Mutations in KCTD1 cause scalp-ear-nipple syndrome.

Scalp-ear-nipple (SEN) syndrome is a rare, autosomal-dominant disorder characterized by cutis aplasia of the scalp; minor anomalies of the external ears, digits, and nails; and malformations of the breast. We used linkage analysis and exome sequencing of a multiplex family affected by SEN syndrome to identify potassium-channel tetramerization-domain-containing 1 (KCTD1) mutations that cause SEN syndrome. Evaluation of a total of ten families affected by SEN syndrome revealed KCTD1 missense mutations in each family tested. All of the mutations occurred in a KCTD1 region encoding a highly conserved bric-a-brac, tram track, and broad complex (BTB) domain that is required for transcriptional repressor activity. KCTD1 inhibits the transactivation of the transcription factor AP-2α (TFAP2A) via its BTB domain, and mutations in TFAP2A cause cutis aplasia in individuals with branchiooculofacial syndrome (BOFS), suggesting a potential overlap in the pathogenesis of SEN syndrome and BOFS. The identification of KCTD1 mutations in SEN syndrome reveals a role for this BTB-domain-containing transcriptional repressor during ectodermal development.

Interleukin-18 is associated with protection against rhinovirus-induced colds and asthma exacerbations.

Rhinoviruses cause the common cold and exacerbations of asthma. Animal models of infection have identified a protective role for interleukin-18 (IL-18). Following experimental rhinovirus infection, we observed increased respiratory symptoms in healthy and asthmatic subjects with low nasal and bronchial IL-18 levels.

IL-33-dependent type 2 inflammation during rhinovirus-induced asthma exacerbations in vivo.

RATIONALE: Rhinoviruses are the major cause of asthma exacerbations; however, its underlying mechanisms are poorly understood. We hypothesized that the epithelial cell-derived cytokine IL-33 plays a central role in exacerbation pathogenesis through augmentation of type 2 inflammation. OBJECTIVES: To assess whether rhinovirus induces a type 2 inflammatory response in asthma in vivo and to define a role for IL-33 in this pathway. METHODS: We used a human experimental model of rhinovirus infection and novel airway sampling techniques to measure IL-4, IL-5, IL-13, and IL-33 levels in the asthmatic and healthy airways during a rhinovirus infection. Additionally, we cultured human T cells and type 2 innate lymphoid cells (ILC2s) with the supernatants of rhinovirus-infected bronchial epithelial cells (BECs) to assess type 2 cytokine production in the presence or absence of IL-33 receptor blockade. MEASUREMENTS AND MAIN RESULTS: IL-4, IL-5, IL-13, and IL-33 are all induced by rhinovirus in the asthmatic airway in vivo and relate to exacerbation severity. Further, induction of IL-33 correlates with viral load and IL-5 and IL-13 levels. Rhinovirus infection of human primary BECs induced IL-33, and culture of human T cells and ILC2s with supernatants of rhinovirus-infected BECs strongly induced type 2 cytokines. This induction was entirely dependent on IL-33. CONCLUSIONS: IL-33 and type 2 cytokines are induced during a rhinovirus-induced asthma exacerbation in vivo. Virus-induced IL-33 and IL-33-responsive T cells and ILC2s are key mechanistic links between viral infection and exacerbation of asthma. IL-33 inhibition is a novel therapeutic approach for asthma exacerbations.

Paediatric hospitalisations for lower respiratory tract infections in Mount Isa.

OBJECTIVE: To compare the rates of acute lower respiratory tract infection (ALRI) among children in north-west Queensland, according to age, sex and Indigenous status. DESIGN, SETTING AND PATIENTS: Retrospective chart review of hospitalisations at Mt Isa Base Hospital, Queensland, from 1 January 2007 to 31 December 2011 among children < 15 years of age. MAIN OUTCOME MEASURES: Rates of admission for bronchiolitis, pneumonia and bronchiectasis, calculated using population data from the Australian Bureau of Statistics. RESULTS: There were 356 admissions for ALRI, involving 276 children. Of the 162 children aged < 12 months old, 125 (77.2%) were Indigenous. Hospitalisations increased over the study period, and rates were significantly higher among Indigenous children compared with non-indigenous children (24.1 v 4.5 per 1000 population per year). There were 195 admissions of 164 children with pneumonia, 126 (76.8%) of whom were Indigenous. Annual rates for Indigenous children were higher than for non-Indigenous children (13.7 v 2.3 per 1000 population). Multiple admissions were common. One-third presented with gastrointestinal symptoms and signs. Pneumococcal disease persisted despite vaccination. There were 160 hospitalisations for bronchiolitis; 114 occasions (71.3%) involved Indigenous children. Seven children had bronchiectasis; all were Indigenous. CONCLUSION: Rates of ALRI in Mt Isa are comparable to those in the Northern Territory, which is reported to have rates of pneumonia among the highest in the world for children < 12 months of age. Multiple admissions are common, suggesting an even higher rate of bronchiectasis. Pneumonia may present as gastrointestinal disease, and invasive pneumococcal infection must be suspected despite vaccination.

Expression and cellular provenance of thymic stromal lymphopoietin and chemokines in patients with severe asthma and chronic obstructive pulmonary disease.

Asthma and chronic obstructive pulmonary disease (COPD) are associated with Th2 and Th1 differentiated T cells. The cytokine thymic stromal lymphopoietin (TSLP) promotes differentiation of Th2 T cells and secretion of chemokines which preferentially attract them. We hypothesized that there is distinct airways expression of TSLP and chemokines which preferentially attract Th1- and Th2-type T cells, and influx of T cells bearing their receptors in asthma and COPD. In situ hybridization, immunohistochemistry, and ELISA were used to examine the expression and cellular provenance of TSLP, Th2-attracting (TARC/CCL17, MDC/CCL22, I-309/CCL1), and Th1-attracting (IP-10/CXCL10, I-TAC/CXCL11) chemokines in the bronchial mucosa and bronchoalveolar lavage fluid of subjects with moderate/severe asthma, COPD, and controls. Cells expressing mRNA encoding TSLP, TARC/CCL17, MDC/CCL22, and IP-10/CXCL10, but not I-TAC/CXCL11 and I-309/CCL1, were significantly increased in severe asthma and COPD as compared with non-smoker controls (p < 0.02). This pattern was reflected in bronchoalveolar lavage fluid protein concentrations. Expression of the same chemokines was also increased in ex- and current smokers. The cellular sources of TSLP and chemokines were strikingly similar in severe asthma and COPD. The numbers of total bronchial mucosal T cells expressing the chemokine receptors CCR4, CCR8, and CXCR3 did not significantly differ in asthma, COPD, and controls. Both asthma and COPD are associated with elevated bronchial mucosal expression of TSLP and the same Th1- and Th2-attracting chemokines. Increased expression of these chemokines is not, however, associated with selective accumulation of T cells bearing their receptors.

Magma fragmentation and particle size distributions in low intensity mafic explosions: the July/August 2015 Piton de la Fournaise eruption.

Understanding magma fragmentation mechanisms in explosive eruptions is a key requirement for volcanic hazard assessment, eruption management and risk mitigation. This paper focuses on a type case small explosivity eruption (July-August 2015 eruption of Piton de la Fournaise). These eruptions, despite being often overlooked, are exceedingly frequent on local-to-global scales and constitute a significant hazard in vent-proximal areas, which are often populated by guides, tourists and, indeed, volcanologists due to their accessibility. The explosions presented here are ideal cases for the study of the dynamics of magma fragmentation and how it relates to the size distribution of scoria generated at the vent. We documented these events visually and thermally, and characterised the products through sample-return. This allowed us to describe small-scale gas bursts sending ejecta up to 30 m during intermittent lava fountains. Surface tension instabilities and inertial forces played a major role in fragmentation processes and generated particles with coarse-skewed distributions and median diameters ranging from - 8 to - 10 ϕ. However, with time distributions of particles in the most energetic fountains shifted towards more symmetrical shapes as median grains sizes became finer. Analyses of sequences of images demonstrate that the evolution of particle size distributions with time is due to instability of magma droplets and (in-flight) fragmentation.

Essential role of phosphoinositide 3-kinase gamma in eosinophil chemotaxis within acute pulmonary inflammation.

We and others have established an important role for phosphoinositide-3 kinase gamma (PI3Kgamma) in the chemotactic responses of macrophages and neutrophils. The involvement of this lipid kinase in allergic inflammatory responses is, however, yet to be fully determined. Here we compare wild-type (WT) and PI3Kgamma(-/-) (KO) mice within a model of ovalbumin (OVA) -specific pulmonary inflammation. Upon OVA aerosol challenge, cell influx into the bronchoalveolar lavage (BAL) fluid consisted of neutrophils, macrophages and, more significantly, eosinophils - which are key effector cells in allergic inflammation. Each population was reduced by up to 80% in KO mice, demonstrating a role for PI3Kgamma in cell infiltration into the airways. The mechanism of reduced eosinophilia was analysed within both development and effector stages of the immune response. Comparable levels of OVA-specific T-cell proliferation and immunoglobulin production were established in both strains. Furthermore, no significant differences between WT and KO chemokine production were observed. Having identified the critical point of PI3Kgamma involvement, KO eosinophil chemotactic dysfunction was confirmed in vitro. These data are the first to demonstrate the vital role of PI3Kgamma in acute allergic inflammation. The profound dependency of eosinophils on PI3Kgamma for pulmonary influx identifies this lipid kinase as an attractive target for the pharmacological intervention of asthma.

Therapy directed against thymic stromal lymphopoietin.

Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-7-like cytokine and has been shown to be one of the factors released by epithelial cells following allergen contact with an important role instructing dendritic cells (DCs) to induce a T-helper type 2 (Th2) response. These TSLP-DC stimulate CD4(+) T cells to induce a proallergic cytokine profile, suggesting TSLP plays a crucial role in the initiation of the allergic cascade. Recently, evidence has also accumulated that TSLP could play a role in enhancement of the effector stages of the allergic response, with TSLP in synergy with IL-1 and tumor necrosis factor (TNF)-alpha shown to amplify cytokine secretion from mast cells. Also, the clinical relevance of TSLP has been demonstrated by both high levels of TSLP in skin biopsies from lesional atopic dermatitis patients and also increased expression of TSLP in asthmatic airway epithelial cells which correlated with reduced lung function. These studies suggest a critical role for TSLP as a driving factor in the emerging concept of tissue-specific control of immunity with TSLP secretion at the epithelial-DC interface acting as an initial factor in the proallergic cascade.

IL-1α mediates cellular cross-talk in the airway epithelial mesenchymal trophic unit.

The bronchial epithelium and underlying fibroblasts form an epithelial mesenchymal trophic unit (EMTU) which controls the airway microenvironment. We hypothesized that cell-cell communication within the EMTU propagates and amplifies the innate immune response to respiratory viral infections. EMTU co-culture models incorporating polarized (16HBE14o-) or differentiated primary human bronchial epithelial cells (HBECs) and fibroblasts were challenged with double-stranded RNA (dsRNA) or rhinovirus. In the polarized EMTU model, dsRNA affected ionic but not macromolecular permeability or cell viability. Compared with epithelial monocultures, dsRNA-stimulated pro-inflammatory mediator release was synergistically enhanced in the basolateral compartment of the EMTU model, with the exception of IL-1α which was unaffected by the presence of fibroblasts. Blockade of IL-1 signaling with IL-1 receptor antagonist (IL-1Ra) completely abrogated dsRNA-induced basolateral release of mediators except CXCL10. Fibroblasts were the main responders to epithelial-derived IL-1 since exogenous IL-1α induced pro-inflammatory mediator release from fibroblast but not epithelial monocultures. Our findings were confirmed in a differentiated EMTU model where rhinovirus infection of primary HBECs and fibroblasts resulted in synergistic induction of basolateral IL-6 that was significantly abrogated by IL-1Ra. This study provides the first direct evidence of integrated IL-1 signaling within the EMTU to propagate inflammatory responses to viral infection.

Barrier disrupting effects of alternaria alternata extract on bronchial epithelium from asthmatic donors.

Sensitization and exposure to the allergenic fungus Alternaria alternata has been associated with increased risk of asthma and asthma exacerbations. The first cells to encounter inhaled allergens are epithelial cells at the airway mucosal surface. Epithelial barrier function has previously been reported to be defective in asthma. This study investigated the contribution of proteases from Alternaria alternata on epithelial barrier function and inflammatory responses and compared responses of in vitro cultures of differentiated bronchial epithelial cells derived from severely asthmatic donors with those from non-asthmatic controls. Polarised 16HBE cells or air-liquid interface (ALI) bronchial epithelial cultures from non-asthmatic or severe asthmatic donors were challenged apically with extracts of Alternaria and changes in inflammatory cytokine release and transepithelial electrical resistance (TER) were measured. Protease activity in Alternaria extracts was characterised and the effect of selectively inhibiting protease activity on epithelial responses was examined using protease inhibitors and heat-treatment. In 16HBE cells, Alternaria extracts stimulated release of IL-8 and TNFα, with concomitant reduction in TER; these effects were prevented by heat-treatment of the extracts. Examination of the effects of protease inhibitors suggested that serine proteases were the predominant class of proteases mediating these effects. ALI cultures from asthmatic donors exhibited a reduced IL-8 response to Alternaria relative to those from healthy controls, while neither responded with increased thymic stromal lymphopoietin (TSLP) release. Only cultures from asthmatic donors were susceptible to the barrier-weakening effects of Alternaria. Therefore, the bronchial epithelium of severely asthmatic individuals may be more susceptible to the deleterious effects of Alternaria.

A role for the transcription factor RelB in IFN-alpha production and in IFN-alpha-stimulated cross-priming.

Chimeric mice generated with bone marrow from RelB-deficient (-/-), RelB-heterozygous (+/-) and wild-type (+/+) mice were used to determine how total or partial absence of the transcription factor RelB in haematopoietic cells affects the immune response generated after lymphocytic choriomeningitis virus (LCMV) infection. In RelB(-/-) chimeras, early virus replication was enhanced and LCMV clearance was impaired. Although plasmacytoid dendritic cell numbers were similar, serum interferon (IFN)-alpha levels in RelB(-/-) and RelB(+/-) chimeras were markedly lower than in RelB(+/+) chimeras during early LCMV infection. Further, both RelB(-/-) and RelB(+/-) chimeras mounted a lower-magnitude LCMV-specific CD8(+) T cell response than their RelB(+/+) counterparts, although the LCMV-specific CD8(+) T cells present were differentiated into functional cytotoxic cells. In LCMV-infected RelB(-/-) mice, induction of cross-priming to an independently injected soluble protein, which depends on the IFN-alpha/beta made during the viral infection, was also impaired. Notably, provision of exogenous IFN-alpha did not restore the ability of RelB(-/-) mice to cross-prime. In summary, these results show that the RelB/NF-kappaB pathway is required for optimal IFN-alpha production after LCMV infection and suggest a crucial role for RelB in IFN-alpha-stimulated cross-priming of CD8(+) T cell responses.

Reciprocal immunomodulation in a schistosome and hepatotropic virus coinfection model.

Human coinfection with the helminth parasite Schistosoma mansoni and hepatitis B and hepatitis C viruses is associated with increased hepatic viral burdens and severe liver pathology. In this study we developed a murine S. mansoni/lymphocytic choriomeningitis virus (LCMV) coinfection model that reproduces the enhanced viral replication and liver pathology observed in human coinfections, and used this model to explore the mechanisms involved. Viral coinfection during the Th2-dominated granulomatous phase of the schistosome infection resulted in induction of a strong LCMV-specific T cell response, with infiltration of high numbers of LCMV-specific IFN-gamma-producing CD8+ cells into the liver. This was associated with suppression of production of the Th2 cytokines dominant during S. mansoni infection and a rapid increase in morbidity, linked to hepatotoxicity. Interestingly, the liver of coinfected mice was extremely susceptible to viral replication. This correlated with a reduced intrahepatic type I IFN response following virus infection. Schistosome egg Ags were found to suppress the type I IFN response induced in murine bone marrow-derived dendritic cells by polyinosinic-polycytidylic acid. These results suggest that suppression of the antiviral type I IFN response by schistosome egg Ags in vivo predisposes the liver to enhanced viral replication with ensuing immunopathological consequences, findings that may be paralleled in human schistosome/hepatotropic virus coinfections.

Rapid activation of spleen dendritic cell subsets following lymphocytic choriomeningitis virus infection of mice: analysis of the involvement of type 1 IFN.

In this study, we report the dynamic changes in activation and functions that occur in spleen dendritic cell (sDC) subsets following infection of mice with a natural murine pathogen, lymphocytic choriomeningitis virus (LCMV). Within 24 h postinfection (pi), sDCs acquired the ability to stimulate naive LCMV-specific CD8+ T cells ex vivo. Conventional (CD11chigh CD8+ and CD4+) sDC subsets rapidly up-regulated expression of costimulatory molecules and began to produce proinflammatory cytokines. Their tendency to undergo apoptosis ex vivo simultaneously increased, and in vivo the number of conventional DCs in the spleen decreased markedly, dropping approximately 2-fold by day 3 pi. Conversely, the number of plasmacytoid (CD11clowB220+) DCs in the spleen increased, so that they constituted almost 40% of sDCs by day 3 pi. Type 1 IFN production was up-regulated in plasmacytoid DCs by 24 h pi. Analysis of DC activation and maturation in mice unable to respond to type 1 IFNs implicated these cytokines in driving infection-associated phenotypic activation of conventional DCs and their enhanced tendency to undergo apoptosis, but also indicated the existence of type 1 IFN-independent pathways for the functional maturation of DCs during LCMV infection.

Defective B cell responses in the absence of SH2D1A.

More than half of patients with X-linked lympho-proliferative disease, which is caused by a defect in the intracellular adapter protein SH2D1A, suffer from an extreme susceptibility to Epstein-Barr virus. One-third of these patients, however, develop dysgammaglobulenemia without an episode of severe mononucleosis. Here we show that in SH2D1A(-/-) mice, both primary and secondary responses of all Ig subclasses are severely impaired in response to specific antigens. Because germinal centers were absent in SH2D1A(-/-) mice upon primary immunization, and because SH2D1A was detectable in wt germinal center B cells, we examined whether SH2D1A(-/-) B cell functions were impaired. Using the adoptive cotransfer of B lymphocytes from hapten-primed SH2D1A(-/-) mice with CD4(+) T cells from primed wt mice into irradiated wt mice provided evidence that signal transduction events controlled by SH2D1A are essential for B cell activities resulting in antigen specific IgG production. Defects in naive SH2D1A(-/-) B cells became evident upon cotransfer with non-primed wt CD4(+) cells into Rag2(-/-) recipients. Thus, both defective T and B cells exist in the absence of SH2D1A, which may explain the progressive dysgammaglobulinemia in a subset of X-linked lympho-proliferative disease patients without involvement of Epstein-Barr virus.

Ectopia lentis phenotypes and the FBN1 gene.

Mutations of the fibrillin-1 (FBN1) gene on chromosome 15 have been described in patients with classical Marfan syndrome (MFS), neonatal MFS, the "MASS" phenotype, autosomal dominant ascending aortic aneurysms, autosomal dominant ectopia lentis (EL), Marfanoid skeletal features [Milewicz et al., 1995: J Clin Invest 95:2373-2378], familial arachnodactyly, Shprintzen-Goldberg syndrome [Hayward et al., 1994: Mol Cell Probes 8:325-327; Furthmayr and Francke, 1997: Semin Thorac Cardiovasc Surg 9:191-205], and severe progressive kyphoscoliosis [Adès et al., 2002: Am J Med Genet 109:261-270]. We report the use of denaturing high performance liquid chromatography (DHPLC) to facilitate the characterization of a previously elusive FBN1 mutation in the large autosomal dominant EL kindred described by Edwards et al. [1994: Am J Med Genet 53:65-71]. This isolated EL kindred remains the largest for which detailed clinical data is available. Nine years on, we present an update of the clinical status of the family. We report a recurrent FBN1 mutation, R240C, in the kindred. This mutation has been reported three times before, once in a family with classic MFS [Loeys et al., 2001: Arch Intern Med 161:2447-2454], once in one member of a multi-generation EL kindred, [Körkkö et al., 2002: J Med Genet 39:34-41], and once in an adult from a familial EL kindred who had EL, and involvement of the integument, without cardiovascular involvement [Comeglio et al., 2002: Br J Ophthalmol 86:1359-1362]. This is the second report of the R240C mutation in association with isolated EL, and supports the existing evidence that the R240C mutation can result in two quite distinct, yet related, phenotypes. It also raises the possibility that R240C may prove to be a relative mutational "hot-spot" for isolated EL. We review the current literature regarding EL (isolated and other) and FBN1 mutations.

Case-control study of cleft lip or palate after maternal use of topical corticosteroids during pregnancy.

A case-control survey of 48 children with nonsyndromic cleft lip or palate showed a significant increase in prevalence of maternal use of topical corticosteroid preparations in the first trimester of pregnancy, compared to 58 controls born in the same hospital; the odds ratio was 13.154, 95% confidence interval 1.67-586, P = 0.0049 on Fisher's exact two-tail test. The results were statistically significant although the wide confidence interval reflected the small sample size. Although older epidemiological studies have not detected any association between systemic corticosteroid treatment and the combined incidence of all congenital malformations, experimental studies over several decades have shown that maternal corticosteroid exposure in several species of animals is specifically associated with oral clefts. This association has been confirmed by more specific case-control surveys where the cases were children with cleft lip or palate and the exposure was maternal systemic corticosteroid treatment in the first trimester. Only one previous survey also analyzed topical corticosteroids, and it demonstrated an increased odds ratio for cleft lip or palate. A national survey of children with cleft palate will be necessary to evaluate the results of this pilot study.