ABSTRACT
PROBLEM: Human chorionic gonadotropin (hCG) and regulatory T cells (Tregs) have been suggested to play important roles during the initial stage of pregnancy. However, the clinical relevance and mechanism of the effects of hCG on Treg functions in women with recurrent implantation failure (RIF) remain to be elucidated. METHOD OF STUDY: Thirty-four RIF and twenty-three control women were included in the study. Endometrial and peripheral Tregs were analyzed by immunohistochemistry and flow cytometry, respectively. Tregs were generated from naïve CD4+ T cells by stimulation with anti-CD3/CD28 in the presence or absence of hCG, and the subsets were analyzed by flow cytometry, Western blotting, and qPCR. RESULTS: The percentages of endometrial FOXP3+ Tregs and peripheral CCR4+ FOXP3+ Tregs were significantly lower in the women with RIF than in the healthy controls. In addition, the percentages of CCR4+ FOXP3+ Tregs and TGF-ß-expressing FOXP3+ Tregs were increased following the stimulation of naïve CD4+ T cells with anti-CD3/CD28, and these increases were concomitant with AKT and ERK dephosphorylation. CONCLUSIONS: The results of this study provide novel evidence supporting a role of hCG in regulating the differentiation of peripheral FOXP3+ Tregs. The alterations of circulating Tregs may positively affect the pregnancy outcomes of patients with a history of RIF.
Subject(s)
Chorionic Gonadotropin/metabolism , Endometrium/immunology , Infertility, Female/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , Adolescent , Adult , Cell Movement , Cells, Cultured , Embryo Implantation , Female , Forkhead Transcription Factors/metabolism , Humans , Pregnancy , Pregnancy Outcome , Receptors, CCR4/metabolism , Receptors, LH/metabolism , Receptors, Lymphocyte Homing/metabolism , Transforming Growth Factor beta/metabolism , Young AdultABSTRACT
PROBLEM: We aimed to investigate the modulatory effects of vitamin D on peripheral blood cellular immune response in patients with recurrent miscarriage (RM). METHOD OF STUDY: The effect of vitamin D on the number of peripheral blood cells, T helper 1 (Th1) cytokines, and NK cytotoxicity was measured in 99 women with RM. RESULTS: The percentage of CD19+ B cells and NK cytotoxicity at an effector-to-target cell (E:T) ratio of 50:1, 25:1, and 12.5:1 were significantly higher in the vitamin D insufficiency group (VDI) than in the vitamin D normal group (VDN) (P<.05 each). The proportion of TNF-α-expressing Th cells was significantly higher in the vitamin D deficiency group (VDD) than in VDN (P<.05). However, there were no significant differences between VDI and VDD. This dysregulation was significantly reduced with 1,25(OH)2 D supplementation. CONCLUSION: The data suggest that the abnormalities of cellular immune response were observed in RM patients with a low vitamin D level, which could be regulated to some extent with 1,25(OH)2 D supplementation.
Subject(s)
Abortion, Habitual/immunology , Calcitriol/administration & dosage , Immunologic Factors/administration & dosage , Vitamin D Deficiency/immunology , Abortion, Habitual/diet therapy , Abortion, Habitual/genetics , Abortion, Habitual/pathology , Administration, Oral , Adult , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , B-Lymphocytes/pathology , Case-Control Studies , Cytotoxicity, Immunologic , Female , Gene Expression , Humans , Immunophenotyping , Interferon-gamma/genetics , Interferon-gamma/immunology , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Killer Cells, Natural/pathology , Pregnancy , Th1 Cells/drug effects , Th1 Cells/immunology , Th1 Cells/pathology , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology , Vitamin D Deficiency/diet therapy , Vitamin D Deficiency/genetics , Vitamin D Deficiency/pathologyABSTRACT
Limited information is available on the balance state of pro- and anti-inflammatory cytokines in patients with recurrent implantation failure (RIF). This study assessed the pro- and anti-inflammatory cytokines in plasma of 34 patients with RIF, compared with those of 25 women with a successful pregnancy in the first IVF/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) cycle. The IFN-γ, IL-1ß, IL-6 and IL-4 concentrations were higher, whereas the TGF-ß1 concentration was lower in the RIF group compared with the control group. Furthermore, the ratios of pro-inflammatory and anti-inflammatory cytokines IFN-γ/IL-4, IFN-γ/IL-10, IFN-γ/TGF-ß1, IL-6/IL-10, IL-6/TGF-ß1, IL-1ß/TGF-ß1 and TNF-α/TGF-ß1 were higher in the RIF group (all P < 0.01). The results suggested a shift toward a pro-inflammatory state in peripheral blood of the patients with RIF.
