratamento
14.
Ceska Gynekol ; 84(3): 184-189, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31324107

RESUMO

OBJECTIVE: An increased number of NK cells is associated with autoimmune disorder and is known to play a role in infertility. The aim of our research was to monitor the density of NK cells CD56+ and CD16+ in ovulatory cervical mucus (OCM) and in endometrium in infertile women as well as in connection with the actual status of antibodies against phospholipids, sperm and HHV-6 antibodies. TYPE OF STUDY: Original aticle. SETTING: Genetika - Plzeň. METHODS: Seventy-two randomly selected women aged 20-39 (mean age: 32.3) years old resulted in fifty-seven patients with repeated unexplained miscarriages, and fifteen fertile healthy women. The hormonal status was studied including ovulation, the humoral autoimmune responses to eight phospholipids, trombophilia, karyotyping, hysteroscopy, and endometrium immunohistology. Patients were without any clinical and laboratory symptoms of vaginitis at the time of OCM sampling and endometrium study. In one patient antiphospholipid syndrome was present, and in one woman diabetes mellitus was identified. Uterine NK cells CD56+ , CD16+ and NK cells in OCM were identified by immunocytochemistry, antiphospholipid antiboides by ELISA. We used indirect MAR-test for study of local spermagglutinating antibodies in OCM. Indirect immunofluorescent method was used for detection of serum and OCM IgM, IgG antibodies against HHV-6 levels at the time of ovulation. RESULTS: We found both high density of NK cells CD56+ and CD16+ in OCM and in endometrium in only two infertile women with repeated abortions. NK cells in OCM were missing in other samples of patients. The prevalence of high density of NK cells CD56+ in the endometrium was seen in twenty three (40%), NK cells CD16+ in eleven (19%), NK cells 56+ and NK cells 16+ together in eight (14%). Levels of serum and OCM IgG against HHV-6 in all examined patients were not elevated, no cervical sperm antibodies were found. CONCLUSION: We compared density of NK cells CD56+ and CD16+ in OCM and secretory endometrium in all infertile patients. Our results show that cell mucosal activity in the cervical area at the time of ovulation in two infertile patients was evident. We excluded the abnormal number of NK cells owing to local and general viral infection (HHV-6). But our question still remains - are cervical NK cells fixed or still migrating from endometrium into OCM? New research is planned.


Assuntos
Antígenos CD/sangue , Antígeno CD56/imunologia , Muco do Colo Uterino/fisiologia , Endométrio/imunologia , Fertilidade/imunologia , Infertilidade Feminina/imunologia , Células Matadoras Naturais/imunologia , Aborto Habitual/sangue , Aborto Habitual/imunologia , Adulto , Estudos de Casos e Controles , Endométrio/metabolismo , Endométrio/patologia , Feminino , Humanos , Infertilidade Feminina/sangue , Células Matadoras Naturais/metabolismo , Masculino , Gravidez , Adulto Jovem
15.
Am J Reprod Immunol ; 82(4): e13170, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31310689

RESUMO

PROBLEM: Increased oxidative stress (OS) and inflammatory factors in metabolic syndrome (MS) patients are considered as risk factors for recurrent implantation failure (RIF). The aim of this study was to investigate OS markers, inflammatory factors, related microRNAs (miRNA) expression, and cytokine and transcription factors RNA expression. METHOD OF STUDY: We evaluated the frequency of helper T (Th) 17 and regulatory T (Treg) cells in recurrent implantation failure (RIF) women with or without MS. miRNA expression, an inflammatory cytokine, and transcription factors were measured by real-time PCR. The level of interleukin (IL)-1ß, IL-6, IL-17, tumour necrosis factor-alpha (TNF-alpha) and chemokine (C-C motif) ligand 2 (CCL-2), and C-X-C motif chemokine ligand 8 (CXCL-8) were measured by enzyme-linked immunosorbent assay (ELISA). OS markers were evaluated by spectrophotometric assay. Th17 and Treg cell frequencies were determined by flow cytometry. RESULTS: The expression of AP1, NF-κB, FOXP3, miRNA-21; serum or plasma level of OS markers (ie, nitric oxide, total oxidant status, and myeloperoxidase); serum level of inflammatory factors (ie, IL1-ß, IL-6, IL-17, TNF-alpha, CXCL-8, and CCL-2); and frequency of Th17 cells were increased in RIF-MS patients in comparison with RIF women without MS (RIF-NMS) and control group. The expression of miRNA-223 and 146a, antioxidant enzymes, namely superoxide dismutase (SOD) and catalase (CAT), and frequency of Treg also declined in RIF-MS patients. CONCLUSION: Overall, our findings suggest that MS in RIF patients causes increased inflammatory factors and OS, which in turn leads to implantation failure.


Assuntos
Infertilidade Feminina/imunologia , Síndrome Metabólica/imunologia , Adulto , Citocinas/sangue , Citocinas/genética , Feminino , Fatores de Transcrição Forkhead/genética , Humanos , Infertilidade Feminina/sangue , Infertilidade Feminina/genética , Inflamação/sangue , Inflamação/genética , Inflamação/imunologia , Síndrome Metabólica/sangue , Síndrome Metabólica/genética , MicroRNAs , NF-kappa B/genética , Estresse Oxidativo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Fator de Transcrição AP-1/genética , Adulto Jovem
16.
Iran J Immunol ; 16(2): 151-162, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31182689

RESUMO

BACKGROUND: Endometriosis is a chronic inflammatory disease with the growth of endometrial cells out of uterus and in the peritoneal cavity. T cell subsets participate in the establishment and progress of the disease by producing different cytokines. OBJECTIVE: To investigate a group of cytokines related to Th1/Th2/Th17/Treg subsets within both peripheral blood and peritoneal fluid (PF) samples from infertile endometriosis women. METHODS: Peripheral blood and PF samples were collected from 30 infertile endometriosis and 30 non-endometriosis fertile women during laparoscopy. Concentration of cytokines, including TNF-α, IFN-γ, TGF-ß1, IL-4, IL-10, IL-17 and IL-23 were evaluated using ELISA method. RESULTS: Results indicated that the concentration of IFN-γ within serum was significantly reduced in endometriosis group (p=0.001). Regarding PF cytokines, TGF-ß1 was increased in endometriosis group (p=0.030). Furthermore, the ratios of IFN-γ/TGF-ß1 and IL-17/IL-23 were significantly different between endometriosis and non-endometriosis women in serum samples (p<0.001 and p<0.01 respectively). The ratios of TNF-α/IL-10 and IL-17/IL-10 were also significantly different regarding PF samples between the two studied groups (p<0.04 and p<0.03 respectively). Finally, significant correlations were observed between the levels of IL-17 and IL-23, inflammatory and anti-inflammatory cytokines, in both samples and serum to PF inflammatory cytokines. CONCLUSION: Based on the results of the present study, in women with endometriosis, the disturbance of cytokines network might gradually activate the inflammatory responses and tissue repair, resulting in endometriosis development after several years.


Assuntos
Citocinas/imunologia , Endometriose/imunologia , Endométrio/patologia , Infertilidade Feminina/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto , Líquido Ascítico/química , Líquido Ascítico/imunologia , Citocinas/análise , Citocinas/sangue , Endometriose/complicações , Feminino , Humanos , Infertilidade Feminina/complicações , Pessoa de Meia-Idade , Adulto Jovem
17.
Clin Chim Acta ; 495: 545-551, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31158356

RESUMO

BACKGROUND: Autoimmune reactions and subsequent inflammation may underlie spermatogenic dysfunction and endometriosis-related infertility. The aim of this study is to identify disease-specific antigens in immune complexes (ICs) in seminal plasma (SP) and in follicular fluid (FF). METHODS: Immune complexome analysis, in which nano-liquid chromatography-tandem mass spectrometry is employed to comprehensively identify antigens incorporated into ICs in biological fluids, was performed for specimens collected from infertile couples undergoing assisted reproduction. Forty-two male patients consisting of subjects with oligozoospermia (n = 6), asthenozoospermia (n = 8), and normal semen analysis (n = 28). Fifty-eight female patients consisting of subjects with ovarian endometriosis (n = 10) and control women without disease (n = 48). RESULTS: Four disease-specific antigens were identified in subjects with oligozoospermia, while five disease-specific antigens were detected in subjects with asthenozoospermia, some of which are involved in sprematogenesis. Eight antigens were detected only in subjects with endometriosis. CONCLUSION: Functional characteristics of disease-specific antigens were found to correspond to the pathogenesis of male and female infertility. The formation of ICs may contribute to spermatogenic dysfunction and endometriosis-related infertility via loss of function of the related proteins. Immune complexome analysis is expected to be a valuable tool for the investigation of novel diagnostic methods and treatment strategies for infertility.


Assuntos
Antígenos/imunologia , Líquido Folicular/imunologia , Infertilidade Feminina/imunologia , Infertilidade Masculina/imunologia , Sêmen/imunologia , Adulto , Feminino , Humanos , Masculino
18.
Iran J Allergy Asthma Immunol ; 18(2): 163-172, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31066252

RESUMO

Unexplained infertility (UI) is one of the most common diagnoses in the fertility care. Seminal plasma (SP) plays a crucial role in the regulation of female immune responses and the success of a pregnancy. In vitro fertilization (IVF) is a well-known method for the treatment of UI. In this study, we aimed to investigate the effect of SP on the differentiation of T helper (Th) cell subsets and the relationship between these subsets with the rate of IVF success in a group of women complicated with UI compared to those with normal pregnancy. This study was conducted on 20 UI couples (ten with successful and ten with unsuccessful IVF outcome) and 10 fertile couples as the control group. Four color flow cytometry technique was used to detect Th cell subsets in the peripheral blood mononuclear cells (PBMC) with or without stimulation by SP. Results indicated that the frequencies of IL-17+ and Foxp3+ T cells after incubation with SP was significantly increased in couples with unsuccessful IVF outcome as compared to successful and healthy groups (p<0.05). Additionally, a positive correlation was observed between Th1 and Th2 cells in the unsuccessful IVF group (R=0.6, p=0.03). In summary, the results of the present study demonstrated that exposure to SP might increase Th17 and Treg cell frequencies in infertile women with unsuccessful IVF, and might also balance inflammatory to regulatory responses to finally tune-up the Th1/Th2/Th17/Treg balance and support the success of IVF.


Assuntos
Fertilização In Vitro/métodos , Infertilidade Feminina/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Adulto , Biomarcadores , Células Cultivadas , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imunofenotipagem , Infertilidade Feminina/diagnóstico , Interleucina-17/metabolismo , Masculino , Prognóstico , Sêmen/metabolismo , Resultado do Tratamento
19.
Sci Rep ; 9(1): 6040, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988342

RESUMO

Immune responses play an important role in the pathogenesis of polycystic ovary syndrome (PCOS). However, the characteristics of T lymphocyte subsets in PCOS remain insufficiently understood. In this study, lymphocytes of follicular fluid (FF) were obtained from oocyte retrieval before in-vitro fertilization (IVF) in infertile women with or without PCOS. The levels of cluster of differentiation 25 (CD25), CD69, programmed death 1 (PD-1), interferon-γ (IFN-γ), interleukin 17A (IL-17A) and IL-10 in T lymphocytes were determined by flow cytometry. Our results showed that the percentage of FF CD8+ T cells was significantly decreased in infertile patients with PCOS (P < 0.05). Furthermore, the levels of CD69 and IFN-γ were significantly decreased and the level of PD-1 was increased in both CD4+ and CD8+ T cells from infertile patients with PCOS (P < 0.05). Moreover, the expression of PD-1 on CD4+ or CD8+ T cells was positively correlated with the estradiol (E2) levels in the serum and reversely correlated with the expression of IFN-γ in CD4+ or CD8+ T cells in infertile patients with PCOS. These results suggested that T cell dysfunction may be involved in the pathogenesis of PCOS.


Assuntos
Líquido Folicular/imunologia , Síndrome do Ovário Policístico/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto , Antígenos CD/análise , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/análise , Antígenos de Diferenciação de Linfócitos T/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Citocinas/análise , Citocinas/imunologia , Feminino , Fertilização In Vitro , Humanos , Infertilidade Feminina/complicações , Infertilidade Feminina/imunologia , Subunidade alfa de Receptor de Interleucina-2/análise , Subunidade alfa de Receptor de Interleucina-2/imunologia , Lectinas Tipo C/análise , Lectinas Tipo C/imunologia , Síndrome do Ovário Policístico/complicações , Adulto Jovem
20.
Hum Reprod ; 34(6): 1139-1145, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-30927428

RESUMO

STUDY QUESTION: Is the risk of juvenile idiopathic arthritis (JIA) increased in children conceived after fertility treatment, and is an observed association caused by specific types of fertility treatment or by factors associated with the underlying infertility? SUMMARY ANSWER: The risk of JIA in children conceived after fertility treatment (any and specific types of fertility treatment) was not convincingly affected when compared with children born to fertile women. WHAT IS KNOWN ALREADY: It has been suggested that fertility treatment may affect the development of the immune system and thereby increase the risk of developing autoimmune diseases, including JIA. STUDY DESIGN, SIZE, DURATION: This retrospective population-based cohort study included all live-born children in Denmark between 1 January 1996 and 31 December 2012 (n = 1 084 184). The study population was followed from date of birth until first diagnosis of JIA as registered in the Danish National Patient Registry, date of 16th birthday, date of emigration, date of death or end of follow-up (31 December 2014), whichever occurred first. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study cohort was linked to the Danish Infertility Cohort in order to identify children born to women with fertility problems (n = 174 702) and fertility treatment (n = 89 931). Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: During a median follow-up period of 10.3 years, 2237 children were diagnosed with JIA. Children born to women with fertility problems had an increased risk of JIA (HR 1.18, 95% CI 1.05-1.32) compared with children born to fertile women. However, the risk was not increased in children conceived after any fertility treatment (HR 1.11; 95% CI 0.95-1.29), or after specific types of fertility treatment being ART (HR 1.05; 95% CI 0.83-1.33), IVF (HR 1.01; 95% CI 0.73-1.38), ICSI (HR 0.98; 95% CI 0.64-1.50) or any fertility drugs (HR 1.10; 95% CI 0.94-1.28) compared with children born to fertile women. The associations between fertility treatment and JIA were also assessed by using children born to women with fertility problems without fertility treatment in the index pregnancy as a reference group, however, the findings did not change substantially. LIMITATIONS REASONS FOR CAUTION: Despite a large study population, the statistical precision in some subgroup analyses may be affected due to the low number of JIA cases. There may be some misclassification of fertility problems, as some women have undiagnosed fertility problems and are therefore not included in the Danish Infertility Cohort; potentially leading to slight attenuation of the association between fertility problems and JIA. WIDER IMPLICATIONS OF THE FINDINGS: The results are based on national data and our findings can therefore be applied to other similar populations. Our results indicate that fertility treatment per se do not increase the risk of JIA but merely that the increased risk of JIA observed among children born to women with fertility problems may be due to underlying factors related to both infertility and JIA. However, as this is the first large study in this field, further studies are needed to confirm our findings. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by grants from the Jascha Foundation, the Aase and Ejner Danielsens Foundation and The Danish Rheumatism Association. All authors report no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.


Assuntos
Artrite Juvenil/epidemiologia , Fármacos para a Fertilidade/efeitos adversos , Fertilização In Vitro/efeitos adversos , Infertilidade Feminina/terapia , Exposição Materna/efeitos adversos , Adulto , Artrite Juvenil/imunologia , Criança , Pré-Escolar , Dinamarca/epidemiologia , Prescrições de Medicamentos/estatística & dados numéricos , Feminino , Fertilização In Vitro/métodos , Fertilização In Vitro/estatística & dados numéricos , Seguimentos , Humanos , Infertilidade Feminina/imunologia , Idade Materna , Idade Paterna , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Medição de Risco , Fatores de Risco
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