Coexistence of lymphocyte dysregulation, alloimmunity and autoimmunity in a patient with recurrent failed in vitro embryo transfer fertilization / Coexistencia de alteracion inmunofenotipica linfocitaria, aloinmunidad y autoinmunidad en una paciente con fallo de implantacion recurrente tras fecundacion in vitro

Objective. To describe a patient with primary infertility and recurrent implantation failure (RIF) and coexistence of peripheral blood immunophenotypic dysregulation of lymphocytes and alloimmune and autoimmune abnormalities. The hypothesis is that functionally distinct immunological abnormalities might better explain the immunological etiology of RIF than individual abnormalities in some patients. Subjects and methods. We present clinical and immunological data. Results. A patient with primary infertility and RIF had peripheral blood immunophenotypic abnormalities of T, B and NK-cells, unusually high shared HLA antigens with her partner, and antiphospholipid antibodies. Conclusion. Functionally distinct immunological abnormalities may coexist in some women with RIF after in vitro fertilization (AU)

Objetivo. Describir un caso de fallo recurrente tras fecundación in vitro en el que coexisten varias alteraciones inmunológicas potencialmente relacionadas con este problema. La hipótesis es que esta coexistencia de factores podría explicar mejor la etiología inmunológica que alteraciones individuales. Sujetos y métodos. Se presentan datos clínicos e inmunológicos. Resultados. Una paciente con infertilidad primaria y fallo recurrente tras 4 intentos de fecundacion in vitro tenía alteraciones inmunofenotípicas de células T, B y NK, antígenos compartidos por la pareja en una frecuencia inusualmente alta y anticuerpos antifosfolípidos. Conclusiones. Distintas alteraciones inmunológicas pueden coexistir en casos aislados de fallo recurrente tras fecundación in vitro (AU)

New decision-tree model for defining the risk of reproductive failure.

PROBLEM: Natural killer (NK) cells play a key role in embryo implantation and pregnancy success, whereas blood and uterine NK expansions have been involved in the pathophysiology of reproductive failure (RF). Our main goal was to design in a large observational study a tree-model decision for interpretation of risk factors for RF. METHODS OF STUDY: A hierarchical multivariate decision model based on a classification and regression tree was developed. NK and NKT-like cell subsets were analyzed by flow cytometry. RESULTS: By multivariate analysis, blood NK cells expansion was an independent risk factor for RF (both recurrent miscarriages and implantation failures). We propose a new decision-tree model for the risk interpretation of women with RF based on a combination of main risk factors. CONCLUSIONS: Women with age above 35 years and >13% CD56⁺CD16⁺ NK cells showed the highest risk of further pregnancy loss (100%).

Intravenous immunoglobulin treatment increased live birth rate in a Spanish cohort of women with recurrent reproductive failure and expanded CD56(+) cells.

PROBLEM: Natural killer (NK, CD3(-)CD56(+)/CD16(+)) and NKT-like cells (CD3(+)CD56(+)/CD16(+)) activity is considered among the key factors for reproductive success. In the absence of immunological screening, beneficial effects of intravenous immunoglobulin (IVIG) in preventing recurrent reproductive failure (RRF) have not been reported. Here, we analyse the IVIG influence on pregnancy success in women with RRF and circulating NK or/and NKT-like cells expansion. METHOD OF STUDY: One hundred fifty-seven women with previous recurrent miscarriage and/or recurrent implantation failure after in vitro fertilization were consecutively studied. Sixty-four patients with CD56(+) cell expansion, no apparent underlying disease and who maintained their desire to conceive were selected. Forty of them received IVIG during pregnancy. RESULTS: Overall, the clinical pregnancy rate for the women under IVIG therapy was 92.5% and the live birth rate was 82.5%. Significantly lower pregnancy and live birth rates (25% and 12.5%, respectively) were observed for the patients with recurrent pregnancy loss and NK/NKT-like cells expansion without IVIG. After three cycles of IVIG, NK cell percentages decreased significantly and these values persisted throughout gestation. CONCLUSION: Intravenous immunoglobulin therapy for women with RRF and NK or NKT-like cell expansion was a safe and beneficial therapeutic strategy that associated with high clinical pregnancy and live birth rates.

Quantitative abnormalities of peripheral blood distinct T, B, and natural killer cell subsets and clinical findings in obstetric antiphospholipid syndrome.

OBJECTIVE: Few studies have assessed immunophenotypic abnormalities on lymphocyte subsets in patients with antiphospholipid syndrome (APS). We performed an extended immunological study to define alterations of distinct T, B, and natural killer (NK) cell subsets in obstetric patients with APS and their relationship with APS-associated complications. PATIENTS AND CONTROLS: 36 women with APS [Sydney criteria, Group A1 without thrombosis (n=26), Group A2 with thrombosis (n=10)]; and 36 age matched women with recurrent abortion without antiphospholipid antibodies (disease controls; Group B), 36 healthy parous women (healthy controls; Group C), and 36 healthy nonparous women (healthy controls; Group D). Thrombotic events occurred after history of abortions in all A2 women. Three-color whole-blood flow cytometry was used to characterize the distinct immunophenotypes. RESULTS: A1 patients had significantly higher percentages of CD4+CD45RA-CCR7+ central memory cells (A1 vs D), higher percentages of activated CD4+CD25+ T cells (A1 vs D), and lower percentages and absolute counts of CD4+CD45RA-CCR7- effector memory cells (A1 vs D). Group A2 patients had higher percentages and absolute numbers of CD19+CD27-IgD+ naive B cells (A2 vs A1 vs all controls), lower percentages and absolute numbers of CD3-CD56+CD16+ NK cells (A2 vs all controls), and higher percentages of activated CD4+DR+ (A2 vs all controls), CD8+DR+ (A2 vs A1 vs C vs D), CD4+CD38+DR+ (A2 vs D), and CD4+CD25+DR+ T cells (A2 vs all controls). Increased percentages of CD8+DR+ T cells [relative risk (RR) 2.43, 95% CI 1.09-5.44, p=0.02] and of naive B cells (RR 3.05, 95% CI 1.30-7.11, p=0.009) were associated with development of thrombosis. CONCLUSION: In obstetric patients with APS we documented significant changes in T, B, and NK cell homeostasis. Increased levels of CD8+DR+ and CD19+CD27-IgD+ cells might identify obstetric patients with APS at risk of having thrombosis.

NK cell increase in neonates from the preterm to the full-term period of gestation.

BACKGROUND: Several studies have reported differences in lymphocyte phenotype in preterm and full-term neonates as compared to children and adults. However, a detailed description of the immunologic cell populations of neonates corresponding to the gestational age is needed. This will be helpful for clinical practice to find the best way to prevent neonatal infections or strengthen the immune system of newborns with some kind of immunodeficiency. OBJECTIVE: To study maturation of the immune system throughout gestation, describing the variations of the lymphocyte populations in function of the gestational week when born. METHODS: We performed a descriptive study in 134 healthy newborns (gestation age 25-42 weeks), quantifying the relative and absolute counts of cell populations in umbilical cord blood obtained during delivery, by a four-color flow cytometry single platform. RESULTS: We first compared the very-preterm (25-30 weeks), preterm (31-36 weeks) and full-term (37-42 weeks) neonates. We found higher absolute counts of all cell populations in the full-term group and lower absolute and relative values of NK cells in the very-preterm group. After that, we analyzed the lymphocyte populations week to week (from week 31 to 41) and found the lowest values of T cells (CD4+ and CD8+) for week 36. However, lower percentages of CD4+ T cells and higher percentages of NK cells were observed in week 38 and 41. CONCLUSION: We found an increase in cord blood NK cells with gestational age, both in terms of absolute counts and of percentage values. Moreover, the %NK cells showed a pattern opposite to %CD4+ T cells along the studied period.