ABSTRACT
Conventional dendritic cells (cDC) play key roles in immune induction, but what drives their heterogeneity and functional specialization is still ill-defined. Here we show that cDC-specific deletion of the transcriptional repressor Bcl6 in mice alters the phenotype and transcriptome of cDC1 and cDC2, while their lineage identity is preserved. Bcl6-deficient cDC1 are diminished in the periphery but maintain their ability to cross-present antigen to CD8+ T cells, confirming general maintenance of this subset. Surprisingly, the absence of Bcl6 in cDC causes a complete loss of Notch2-dependent cDC2 in the spleen and intestinal lamina propria. DC-targeted Bcl6-deficient mice induced fewer T follicular helper cells despite a profound impact on T follicular regulatory cells in response to immunization and mounted diminished Th17 immunity to Citrobacter rodentium in the colon. Our findings establish Bcl6 as an essential transcription factor for subsets of cDC and add to our understanding of the transcriptional landscape underlying cDC heterogeneity.
Subject(s)
Citrobacter rodentium , Dendritic Cells , Proto-Oncogene Proteins c-bcl-6 , Th17 Cells , Animals , Proto-Oncogene Proteins c-bcl-6/genetics , Proto-Oncogene Proteins c-bcl-6/metabolism , Dendritic Cells/immunology , Dendritic Cells/metabolism , Th17 Cells/immunology , Th17 Cells/metabolism , Mice , Citrobacter rodentium/immunology , Mice, Inbred C57BL , Mice, Knockout , T Follicular Helper Cells/immunology , T Follicular Helper Cells/metabolism , CD8-Positive T-Lymphocytes/immunology , Gene Deletion , Spleen/immunology , Spleen/cytology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolismABSTRACT
OBJECTIVE: To determine whether women with a history of fertility problems have a higher risk of gestational diabetes mellitus (GDM) than women without a history of fertility problems after adjustment for maternal factors. DESIGN: Nationwide population-based cohort study. SETTING: Not applicable. PATIENT(S): All live and stillbirths during 2004-2010 among women with fertility problems (n = 49,616) and women without fertility problems (n = 323,061) were identified by linkage between the Danish Medical Birth Registry and the Danish Infertility Cohort. Information on GDM was obtained from the Danish National Patient Registry. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Odds ratios and 95% confidence intervals for the association between fertility problems and risk of GDM after adjustment for potentially confounding factors, including maternal age, prepregnancy BMI, parity, parental history of diabetes, level of education, and smoking during pregnancy. RESULT(S): In total, 7,433 (2%) pregnant women received a diagnosis of GDM. Multivariate analysis showed that pregnant women with a history of fertility problems had a statistically significantly higher risk of GDM than pregnant women without fertility problems. In stratified analyses, the association between fertility problems and risk of GDM attenuated with increasing age and was more pronounced among primiparous women and women with polycystic ovary syndrome. CONCLUSION(S): Our findings suggest that pregnant women with a history of fertility problems are at increased risk of GDM.
Subject(s)
Diabetes, Gestational/epidemiology , Infertility, Female/therapy , Reproductive Techniques, Assisted/adverse effects , Adult , Cohort Studies , Denmark/epidemiology , Diabetes, Gestational/diagnosis , Female , Humans , Infertility, Female/diagnosis , Infertility, Female/epidemiology , Infertility, Female/physiopathology , Linear Models , Logistic Models , Maternal Age , Multivariate Analysis , Odds Ratio , Parity , Polycystic Ovary Syndrome/epidemiology , Pregnancy , Registries , Risk Assessment , Risk Factors , Young AdultABSTRACT
OBJECTIVE: In spite of the high incidence of cervical cancer in Greenland, no assessment has been made of the impact of organized cervical screening, introduced in 1998, in relation to occurrence of high-grade cervical lesions. The objectives of the present study were to estimate coverage of the screening program and to examine possible changes in cervical intraepithelial neoplasia (CIN3) incidence in Greenland during 1997-2011 according to calendar period and age. METHODS: Using nationwide registries, we calculated age-standardized incidence rates for all women born and living in Greenland. To investigate whether possible variation in the incidence of CIN3 were related to differences in screening coverage, we further estimated relative risks of CIN3 within two years of screening among women who participated in the screening program using log-linear binomial regression. RESULTS: Coverage of the screening program was low during 1997-2011 with the highest level of 54% observed in 2011. Peaks in CIN3 incidence of around 300 per 100,000 person-years were observed in 1999 and between 2009 and 2011, while the incidence was lower of approximately 100 per 100,000 person-years between 2000 and 2008. During 2009-2011, the highest incidence was found among women aged 25-34 years. Similar patterns of CIN3 risk according to calendar period and age groups were observed among screened women. CONCLUSIONS: The great variations in CIN3 incidence and low screening coverage observed during 1997-2011 suggest that improvements in the Greenlandic screening program are warranted.
