Systems biology and big data in asthma and allergy: recent discoveries and emerging challenges

Asthma is a common condition caused by immune and respiratory dysfunction, and it is often linked to allergy. A systems perspective may prove helpful in unravelling the complexity of asthma and allergy. Our aim is to give an overview of systems biology approaches used in allergy and asthma research. Specifically, we describe recent “omic”-level findings, and examine how these findings have been systematically integrated to generate further insight. Current research suggests that allergy is driven by genetic and epigenetic factors, in concert with environmental factors such as microbiome and diet, leading to early-life disturbance in immunological development and disruption of balance within key immuno-inflammatory pathways. Variation in inherited susceptibility and exposures causes heterogeneity in manifestations of asthma and other allergic diseases. Machine learning approaches are being used to explore this heterogeneity, and to probe the pathophysiological patterns or “endotypes” that correlate with subphenotypes of asthma and allergy. Mathematical models are being built based on genomic, transcriptomic, and proteomic data to predict or discriminate disease phenotypes, and to describe the biomolecular networks behind asthma. The use of systems biology in allergy and asthma research is rapidly growing, and has so far yielded fruitful results. However, the scale and multidisciplinary nature of this research means that it is accompanied by new challenges. Ultimately, it is hoped that systems medicine, with its integration of omics data into clinical practice, can pave the way to more precise, personalised and effective management of asthma.This work was supported by the National Health and Medical Research Council (NHMRC) of Australia via a postgraduate scholarship (ref. no. 1114753) to HHF Tang, research grant (1049539) to M Inouye and K Holt, and Fellowships (1061409) to K Holt and (1061435) to M Inouye. K Holt was further supported by a Senior Medical Research Fellowship from the Viertel Foundation of Australia

Differential gene network analysis for the identification of asthma-associated therapeutic targets in allergen-specific T-helper memory responses

Fifty most significant differentially expressed genes in HDM-stimulated versus resting CD4 T cells from HDM-sensitized atopics with asthmatics. Gene expression patterns were compared between HDM-stimulated and unstimulated CD4 T cells from HDM-sensitized atopics with asthma. Here we present the 50 most significant differentially expressed genes. (XLS 34 kb

Soothing signals: transplacental transmission of resistance to asthma and allergy

The progressive rise in the prevalence of allergic diseases since the 1970s is widely attributed to diminished exposure to microbial stimuli, resulting in dysregulated immune functions during early life. Most studies investigating the mechanism behind this phenomenon have focused on postnatal microbial exposure. But emerging evidence suggests that such programming may also occur in the developing fetus as a result of microbial stimulation of the pregnant mother

The free volume of poly(vinyl methylether) as computed in a wide temperature range and at length scales up to the nanoregion

14 páginas, 12 figuras.In the present work, we focus on the free volume evaluations from different points of view, including the aspect of probe sizes, temperature, and cavity threshold. The free volume structure is analyzed on structures of poly(vinyl methylether) prepared by fully atomistic molecular dynamics. At first, the temperature behavior of an overall free volume and a free volume separated into individual cavities is shown. The origin of large free volume cavities is explained. A complex view on the cavity number is provided, while a complicated behavior previously observed is now explained. The number of large cavities remained almost constant with the temperature. Oppositely, the number of small cavities related to the atomic packing changes with temperature in a distinct way for glassy and supercooled regions. The cavity number maxima determine a percolation threshold according to percolation theory. The change in polymer properties with temperature can be related to a percolation of the free volume according to the free volume theory, when proper probe radii ∼0.8 Å are used for its observation. A construction of probabilistic distribution of free volume sizes is suggested. The free volume distributions reported here are bimodal. The bimodal character is explained by two different packings—atomic and segmental—forming a prepeak and a main peak on the distribution. Further attention is dedicated to comparisons of the computed free volume sizes and the ortho-positronium (o-Ps) lifetimes. The prepeak of the free volume distribution is probably unseen by o-Ps because of a cavity threshold limit. The effect of the shape factor on the computed o-Ps lifetimes is tested. The quasicavities obtained by redistributing the free volume maintain the ratio of the main dimensions with temperature. Finally, novel data on the cavity environment are provided, while it is suggested how these can be useful with the recent developments in the positron annihilation methods. The coordination number of large cavities with the polymer segments is around 1, as predicted in the free volume theory. Similarly to the percolation and the cavity number, the coordination number exhibits a change when explored by a suitable probe radius ∼0.8 Å. The insightful visualizations showed properties of interest investigated within the actual work.This work was supported by Project No. MAT2007– 63681 (Spanish Ministry of Education) and Grant No. IT- 436–07 (Basque Government). Support from Spanish Ministry of Education Grant No. CSD2006-53 is also acknowledged.Peer reviewe

Primary prevention of severe lower respiratory illnesses in at-risk infants using the immunomodulator OM85

Severe lower respiratory illnesses (sLRI) during infancy increase the risk of asthma. The immunomodulator BronchVaxom® can increase the time to the first sLRI and reduce the cumulative burden of sLRI in "at risk" infants

Lipopolysaccharide-induced interferon response networks at birth are predictive of severe viral lower respiratory infections in the first year of life

Appropriate innate immune function is essential to limit pathogenesis and severity of severe lower respiratory infections (sLRI) during infancy, a leading cause of hospitalization and risk factor for subsequent asthma in this age group. Employing a systems biology approach to analysis of multi-omic profiles generated from a high-risk cohort (n = 50), we found that the intensity of activation of an LPS-induced interferon gene network at birth was predictive of sLRI risk in infancy (AUC = 0.724). Connectivity patterns within this network were stronger among susceptible individuals, and a systems biology approach identified IRF1 as a putative master regulator of this response. These findings were specific to the LPS-induced interferon response and were not observed following activation of viral nucleic acid sensing pathways. Comparison of responses at birth versus age 5 demonstrated that LPS-induced interferon responses but not responses triggered by viral nucleic acid sensing pathways may be subject to strong developmental regulation. These data suggest that the risk of sLRI in early life is in part already determined at birth, and additionally that the developmental status of LPS-induced interferon responses may be a key determinant of susceptibility. Our findings provide a rationale for the identification of at-risk infants for early intervention aimed at sLRI prevention and identifies targets which may be relevant for drug development

Reversal of airway hyperresponsiveness by induction of airway mucosal CD4+CD25+ regulatory T cells

An important feature of atopic asthma is the T cell–driven late phase reaction involving transient bronchoconstriction followed by development of airways hyperresponsiveness (AHR). Using a unique rat asthma model we recently showed that the onset and duration of the aeroallergen-induced airway mucosal T cell activation response in sensitized rats is determined by the kinetics of functional maturation of resident airway mucosal dendritic cells (AMDCs) mediated by cognate interactions with CD4+ T helper memory cells. The study below extends these investigations to chronic aeroallergen exposure. We demonstrate that prevention of ensuing cycles of T cell activation and resultant AHR during chronic exposure of sensitized rats to allergen aerosols is mediated by CD4+CD25+Foxp3+LAG3+ CTLA+CD45RC+ T cells which appear in the airway mucosa and regional lymph nodes within 24 h of initiation of exposure, and inhibit subsequent Th-mediated upregulation of AMDC functions. These cells exhibit potent regulatory T (T reg) cell activity in both in vivo and ex vivo assay systems. The maintenance of protective T reg activity is absolutely dependent on continuing allergen stimulation, as interruption of exposure leads to waning of T reg activity and reemergence of sensitivity to aeroallergen exposure manifesting as AMDC/T cell upregulation and resurgence of T helper 2 cytokine expression, airways eosinophilia, and AHR