Pathogenesis of atopic dermatitis

Atopic dermatitis (AD) is the most common allergic inflammatory skin disease. Interactions of genetic, environmental and immunological factors result in the initiation and progress of AD. Although the clinical picture, characterized by acute flare‐ups of eczematous, pruritic lesions on dry skin at typical predilection such as the flexural folds, is quite homogenous, the trigger factors of the disease are diverse and the pathophysiologic network involved is complex. Therefore, first attempts have been made to classify subtypes of AD based on the most relevant causal factors in the individual patient. To optimize such a stratification of patients, detailed knowledge about cofactors impacting on manifestation of AD as well as impairment of the course of the disease is indispensable. AD shares general features of barrier dysfunction and skin inflammation with other inflammatory diseases of the skin such as psoriasis or allergic contact dermatitis, but a plethora of disease‐specific genetic, immunologic and environmental factors have been identified in AD as well. It is the purpose of this review to illustrate key concepts of the pathogenesis of AD. Important findings of recent years will be summarized and cofactors of the pathogenesis will be controversially discussed. We will summarize knowledge on pathogenic factors on the immunologic level contributing to skin barrier dysfunction in AD and the role of the microbiome as first line of defence. Furthermore, we will elucidate the role of innate lymphoid cells in AD and outline the pattern of T helper cell subtypes present in the skin during different stages of AD.     

Distinct patterns of gene expression in the skin lesions of atopic dermatitis and psoriasis: a gene microarray analysis

BACKGROUND: Atopic dermatitis (AD) and psoriasis are the two most common chronic inflammatory skin diseases. Both of these diseases have distinct clinical findings and specific inflammatory cell infiltrates. Previous reports have focused individually on one or two genes or gene products in the lesions of both skin diseases. However, they have not captured the complex gene expression that must occur to induce specific cellular infiltrates in the skin lesions of these two diseases. DNA microarray studies allow the simultaneous comparison of thousands of messenger RNAs that may identify the disease-specific pattern of tissue inflammatory responses. OBJECTIVE: To compare the complex gene expression pattern of AD versus psoriasis skin lesions. METHODS: RNA was extracted from skin biopsy specimens of 6 patients with AD and 7 patients with psoriasis and analyzed with the use of Hu-U95Av.GeneChip microarrays. To confirm GeneChip results, real-time PCR of selected genes were performed. RESULTS: In AD skin, a total of 18 genes including the CC chemokines, CCL-13/MCP-4, CCL-18/PARC, and CCL-27/CTACK showed a statistically significant, >2-fold increase of gene expression compared with psoriasis. In psoriasis skin, a total of 62 genes including CCL-4/MIP-1beta, CCL-20/MIP-3alpha, CXCL-2/GRO-beta CXCL-8/IL-8, and CXCR2/IL-8R showed a >2-fold increase of gene expression compared with AD skin. Real-time PCR confirmed several of these GeneChip results. CONCLUSIONS: These results show a very distinctive gene expression pattern in AD as compared with psoriasis that may explain several features of AD and psoriasis including the specific inflammatory cell infiltrates observed in these disorders, that is, T(H)2 cells, eosinophils, and mast cells in AD and T(H)1 cells and neutrophils in psoriasis. Such observations may contribute to a characteristic "signature" for these two skin diseases.     

Atopic dermatitis in children and adults

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease characterized by itching and typical clinical features, depending on patient age. It is often associated with other atopic diseases such as asthma or allergic rhinitis, resulting from the complex etiology and pathogenesis. It occurs more frequently in people with genetic predisposition for atopic diseases. The intensity and extent of skin lesions (Scoring of Atopic Dermatitis, SCORAD Index) vary significantly among AD patients, depending on whether it is acute or chronic, and there are variations in laboratory parameters, especially immune. In the future, it will be necessary to reach consensus on the new criteria for defining AD instead of the old ones (brought by Hanifin and Rajka 31 years ago). What is needed is effective and safe treatment, and control of the early stages of AD as well as maintaining AD remission. The new therapeutic approach in AD has greatly improved the quality of life of AD patients. As the prevalence of the disease continues to increase, we emphasize the importance of prevention, prompt recognition and optimal treatment of the many patients with AD.     

Atopic dermatitis: new insights and opportunities for therapeutic intervention

Atopic dermatitis (AD) is a chronic inflammatory skin disease that frequently predates the development of allergic rhinitis or asthma. It is an important skin condition with significant costs and morbidity to patients and their families; the disease affects more than 10% of children. Recent studies have demonstrated the complex interrelationship of genetic, environmental, skin barrier, pharmacologic, psychologic, and immunologic factors that contribute to the development and severity of AD. The current review will examine the cellular and molecular mechanisms that contribute to AD as well as the immunologic triggers involved in its pathogenesis. These insights provide new opportunities for therapeutic intervention in this common skin condition.     

Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease with a strong genetic background. One of the characteristic features of AD and causative factor for the disease is an impaired epidermal skin barrier based on a primary defect of epidermal differentiation. OBJECTIVES: Recently, 2 loss-of-function mutations (R501X and 2282derl4) in the filaggrin gene (FLG) that cause ichthyosis vulgaris, one of the most common inherited skin disorders of keratinization, have been reported to be strong predisposing factors for AD. METHODS: We evaluated the association of the loss-of-function mutations R501X and 2282del4 within the FLG gene in a large collection of 476 well-characterized white German families with AD by using the transmission-disequilibrium test. RESULTS: Our family-based approach revealed prominent associations between the 2 loss-of-function FLG mutations and AD, as previously observed in a traditional Mendelian linkage analysis and case-control cohort analysis approach. In addition, we observed associations of the FLG mutations in particular with the extrinsic subtype of AD, which is characterized by high total serum IgE levels and concomitant allergic sensitizations. Furthermore, FLG mutations are significantly associated with palmar hyperlinearity in patients with AD, which represents a shared feature of AD and ichthyosis vulgaris. CONCLUSION: Together these data implicate that FLG is the first really strong genetic factor identified in a common complex disease. CLINICAL IMPLICATIONS: These findings underline the crucial role of the skin barrier in preventing allergic sensitization.     

Genetic risk factors for the development of allergic disease identified by genome‐wide association

An increasing proportion of the worldwide population is affected by allergic diseases such as allergic rhinitis (AR), atopic dermatitis (AD) and allergic asthma and improved treatment options are needed particularly for severe, refractory disease. Allergic diseases are complex and development involves both environmental and genetic factors. Although the existence of a genetic component for allergy was first described almost 100 years ago, progress in gene identification has been hindered by lack of high throughput technologies to investigate genetic variation in large numbers of subjects. The development of Genome‐Wide Association Studies (GWAS), a hypothesis‐free method of interrogating large numbers of common variants spanning the entire genome in disease and non‐disease subjects has revolutionised our understanding of the genetics of allergic disease. Susceptibility genes for asthma, AR and AD have now been identified with confidence, suggesting there are common and distinct genetic loci associated with these diseases, providing novel insights into potential disease pathways and mechanisms. Genes involved in both adaptive and innate immune mechanisms have been identified, notably including multiple genes involved in epithelial function/secretion, suggesting that the airway epithelium may be particularly important in asthma. Interestingly, concordance/discordance between the genetic factors driving allergic traits such as IgE levels and disease states such as asthma have further supported the accumulating evidence for heterogeneity in these diseases. While GWAS have been useful and continue to identify novel genes for allergic diseases through increased sample sizes and phenotype refinement, future approaches will integrate analyses of rare variants, epigenetic mechanisms and eQTL approaches, leading to greater insight into the genetic basis of these diseases. Gene identification will improve our understanding of disease mechanisms and generate potential therapeutic opportunities.     

The genetics of atopic dermatitis: recent findings and future options

Atopic dermatitis (AD) is a chronic pruritic skin disease affecting up to 15% of children in industrialized countries. AD belongs to the group of allergic disorders that include food allergy, allergic rhinitis, and asthma. A multifactorial background for AD has been suggested, with genetic as well as environmental factors influencing disease development. Genome-wide screens for AD have been completed in four different populations to date. Interestingly, the susceptibility regions identified for AD show little overlap with asthma susceptibility regions, suggesting that, at least in part, separate genes might be involved in the pathogenesis of the different atopic disorders. Instead, some of the identified regions overlap with susceptibility regions for psoriasis, another chronic skin disease. Thus, genes expressed in the skin might play an important role in AD pathogenesis, in addition to genes influencing atopic diatheses. Although no veritable AD gene has been identified by positional cloning to date, examples from other complex genetic disorders such as asthma show that this goal is likely to be reached in the near future. Candidate gene studies, on the other hand, have identified 19 genes that were shown to be associated with AD in at least one study. The results of genome-wide screens as well as candidate gene studies are evaluated here in detail.     

Atopic dermatitis 2.0: from the clinical phenotype to the molecular taxonomy and stratified medicine

Atopic dermatitis (AD) is a paradigmatic inflammatory chronic skin disease. As for other chronic skin diseases, (i) the spectrum of the clinical phenotype and severity as well as (ii) the genetic background and (iii) the underlying mechanisms strongly suggest a high degree of pathophysiological heterogeneity yet leading to a similar clinical pattern, that is, the eczematous skin lesion, but showing distinct progression patterns. This review suggests to exploit the recent knowledge about AD for a novel approach proposing a tentative first molecular taxonomy of this disease based on the genotype and endophenotype. The consequences in terms of personalized prevention and management are delineated.     

Natural History and Risk Factors of Atopic Dermatitis in Children

Atopic dermatitis (AD) is one of the most common inflammatory allergic diseases with pruritic skin lesions particularly in infancy. It is considered to be the first step of atopic march and has variable disease courses. Many children with AD may resolve their AD symptoms with increasing age and may develop respiratory allergies such as asthma and rhinoconjunctivitis at certain ages. Natural course of AD has been supported by many cross-sectional and longitudinal studies in many countries. In general, atopic dermatitis tends to be more severe and persistent in young children, particularly if they have some risk factors including genetic factors. It appears that approximately 40%-70% of childhood AD will get resolved when they reach the age of 6-7 years. However, it is also observed that over half of the children with AD developed respiratory allergy during late childhood.     

Alzheimers disease is not associated with the hypertension genetic risk factors PLA(2) or G protein beta3, either independently or interactively with apolipoprotein E.

Growing evidence suggests that hypertension and Alzheimers disease (AD) may share a common etiology. To evaluate the contribution to AD of genetic factors associated with hypertension, we genotyped clinic and community-based AD cases and controls for polymorphisms within the pancreatic PLA(2) gene and the G protein beta3 subunit gene, both of which are located on chromosome 12. Our results do not support an independent association between either of these genes and AD. We further assessed the possibility that either of these genes may interact with the apolipoprotein E gene, a known risk factor for hypertension and AD, on predicting AD. We were unable to find statistical interaction between either the pancreatic PLA(2) or Gbeta3 genes and the apolipoprotein E gene on risk for AD. These results do not support a shared genetic etiology between hypertension and AD. Possibly, a clinical association between these diseases could be due to pathophysiologic interactions.     

Association of cyclin-dependent kinase 5 and neuronal activators p35 and p39 complex in early-onset Alzheimer's disease

Malfunctioning of cyclin-dependent kinase 5 (CDK5) through aberrant proteolytic cleavage of its neuronal activators p35 and p39 is involved in neurodegeneration in Alzheimer's disease (AD) and other neurodegenerative brain diseases. By extensive genetic analysis of the genes encoding CDK5 (CDK5), p35 (CDK5R1) and p39 (CDK5R2), we excluded causal mutations in 70 familial early-onset AD patients. We performed an association study with five informative SNPs in CDK5 in two independent samples of early-onset AD patients and matched control individuals from The Netherlands and northern Sweden. Association was observed with g.149800G>C in intron 5 of CDK5, and a two times increased risk was observed in both patient samples for carriers of the C-allele. Our data are indicative for a role of the CDK5 molecular complex in the genetic etiology of early-onset AD, and suggest that a yet unknown functional variant in CDK5 or in a nearby gene might lead to increased susceptibility for early-onset AD.     

Innate Immunity in Atopic Dermatitis

Atopic dermatitis (AD) is a clinically defined, highly pruritic, chronic inflammatory skin disease. In AD patients, the combination of a genetic predisposition for skin barrier dysfunction and dysfunctional innate and adaptive immune responses leads to a higher frequency of bacterial and viral skin infections. The innate immune system quickly mobilizes an unspecific, standardized first-line defense against different pathogens. Defects in this system lead to barrier dysfunction which results in increased protein allergen penetration through the epidermis and predisposes to secondary skin infections. Two loss-of-function mutations in the epidermal filaggrin gene are associated with AD. Also, inducible endogenous antibiotics such as the antimicrobial peptides cathelicidin and the beta-defensins may show defective function in lesional AD skin. Eczema herpeticum is a disseminated viral infection almost exclusively diagnosed in AD patients, which is based on unmasking of the viral entry receptor nectin-1, lack of cathelicidin production by keratinocytes, and depletion of Type I IFN-producing plasmacytoid dendritic cells from AD skin. Future therapeutic approaches to AD may include enhancement of impaired innate in addition to downregulation of dysfunctional adaptive immunity.     

Association between polymorphisms in the SPINK5 gene and atopic dermatitis in the Japanese

Atopy, which is characterized by increased levels of immunoglobulin E (IgE) against common environmental allergens, is considered the strongest predisposing factor for asthma and atopic dermatitis (AD). Mutations in the gene encoding serine protease inhibitor Kazal-type 5 (SPINK5) are responsible for Netherton syndrome, a rare skin disorder characterized by greatly elevated IgE levels with atopic manifestations. A recent study of Caucasian AD families showed that maternally derived alleles of the SPINK5 gene are associated with development of AD and asthma, suggesting the parent-of-origin effect for the development of atopic diseases in the SPINK5 gene. We studied the possible association of the SPINK5 gene for the development of atopic diseases by determining the genotypes of five polymorphisms in a Japanese population. Ttransmission disequilibrium tests revealed an association of SPINK5 polymorphisms with AD but not with asthma. Our data indicate that the SPINK5 gene is associated with AD across ethnicities.     

Gene diagnosis of Alzheimer's disease and Parkinson's disease

Alzheimer's disease(AD) is the most common form of neurodegenerative diseases that causes intellectual dysfunction. AD is a genetically heterogenous disorder. Over 100 mutations have been identified in three causative genes, i.e. amyloid protein precursor(APP), presenilin 1(PS1) and presenilin 2(PS2) genes, for early-onset autosomal dominant familial AD(FAD). Apolipoprotein E(APOE) gene has been identified as susceptibility gene for late-onset FAD. The missense mutations in the causative genes lead to abnormal APP processing with overproduction of total A beta protein or A beta 42(43) isoform. The epsilon 4 allele of APOE gene is a genetic risk factor for sporadic AD as well as FAD. Parkinson's disease(PD) is another common form of neurodegenerative disease that causes movement dysfunction. Three genes, i.e. alpha-synuclein (SNCA), parkin(PARK2), and ubiquitin carboxy-terminal hydrolase L1(UCHL1) genes, have been identified as causative genes for familial PD. The B mutation of CYP2D6 gene(CYP2D6*4 allele) is a genetic risk factor for PD. Lewy body(LB), that is an intracellular inclusion body characteristic of PD, is widely distributed in the cerebral cortex of 20 to 30% of AD patients. This disease entity is called as Lewy body variant(LBV) of AD. LBV shares the genetic risk factor with AD and PD, i.e. APOE epsilon 4 allele and CYP2D6 B mutation. Gene diagnosis is possible for familial AD and PD. APOE and CYP2D6 genotyping is also applicable to the future prediction of AD and PD, respectively.     

Genetic basis for Alzheimer's disease and other dementias and prospects of molecular diagnosis

Dementias are diseases of progressive memory loss and intellectual impairment in adults. Alzheimer's disease (AD) amounts to 50-80% of all forms of dementias in middle-aged and elderly individuals. AD includes several clinical and genetic subtypes characterized by the common pattern of specific cerebral hallmarks. Aging and genetic factors are the most important risk factors predisposing to AD. Three gene-bearing mutations for AD have been identified. These included presenilin 1, presenilin 2, and amyloid precursor protein (APP). In addition, the polymorphic isoform of apolyprotein E e4 gene has been found to be a genetic risk factor for some forms of familial and sporadic AD. Other genes for AD are to be identified. The genetic loci or mutations in genes leading to several other neurodegenerative diseases and dementia have been also discovered. These genetic achievements contribute to the development of markers for the presymptomatic diagnosis of dementias and the development of transgenic models in vitro and in vivo for rational therapy of these dramatic diseases.     

Eczema herpeticum in atopic dermatitis

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases leading to pruritic skin lesions. A subset of AD patients exhibits a disseminated severe HSV infection called eczema herpeticum (EH) that can cause life-threatening complications. This review gives an overview of the clinical picture, and characteristics of the patients as well as the diagnosis and therapy of EH. A special focus lies on the pathophysiological hallmarks identified so far that predispose for EH. This aspect covers genetic aberrations, immunological changes, and environmental influences displaying a complex multifactorial situation, which is not completely understood. Type 2 skewing of virus-specific T cells in ADEH⁺ patients has been implicated in immune profile abnormalities, along with impaired functions of dendritic cells and natural killer cells. Furthermore, aberrations in interferon pathway-related genes such as IFNG and IFNGR1 have been identified to increase the risk of EH. IL-4, IL-25, and thymic stromal lymphopoietin (TSLP) are overexpressed in EH, whereas antimicrobial peptides like human β-defensins and LL-37 are reduced. Concerning the epidermal barrier, single nucleotide polymorphisms (SNPs) in skin barrier proteins such as filaggrin were identified in ADEH⁺ patients. A dysbalance of the skin microbiome also contributes to EH due to an increase of Staphylococcus aureus, which provides a supporting role to the viral infection via secreted toxins such as α-toxin. The risk of EH is reduced in AD patients treated with dupilumab. Further research is needed to identify and specifically target risk factors for EH in AD patients.     

The role of filaggrin in the atopic diathesis

Atopic dermatitis (AD) is an inflammatory disease characterized by pruritic skin lesions, immunodysregulation, disrupted epidermal barrier function and IgE‐mediated sensitization to food and environmental allergens. Identification of the aetiology of AD has become increasingly a priority, as it is clear that the disease burden exceeds AD alone, with many children suffering severe, multi‐system and occasionally life‐threatening allergic disease. Previous approaches to understanding AD have centred on mechanisms in the adaptive immune system, often with an emphasis on the Th1–Th2 paradigm. Recently, the conceptual focus has increasingly shifted to include a primary defect in the epithelial barrier as a threshold event in moderate‐to‐severe AD. Familial aggregation of the disease is well established through many family studies of AD, asthma and allergic rhinitis, suggesting a significant heritable component. The identification of loss‐of‐function mutations in the filaggrin (FLG) gene, whose product is a key structural protein in the outermost layer of the epidermis in up to 50% of patients with AD, provides a significant insight into explaining disease initiation and points to a complex secondary interplay of environmental and immunological sequelae once barrier disruption is established. The elucidation of the environmental, genetic and immunobiological modifiers of this structural molecule may also direct our understanding of the pathomechanisms and endotypes central to the atopic diathesis. The recent identification of a murine model for FLG‐AD, with the detection of a homozygous frame‐shift mutation in the Flg gene in flaky‐tail (ft/ft) mice, stands to rapidly accelerate our understanding of mechanisms and therapeutic intervention points in AD. Refining the molecular understanding of AD and its subtypes will allow for specific diagnostic, treatment and ultimately, preventative algorithms, and has opened an exciting new world of investigative challenges and collaborations. Cite this as: G. M. O'Regan and A. D. Irvine, Clinical & Experimental Allergy, 2010 (40) 965–972.     

The interplay between genetic and environmental factors in the pathogenesis of atopic dermatitis

Atopic dermatitis (AD) is a chronic skin disorder characterized by pruritus and recurrent eczematous lesions that are accompanied by T-helper (Th)2-dominated inflammation. AD Etiology is not yet completely understood, but it is multifactorial. Moreover, the disease is characterized by complex interactions between genetic and environmental factors, such as skin barrier dysfunctions, allergy/immunity, and pruritus. For example, filaggrin is a key protein involved in skin barrier function. Th2 cells produce interleukin (IL)-31, which provokes pruritus, and other Th2 cytokines decrease filaggrin expression by keratinocytes. Dupilumab has recently been developed for AD treatment; its mechanism of action is to bind to IL-4 receptor α and inhibit downstream signaling induced by IL-4 and IL-13. This review summarizes the etiopathogenesis of AD and provides the rationale for selecting a novel targeted therapy.