Science, medicine, and the future. Prospecting for gold in the human genome

Doctors struggling with the daily problems of clinical medicine usually have little time for molecular and cell biology. But genetic research is producing an explosion of knowledge which doctors will need to understand in order to join in the ethical and financial debates that will inevitably follow the new treatments discovered. There may, indeed, be therapeutic gold hidden in our genes, but the price for it could be more than we can afford. This is the first of three articles introducing a series which aims to convey the excitement and potential power of biomedical science by speculating how current research will impinge on clinical management of common conditions

Divergent functions for airway epithelial matrix metalloproteinase 7 and retinoic acid in experimental asthma.

The innate immune response of airway epithelial cells to airborne allergens initiates the development of T cell responses that are central to allergic inflammation. Although proteinase allergens induce the expression of interleukin 25, we show here that epithelial matrix metalloproteinase 7 (MMP7) was expressed during asthma and was required for the maximum activity of interleukin 25 in promoting the differentiation of T helper type 2 cells. Allergen-challenged Mmp7(-/-) mice had less airway hyper-reactivity and production of allergic inflammatory cytokines and higher expression of retinal dehydrogenase 1. Inhibition of retinal dehydrogenase 1 restored the asthma phenotype of Mmp7(-/-) mice and inhibited the responses of lung regulatory T cells, whereas exogenous administration of retinoic acid attenuated the asthma phenotype. Thus, MMP7 coordinates allergic lung inflammation by activating interleukin 25 while simultaneously inhibiting retinoid-dependent development of regulatory T cells

Diagnosis and management of eosinophilic asthma: a US perspective.

Eosinophilic asthma is now recognized as an important subphenotype of asthma based on the pattern of inflammatory cellular infiltrate in the airway. Eosinophilic asthma can be associated with increased asthma severity, atopy, late-onset disease, and steroid refractoriness. Induced sputum cell count is the gold standard for identifying eosinophilic inflammation in asthma although several noninvasive biomarkers, including fractional exhaled nitric oxide and periostin, are emerging as potential surrogates. As novel therapies and biologic agents become increasingly available, there is an increased need for specific phenotype-directed treatment strategies. Greater recognition and understanding of the unique immunopathology of this asthma phenotype has important implications for management of the disease and the potential to improve patient outcomes. The present review provides a summary of the clinical features, pathogenesis, diagnosis, and management of eosinophilic asthma

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis

Mechanisms and biomarkers of airway epithelial cell damage in asthma: a review

Bronchial asthma is a heterogeneous disease with complex pathological mechanisms representing different phenotypes, including severe asthma. The airway epithelium is a major site of complex pathological changes in severe asthma due, in part, to activation of inflammatory and immune mechanisms in response to noxious agents. Current imaging procedures are unable to accurately measure epithelial and airway remodeling. Damage of airway epithelial cells occurs is linked to specific phenotypes and endotypes which provides an opportunity for the identification of biomarkers reflecting epithelial, and airway, remodeling. Identification of patients with more severe epithelial disruption using biomarkers may also provide personalized therapeutic opportunities and/or markers of successful therapeutic intervention. Here, we review the evidence for ongoing epithelial cell dysregulation in the pathogenesis of asthma, the sentinel role of the airway epithelium and how understanding these molecular mechanisms provides the basis for the identification of candidate biomarkers for asthma prediction, prevention, diagnosis, treatment and monitoring

Unraveling the Genetic Basis of Asthma and Allergic Diseases

Asthma and allergic diseases are believed to be complex genetic diseases which may result from the interaction of multiple genetic factors and environmental stimuli. In past decades, great efforts have been exerted in unraveling their genetic basis. The strategies in discovering genes and genetic variants, confirming their importance in pathogenesis of asthma and allergic diseases, as well as their strengths and limitations are summarized comprehensively and concisely. The current consensus about the genetic basis of asthma and allergic diseases is briefly described as well

Gene expression evaluation in patients affected by inflammatory diseases of paranasal sinuses. Valutazione dell\u2019espressione genica in pazienti affetti da patologia infiammatoria dei seni paranasali.

Below the clinical observation level of chronic rhinosinusitis (CRS) there are several consistent pathophysiological mechanisms different from each other and important in the presentation of the underlying inflammation: so we could say that there are inflammatory endotypes (ET) of CRS. These ET are subtypes of disease defined functionally and pathologically by a molecular mechanism. Each ET might be identified by specific biomarkers (BM) which originate from the encoding of specific genes. Analysis of gene expression is the first signal of biologic modifications and leads to the identification of Expression BM. In our study we compared the expression of selected genes between healthy patients and patients affected by CRS with nasal polyps without hypereosinophilia and/or other comorbidities. These candidate genes were selected from literature because of their demonstrated hyper/hypo-expression at level of pathological polypoid tissue, sure that replication studies are very important for the progress of science. In our study for the first time in the same population many genes involved in the pathogenesis of the disease were analysed at the same time and we obtained statistically significant result in 5 genes out of 9 analysed; 4 of these corroborate literature results. These 5 genes are the ones towards which future researches could address further efforts. Collaboration between ENT and Biologist is essential both for patients endotyping and in elaborating new treatments. Using well-defined ET in clinical studies might allow to identify patient groups that best benefit from existing as well as new treatments and this could result in personalized multidisciplinary treatments and in a substantial improvement in future patient care

The role of post-transcriptional regulation in chemokine gene expression in inflammation and allergy.

The aim of this review is to discuss recent advances in the understanding of the regulation of chemokine expression occurring during chronic inflammatory conditions, such as allergic diseases. The focus will be on current data, which suggest that post-transcriptional regulation plays a larger role in chemokine gene regulation than previously recognised. In particular, a growing body of data indicates that mechanisms controlling mRNA stability may be relevant in determining, or maintaining, the increased levels of chemokine gene expression in this context. Such regulatory pathways may be important targets of novel anti-inflammatory strategies