Publications by authors named "Scott Presnell"

33 Publications

Endotype of allergic asthma with airway obstruction in urban children.

J Allergy Clin Immunol 2021 Mar 10. Epub 2021 Mar 10.

Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wis.

Background: Black and Hispanic children growing up in disadvantaged urban neighborhoods have the highest rates of asthma and related morbidity in the United States.

Objectives: This study sought to identify specific respiratory phenotypes of health and disease in this population, associations with early life exposures, and molecular patterns of gene expression in nasal epithelial cells that underlie clinical disease.

Methods: The study population consisted of 442 high-risk urban children who had repeated assessments of wheezing, allergen-specific IgE, and lung function through 10 years of age. Phenotypes were identified by developing temporal trajectories for these data, and then compared to early life exposures and patterns of nasal epithelial gene expression at 11 years of age.

Results: Of the 6 identified respiratory phenotypes, a high wheeze, high atopy, low lung function group had the greatest respiratory morbidity. In early life, this group had low exposure to common allergens and high exposure to ergosterol in house dust. While all high-atopy groups were associated with increased expression of a type-2 inflammation gene module in nasal epithelial samples, an epithelium IL-13 response module tracked closely with impaired lung function, and a MUC5AC hypersecretion module was uniquely upregulated in the high wheeze, high atopy, low lung function group. In contrast, a medium wheeze, low atopy group showed altered expression of modules of epithelial integrity, epithelial injury, and antioxidant pathways.

Conclusions: In the first decade of life, high-risk urban children develop distinct phenotypes of respiratory health versus disease that link early life environmental exposures to childhood allergic sensitization and asthma. Moreover, unique patterns of airway gene expression demonstrate how specific molecular pathways underlie distinct respiratory phenotypes, including allergic and nonallergic asthma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2021.02.040DOI Listing
March 2021

Autoreactive CD8+ T cell exhaustion distinguishes subjects with slow type 1 diabetes progression.

J Clin Invest 2020 01;130(1):480-490

Translational Research Program.

Although most patients with type 1 diabetes (T1D) retain some functional insulin-producing islet β cells at the time of diagnosis, the rate of further β cell loss varies across individuals. It is not clear what drives this differential progression rate. CD8+ T cells have been implicated in the autoimmune destruction of β cells. Here, we addressed whether the phenotype and function of autoreactive CD8+ T cells influence disease progression. We identified islet-specific CD8+ T cells using high-content, single-cell mass cytometry in combination with peptide-loaded MHC tetramer staining. We applied a new analytical method, DISCOV-R, to characterize these rare subsets. Autoreactive T cells were phenotypically heterogeneous, and their phenotype differed by rate of disease progression. Activated islet-specific CD8+ memory T cells were prevalent in subjects with T1D who experienced rapid loss of C-peptide; in contrast, slow disease progression was associated with an exhaustion-like profile, with expression of multiple inhibitory receptors, limited cytokine production, and reduced proliferative capacity. This relationship between properties of autoreactive CD8+ T cells and the rate of T1D disease progression after onset make these phenotypes attractive putative biomarkers of disease trajectory and treatment response and reveal potential targets for therapeutic intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI126595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934185PMC
January 2020

A pro-inflammatory CD8+ T-cell subset patrols the cervicovaginal tract.

Mucosal Immunol 2019 09 16;12(5):1118-1129. Epub 2019 Jul 16.

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

The immune system of the cervicovaginal tract (CVT) must balance immunosurveillance and active immunity against pathogens with maintenance of tolerance to resident microbiota and to fetal and partner antigens for reproductive purposes. Thus, we predicted that CVT immunity is characterized by distinctive features compared to blood and other tissue compartments. Indeed, we found that CVT CD8+ T-cells had unique transcriptional profiles, particularly in their cytokine signature, compared to that reported for CD8+ T-cells in other tissue sites. Among these CVT CD8+ T-cells, we identified a CD69- CD103- subset that was characterized by reduced migration in response to tissue-exit signals and higher pro-inflammatory potential as compared to their blood counterpart. These inflammatory mucosal CD8+ T-cells (Tim) were increased in frequency in the CVT of individuals with chronic infection, pointing to a potential role in perpetuating inflammation. Our findings highlight the specialized nature of immunity within the CVT and identify Tim cells as potential therapeutic targets to tame tissue inflammation upon chronic infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41385-019-0186-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717561PMC
September 2019

Infants with evolving bronchopulmonary dysplasia demonstrate monocyte-specific expression of IL-1 in tracheal aspirates.

Am J Physiol Lung Cell Mol Physiol 2019 07 10;317(1):L49-L56. Epub 2019 Apr 10.

Division of Pulmonary and Sleep Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.

Bronchopulmonary dysplasia (BPD) remains a devastating consequence of prematurity. Repeated inflammatory insults worsen lung injury, but there are no predictors for BPD-related respiratory outcomes or targeted therapies. We sought to understand inflammatory mechanisms in evolving BPD through molecular characterization of monocytes in tracheal aspirates from infants at risk for developing BPD. We performed flow cytometry targeting myeloid cell populations on prospectively collected tracheal aspirates from intubated patients born before 29 wk of gestation and <30 days old. We identified CD14CD16 (double-positive) and CD14CD16 (single-positive) monocytes and characterized their gene expression profiles by RNA sequencing and quantitative PCR. We further analyzed differential gene expression between time points to evaluate changes in monocyte function over the first weeks of life. Expression of IL-1A, IL-1B, and IL-1 receptor antagonist mRNA was increased in monocytes collected at () , , and compared with those collected at . This study suggests that early changes in monocyte-specific IL-1 cytokine pathways may be associated with evolving BPD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajplung.00060.2019DOI Listing
July 2019

Transcriptome networks identify mechanisms of viral and nonviral asthma exacerbations in children.

Nat Immunol 2019 05 8;20(5):637-651. Epub 2019 Apr 8.

University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.

Respiratory infections are common precursors to asthma exacerbations in children, but molecular immune responses that determine whether and how an infection causes an exacerbation are poorly understood. By using systems-scale network analysis, we identify repertoires of cellular transcriptional pathways that lead to and underlie distinct patterns of asthma exacerbation. Specifically, in both virus-associated and nonviral exacerbations, we demonstrate a set of core exacerbation modules, among which epithelial-associated SMAD3 signaling is upregulated and lymphocyte response pathways are downregulated early in exacerbation, followed by later upregulation of effector pathways including epidermal growth factor receptor signaling, extracellular matrix production, mucus hypersecretion, and eosinophil activation. We show an additional set of multiple inflammatory cell pathways involved in virus-associated exacerbations, in contrast to squamous cell pathways associated with nonviral exacerbations. Our work introduces an in vivo molecular platform to investigate, in a clinical setting, both the mechanisms of disease pathogenesis and therapeutic targets to modify exacerbations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41590-019-0347-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472965PMC
May 2019

Chronic TLR7 and TLR9 signaling drives anemia via differentiation of specialized hemophagocytes.

Science 2019 01;363(6423)

Immunology Program, Benaroya Research Institute, Seattle, WA, USA.

Cytopenias are an important clinical problem associated with inflammatory disease and infection. We show that specialized phagocytes that internalize red blood cells develop in Toll-like receptor 7 (TLR7)-driven inflammation. TLR7 signaling caused the development of inflammatory hemophagocytes (iHPCs), which resemble splenic red pulp macrophages but are a distinct population derived from Ly6C monocytes. iHPCs were responsible for anemia and thrombocytopenia in TLR7-overexpressing mice, which have a macrophage activation syndrome (MAS)-like disease. Interferon regulatory factor 5 (IRF5), associated with MAS, participated in TLR7-driven iHPC differentiation. We also found iHPCs during experimental malarial anemia, in which they required endosomal TLR and MyD88 signaling for differentiation. Our findings uncover a mechanism by which TLR7 and TLR9 specify monocyte fate and identify a specialized population of phagocytes responsible for anemia and thrombocytopenia associated with inflammation and infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aao5213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413693PMC
January 2019

Elevated T cell levels in peripheral blood predict poor clinical response following rituximab treatment in new-onset type 1 diabetes.

Genes Immun 2019 04 21;20(4):293-307. Epub 2018 Jun 21.

Systems Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.

Biologic treatment of type 1 diabetes (T1D) with agents including anti-CD3 (otelixizumab and teplizumab), anti-CD20 (rituximab), LFA3Ig (alafacept), and CTLA4Ig (abatacept) results in transient stabilization of insulin C-peptide, a surrogate for endogenous insulin secretion. With the goal of inducing more robust immune tolerance, we used systems biology approaches to elucidate mechanisms associated with C-peptide stabilization in clinical trial blood samples from new-onset T1D subjects treated with the B cell-depleting drug, rituximab. RNA sequencing (RNA-seq) analysis of whole-blood samples from this trial revealed a transient increase in heterogeneous T cell populations, which were associated with decreased pharmacodynamic activity of rituximab, increased proliferative responses to islet antigens, and more rapid C-peptide loss. Our findings illustrate complexity in hematopoietic remodeling that accompanies B cell depletion by rituximab, which impacts and predicts therapeutic efficacy in T1D. Our data also suggest that a combination of rituximab with therapy targeting CD4 + T cells may be beneficial for T1D subjects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41435-018-0032-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477779PMC
April 2019

A collection of annotated and harmonized human breast cancer transcriptome datasets, including immunologic classification.

F1000Res 2017 20;6:296. Epub 2017 Mar 20.

Tumor Biology, Immunology and Therapy section, Sidra Medical and Research Center, Doha, Qatar.

The increased application of high-throughput approaches in translational research has expanded the number of publicly available data repositories. Gathering additional valuable information contained in the datasets represents a crucial opportunity in the biomedical field. To facilitate and stimulate utilization of these datasets, we have recently developed an interactive data browsing and visualization web application, the Gene Expression Browser (GXB). In this note, we describe a curated compendium of 13 public datasets on human breast cancer, representing a total of 2142 transcriptome profiles. We classified the samples according to different immune based classification systems and integrated this information into the datasets. Annotated and harmonized datasets were uploaded to GXB. Study samples were categorized in different groups based on their immunologic tumor response profiles, intrinsic molecular subtypes and multiple clinical parameters. Ranked gene lists were generated based on relevant group comparisons. In this data note, we demonstrate the utility of GXB to evaluate the expression of a gene of interest, find differential gene expression between groups and investigate potential associations between variables with a specific focus on immunologic classification in breast cancer. This interactive resource is publicly available online at: http://breastcancer.gxbsidra.org/dm3/geneBrowser/list.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12688/f1000research.10960.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820610PMC
March 2017

Allergen-induced activation of natural killer cells represents an early-life immune response in the development of allergic asthma.

J Allergy Clin Immunol 2018 12 5;142(6):1856-1866. Epub 2018 Mar 5.

University of Wisconsin School of Medicine and Public Health, Madison, Wis.

Background: Childhood asthma in inner-city populations is a major public health burden, and understanding early-life immune mechanisms that promote asthma onset is key to disease prevention. Children with asthma demonstrate a high prevalence of aeroallergen sensitization and T2-type inflammation; however, the early-life immune events that lead to T2 skewing and disease development are unknown.

Objective: We sought to use RNA sequencing of PBMCs collected at age 2 years to determine networks of immune responses that occur in children with allergy and asthma.

Methods: In an inner-city birth cohort with high asthma risk, we compared gene expression using RNA sequencing in PBMCs collected at age 2 years between children with 2 or more aeroallergen sensitizations, including dust mite, cockroach, or both, by age 3 years and asthma by age 7 years (cases) and matched control subjects who did not have any aeroallergen sensitization or asthma by age 7 years.

Results: PBMCs from the cases showed higher levels of expression of natural killer (NK) cell-related genes. After cockroach or dust mite allergen but not tetanus antigen stimulation, PBMCs from the cases compared with the control subjects showed differential expression of 244 genes. This gene set included upregulation of a densely interconnected NK cell-like gene network reflecting a pattern of cell activation and induction of inflammatory signaling molecules, including the key T2-type cytokines IL9, IL13, and CCL17, as well as a dendritic cell-like gene network, including upregulation of CD1 lipid antigen presentation molecules. The NK cell-like response was reproducible in an independent group of children with later-onset allergic sensitization and asthma and was found to be specific to only those children with both aeroallergen sensitization and asthma.

Conclusion: These findings provide important mechanistic insight into an early-life immune pathway involved in T2 polarization, leading to the development of allergic asthma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2018.02.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123299PMC
December 2018

Transcriptomic evidence for modulation of host inflammatory responses during febrile Plasmodium falciparum malaria.

Sci Rep 2016 08 10;6:31291. Epub 2016 Aug 10.

Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.

Identifying molecular predictors and mechanisms of malaria disease is important for understanding how Plasmodium falciparum malaria is controlled. Transcriptomic studies in humans have so far been limited to retrospective analysis of blood samples from clinical cases. In this prospective, proof-of-principle study, we compared whole-blood RNA-seq profiles at pre-and post-infection time points from Malian adults who were either asymptomatic (n = 5) or febrile (n = 3) during their first seasonal PCR-positive P. falciparum infection with those from malaria-naïve Dutch adults after a single controlled human malaria infection (n = 5). Our data show a graded activation of pathways downstream of pro-inflammatory cytokines, with the highest activation in malaria-naïve Dutch individuals and significantly reduced activation in malaria-experienced Malians. Newly febrile and asymptomatic infections in Malians were statistically indistinguishable except for genes activated by pro-inflammatory cytokines. The combined data provide a molecular basis for the development of a pyrogenic threshold as individuals acquire immunity to clinical malaria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep31291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4978957PMC
August 2016

A curated transcriptome dataset collection to investigate the functional programming of human hematopoietic cells in early life.

F1000Res 2016 30;5:414. Epub 2016 Mar 30.

Sidra Medical and Research Center, Doha, Qatar.

Compendia of large-scale datasets made available in public repositories provide an opportunity to identify and fill gaps in biomedical knowledge. But first, these data need to be made readily accessible to research investigators for interpretation. Here we make available a collection of transcriptome datasets to investigate the functional programming of human hematopoietic cells in early life. Thirty two datasets were retrieved from the NCBI Gene Expression Omnibus (GEO) and loaded in a custom web application called the Gene Expression Browser (GXB), which was designed for interactive query and visualization of integrated large-scale data. Quality control checks were performed. Multiple sample groupings and gene rank lists were created allowing users to reveal age-related differences in transcriptome profiles, changes in the gene expression of neonatal hematopoietic cells to a variety of immune stimulators and modulators, as well as during cell differentiation. Available demographic, clinical, and cell phenotypic information can be overlaid with the gene expression data and used to sort samples. Web links to customized graphical views can be generated and subsequently inserted in manuscripts to report novel findings. GXB also enables browsing of a single gene across projects, thereby providing new perspectives on age- and developmental stage-specific expression of a given gene across the human hematopoietic system. This dataset collection is available at: http://developmentalimmunology.gxbsidra.org/dm3/geneBrowser/list.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12688/f1000research.8375.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916988PMC
June 2016

A curated transcriptome dataset collection to investigate the development and differentiation of the human placenta and its associated pathologies.

F1000Res 2016 9;5:305. Epub 2016 Mar 9.

Sidra Medical and Research Center, Doha, Qatar.

Compendia of large-scale datasets made available in public repositories provide a precious opportunity to discover new biomedical phenomena and to fill gaps in our current knowledge. In order to foster novel insights it is necessary to ensure that these data are made readily accessible to research investigators in an interpretable format. Here we make a curated, public, collection of transcriptome datasets relevant to human placenta biology available for further analysis and interpretation via an interactive data browsing interface. We identified and retrieved a total of 24 datasets encompassing 759 transcriptome profiles associated with the development of the human placenta and associated pathologies from the NCBI Gene Expression Omnibus (GEO) and present them in a custom web-based application designed for interactive query and visualization of integrated large-scale datasets ( http://placentalendocrinology.gxbsidra.org/dm3/landing.gsp). We also performed quality control checks using relevant biological markers. Multiple sample groupings and rank lists were subsequently created to facilitate data query and interpretation. Via this interface, users can create web-links to customized graphical views which may be inserted into manuscripts for further dissemination, or e-mailed to collaborators for discussion. The tool also enables users to browse a single gene across different projects, providing a mechanism for  developing new perspectives on the role of a molecule of interest across multiple biological states. The dataset collection we created here is available at: http://placentalendocrinology.gxbsidra.org/dm3.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4897750PMC
http://dx.doi.org/10.12688/f1000research.8210.2DOI Listing
June 2016

A curated compendium of monocyte transcriptome datasets of relevance to human monocyte immunobiology research.

F1000Res 2016 25;5:291. Epub 2016 Apr 25.

Systems Biology Department, Sidra Medical and Research Center, Doha, Qatar.

Systems-scale profiling approaches have become widely used in translational research settings. The resulting accumulation of large-scale datasets in public repositories represents a critical opportunity to promote insight and foster knowledge discovery. However, resources that can serve as an interface between biomedical researchers and such vast and heterogeneous dataset collections are needed in order to fulfill this potential. Recently, we have developed an interactive data browsing and visualization web application, the Gene Expression Browser (GXB). This tool can be used to overlay deep molecular phenotyping data with rich contextual information about analytes, samples and studies along with ancillary clinical or immunological profiling data. In this note, we describe a curated compendium of 93 public datasets generated in the context of human monocyte immunological studies, representing a total of 4,516 transcriptome profiles. Datasets were uploaded to an instance of GXB along with study description and sample annotations. Study samples were arranged in different groups. Ranked gene lists were generated based on relevant group comparisons. This resource is publicly available online at http://monocyte.gxbsidra.org/dm3/landing.gsp.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12688/f1000research.8182.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4856112PMC
May 2016

A compendium of monocyte transcriptome datasets to foster biomedical knowledge discovery.

F1000Res 2016 7;5:291. Epub 2016 Mar 7.

Systems Biology Department, Sidra Medical and Research Center, Doha, Qatar.

Systems-scale profiling approaches have become widely used in translational research settings. The resulting accumulation of large-scale datasets in public repositories represents a critical opportunity to promote insight and foster knowledge discovery. However, resources that can serve as an interface between biomedical researchers and such vast and heterogeneous dataset collections are needed in order to fulfill this potential. Recently, we have developed an interactive data browsing and visualization web application, the Gene Expression Browser (GXB). This tool can be used to overlay deep molecular phenotyping data with rich contextual information about analytes, samples and studies along with ancillary clinical or immunological profiling data. In this note, we describe a curated compendium of 93 public datasets generated in the context of human monocyte immunological studies, representing a total of 4,516 transcriptome profiles. Datasets were uploaded to an instance of GXB along with study description and sample annotations. Study samples were arranged in different groups. Ranked gene lists were generated based on relevant group comparisons. This resource is publicly available online at http://monocyte.gxbsidra.org/dm3/landing.gsp.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12688/f1000research.8182.1DOI Listing
May 2016

A curated transcriptome dataset collection to investigate the immunobiology of HIV infection.

F1000Res 2016 11;5:327. Epub 2016 Mar 11.

Sidra Medical and Research Center, Doha, Qatar.

Compendia of large-scale datasets available in public repositories provide an opportunity to identify and fill current gaps in biomedical knowledge. But first, these data need to be readily accessible to research investigators for interpretation. Here, we make available a collection of transcriptome datasets relevant to HIV infection. A total of 2717 unique transcriptional profiles distributed among 34 datasets were identified, retrieved from the NCBI Gene Expression Omnibus (GEO), and loaded in a custom web application, the Gene Expression Browser (GXB), designed for interactive query and visualization of integrated large-scale data. Multiple sample groupings and rank lists were created to facilitate dataset query and interpretation via this interface. Web links to customized graphical views can be generated by users and subsequently inserted in manuscripts reporting novel findings, such as discovery notes. The tool also enables browsing of a single gene across projects, which can provide new perspectives on the role of a given molecule across biological systems. This curated dataset collection is available at: http://hiv.gxbsidra.org/dm3/geneBrowser/list.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12688/f1000research.8204.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838008PMC
May 2016

Blood Interferon Signatures Putatively Link Lack of Protection Conferred by the RTS,S Recombinant Malaria Vaccine to an Antigen-specific IgE Response.

F1000Res 2015 29;4:919. Epub 2015 Sep 29.

Sidra Medical and Research Center, Doha, Qatar.

Malaria remains a major cause of mortality and morbidity worldwide. Progress has been made in recent years with the development of vaccines that could pave the way towards protection of hundreds of millions of exposed individuals. Here we used a modular repertoire approach to re-analyze a publically available microarray blood transcriptome dataset monitoring the response to malaria vaccination. We report the seminal identification of interferon signatures in the blood of subjects on days 1, 3 and 14 following administration of the third dose of the RTS,S recombinant malaria vaccine. These signatures at day 1 correlate with protection, and at days 3 and 14 to susceptibility to subsequent challenge of study subjects with live parasites. In addition we putatively link the decreased abundance of interferon-inducible transcripts observed at days 3 and 14 post-vaccination with the elicitation of an antigen-specific IgE response in a subset of vaccine recipients that failed to be protected by the RTS,S vaccine. Furthermore, profiling of antigen-specific levels of IgE in a Mozambican cohort of malaria-exposed children vaccinated with RTS,S identified an association between elevated baseline IgE levels and subsequent development of naturally acquired malaria infection during follow up. Taken together these findings warrant further investigation of the role of antigen-specific IgE in conferring susceptibility to malaria infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12688/f1000research.7093.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5580375PMC
September 2015

An interactive web application for the dissemination of human systems immunology data.

J Transl Med 2015 Jun 19;13:196. Epub 2015 Jun 19.

Benaroya Research Institute, Systems Immunology Laboratory, 1201 Ninth Ave., Seattle, WA, 98101, USA.

Background: Systems immunology approaches have proven invaluable in translational research settings. The current rate at which large-scale datasets are generated presents unique challenges and opportunities. Mining aggregates of these datasets could accelerate the pace of discovery, but new solutions are needed to integrate the heterogeneous data types with the contextual information that is necessary for interpretation. In addition, enabling tools and technologies facilitating investigators' interaction with large-scale datasets must be developed in order to promote insight and foster knowledge discovery.

Methods: State of the art application programming was employed to develop an interactive web application for browsing and visualizing large and complex datasets. A collection of human immune transcriptome datasets were loaded alongside contextual information about the samples.

Results: We provide a resource enabling interactive query and navigation of transcriptome datasets relevant to human immunology research. Detailed information about studies and samples are displayed dynamically; if desired the associated data can be downloaded. Custom interactive visualizations of the data can be shared via email or social media. This application can be used to browse context-rich systems-scale data within and across systems immunology studies. This resource is publicly available online at [Gene Expression Browser Landing Page ( https://gxb.benaroyaresearch.org/dm3/landing.gsp )]. The source code is also available openly [Gene Expression Browser Source Code ( https://github.com/BenaroyaResearch/gxbrowser )].

Conclusions: We have developed a data browsing and visualization application capable of navigating increasingly large and complex datasets generated in the context of immunological studies. This intuitive tool ensures that, whether taken individually or as a whole, such datasets generated at great effort and expense remain interpretable and a ready source of insight for years to come.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12967-015-0541-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4474328PMC
June 2015

Modular transcriptional repertoire analyses of adults with systemic lupus erythematosus reveal distinct type I and type II interferon signatures.

Arthritis Rheumatol 2014 Jun;66(6):1583-95

Benaroya Research Institute, Seattle, Washington, and Aix-Marseille University and Hôpital de la Conception, APHM, Marseille, France.

Objective: The role of interferon-α (IFNα) in the pathogenesis of systemic lupus erythematosus (SLE) is strongly supported by gene expression studies. The aim of this study was to improve characterization of the blood IFN signature in adult SLE patients.

Methods: Consecutive patients were enrolled and followed up prospectively. Microarray data were generated using Illumina BeadChips. A modular transcriptional repertoire was used as a framework for the analysis.

Results: Our repertoire of 260 modules, which consisted of coclustered gene sets, included 3 IFN-annotated modules (M1.2, M3.4, and M5.12) that were strongly up-regulated in SLE patients. A modular IFN signature was observed in 54 of 62 patients (87%) or 131 of all 157 samples (83%). The IFN signature was more complex than expected, with each module displaying a distinct activation threshold (M1.2 < M3.4 < M5.12), thus providing a modular score by which to stratify SLE patients based on the presence of 0, 1, 2, or 3 active IFN modules. A similar gradient in modular IFN signature was observed within patients with clinically quiescent disease, for whom moderate/strong modular scores (2 or 3 active IFN modules) were associated with higher anti-double-stranded DNA titers and lower lymphocyte counts than those in patients with absent/mild modular scores (0 or 1 active IFN modules). Longitudinal analyses revealed both stable (M1.2) and variable (M3.4 and M5.12) components of modular IFN signature over time in single patients. Interestingly, mining of other data sets suggested that M3.4 and M5.12 could also be driven by IFNβ and IFNγ.

Conclusion: Modular repertoire analysis reveals complex IFN signatures in SLE, which are not restricted to the previous IFNα signature, but which also involve IFNβ and IFNγ.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/art.38628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157826PMC
June 2014

A transcriptomic reporter assay employing neutrophils to measure immunogenic activity of septic patients' plasma.

J Transl Med 2014 Mar 11;12:65. Epub 2014 Mar 11.

Systems Immunology Division, Benaroya Research Institute, 1201 Ninth Avenue, Seattle, WA 98101, USA.

Background: There are diverse molecules present in blood plasma that regulate immune functions and also present a potential source of disease biomarkers and therapeutic targets. Genome-wide profiling has become a powerful method for assessing immune responses on a systems scale, but technologies that can measure the plasma proteome still face considerable challenges. An alternative approach to direct proteome assessment is to measure transcriptome responses in reporter cells exposed in vitro to plasma. In this report we describe such a "transcriptomic reporter assay" to assess plasma from patients with sepsis, which is a common and severe systemic infectious process for which physicians lack efficient diagnostic or prognostic markers.

Methods: Plasma samples collected from patients with culture-confirmed bacterial sepsis and uninfected healthy controls were used to stimulate three separate cell types - neutrophils, peripheral blood mononuclear cells, and monocyte-derived dendritic cells. Whole genome microarrays were generated from stimulated cells to assess transcriptional responses. Unsupervised analysis and enriched functional networks were evaluated for each cell type. Principal component analyses were used to assess variability in responses. A random K-nearest neighbor - feature selection algorithm was used to identify markers predictive of sepsis severity, which were then validated in an independent data set.

Results: Neutrophils demonstrated the most distinct response to plasma from septic patients with 709 genes showing altered expression profiles, many of which are involved in established immunologic pathways. The amplitude of the neutrophil transcriptomic response was shown to be correlated with sepsis severity in two independent sets of patients comprised of 64 total septic patients. A subset of 30 transcripts selected using one set of patients was demonstrated to have a high degree of accuracy (82-90%) in predicting sepsis severity and outcomes in the other independent set. This subset included several genes previously established in sepsis pathogenesis as well as novel genes.

Conclusions: These results demonstrate both the suitability and potential clinical relevance of a neutrophil reporter assay for studying plasma, in this case from septic patients. The distinctive transcriptional signature we found could potentially help predict severity of disease and guide treatment. Our findings also shed new light on mechanisms of immune dysregulation in sepsis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1479-5876-12-65DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007645PMC
March 2014

Molecular signatures of antibody responses derived from a systems biology study of five human vaccines.

Nat Immunol 2014 Feb 15;15(2):195-204. Epub 2013 Dec 15.

1] Emory Vaccine Center, Emory University, Atlanta, Georgia, USA. [2] Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA. [3] Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA.

Many vaccines induce protective immunity via antibodies. Systems biology approaches have been used to determine signatures that can be used to predict vaccine-induced immunity in humans, but whether there is a 'universal signature' that can be used to predict antibody responses to any vaccine is unknown. Here we did systems analyses of immune responses to the polysaccharide and conjugate vaccines against meningococcus in healthy adults, in the broader context of published studies of vaccines against yellow fever virus and influenza virus. To achieve this, we did a large-scale network integration of publicly available human blood transcriptomes and systems-scale databases in specific biological contexts and deduced a set of transcription modules in blood. Those modules revealed distinct transcriptional signatures of antibody responses to different classes of vaccines, which provided key insights into primary viral, protein recall and anti-polysaccharide responses. Our results elucidate the early transcriptional programs that orchestrate vaccine immunity in humans and demonstrate the power of integrative network modeling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ni.2789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3946932PMC
February 2014

Systems scale interactive exploration reveals quantitative and qualitative differences in response to influenza and pneumococcal vaccines.

Immunity 2013 Apr;38(4):831-44

Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, TX 75204, USA.

Systems immunology approaches were employed to investigate innate and adaptive immune responses to influenza and pneumococcal vaccines. These two non-live vaccines show different magnitudes of transcriptional responses at different time points after vaccination. Software solutions were developed to explore correlates of vaccine efficacy measured as antibody titers at day 28. These enabled a further dissection of transcriptional responses. Thus, the innate response, measured within hours in the peripheral blood, was dominated by an interferon transcriptional signature after influenza vaccination and by an inflammation signature after pneumococcal vaccination. Day 7 plasmablast responses induced by both vaccines was more pronounced after pneumococcal vaccination. Together, these results suggest that comparing global immune responses elicited by different vaccines will be critical to our understanding of the immune mechanisms underpinning successful vaccination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.immuni.2012.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681204PMC
April 2013

Finding evidence to support practice in allied health: peers, experience, and the internet.

J Allied Health 2012 ;41(4):154-61

La Trobe University, Melbourne 3004, Australia.

Objective: Barriers to evidence-based practice (EBP) amongst allied health professionals have been well documented; however, the impact of electronic evidence sources on the acquisition of evidence has not been described. This study aimed to determine methods used to acquire evidence amongst allied health professionals, along with barriers to evidence acquisition and implementation.

Design: A cross-sectional survey developed using focus groups and a two-round Delphi process.

Setting: One healthcare network in metropolitan Melbourne, Australia, comprising a tertiary hospital, subacute facility, and community health facilities.

Participants: Allied health clinicians employed in a clinical role.

Results: There were 166 respondents to the survey, a response rate of 38%. The majority held a bachelor's degree (n = 84, 51%), had graduated <5 years ago (49, 29%), and worked predominantly in the acute setting (84, 51%). Colleagues within the respondent's profession (n = 135, 84%), general internet search engines (137, 83%), and clinical experience (131, 79%) were the most frequently consulted sources of information. Despite time and clinical workload being cited as important barriers to EBP, electronic evidence sources such as internet forums (n = 30, 18%) and emailed evidence summaries (n = 41, 25%) were infrequently used. Barriers to implementing evidence were reported less frequently than barriers to finding evidence.

Conclusions: Allied health clinicians rely on colleagues, experience, and general internet search engines to source evidence. Care must be taken to ensure that allied health clinicians have adequate information literacy skills and are aware of accessible, high-quality evidence sources.
View Article and Find Full Text PDF

Download full-text PDF

Source
May 2013

Improving older trauma patients' outcomes through targeted occupational therapy and functional conditioning.

Am J Occup Ther 2012 Jul-Aug;66(4):431-7

Occupational Therapy Department, The Alfred Hospital, PO Box 315, Prahran 3181, Melbourne, Victoria, Australia.

Objective: Hospitalized older people are at risk of functional decline, and risk increases with length of stay (LOS). We measured the impact on LOS and discharge destination of targeted occupational therapy and a functional conditioning program (FCP) for older adults admitted to a metropolitan trauma unit.

Method: The intervention group consisted of 50 participants > 65 yr old living independently in the community before admission. Outcomes were compared with historical control group data (N = 105).

Results: The intervention group's mean LOS was 2 days less than that of the control group (p = .04). A higher proportion in the intervention group was also discharged to home, but the difference was not statistically significant. Referrals to occupational therapy increased significantly (p = .05), and participants were seen 1.5 days sooner (p = .003) than the control group. Referral to FCP was 7 times higher in the intervention group (p = .001).

Conclusion: Targeted occupational therapy and FCP can improve LOS in older trauma patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5014/ajot.2012.003137DOI Listing
December 2013

Pain impacts on quality of life and interferes with treatment in adults with cystic fibrosis.

Physiother Res Int 2012 Sep 25;17(3):132-41. Epub 2011 Oct 25.

Physiotherapy, La Trobe University, Bundoora, Victoria, Australia.

Background And Purpose: Pain has been reported in cystic fibrosis (CF), but its clinical significance and the physical and psychosocial impact in adults who are clinically stable and acutely unwell have not been well described. The aim of this study was to describe the intensity and location of pain and its relationship with health-related quality of life (HRQOL) and pain catastrophizing in adults with CF.

Methods: This study was an observational study of adults with CF. Participants completed three questionnaires, the Brief Pain Inventory, Pain Catastrophizing Scale and the CF-Quality of Life questionnaire, when clinically stable and during an acute exacerbation.

Results: A total of 73 participants were included during a period of clinical stability, with 33 repeating the measurements during an acute illness, with a mean (SD) age of 29 (9) years and forced expiratory volume (FEV(1) ) of 60.5 (24.9)% predicted. Mild pain was reported by 89% of stable participants and 79% of those with exacerbations. Severity of lung disease did not affect prevalence or intensity of pain. Pain interfered with airway clearance therapy during exacerbations (p < 0.012) and exercise regimens when participants were clinically stable (p < 0.002) and was related to a poorer physical function, regardless of clinical status (p < 0.05). Although pain intensity was associated with reduced HRQOL (p < 0.001), only FEV(1) and the degree of pain catastrophizing were independent predictors of poorer HRQOL.

Conclusions: Pain is common in adults with CF, irrespective of clinical status, and may interfere with important physiotherapy treatments. Although pain intensity is generally mild, those with a negative emotional response to pain have significantly impaired HRQOL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pri.524DOI Listing
September 2012

Older people's experiences of acute hospitalisation: an investigation of how occupations are affected.

Aust Occup Ther J 2011 Apr 23;58(2):120-8. Epub 2011 Feb 23.

Southern Health, Dandenong Hospital, La Trobe University, Melbourne, Victoria 3086, Australia.

Background/aim: Few qualitative studies have investigated older people's experiences of hospital admission and none has done so from an occupational perspective. The purpose of this study was to examine older people's experience of acute hospitalisation.

Methods:   In-depth semi-structured interviews were conducted with six participants recruited from the Alfred hospital, Melbourne, Victoria. Data were analysed using Colaizzi's (1978) approach to phenomenological analysis.

Results: Five themes describing older people's experience of acute hospitalisation emerged from the analysis: (i) not part of 'normal life'; (ii) undesirable, but for the good of my health; (iii) understanding my condition and abilities; (iv) subject to approval; and (v) getting back into life. The importance of the individual's occupational narrative emerged as a central theme in understanding the older person's experience of acute hospitalisation.

Conclusions: Occupational therapists have a unique contribution to make in encouraging meaningful occupation on hospital wards. Identifying the manner by which occupational therapists can most effectively implement the assessment of occupational performance in the acute care setting should constitute a research priority for future investigations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1440-1630.2010.00878.xDOI Listing
April 2011

Patient experience of distraction splinting for complex finger fracture dislocations.

J Hand Ther 2010 Jul-Sep;23(3):249-9; quiz 260

Department of Occupational Therapy, The Alfred Hospital, Monash University, Melbourne, Australia.

The study design is qualitative phenomenological and grounded theory. Intraarticular fractures of the finger joints can severely limit function due to stiffness and pain. Distraction with early movement is thought to deliver the best results and this has been used to treat these types of injuries at The Alfred Hospital for eight years. Qualitative data from patient interviews were used to describe patients' own experiences of treatment with distraction splinting and identify key issues in patient adherence. The key finding was a disconnect between perceived complexity of injury and treatment. Those who adhered with the treatment regime felt that they were well informed of the reasoning behind it. The hand surgery and therapy team must be aware of the patient experience of complex finger injuries and should ensure patients are well supported with education about their injury and treatment. Early preemptive pain control may help optimize adherence to the splint and exercise regime. Findings can be applied to other acute conditions requiring cumbersome splinting and potentially uncomfortable early exercise routines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jht.2010.01.002DOI Listing
November 2010

A dual-targeting PDGFRbeta/VEGF-A molecule assembled from stable antibody fragments demonstrates anti-angiogenic activity in vitro and in vivo.

MAbs 2010 Jan-Feb;2(1):20-34. Epub 2010 Jan 2.

Antibody Discovery and Assay Technology, ZymoGenetics, Inc., Seattle, WA, USA.

Targeting angiogenesis is a promising approach to the treatment of solid tumors and age-related macular degeneration (AMD). Inhibition of vascularization has been validated by the successful marketing of monoclonal antibodies (mAbs) that target specific growth factors or their receptors, but there is considerable room for improvement in existing therapies. Combination of mAbs targeting both the VEGF and PDGF pathways has the potential to increase the efficacy of anti-angiogenic therapy without the accompanying toxicities of tyrosine kinase inhibitors and the inability to combine efficiently with traditional chemotherapeutics. However, development costs and regulatory issues have limited the use of combinatorial approaches for the generation of more efficacious treatments. The concept of mediating disease pathology by targeting two antigens with one therapeutic was proposed over two decades ago. While mAbs are particularly suitable candidates for a dual-targeting approach, engineering bispecificity into one molecule can be difficult due to issues with expression and stability, which play a significant role in manufacturability. Here, we address these issues upstream in the process of developing a bispecific antibody (bsAb). Single-chain antibody fragments (scFvs) targeting PDGFRbeta and VEGF-A were selected for superior stability. The scFvs were fused to both termini of human Fc to generate a bispecific, tetravalent molecule. The resulting molecule displays potent activity, binds both targets simultaneously, and is stable in serum. The assembly of a bsAb using stable monomeric units allowed development of an anti-PDGFRB/VEGF-A antibody capable of attenuating angiogenesis through two distinct pathways and represents an efficient method for rapid engineering of dual-targeting molecules.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828575PMC
http://dx.doi.org/10.4161/mabs.2.1.10498DOI Listing
June 2010

Engineering of stable bispecific antibodies targeting IL-17A and IL-23.

Protein Eng Des Sel 2010 Mar 18;23(3):115-27. Epub 2009 Dec 18.

ZymoGenetics, Inc., Seattle, WA 98102, USA.

Bispecific antibodies (bsAbs) present an attractive opportunity to combine the additive and potentially synergistic effects exhibited by combinations of monoclonal antibodies (mAbs). Current challenges for engineering bsAbs include retention of the binding affinity of the parent mAb or antibody fragment, the ability to bind both targets simultaneously, and matching valency with biology. Other factors to consider include structural stability and expression of the recombinant molecule, both of which may have significant impact on its development as a therapeutic. Here, we incorporate selection of stable, potent single-chain variable fragments (scFvs) early in the engineering process to assemble bsAbs for therapeutic applications targeting the cytokines IL-17A/A and IL-23. Stable scFvs directed against human cytokines IL-23p19 and IL-17A/A were isolated from a human Fab phage display library via batch conversion of panning output from Fabs to scFvs. This strategy integrated a step for shuffling V regions during the conversion and permitted the rescue of scFv molecules in both the V(H)V(L) and the V(L)V(H) orientations. Stable scFvs were identified and assembled into several bispecific formats as fusions to the Fc domain of human IgG1. The engineered bsAbs are potent neutralizers of the biological activity of both cytokines (IC(50) < 1 nM), demonstrate the ability to bind both target ligands simultaneously and display stability and productivity advantageous for successful manufacture of a therapeutic molecule. Pharmacokinetic analysis of the bsAbs in mice revealed serum half-lives similar to human mAbs. Assembly of bispecific molecules using stable antibody fragments offers an alternative to reformatting mAbs and minimizes subsequent structure-related and manufacturing concerns.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/protein/gzp073DOI Listing
March 2010

Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F.

J Immunol 2007 Oct;179(8):5462-73

Department of Molecular and Cell Based Discovery, ZymoGenetics Incroporated, Seattle, WA 98102, USA.

The proinflammatory cytokines IL-17A and IL-17F have a high degree of sequence similarity and share many biological properties. Both have been implicated as factors contributing to the progression of inflammatory and autoimmune diseases. Moreover, reagents that neutralize IL-17A significantly ameliorate disease severity in several mouse models of human disease. IL-17A mediates its effects through interaction with its cognate receptor, the IL-17 receptor (IL-17RA). We report here that the IL-17RA-related molecule, IL-17RC is the receptor for IL-17F. Notably, both IL-17A and IL-17F bind to IL-17RC with high affinity, leading us to suggest that a soluble form of this molecule may serve as an effective therapeutic antagonist of IL-17A and IL-17F. We generated a soluble form of IL-17RC and demonstrate that it effectively blocks binding of both IL-17A and IL-17F, and that it inhibits signaling in response to these cytokines. Collectively, our work indicates that IL-17RC functions as a receptor for both IL-17A and IL-17F and that a soluble version of this protein should be an effective antagonist of IL-17A and IL-17F mediated inflammatory diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849293PMC
http://dx.doi.org/10.4049/jimmunol.179.8.5462DOI Listing
October 2007

Return to work for individuals with Human Immunodeficiency Virus (HIV) disease: dichotomous outcome variable or personally-constructed narrative challenge?

Authors:
Scott Presnell

Work 2006 ;27(3):305-12

Senior Clinician, Caulfield Pain Management & Research Centre, 260 Kooyong Road, Caulfield 3162, Australia.

Advances in the management of HIV disease have increasingly focused attention on the possibilities of return to employment for individuals with HIV disease. However whilst mortality has decreased and life expectancies have lengthened, life for the individual with HIV remains both complex and unpredictable. This article explores the notion of return to work as narrative theme. A case study highlighting the narrative nature of how return to work might be conceptualised by the HIV positive individual is presented; ahead of a brief discussion as to how the lived reality of combination therapy may impact upon the individual's conceptualisation of employment in the broader context of their life story.
View Article and Find Full Text PDF

Download full-text PDF

Source
December 2006