New Insights into Atopic Dermatitis: Role of Skin Barrier and Immune Dysregulation

Atopic dermatitis (AD) is a chronic inflammatory skin disease that is often associated with the development of food allergy and asthma. New insights into AD reveals an important role for structural abnormalities in the epidermis resulting in a leaky epithelial barrier as well as chronic immune activation that contribute to the pathophysiology of this common skin disease. Patients with AD have a predisposition to colonization or infection by microbial organisms, most notably Staphylococcus aureus and herpes simplex virus (HSV). Measures directed at healing and protecting the skin barrier and controlling the immune activation are needed for effective management of AD. Early intervention may improve outcomes for AD as well as reduce the systemic allergen sensitization that may lead to associated allergic diseases in other organs.     

Subtypes of atopic dermatitis: From phenotype to endotype

Atopic dermatitis (AD) is a heterogenous disorder and can be classified into different types. Stratification of subtypes may enable personalized medicine approaches. AD can be categorized into the IgE-high, extrinsic subtype and the IgE-normal, intrinsic subtype. While extrinsic AD is the major subtype possessing skin barrier impairment (high incidence of filaggrin mutations), intrinsic AD occupies about 20% of AD with female dominance and preserved barrier. Extrinsic AD exhibits protein allergy and food allergy, but intrinsic AD shows metal allergy possibly in association with suprabasin deficiency. In particular, accumulated knowledge of food allergy has more clearly characterized extrinsic AD. European American (EA) and Asian AD subtypes have been also proposed. Asian patients with AD are characterized by a unique blended immune dysregulation and barrier feature phenotype between EA patients with AD and those with psoriasis. In another ethnic study, filaggrin loss-of-function mutations are not prevalent in African American patients with AD, and Th1/Th17 attenuation and Th2/Th22 skewing were seen in these patients. Recent endotype classification provides new insights for AD and other allergic disorders. Endotype is defined as the molecular mechanisms underlying the visible features/phenotype. Endotype repertoire harbors activation of type 2 cytokines, type 1 cytokines, and IL-17/IL-22, impairment of epidermal barrier, and abnormalities of intercellular lipids. Classification of endotype has been attempted with serum markers. These lines of evidence indicate a need for personalized or precision medicine appropriate for each subtype of AD.     

Circulating, imaging, and genetic biomarkers in cardiovascular risk prediction

In the primary prevention of cardiovascular disease, the study of biomarkers to identify at-risk individuals is an expanding field. Several developments have fueled this trend, including improved understanding of the pathophysiological processes underlying atherosclerosis, advances in imaging technology to enable the quantification of subclinical disease burden, and the identification of new genetic susceptibility variants for cardiovascular disease. Furthermore, the advent of high-throughput platforms for molecular profiling has increased the pace of biomarker discovery. The rising interest in biomarkers has been balanced by the recognition that standardized and rigorous statistical approaches are needed to evaluate the clinical utility of candidate risk markers. This article reviews the issues surrounding the evaluation of biomarkers, evidence from studies of existing biomarkers, and recent applications of biomarker discovery platforms.     

Strategies for primary prevention of atopy in children

In recent decades, the prevalence of atopic diseases such as asthma, hayfever, food allergy, and atopic dermatitis has been steadily increasing. Unfortunately, more advances have been made in secondary prevention of symptoms and exacerbations than in primary prevention. One barrier to adopting prevention strategies is uncertainty regarding the cause of atopy. A genetic predisposition has been well documented. However, other factors, including diet, environment, infections, medications, and gastrointestinal flora, all play a role in the development of atopic disease. Modifying these factors holds promise for stopping the atopic march in the future. This paper reviews advances that have been made in the primary prevention of atopic disease.     

Utilizing state‐of‐the‐art “omics” technology and bioinformatics to identify new biological mechanisms and biomarkers for coronary artery disease

Identification of the four standard modifiable cardiovascular risk factors (SMuRFs)—diabetes mellitus, hyperlipidaemia, hypertension, and cigarette smoking—has allowed the development of risk scores. These have been used in conjunction with primary and secondary prevention strategies targeting SMuRFs to reduce the burden of CAD. Recent studies show that up to 25% of ACS patients do not have any SMuRFs. Thus, SMuRFs do not explain the entire burden of CAD. There appears to be variation at the individual level rendering some individuals relatively susceptible or resilient to developing atherosclerosis. Important disease pathways remain to be discovered, and there is renewed enthusiasm to discover novel biomarkers, biological mechanisms, and therapeutic targets for atherosclerosis. Two broad approaches are being taken: traditional approaches investigating known candidate pathways and unbiased omics approaches. We review recent progress in the field and discuss opportunities made possible by technological and data science advances. Developments in network analytics and machine learning algorithms used in conjunction with large‐scale multi‐omic platforms have the potential to uncover biological networks that may not have been identifiable using traditional approaches. These approaches are useful for both biomedical research and precision medicine strategies.     

Poussées de dermatite atopique : définitions et causes

Atopic dermatitis (AD) is by definition a chronic pruritic skin disease characterised by a history of flares and remissions. Genetic studies have recently demonstrated a link of causality between an impaired permeability barrier defect and both AD and mucosal allergic disorders, putting the skin stratum corneum at the centre of the pathophysiology of these disorders. The respective importance of flare factors is difficult to sort out in published papers. Some of them, such as temperature, irritants and aeroallergens have a demonstrated impact on the permeability barrier anomaly, based on epidemiological or experimental evidence. However, a better methodology and terminology are needed to identify the most significant flare factors and promote an efficient prevention.     

The genetics of congenital heart disease: a point in the revolution

Extraordinary diagnostic precision and definitive therapies characterize the current management of congenital heart disease, but the state of the art is not perfect; and in spite of tremendous progress in diagnosis and treatment, our understanding of cause is rudimentary. During the past decade, advances in molecular genetics have defined disease gene loci and lead to identification of genes whose mutations cause congenital heart disease. Identification of additional genes and mutations will lead to improved understanding of pathophysiology of cardiovascular disease in the young. Better understanding of pathophysiology and identification of individuals at risk will provide an opportunity to develop preventive strategies. Taken as a whole, the prospect of understanding the genetic basis of congenital heart disease and translating it into improved diagnostic and therapeutic strategies has never been better.     

Biomarkers in Food Allergy

Purpose of Review

To familiarize the reader with the concept of precision medicine in food allergy by dealing with the current biomarkers for the diagnosis, prognosis, and management of the disease.

Recent Findings

Many efforts have been devoted in order to characterize reliable biomarkers able to identify specific phenotypes and endotypes in food allergy. Specific IgE (sIgE), sIgE/total IgE ratios, and T cell assays are just a few candidates that have been investigated over time. With the advent of omics sciences, a new era is commencing. A better understanding of pathogenesis of food allergy and mechanisms of action of the different therapeutic options will allow the accurate selection of the appropriate patient.

Summary

In the near future, advances in technologies and data interpretation will allow a better understanding of the pathogenesis of food allergy and the identification of proper biomarkers for a personalized treatment tailored on the specific patient’s profile.

     

The role of food allergy in atopic dermatitis

Atopic dermatitis (AD) is a chronic, pruritic, inflammatory skin disease affecting more than 10% of all children. Sensitization to foods triggers isolated skin symptoms in about 30% of children. These symptoms include immediate reactions within minutes after ingesting food without exacerbation of AD and early and late exacerbations of AD. It is important to identify clinically relevant sensitizations to foods using skin prick tests, a specific IgE blood test (ImmunoCAP; Phadia, Portage, MI, USA), and double-blind, placebo-controlled food challenges to initiate appropriate dietary interventions and avoid unnecessary dietary restrictions. Children with AD triggered by food allergens demonstrate a distinct immune response upon stimulation of their peripheral blood mononuclear cells with food allergen. A defective skin barrier and increased intestinal permeability appear to facilitate allergen sensitization. Appropriate skin care to maintain skin barrier function and dietary avoidance of highly allergenic foods during infancy may help to prevent allergen sensitization, thereby reducing the severity of AD and food allergies.     

Cell therapies and regenerative medicine

Molecular and cell biology has resulted in major advances in our understanding of disease pathogenesis as well as in novel strategies for the diagnosis, therapy and prevention of human diseases. Based on modern molecular, genetic and biochemical methodologies, it is on the one hand possible to identify disease-related point mutations and single nucleotide polymorphisms, for example. On the other hand, using high throughput array and other technologies, it is for example possible to simultaneously analyze thousands of genes or gene products (RNA and proteins), resulting in an individual gene or gene expression profile (‘signature’). Such data increasingly allow defining the individual disposition for a given disease and predicting disease prognosis as well as the efficacy of therapeutic strategies in the individual patient (‘personalized medicine’). At the same time, the basic discoveries in cell biology, including embryonic and adult stem cells, induced pluripotent stem cells, genetically modified cells and others, have moved regenerative medicine into the center of biomedical research worldwide with a major translational impact on tissue engineering as well as transplantation medicine. All these aspects have greatly contributed to the recent advances in regenerative medicine and the development of novel concepts for the treatment of many human diseases, including liver diseases.     

Primer: genomic and proteomic tools for the molecular dissection of disease

Completion of the Human Genome Project has been rapidly followed by the emergence of high-throughput technologies that combine automation, miniaturization, and many other strategies and tools to enable systematic surveys of genome composition and gene expression. Of particular relevance to the prevention and management of disease are technologies such as high-throughput DNA genotyping, microarray-based gene-expression profiling, and mass spectrometry-facilitated protein profiling--platforms that collectively support the comprehensive analysis of DNA sequence variants across the genome and the global gene and protein expression changes that distinguish health from disease. Now used extensively in all facets of biomedical investigation, genomic and proteomic tools are already beginning to pinpoint molecular variants that influence risk and outcome in common diseases, and to thereby inform and direct development of novel molecular biomarkers and drug targets. As evidenced by recent advances in DNA sequencing methods, continued improvements in the scope, power, and cost efficiency of genomic and proteomic technologies should ensure their capacity to provide the scale and depth of knowledge required for translating genome sequence information into major medical impact.     

Dissecting the causes of atopic dermatitis in children: less foods, more mites

Atopic dermatitis (AD) is a common, chronic or chronically relapsing, multifactorial skin disease that mainly occurs in children but affects also adults. AD usually begins early in life and often concerns people with a personal or family history of asthma and allergic rhinitis. AD is characterized by eczematous changes in the epidermis and originates from a late, T-cell mediated reaction associated to the formation and production of memory T-cell of TH2 type, occurrence of homing receptor at skin level and cutaneous lymphocyte-associated (CLA) antigens. Extrinsic or allergic AD, but not intrinsic AD, shows high total serum IgE levels and the presence of specific IgE for environmental and food allergens. A pivotal role in the pathogenesis of AD is played by filaggrin, a protein contained in the granular layer of the epidermis regulating the aggregation of keratin filaments. Mutation in the filaggrin gene causes decreased barrier function of the corny layers of the epidermis. This favours the enter through the skin of environmental allergens, especially the house dust mite, that further facilitates such entering by the proteolytic activity of its major allergen Der p 1. In fact, recent advances suggest that the dust mite, more than foods, is the major cause of allergic AD. As far as the causal diagnosis of AD is concerned, there is notable evidence supporting the capacity of the atopy patch test (APT) to reproduce the pathophysiologic events of AD. This makes APT a valuable diagnostic tool for AD.     

Precision medicine in diabetes prevention,classification and management

Diabetes has become a major burden of healthcare expenditure. Diabetes management following a uniform treatment algorithm is often associated with progressive treatment failure and development of diabetic complications. Recent advances in our understanding of the genomic architecture of diabetes and its complications have provided the framework for development of precision medicine to personalize diabetes prevention and management. In the present review, we summarized recent advances in the understanding of the genetic basis of diabetes and its complications. From a clinician's perspective, we attempted to provide a balanced perspective on the utility of genomic medicine in the field of diabetes. Using genetic information to guide management of monogenic forms of diabetes represents the best‐known examples of genomic medicine for diabetes. Although major strides have been made in genetic research for diabetes, its complications and pharmacogenetics, ongoing efforts are required to translate these findings into practice by incorporating genetic information into a risk prediction model for prioritization of treatment strategies, as well as using multi‐omic analyses to discover novel drug targets with companion diagnostics. Further research is also required to ensure the appropriate use of this information to empower individuals and healthcare professionals to make personalized decisions for achieving the optimal outcome.     

Predictive proteomic biomarkers for inflammatory bowel disease-associated cancer: Where are we now in the era of the next generation proteomics?

Recent advances in genomic medicine have opened up the possibility of tailored medicine that may eventually replace traditional "one-size-fits all" approaches to the treatment of inflammatory bowel disease(IBD). In addition to exploring the interactions between hosts and microbes, referred to as the microbiome, a variety of strategies that can be tailored to an individual in the coming era of personalized medicine in the treatment of IBD are being investigated. These include prompt genomic screening of patients at risk of developing IBD, the utility of molecular discrimination of IBD subtypesamong patients diagnosed with IBD, and the discovery of proteome biomarkers to diagnose or predict cancer risks. Host genetic factors influence the etiology of IBD, as do microbial ecosystems in the human bowel, which are not uniform, but instead represent many different microhabitats that can be influenced by diet and might affect processes essential to bowel metabolism. Further advances in basic research regarding intestinal inflammation may reveal new insights into the role of inflammatory mediators, referred to as the inflammasome, and the macromolecular complex of metabolites formed by intestinal bacteria. Collectively, knowledge of the inflammasome and metagenomics will lead to the development of biomarkers for IBD that target specific pathogenic mechanisms involved in the spontaneous progress of IBD. In this review article, our recent results regarding the discovery of potential proteomic biomarkers using a label-free quantification technique are introduced and on-going projects contributing to either the discrimination of IBD subtypes or to the prediction of cancer risks are accompanied by updated information from IBD biomarker research.     

Transitioning from cerebrospinal fluid to blood tests to facilitate diagnosis and disease monitoring in Alzheimer's disease

Alzheimer’s disease (AD) is increasingly prevalent worldwide, and disease-modifying treatments may soon be at hand; hence, now, more than ever, there is a need to develop techniques that allow earlier and more secure diagnosis. Current biomarker-based guidelines for AD diagnosis, which have replaced the historical symptom-based guidelines, rely heavily on neuroimaging and cerebrospinal fluid (CSF) sampling. While these have greatly improved the diagnostic accuracy of AD pathophysiology, they are less practical for application in primary care, population-based and epidemiological settings, or where resources are limited. In contrast, blood is a more accessible and cost-effective source of biomarkers in AD. In this review paper, using the recently proposed amyloid, tau and neurodegeneration [AT(N)] criteria as a framework towards a biological definition of AD, we discuss recent advances in biofluid-based biomarkers, with a particular emphasis on those with potential to be translated into blood-based biomarkers. We provide an overview of the research conducted both in CSF and in blood to draw conclusions on biomarkers that show promise. Given the evidence collated in this review, plasma neurofilament light chain (N) and phosphorylated tau (p-tau; T) show particular potential for translation into clinical practice. However, p-tau requires more comparisons to be conducted between its various epitopes before conclusions can be made as to which one most robustly differentiates AD from non-AD dementias. Plasma amyloid beta (A) would prove invaluable as an early screening modality, but it requires very precise tests and robust pre-analytical protocols.     

The Indian Consensus Document on cardiac biomarker

Despite recent advances, the diagnosis and management of heart failure evades the clinicians. The etiology of congestive heart failure (CHF) in the Indian scenario comprises of coronary artery disease, diabetes mellitus and hypertension. With better insights into the pathophysiology of CHF, biomarkers have evolved rapidly and received diagnostic and prognostic value. In CHF biomarkers prove as measures of the extent of pathophysiological derangement; examples include biomarkers of myocyte necrosis, myocardial remodeling, neurohormonal activation, etc. In CHF biomarkers act as indicators for the presence, degree of severity and prognosis of the disease, they may be employed in combination with the present conventional clinical assessments. These make the biomarkers feasible options against the present expensive measurements and may provide clinical benefits.     

Amyloid β and APP as biomarkers for Alzheimer’s disease

Intense research during the past decade has aimed at dissecting the molecular pathogenesis of Alzheimer’s disease (AD). Primarily, the focus has been directed towards brain amyloid pathology and its relation to synaptic and neuronal loss. Clearly, AD is associated with accumulation of amyloid β (Aβ) in the brain. Further, the results of many experimental studies suggest that certain forms of Aβ may act as initiators in the disease process with potent toxic effects at the synaptic level. Molecular aberrations in the AD brain are reflected in the cerebrospinal fluid (CSF). Core CSF biomarkers include secreted Aβ and amyloid precursor protein (APP) isoforms, Aβ oligomers and β-site APP-cleaving enzyme 1 (BACE1). This article reviews recent research advances on CSF and plasma Aβ-related biomarkers for AD and how they may reflect pathogenic changes in AD-affected neuronal networks. We also consider their usefulness in clinical practice and in clinical trials.     

Alzheimer's disease, cerebrovascular dysfunction and the benefits of exercise: from vessels to neurons

Exercise training promotes extensive cardiovascular changes and adaptive mechanisms in both the peripheral and cerebral vasculature, such as improved organ blood flow, induction of antioxidant pathways, and enhanced angiogenesis and vascular regeneration. Clinical studies have demonstrated a reduction of morbidity and mortality from cardiovascular disease among exercising individuals. However, evidence from recent large clinical trials also suggests a substantial reduction of dementia risk - particularly regarding Alzheimer's disease (AD) - with regular exercise. Enhanced neurogenesis and improved synaptic plasticity have been implicated in this beneficial effect. However, recent research has revealed that vascular and specifically endothelial dysfunction is essentially involved in the disease process and profoundly aggravates underlying neurodegeneration. Moreover, vascular risk factors (VRFs) are probably determinants of incidence and course of AD. In this review, we emphasize the interconnection between AD and VRFs and the impact of cerebrovascular and endothelial dysfunction on AD pathophysiology. Furthermore, we describe the molecular mechanisms of the beneficial effects of exercise on the vasculature such as activation of the vascular nitric oxide (NO)/endothelial NO synthase (eNOS) pathway, upregulation of antioxidant enzymes, and angiogenesis. Finally, recent prospective clinical studies dealing with the effect of exercise on the risk of incident AD are briefly reviewed. We conclude that, next to upholding neuronal plasticity, regular exercise may counteract AD pathophysiology by building a vascular reserve.     

Pathogenesis of atopic dermatitis: New developments

Atopic dermatitis (AD) is a paradigmatic skin disease in which multiple gene-gene and gene-environment interactions play a pivotal role. Although the complex pathophysiologic network of AD explains the large spectrum of risk and trigger factors, it is far from being comprehensively understood. Hence, genetic modifications underlying the dysfunction of the epidermal skin barrier as well as the close interaction of innate and adaptive immune mechanisms were the focus of intensive research studies. This review aims to summarize the most recent findings in this field.