Dysregulated uterine natural killer cells and vascular remodeling in women with recurrent pregnancy losses.

PROBLEM: Angiogenesis and vascular remodeling in secretory endometrium represent one of the crucial steps in pregnancy establishment, for which uterine NK (uNK) cells have an important role. Impairment of these steps may proceed to implantation and instigate initial pathology of recurrent pregnancy losses (RPL). In this study, we aim to investigate vascular development and density of uNK cells in secretory endometrium of women with RPL. METHODS OF STUDY: Mid-secretory phase endometrial tissues from women with RPL (n = 15) and fertile controls (n = 7) were investigated. CD56+ and CD16+ uNK cells, CD31+ vascular endothelial cells and smooth muscle myosin (SMM)+ . Vascular smooth muscle cells (VSMC) expressing SMM were investigated using immunohistochemistry and western blot. High-throughput quantitative real-time polymerase chain reaction (qRT-PCR) was used as well. RESULTS: CD56+ uNK number was significantly higher in women with RPL compared to controls (P < 0.0001). uNK cell density by immunohistochemistry was positively correlated with CD56 mRNA expression by qRT-PCR (r2  = 0.43, P = 0.0137). The number of blood vessels represented by the expression of either CD31 or SMM was higher in women with RPL as compared to controls (P < 0.05 and P < 0.0001, respectively), and correlated with the number of uNK cell (r2  = 0.18, P < 0.04, and r2  = 0.65, P < 0.0001, respectively). The wall thickness of spiral arteries was significantly higher in women with RPL as compared with that of controls (P = 0.0027). CONCLUSION: Increased uNK cells in mid-secretory endometrium are associated with increased vascularization and defective vascular transformation of spiral arteries in women with RPL.

Inflammation induced preterm labor and birth.

Preterm birth which occurs before 37 weeks gestation is one of the most common obstetrical complication in humans. After many studies, it appears that "not one answer fits all" regarding the risk factors, causes and the treatments for this syndrome. However, it is becoming more evident that one of the major risk factors is inflammation and/or infection in the fetoplacental unit. In animal models (usually consisting of mice injected with lipopolysaccharide at 14 days of gestation), IL-22 and IL-6 have been identified as factors related to preterm birth. There are some clinical tests available to determine the risk for preterm labor and delivery, which can be identified before, during early, or at mid-gestation. However, treatment of preterm birth with antibiotics so far has not been "curable" and studies using anti-inflammatory treatments are not readily available. More studies regarding causes and treatments for preterm labor and delivery in humans are necessary to prevent neonatal deaths and/or developmental abnormalities associated with this common syndrome.

Prevalence of HHV-6 in endometrium from women with recurrent implantation failure.

PROBLEM: To study the prevalence of HHV-6 in endometrial biopsies among women experiencing recurrent implantation failure (RIF) after IVF/ET compared with controls. METHOD OF STUDY: Thirty women experiencing RIF after IVF/ET and 10 fertile women participated in the study. All women had endometrial biopsies taken in the luteal phase of their menstrual cycle for an endometrial immune profile (EIP) and HHV-6 mRNA as well as lymphocyte and granulocyte populations. The prevalence of HHV-6 in endometrial biopsies was determined, and biopsies for positive and negative expression of HHV-6 were compared with the results of their EIP and lymphocyte and granulocyte populations. RESULTS: Thirty-seven percentage of women with a history of RIF and 0% of controls demonstrated the presence of HHV-6 in their endometrial biopsies. No associations were found when the results of the endometrial immune profile were compared with the presence or absence of HHV-6. Significant increase in neutrophil-specific CD16b mRNA was found in HHV-6-positive samples, and the levels of B cells-related CD19 mRNA were lower in biopsies from women with RIF in comparison with normal controls. CONCLUSION: HHV-6 infection is an important factor in RIF.

Low-dose prednisone and immunoglobulin G treatment for woman at risk for neonatal alloimmune thrombocytopenia and T helper 1 immunity.

PROBLEM: Fetal and neonatal alloimmune thrombocytopenia is an alloimmune disorder resulting from platelet opsonization by maternal antibodies that destroy fetal platelets. As there is no antenatal screening or immunization to prevent sensitization, selection of high-risk population or the prevention of antenatal sensitization is significantly limited. METHOD OF STUDY: (i) A case report of ante- and postnatal management of a woman with paternal homozygosity for human platelet antigen-1(HPA) incompatibility. (ii) A retrospective case-control study of 11 confirmed FNAIT patients, 8 possible-FNAIT women, and 10 women with confirmed ITP. RESULT: Antenatal screening, prevention of maternal sensitization by serial monitoring and immunosuppression with prednisone and intravenous immunoglobulin G (IVIG) infusion resulted in two successful pregnancies without sensitization. CONCLUSION: Screening for couples at risk and prednisone and/or IVIG treatment is an option for women with paternal homozygosity for offending HPA antigen to prevent antenatal sensitization. HPA incompatibility is associated with increased Th1 immunity and NK cell cytotoxicity.

Gonadotropin-releasing hormone analogues lead to pro-inflammatory changes in T lymphocytes.

PROBLEM: We aimed to investigate the effect of gonadotropin-releasing hormone (GnRH) analogues on T-cell immunity. METHOD OF STUDY: TNF-α(+) -, INF-É£(+) -, IL-10(+) -, and IL-17(+) -expressing T cells in peripheral blood mononuclear cells (PBMCs) were treated with various concentrations (0.1, 1, 5, and 10 µm) of GnRH agonist (buserelin acetate) and antagonist (cetrorelix acetate) for 4 hours in vitro and they were analyzed with flow cytometry. RESULTS: TNF-α(+) /IL-10(+) T helper (TH) cell ratios were increased in PBMCs treated with 1, 5, and 10 µm GnRH agonist when compared to controls (P=.006, P=.014 and P=.030, respectively). IFN-É£(+) /IL-10(+) TH cell ratios were significantly increased with 0.1, 1, 5, and 10 µm GnRH agonist as compared with controls (P=.046, P=.004, P=.013, and P=.011, respectively). TNF-α(+) TH cell levels, and IFN-γ(+) /IL-10(+) TH cell ratios were significantly different (P<.001 and P<.004, respectively) between GnRH agonist- and antagonist-treated cells. CONCLUSION: GnRH analogues induce pro-inflammatory TH1 shift in T-cell immunity, in vitro. GnRH treatment during assisted reproductive technology cycle might explain a possible cause of inflammatory flare in women with inflammatory conditions.

Plasminogen Activator Inhibitor-1 4G/5G Polymorphism is Associated with Reproductive Failure: Metabolic, Hormonal, and Immune Profiles.

PROBLEM: Association between PAI-1 4G/5G polymorphism and reproductive failures has been postulated. We aimed to investigate its impact on metabolic, hormonal, and immune profiles of women with reproductive failures. METHOD OF STUDY: A retrospective study was carried out in 208 women with a history of reproductive failure. Study patients were divided into three groups: women with repeated implantation failure (RIF, n = 40), recurrent pregnancy loss (RPL, n = 113), and both RIF and RPL (n = 55). Fertile controls were 92. RESULTS: PAI-1 4G/4G was prevalent in RPL, RIF, and RIF/RPL groups when compared with controls (P = 0.003) and associated with increased risks of RIF, RPL, and RIF with RPL (OR = 4.5, 2.2 and 2.7). Women with PAI-1 4G/4G have significantly higher BMI, glucose, and PAI-1 levels and lower NK cytotoxicity when compared with women without PAI-1 4G/4G. CONCLUSION: PAI-1 4G/5G polymorphism plays a major role in the pathogenesis of RPL and RIF by altering metabolic and immunological profiles.