Marijo Aguilera

Foxp3(+) regulatory T cell expansion required for sustaining pregnancy compromises host defense against prenatal bacterial pathogens.

Although pregnancy confers unique susceptibility to infection, the pregnancy-associated immune defects that erode host defense remain largely undefined. Herein, we demonstrate that expansion of immune-suppressive Foxp3(+) regulatory T cells (Tregs) which occurs physiologically during pregnancy or when experimentally induced in transgenic mice caused enhanced susceptibility to prenatal pathogens including Listeria and Salmonella species. Reciprocally, infection susceptibility was uniformly reduced with Treg ablation. Importantly however, the sustained expansion of maternal Tregs was essential for maintaining immune tolerance to the developing fetus because even partial transient ablation of Foxp3-expressing cells fractured maternal tolerance to fetal antigen and triggered fetal resorption. Interestingly, Foxp3 cell-intrinsic defects in the immune-suppressive cytokine IL-10 alone were sufficient to override Treg-mediated infection susceptibility, while IL-10 was nonessential for sustaining pregnancy. Thus, maternal Treg expansion required for sustaining pregnancy creates naturally occurring holes in host defense that confer prenatal infection susceptibility.

Foxp3+ Regulatory T Cells Impede the Priming of Protective CD8+ T Cells

T cell activation is controlled by incompletely defined opposing stimulation and suppression signals that together sustain the balance between optimal host defense against infection and peripheral tolerance. In this article, we explore the impacts of Foxp3+ regulatory T cell (Treg) suppression in priming Ag-specific T cell activation under conditions of noninfection and infection. We find the transient ablation of Foxp3+ Tregs unleashes the robust expansion and activation of peptide-stimulated CD8+ T cells that provide protection against Listeria monocytogenes infection in an Ag-specific fashion. By contrast, Treg ablation had nonsignificant impacts on the CD8+ T cell response primed by infection with recombinant L. monocytogenes. Similarly, nonrecombinant L. monocytogenes administered with peptide stimulated the expansion and activation of CD8+ T cells that paralleled the response primed by Treg ablation. Interestingly, these adjuvant properties of L. monocytogenes did not require CD8+ T cell stimulation by IL-12 produced in response to infection, but instead were associated with sharp reductions in Foxp3+ Treg suppressive potency. Therefore, Foxp3+ Tregs impose critical barriers that, when overcome naturally during infection or artificially with ablation, allow the priming of protective Ag-specific CD8+ T cells.

Selective culling of high avidity antigen-specific CD4+ T cells after virulent Salmonella infection

Typhoid fever is a persistent infection caused by host‐adapted Salmonella strains adept at circumventing immune‐mediated host defences. Given the importance of T cells in protection, the culling of activated CD4+ T cells after primary infection has been proposed as a potential immune evasion strategy used by this pathogen. We demonstrate that the purging of activated antigen‐specific CD4+ T cells after virulent Salmonella infection requires SPI‐2 encoded virulence determinants, and is not restricted only to cells with specificity to Salmonella‐expressed antigens, but extends to CD4+ T cells primed to expand by co‐infection with recombinant Listeria monocytogenes. Unexpectedly, however, the loss of activated CD4+ T cells during Salmonella infection demonstrated using a monoclonal population of adoptively transferred CD4+ T cells was not reproduced among the endogenous repertoire of antigen‐specific CD4+ T cells identified with MHC class II tetramer. Analysis of T‐cell receptor variable segment usage revealed the selective loss and reciprocal enrichment of defined CD4+ T‐cell subsets after Salmonella co‐infection that is associated with the purging of antigen‐specific cells with the highest intensity of tetramer staining. Hence, virulent Salmonella triggers the selective culling of high avidity activated CD4+ T‐cell subsets, which re‐shapes the repertoire of antigen‐specific T cells that persist later after infection.

A Case of Fetal Diagnosis of Noncompaction Cardiomyopathy and Coarctation of the Aorta

Background Left ventricular noncompaction (LVNC) cardiomyopathy is a rare form of cardiomyopathy. It is difficult to diagnose prenatally and therefore not well described in the fetal population. There have been a few reports in the literature detailing isolated cases of fetal and neonatal LVNC cardiomyopathy. Case Report We present a case of LVNC cardiomyopathy and coarctation of the aorta detected prenatally at 29 + 6 weeks of gestation with survival in infancy. This is the first case report in the literature describing the fetal diagnosis of noncompaction cardiomyopathy and associated coarctation of the aorta; a rare combination. Conclusion  With a high index of suspicion, the antenatal diagnosis of noncompaction cardiomyopathy may improve neonatal morbidity and mortality.

Effect of maternal cystic fibrosis genotype on diabetes in pregnancy.

OBJECTIVE: To evaluate the association between the cystic fibrosis (CF) genotype and the rate of diabetes complicating pregnancy. METHODS: We conducted a retrospective cohort analysis of all pregnant patients with CF from 1972–2011 at a single institution. Patients who were homozygous for the &Dgr;F508 mutation were compared with patients who were heterozygous for the &Dgr;F508 mutation. Primary outcomes measured were incidence of CF-related diabetes and gestational diabetes mellitus (GDM) stratified by CF genotype. Secondary outcomes measured included pancreatic insufficiency, preterm premature rupture of membranes, preterm delivery, mode of delivery, gestational age at delivery, and maternal mortality. RESULTS: We identified 54 pregnancies among 36 women who met inclusion criteria. Of these pregnancies, 28 (51.9%) were carried by women who were homozygous for the &Dgr;F508 mutation. Homozygous women had a significantly greater incidence of pancreatic insufficiency (89.3% compared with 61.5%, P=.03) and diabetes complicating pregnancy (60.7% compared with 23.1%, P<.01) compared with heterozygous women. In addition, there was some evidence of an increased incidence of GDM specifically among homozygous women (35.7% compared with 15.4%, P=.12). Regarding neonatal outcome, there was a lower mean birthweight (2,881 g compared with 3,203 g, P=.04) among the women who were homozygous for the &Dgr;F508 mutation. There was no statistical difference in preterm deliveries, mode of delivery, gestational age at delivery, rate of preterm premature rupture of membranes, or incidence of maternal mortality between the two groups. CONCLUSION: Women with CF who are homozygous for the &Dgr;F508 mutation have an increased risk of having a pregnancy complicated by diabetes. LEVEL OF EVIDENCE: III

Prenatal Diagnosis and Outcome of Fetuses with Double-Inlet Left Ventricle

The aim of this study is to characterize the in utero presentation of the subtype of double-inlet left ventricle (DILV), a rare congenital heart disease, and assess the postnatal outcome. We retrospectively studied fetuses diagnosed prenatally with DILV between 2007 and 2011. We reviewed the prenatal and postnatal echocardiograms, clinical presentations, karyotypes, and the postnatal outcomes. There were eight fetuses diagnosed with DILV with L-transposition of the great vessels (S, L, L). Mean gestational age at diagnosis was 24.7 weeks. Of these, four fetuses (50%) had pulmonary atresia. One fetus (12.5%) also had tricuspid atresia and coarctation of the aorta and died at 17 months of age. Complete heart block and long QT syndrome was present in one fetus (12.5%), who died shortly after birth. There were no extracardiac or karyotypic abnormalities. Six (75%) infants are alive and doing well. Double-inlet left ventricle with varied presentation can be accurately diagnosed prenatally. The outcome of fetuses is good in the absence of associated rhythm abnormalities with surgically staged procedures leading to a Fontan circulation.

Routine Use of a Prenatal Weight Gain Curve Improves Patient-Provider Communication on Weight Gain Guidelines [12R]

INTRODUCTION: We sought to increase patient and provider knowledge of recommended weight gain during pregnancy and improve consistency and satisfaction related to weight gain counseling. METHODS: We assigned two obstetric (OB) practices as intervention clinics and two clinics as controls. Intervention clinics provided new OB patients with a handout outlining the 2009 Institute of Medicine (IOM) recommendations on prenatal weight gain, and risks of insufficient or excess gain. Prenatal weight gain curves (per IOM guidelines) were utilized at each prenatal visit to visually plot weight gain, and the graphs were reviewed with patients as an objective counseling tool. Providers and patients completed surveys, at baseline and in the third trimester, respectively. RESULTS: Baseline provider surveys indicate no difference between clinics in frequency of weight gain discussions. Only 43% of providers report consistent counseling, 18% correctly report IOM guidelines for obese patients, and few counsel on risks of insufficient or excess gain (16% and 19%). 332 patients with a singleton pregnancy (149 control and 183 intervention) completed surveys. Patients at intervention clinics were more likely to report accurate counseling on weight gain (92.3% vs 66.4, P<.001), and discussion reviewing risks of inadequate/excess gain (64.3% vs 51.5%, P=.040). Intervention patients were more satisfied with sensitive weight gain discussions (83.1% vs 64.3%, P=.007). CONCLUSION: Use of a visual prenatal weight gain curve as a consistent communication tool increased provider discussions about weight gain and associated risks, and increased patient satisfaction. Implementing its routine use is an effective method to increase counseling.