Diagnostic accuracy of prenatal ultrasound in coarctation of aorta: systematic review and individual participant data meta-analysis.

OBJECTIVE: To determine the diagnostic accuracy of prenatal ultrasound in detecting coarctation of the aorta (CoA). METHODS: An individual participant data meta-analysis was performed to report on the strength of association and diagnostic accuracy of different ultrasound signs in detecting CoA prenatally. MEDLINE, EMBASE and CINAHL were searched for studies published between January 2000 and November 2021. Inclusion criteria were fetuses with suspected isolated CoA, defined as ventricular and/or great vessel disproportion with right dominance on ultrasound assessment. Individual participant-level data were obtained by two leading teams. PRISMA-IPD and PRISMA-DTA guidelines were used for extracting data, and the QUADAS-2 tool was used for assessing quality and applicability. The reference standard was CoA, defined as narrowing of the aortic arch, diagnosed after birth. The most commonly evaluated parameters on ultrasound, both in B-mode and on Doppler, constituted the index test. Summary estimates of sensitivity, specificity, diagnostic odds ratio (DOR) and likelihood ratios were computed using the hierarchical summary receiver-operating-characteristics model. RESULTS: The initial search yielded 72 studies, of which 25 met the inclusion criteria. Seventeen studies (640 fetuses) were included. On random-effects logistic regression analysis, tricuspid valve/mitral valve diameter ratio > 1.4 and > 1.6, aortic isthmus/arterial duct diameter ratio < 0.7, hypoplastic aortic arch (all P < 0.001), aortic isthmus diameter Z-score of < -2 in the sagittal (P = 0.003) and three-vessel-and-trachea (P < 0.001) views, pulmonary artery/ascending aorta diameter ratio > 1.4 (P = 0.048) and bidirectional flow at the foramen ovale (P = 0.012) were independently associated with CoA. Redundant foramen ovale was inversely associated with CoA (P = 0.037). Regarding diagnostic accuracy, tricuspid valve/mitral valve diameter ratio > 1.4 had a sensitivity of 72.6% (95% CI, 48.2-88.3%), specificity of 65.4% (95% CI, 46.9-80.2%) and DOR of 5.02 (95% CI, 1.82-13.9). The sensitivity and specificity values were, respectively, 75.0% (95% CI, 61.1-86.0%) and 39.7% (95% CI, 27.0-53.4%) for pulmonary artery/ascending aorta diameter ratio > 1.4, 47.8% (95% CI, 14.6-83.0%) and 87.6% (95% CI, 27.3-99.3%) for aortic isthmus diameter Z-score of < -2 in the sagittal view and 74.1% (95% CI, 58.0-85.6%) and 62.0% (95% CI, 41.6-78.9%) for aortic isthmus diameter Z-score of < -2 in the three-vessel-and-trachea view. Hypoplastic aortic arch had a sensitivity of 70.0% (95% CI, 42.0-88.6%), specificity of 91.3% (95% CI, 78.6-96.8%) and DOR of 24.9 (95% CI, 6.18-100). The diagnostic yield of prenatal ultrasound in detecting CoA did not change significantly when considering multiple categorical parameters. Five of the 11 evaluated continuous parameters were independently associated with CoA (all P < 0.001) but all had low-to-moderate diagnostic yield. CONCLUSIONS: Several prenatal ultrasound parameters are associated with an increased risk for postnatal CoA. However, diagnostic accuracy is only moderate, even when combinations of parameters are considered. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Maternal complications induced by digoxin treatment of fetal tachycardia: A retrospective series of 18 cases.

OBJECTIVE: To evaluate maternal tolerance to digoxin, used alone or associated to other antiarrhythmic drugs in the management of fetal tachycardia. PATIENTS AND METHODS: This retrospective study was conducted at Rouen University Hospital between January 2009 and July 2016. All women who have received a treatment by either digoxin alone or associated with another antiarrhythmic drug for fetal tachycardia were included in the study. Maternal cardiac and extracardiac adverse effects were reported and comparisons between electrocardiograms before and during treatment with digoxin alone were performed. RESULTS: Eighteen women were treated by digoxin, either alone or associated with another antiarrhythmic (sotalol, flecainide or amiodarone). During treatment, digoxin overdosing (>2ng/mL) was observed in 11 women (61%), among which 4 women had toxic levels of digoxinemia (>3ng/mL) that was symptomatic in 3 women. Cardiac complications such as sinus bradycardia, first-degree auriculo-ventricular block and Mobitz I second-degree auriculo-ventricular block were reported in four women (18.2%). Extracardiac side effects i.e. neurosensorial or digestive were diagnosed in 35.3% of women. The parameters of the electrocardiogram were not altered before and after treatment with digoxin alone. CONCLUSION: Antiarrhythmics can cause maternal cardiac complications and extracardiac side effects that can sometimes be severe but rapidly reversible upon treatment arrest.

CT and MR imaging in congenital cardiac malformations: Where do we come from and where are we going?

The management of patients with congenital heart disease was profoundly changed firstly by the advent of pediatric and prenatal ultrasound and then more recently by cardiac magnetic resonance imaging (MRI) and computed tomography (CT) of the heart and great vessels. The improved life expectancy of these patients has brought about new medical and imaging requirements. MRI and CT are increasing second line techniques in this group of patients. This article summarizes the advantages and limitations of CT and MRI in some frequently encountered situations in children and adults followed up for congenital heart disease.

[Total isolated anomalous pulmonary venous return: Are there any clues for prenatal screening?]. / Retour veineux pulmonaire total isolé : y a-t-il des clés pour le dépistage prénatal ?

Total anomalous pulmonary venous connection (TAPVC) is a serious congenital anomaly. TAPVC with obstruction of pulmonary venous return is an emergency requiring urgent intervention. Before 2010, very few isolated TAPVC were diagnosed prenatally. It has been suggested in the past literature that the use of Color flow Doppler is particularly useful for the screening of TAPVC prenatally. In fact, although color-Doppler is often useful to confirm a TAPVC diagnosis, it can be quite misleading in the screening process of the condition. Looking at data of missed TAPVC, we describe how to identify TAPVC during routine cardiac screening. Since 2010, our isolated TAPVC prenatal diagnosis rate is more than 40%.

Prenatal Detection of Coarctation of the Aorta in a Non-selected Population: A Prospective Analysis of 10 Years of Experience.

The objective of this study was to assess the ability of different parameters to identify fetuses requiring neonatal care for coarctation of the aorta (CoA). Between January 2003 and December 2012, 175 fetuses referred for great vessel disproportion were divided into two groups: group A (n = 51) with high risk of CoA and delivery planned in tertiary care referral center and group B (n = 124) with no increased risk of CoA. In group A, diagnosis of CoA was confirmed in 38/51 (74 %). In group B, 2/124 had CoA. Multiple logistic regression analysis identified the best combination as diffusely hypoplastic and/or angular aortic arches, ventricular septal defect and aortic valve diameter <5 mm at 36-week gestational age (GA). Positive predictive value was 75 % when vessel disproportion was noted before 28-week GA and 73 % in the third trimester. Postnatal diagnosis involved 38 cases of CoA which had not been referred. One case of CoA diagnosed after birth was referred prenatally for difficulty of screening without any defect. The results of our prospective study are in agreement with those of previous series, but our false positive rate was lower especially when the diagnosis of vascular disproportion was made at third trimester. The performance of fetal cardiac screening does not seem to be very good, but prenatal diagnosis is probably not always possible: Among our three false negative cases, two had isolated vascular disproportion and the third no risk factors.

Ebstein's anomaly and tricuspid valve dysplasia: prognosis after diagnosis in utero.

Tricuspid valve malformation is a rare congenital heart disease. Prenatal diagnosis of Ebstein's anomaly (EA) and tricuspid valve dysplasia (TVD) is associated with high mortality. There are conflicting reports concerning accurate prognostication after diagnosis in utero. The aim of our study was to assess prognostic factors based on our experience. We reviewed 37 fetuses between 1984 and June 2010 comprising 26 cases of EA and 11 cases of TVD. There were 10 terminations, 5 intrauterine deaths, 8 neonatal deaths, and 14 survivors. We found that the major prognostic factor for outcome was the flow pattern through the pulmonary valve on the first echocardiogram. Retrograde flow was strongly correlated with fetal or neonatal death (p = 8 × 10(-5)), and anterograde flow predicted good outcome (p = 8 × 10(-5)). In contrast, cardiothoracic indexes, right to left-ventricular ratio, and Celermajer index were not useful prognostic markers. The Simpson Andrews Sharland score, which was more complex, was well correlated with our series. Flow through the pulmonary valve on the first echocardiogram is a simple and excellent prognostic factor when major tricuspid valve disease is diagnosed in utero. Fetuses should be monitored throughout pregnancy, particularly those with retrograde ductus arteriosus, because several hemodynamic factors may worsen the prognosis.

[Diagnosis of congenital heart disease in a nonselected population in Upper Normandy: retrospective study between 2003 and 2007]. / Diagnostic anténatal des cardiopathies congénitales dans une population à bas risque en Haute-Normandie : étude rétrospective de 2003 à 2007.

UNLABELLED: Routine prenatal ultrasound screening for the detection of possible cardiopathy has existed in Upper Normandy since 1987, including the continuous training of obstetric ultrasonographers. We evaluated the profitability and the expected benefit of prenatal detection in a nonselected population in this region. METHODS: A retrospective study was undertaken from October 2003 to September 2007 in the cardiopediatric units of Upper Normandy. All fetuses and infants with a diagnosed major cardiac defect were classified into 3 groups: no possibility of anatomic surgical repair (group 1), risk of early decompensation (group 2), and anatomic surgical repair possible but without early decompensation (group 3). Prenatal and postnatal mortality and morbidity were reported. RESULTS: One hundred and sixty-five major congenital heart defects were detected prenatally and 68 postnatally. The prenatal detection rate was 71% (93, 53, and 77% for groups 1, 2, and 3, respectively; p<0.0001). The rate of pregnancy termination was 92, 17, and 45%, respectively. The mortality rate tended to be higher in the undiagnosed group of urgent neonatal heart cases (10.6% vs 4.4%). The prenatal prevalence of abnormal karyotype was 21% and was 11.5% for congenital malformation syndrome. CONCLUSION: Prenatal detection of major cardiac defects has continued to attain high success in Upper Normandy. However, 50% of urgent neonatal heart cases often remain undiagnosed, and therefore the neonatologist must treat this patient population with particular care. Prenatal diagnosis can reduce preoperative mortality and morbidity of cardiopathy with a risk of early decompensation with specific neonatal intensive care.

[ENVOL study on the medical management of varicella and its complications in French ambulatory care]. / Prise en charge de la varicelle et de ses complications en médecine ambulatoire en France: l'étude ENVOL.

OBJECTIVE: The authors had for aim to describe the management of varicella and its complications in French ambulatory care. METHODS: A descriptive prospective national survey was carried out in France on patients visiting a random sample of French GPs and pediatricians (investigators) having diagnosed varicella. During an inclusion period of 4 months, the investigators enrolled all patients (adults-children) who presented with varicella or varicella related complications, and who had not previously visited the investigator for this episode. Three questionnaires were used to record the data. RESULTS: One thousand two hundred patients were enrolled by 393 physicians 75% of whom were GPs. Ninety-four percent of patients were children under 13 years of age (group I). The sex ratio (M/F) was 1.1. The mean age was 3.5 years in group I and 23.8 years in patients over 13 years of age (group II). The mean length of the varicella episode was about 10.7 days. Most patients were given a pharmaceutical prescription on inclusion, 1% were also prescribed medical procedures, 0.3% were given local treatment, and 0.09% underwent physical therapy sessions. A proportion of 12.6% of patients visited their physician twice or more for the same episode. Six group I children were hospitalized. Eighty-seven patients presented with at least one complication i.e. 7.8% (95%CI=6.3-9.3) of all episodes, mainly bacterial superinfections. CONCLUSIONS: The rate of complications associated with varicella infection was higher than usually reported in France but in the same order of magnitude as in other developed countries. Bacterial superinfections were found to be the most frequent complications of varicella.

Estimating the cost-effectiveness of stroke units in France compared with conventional care.

BACKGROUND AND PURPOSE: The incidence of stroke in France is estimated at between 120 000 and 150 000 cases per year. This modeling study assessed the clinical and economic benefits of establishing specialized stroke units compared with conventional care. METHODS: Data from the Dijon stroke registry were used to determine healthcare trajectories according to the degree of autonomy and organization of patient care. The relative risks of death or institutionalization or death or dependence after passage through a stroke unit were compared with conventional care. These risks were then inserted with the costing data into a Markov model to estimate the cost-effectiveness of stroke units. RESULTS: Patients cared for in a stroke unit survive more trimesters without sequelae in the 5 years after hospitalization than those cared for conventionally (11.6 versus 8.28 trimesters). The mean cost per patient at 5 years was estimated at 30 983 for conventional care and 34 638 in a stroke unit. An incremental cost-effectiveness ratio for stroke units of 1359 per year of life gained without disability was estimated. CONCLUSIONS: The cost-effectiveness ratio for stroke units is much lower than the threshold (53 400 ) of acceptability recognized by the international scientific community. This finding justifies organizational changes in the management of stroke patients and the establishment of stroke units in France.

Dilated coronary sinus in prenatal echocardiography; identification, associations and outcome.

The dilated coronary sinus (DCS) has only recently been clearly visualised in the fetus due to progress in prenatal echography. This is a retrospective study of 22 fetuses presenting with DCS revealed by prenatal echography. We report the circumstances leading to the detection of a DCS and the neonatal outcome of these fetuses. The coronary sinus was defined as dilated depending on its visualisation in cross-section from the '4 chamber' view, as well as a pseudo inter-atrial septal defect from a more posterior view. In each case the gestational age, circumstances of detection, associated anomalies and postnatal outcome are reported. The circumstances were: evaluation of a clearly identified DCS in four cases and during detailed fetal echocardiography because of suspected congenital heart disease in 18 cases. Five cases were associated with a cardiac anomaly, three with an extracardiac anomaly, six with both cardiac and extracardiac anomaly and eight were isolated. Postnatal outcome was related to the associated anomaly. In conclusion, it is important that the echography image be correctly interpreted, as a DCS often implies possible associated defects and therefore affects prognosis. When not associated with other anomalies this condition is not considered serious.

Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology.

We show here that mouse interferon-alpha (IFN-alpha)-producing cells (mIPCs) are a unique subset of immature antigen-presenting cells (APCs) that secrete IFN-alpha upon stimulation with viruses. mIPCs have a plasmacytoid morphology, can be stained with an antibody to Ly6G and Ly6C (anti-Ly6G/C) and are Ly6C+B220+CD11cloCD4+; unlike other dendritic cell subsets, however, they do not express CD8alpha or CD11b. Although mIPCs undergo apoptosis in vitro, stimulation with viruses, IFN-alpha or CpG oligonucleotides enhanced their survival and T cell stimulatory activity. In vivo, mIPCs were the main producers of IFN-alpha in cytomegalovirus-infected mice, as depletion of Ly6G+/C+ cells abrogated IFN-alpha production. mIPCs produced interleukin 12 (IL-12) in response to viruses and CpG oligodeoxynucleotides, but not bacterial products. Although different pathogens can selectively engage various APC subsets for IL-12 production, IFN-alpha production is restricted to mIPCs' response to viral infection.

Initial amplification of duck hepatitis B virus covalently closed circular DNA after in vitro infection of embryonic duck hepatocytes is increased by cell cycle progression.

The relationship between the cell cycle and early amplification of duck hepatitis B virus covalently closed circular (CCC) DNA was studied after in vitro infection of fetal hepatocytes. We first showed that embryonic hepatocytes proliferated for at least 6 days after plating and that complete viral replication including CCC DNA amplification occurred in these proliferating cells. Addition of sodium butyrate or aphidicolin reversibly blocked cells in the G1 phase and diminished CCC DNA synthesis, which was restored after drug withdrawal, concomitantly with the entry of cells into S phase. Cell cycle progression of fetal hepatocytes can be triggered by stimulation with epidermal growth factor (EGF), hepatocyte growth factor (HGF), and tumor growth factor alpha (TGF-alpha). CCC DNA synthesis increased with progression to the S phase induced by EGF, HGF, and TGF-alpha alone or in combination. By contrast, tumor growth factor beta (TGF-beta) alone or in combination with EGF inhibited cell proliferation and viral DNA synthesis. By double labeling, viral nucleocapsids were found predominantly in bromodeoxyuridine-positive hepatocytes, indicating that high viral replication occurs preferentially in proliferating hepatocytes. CCC DNA was also detected mainly in cells in the S and G2/M phases separated from cells in the G1 phase by cell sorting. Taken together, these results show that hepatocyte proliferation may positively regulate the initial amplification of CCC DNA of avian hepadnaviruses, and may explain why mitosis is not necessarily associated with loss of CCC DNA.

Human thymus contains IFN-alpha-producing CD11c(-), myeloid CD11c(+), and mature interdigitating dendritic cells.

Three distinct dendritic cell (DC) subsets capable of stimulating allogeneic naive T cells were isolated from human thymus. The most abundant subset was represented by plasmacytoid DCs (pDCs), which secreted high amounts of IFN-alpha upon stimulation with inactivated influenza virus and thus likely correspond to the recently identified peripheral blood natural IFN-alpha/beta-producing cells (IPCs). Like those latter cells, thymic pDCs had distinctive phenotypic features (i.e., Lin(-), HLA-DR(int), IL-3R alpha(hi), CD45RA(hi), CD11c(-), CD13(-), and CD33(lo)) and developed into mature DCs upon culture in IL-3 and CD40L. Of the two other DC subsets, one displayed a phenotype of immature myeloid DCs (imDCs) (HLA-DR(int), CD11c(+), CD13(+), CD33(+)), and the other represented HLA-DR(hi) CD11c(+) mature DCs (mDCs). Since they also expressed DC-LAMP, these mDCs appear to correspond to interdigitating dendritic cells (IDCs). Thymic pDCs, but not myeloid imDCs, strongly expressed lymphoid-specific transcripts such as pre-T alpha, lambda-like, and Spi-B, thereby suggesting a possible lymphoid origin. The detection of Spi-B mRNA, not only upon in vitro maturation of pDCs, but also in freshly purified IDCs, suggests that in vivo pDCs may differentiate into IDCs.

Cloning of a chick A3 adenosine receptor: characterization of ligand binding and receptor-effector coupling of chick A1 and A3 adenosine receptors.

We have reported previously the cloning and partial characterization of a chick A1 adenosine receptor expressed in the heart. We report herein the cloning of a chick A3 adenosine receptor and a comprehensive characterization of both the A1 and A3 receptors expressed in human embryonic kidney 293 cells. [125I]N6-(p-aminobenzyl)adenosine bound to both receptors with similar affinities and was used in competition studies. Although the selectivities of both agonists and antagonists were less than in other species, two antagonists, 3-ethyl-5-benzyl-2-methyl-6-phenyl-4-phenylethynal-(+/-)-dihydropyridine-3,5-dicarboxylate and 3,6-dichloro-2'-(isopropyloxy)-4'-methylflavone), were at least partially selective for A3 receptors while one antagonist [C8-(N-methylisopropyl)amine-N6-(5'endohydroxy)endonorboman-2-yl-9-methyladenine] was selective for A1 receptors. While both receptors coupled to the inhibition of adenylyl cyclase, we were unable to detect coupling of either receptor to phospholipase C or D.

Sources and mechanisms of inorganic carbon transport for coral calcification and photosynthesis.

The sources and mechanisms of inorganic carbon transport for scleractinian coral calcification and photosynthesis were studied using a double labelling technique with H(14)CO(3) and (45)Ca. Clones of Stylophora pistillata that had developed into microcolonies were examined. Compartmental and pharmacological analyses of the distribution of(45)Ca and H(14)CO(3) in the coelenteron, tissues and skeleton were performed in dark or light conditions or in the presence of various seawater HCO(3)(-) concentrations. For calcification, irrespective of the lighting conditions, the major source of dissolved inorganic carbon (DIC) is metabolic CO(2) (70-75% of total CaCO(3) deposition), while only 25-30% originates from the external medium (seawater carbon pool). These results are in agreement with the observation that metabolic CO(2) production in the light is at least six times greater than is required for calcification. This source is dependent on carbonic anhydrase activity because it is sensitive to ethoxyzolamide. Seawater DIC is transferred from the external medium to the coral skeleton by two different pathways: from sea water to the coelenteron, the passive paracellular pathway is largely sufficient, while a DIDS-sensitive transcellular pathway appears to mediate the flux across calicoblastic cells. Irrespective of the source, an anion exchanger performs the secretion of DIC at the site of calcification. Furthermore, a fourfold light-enhanced calcification of Stylophora pistillata microcolonies was measured. This stimulation was only effective after a lag of 10 min. These results are discussed in the context of light-enhanced calcification. Characterisation of the DIC supply for symbiotic dinoflagellate photosynthesis demonstrated the presence of a DIC pool within the tissues. The size of this pool was dependent on the lighting conditions, since it increased 39-fold after 3 h of illumination. Passive DIC equilibration through oral tissues between sea water and the coelenteric cavity is insufficient to supply this DIC pool, suggesting that there is an active transepithelial absorption of inorganic carbon sensitive to DIDS, ethoxyzolamide and iodide. These results confirm the presence of CO(2)-concentrating mechanisms in coral cells. The tissue pool is not, however, used as a source for calcification since no significant lag phase in the incorporation of external seawater DIC was measured.

FDF03, a novel inhibitory receptor of the immunoglobulin superfamily, is expressed by human dendritic and myeloid cells.

In this study, we describe human FDF03, a novel member of the Ig superfamily expressed as a monomeric 44-kDa transmembrane glycoprotein and containing a single extracellular V-set Ig-like domain. Two potential secreted isoforms were also identified. The gene encoding FDF03 mapped to chromosome 7q22. FDF03 was mostly detected in hemopoietic tissues and was expressed by monocytes, macrophages, and granulocytes, but not by lymphocytes (B, T, and NK cells), indicating an expression restricted to cells of the myelomonocytic lineage. FDF03 was also strongly expressed by monocyte-derived dendritic cells (DC) and preferentially by CD14+/CD1a- DC derived from CD34+ progenitors. Moreover, flow cytometric analysis showed FDF03 expression by CD11c+ blood and tonsil DC, but not by CD11c- DC precursors. The FDF03 cytoplasmic tail contained two immunoreceptor tyrosine-based inhibitory motif (ITIM)-like sequences. When overexpressed in pervanadate-treated U937 cells, FDF03 was tyrosine-phosphorylated and recruited Src homology-2 (SH2) domain-containing protein tyrosine phosphatase (SHP)-2 and to a lesser extent SHP-1. Like engagement of the ITIM-bearing receptor LAIR-1/p40, cross-linking of FDF03 inhibited calcium mobilization in response to CD32/FcgammaRII aggregation in transfected U937 cells, thus demonstrating that FDF03 can function as an inhibitory receptor. However, in contrast to LAIR-1/p40, cross-linking of FDF03 did not inhibit GM-CSF-induced monocyte differentiation into DC. Thus, FDF03 is a novel ITIM-bearing receptor selectively expressed by cells of myeloid origin, including DC, that may regulate functions other than that of the broadly distributed LAIR-1/p40 molecule.

Respective involvement of TGF-beta and IL-4 in the development of Langerhans cells and non-Langerhans dendritic cells from CD34+ progenitors.

In vivo, dendritic cells (DC) form a network comprising different populations. In particular, Langerhans cells (LC) appear as a unique population of cells dependent on transforming growth factor beta(TGF-beta) for its development. In this study, we show that endogenous TGF-beta is required for the development of both LC and non-LC DC from CD34+ hematopoietic progenitor cells (HPC) through induction of DC progenitor proliferation and of CD1a+ and CD14+ DC precursor differentiation. We further demonstrate that addition of exogenous TGF-beta polarized the differentiation of CD34+ HPC toward LC through induction of differentiation of CD14+ DC precursors into E-cadherin+, Lag+CD68-, and Factor XIIIa-LC, displaying typical Birbeck granules. LC generated from CD34+ HPC in the presence of exogenous TGF-beta displayed overlapping functions with CD1a+ precursor-derived DC. In particular, unlike CD14(+)-derived DC obtained in the absence of TGF-beta, they neither secreted interleukin-10 (IL-10) on CD40 triggering nor stimulated the differentiation of CD40-activated naive B cells. Finally, IL-4, when combined with granulocyte-macrophage colony-stimulating factor (GM-CSF), induced TGF-beta-independent development of non-LC DC from CD34+ HPC. Similarly, the development of DC from monocytes with GM-CSF and IL-4 was TGF-beta independent. Collectively these results show that TGF-beta polarized CD34+ HPC differentiation toward LC, whereas IL-4 induced non-LC DC development independently of TGF-beta.

APCs express DCIR, a novel C-type lectin surface receptor containing an immunoreceptor tyrosine-based inhibitory motif.

We have identified a novel member of the calcium-dependent (C-type) lectin family. This molecule, designated DCIR (for dendritic cell (DC) immunoreceptor), is a type II membrane glycoprotein of 237 aa with a single carbohydrate recognition domain (CRD), closest in homology to those of the macrophage lectin and hepatic asialoglycoprotein receptors. The intracellular domain of DCIR contains a consensus immunoreceptor tyrosine-based inhibitory motif. A mouse cDNA, encoding a homologous protein has been identified. Northern blot analysis showed DCIR mRNA to be predominantly transcribed in hematopoietic tissues. The gene encoding human DCIR was localized to chromosome 12p13, in a region close to the NK gene complex. Unlike members of this complex, DCIR displays a typical lectin CRD rather than an NK cell type extracellular domain, and was expressed on DC, monocytes, macrophages, B lymphocytes, and granulocytes, but not detected on NK and T cells. DCIR was strongly expressed by DC derived from blood monocytes cultured with GM-CSF and IL-4. DCIR was mostly expressed by monocyte-related rather than Langerhans cell related DC obtained from CD34+ progenitor cells. Finally, DCIR expression was down-regulated by signals inducing DC maturation such as CD40 ligand, LPS, or TNF-alpha. Thus, DCIR is differentially expressed on DC depending on their origin and stage of maturation/activation. DCIR represents a novel surface molecule expressed by Ag presenting cells, and of potential importance in regulation of DC function.

CD40 expression by human bronchial epithelial cells.

CD40 is a 50-kDa protein expressed on B cells, dendritic cells, monocytes and epithelial cells, but the distribution of CD40 expression in humans is not completely known. It binds to a ligand (CD40L) which is expressed essentially on activated T cells. The interaction between CD40 and CD40L plays important roles in immune responses. CD40 expression was investigated on bronchial tissues and human bronchial cell lines using immunohistochemistry, immunofluorescence staining and analysis with a cytometer, respectively. Constitutive CD40 expression, but not that of CD40L, was slightly detectable on normal human bronchial epithelial cells (HBEC) in situ and on an adult lung adenocarcinoma (SKLU1) cell line, while another cell line, a bronchial transformed SV40 cell line (WI26VA4), was negative for CD40. Among the various cytokines tested, only interferon (IFN)-gamma was found to induce CD40 expression on WI26VA4. Tumour necrosis factor (TNF)-alpha was the best cytokine able to up-regulate CD40 in SKLU1 cells. A combination of IFN-gamma and TNF-alpha was slightly more effective than the cytokine alone at up-regulating CD40 expression on both cell lines. We further investigated the functional consequences of CD40 ligation on both cell lines. These bronchial cells expressed CD40, HLADR and CD54 under basal conditions or when stimulated by cytokines. Stimulation through CD40 did not affect cell-surface-antigen expression on either cell line. The production of cytokines such as interleukin (IL)-6 and granulocyte macrophage-colony stimulating factor (GM-CSF) by HBEC has been described. SKLU1 and WI26VA4 cells released IL-6 and GM-CSF spontaneously. Whatever the case, CD40 engagement did not modulate spontaneous or TNF-alpha-induced production of these two cytokines. These data indicate for the first time that normal HBEC express CD40 in situ. Further investigations are required in order to determine the role of CD40 on normal HBEC.

Toward a role of dendritic cells in the germinal center reaction: triggering of B cell proliferation and isotype switching.

We have reported previously that in vitro generated dendritic cells (DC) can directly regulate B cell responses. Recently, germinal center DC (GCDC) were identified within B cell follicles. Due to their particular localization, we have tested in the present study whether GCDC could contribute to key events characteristic of the GC reaction. Our present results demonstrate that 1) ex vivo GCDC induce a dramatic GC B cell expansion upon CD40 and IL-2 activation and drive plasma cell differentiation, 2) this property is shared by GCDC and blood DC, but not by Langerhans cells, 3) IL-12 production by GCDC is critical in GC B cell expansion and differentiation, and 4) importantly, GCDC also induce IL-10-independent isotype switching toward IgG1. These observations support the novel concept that GCDC directly contribute to the germinal center reaction.