Interleukin 4 (IL-4) induces B-cell differentiation and survival of chronic lymphocytic leukemia (CLL) cells. MicroRNAs (miRNAs) regulate mRNA and protein expression, and several miRNAs, deregulated in CLL, might play roles as oncogenes or tumor suppressors. We have studied the miRNA profile of CLL, and its response to IL-4, by oligonucleotide microarrays, resulting in the detection of a set of 129 mature miRNAs consistently expressed in CLL, which included 41 differentially expressed compared to normal B cells (NBC), and 6 significantly underexpressed in ZAP-70 positive patients. IL-4 stimulation brought about up-regulation of the 5p and 3p mature variants of the miR-21 gene, which maps immediately downstream to the VMP1 gene, and of the mature forms generated from the miR-362 (3p and 5p), miR-500a (3p), miR-502 (3p), and miR-532 (3p and 5p) genes, which map within the third intron of the CLCN5 gene. Both genes are in turn regulated by IL-4, suggesting that these miRNAs were regulated by IL-4 as passengers from their carrier genes. Their levels of up-regulation by IL-4 significantly correlated with cytoprotection. MiR-21 has been reported to be leukemogenic, associated to bad prognosis in CLL, and the miRNA more frequently overexpressed in human cancer. Up-regulation by IL-4 of miR-21 and the miRNAs hosted in the CLCN5 locus may contribute to evasion of apoptosis of CLL cells. These findings indicate that the IL-4 pathway and the miRNAs induced by IL-4 are promising targets for the development of novel therapies in CLL.

It is suggested that programming of the immune system starts before birth and is shaped by environmental influences acting during critical windows of susceptibility for human development. Prenatal and perinatal exposure to physiological, biological, physical, or chemical factors can trigger permanent, irreversible changes to the developing immune system, which may be reflected in cord blood of neonates. The aim of this narrative review is to summarize the evidence on the role of the prenatal and perinatal environment, including season of birth, mode of delivery, exposure to common allergens, a farming environment, pet ownership, and exposure to tobacco smoking and pollutants, in shaping the immune cell populations and cytokines at birth in humans. We also discuss how reported disruptions in the immune system at birth might contribute to the development of asthma and related allergic manifestations later in life.

Dock10 is one of the three members of the Dock-D family of Dock proteins, a class of guanine nucleotide exchange factors (GEFs) for Rho GTPases. Its homologs Dock9 and Dock11 are Cdc42 GEFs. Dock10 is required for maintenance of rounded morphology and amoeboid-type movement. Full-length isoforms of Dock10 have been recently cloned. Here, we address GTPase specificity and GEF activity of Dock10. In order of decreasing intensity, Dock10 interacted with nucleotide-free Rac1, Cdc42, and Rac3, and more weakly with Rac2, RhoF, and RhoG. Inducible expression of Dock10 in HeLa epithelial cells promoted GEF activity on Cdc42 and Rac1, and a morphologic change in two-dimensional culture consisting in loss of cell elongation, increase of filopodia, and ruffles. Area in contact with the substrate of cells that spread with non-elongated morphology was larger in cells expressing Dock10. Inducible expression of constitutively active mutants of Cdc42 and Rac1 in HeLa cells also induced loss of elongation. However, Cdc42 induced filopodia and contraction, and Rac1 induced membrane ruffles and flattening. When co-expressed with Dock10, Cdc42 potentiated filopodia, and Rac1 potentiated ruffles. These results suggest that Dock10 functions as a dual GEF for Cdc42 and Rac1, affecting cell morphology, spreading and actin cytoskeleton protrusions of adherent HeLa cells.

Background: Outdoor air pollution may disturb immune system development. We investigated whether gestational exposure to traffic‐related air pollutants (TRAP) is associated with unstimulated cytokine profiles in newborns.Methods: Data come from 235 newborns of the NELA cohort. Innate response–related cytokines (IL‐6, IFN‐α, IL1‐β, and TNF‐α), Th1‐related (IFN‐γ and IL‐2), Th2‐related (IL‐4, IL‐5, and IL‐13), Th17‐related (IL‐17 and IL‐23), and immunomodulatory cytokine IL‐10 were quantified in the supernatant of unstimulated whole umbilical cord blood cells after 7 days of culture using the Luminex technology. Dispersion/chemical transport modeling was used to estimate long‐term (whole pregnancy and trimesters) and short‐term (15 days before delivery) residential exposures to traffic‐related nitrogen dioxide (NO₂), particulate matter (PM_2.5 and PM₁₀), and ozone (O₃). We fitted multivariable logistic regression, Bayesian kernel machine regression (BKMR), and weighted quantile sum (WQS) regression models.Results: NO₂ during the whole pregnancy increased the odds of detection of IL‐1β (OR per 10 µg/m³ increase = 1.37; 95% CI, 1.02, 1.85) and IL‐6 (OR per 10 µg/m³ increase = 1.32; 95% CI 1.00, 1.75). Increased odds of detected concentrations of IL‐10 was found in newborns exposed during whole pregnancy to higher levels of NO₂ (OR per 10 µg/m³ increase = 1.30; 95% CI 0.99, 1.69), PM₁₀ (OR per 10 µg/m³ increase = 1.49; 95% CI 0.95, 2.33), and PM_2.5 (OR per 5 µg/m³ increase = 1.56; 95% CI 0.97, 2.51). Exposure to O₃ during the whole pregnancy increased the odds of detected IL‐13 (OR per 10 µg/m³ increase = 1.22; 95% CI 1.01, 1.49). WQS model revealed first and third trimesters of gestation as windows of higher susceptibility.Conclusions: Gestational exposure to TRAP may increase detection of pro‐inflammatory, Th2‐related, and T regulatory cytokines in newborns. These changes might influence immune system responses later in life.