Proceedings of the 4th Georg Rajka International Symposium on Atopic Dermatitis, Arcachon, France, September 15-17, 2005

The 4th Georg Rajka International Symposium on Atopic Dermatitis presented a comprehensive view of our current understanding and management of atopic dermatitis (AD). These proceedings highlight contributions related to the history of AD doctrines; genetic and epigenetic background; epidemiology; maturation of the immune system; infection and innate-adaptive immunity; epidermal inflammation, including neurogenic inflammation and pruritus; animal models; skin barrier; evidence-based therapy and education programs; prognostic and severity markers; and allergy testing. Several studies in animal models and human subjects point to impaired skin barrier function as a primary defect that facilitates the effect of environmental factors and immune dysregulation found in AD. The new frontier in AD therapy should, in the near future, reflect our better understanding of the skin barrier. The influence of environmental factors on the skin and other epithelial barriers in the perinatal period needs to be better understood to implement appropriate prevention programs.     

The mechanism of atopic march may be the 'social' event of cells and molecules (Review)

The skin, the conjunctivae, the airways and the digestive tract compose a huge vulnerable biological surface, which is exposed to the external environment. An allergen can often trigger an allergic reaction at a number of sites or result in an atopic march. However, the mechanism of atopic march remains unclear. Less attention has been paid to the connection between the primary site and the atopic site, because current knowledge is established directly against harmful factors. Allergic hypersensitivity manifests in parts of the human body far away from the allergen. Growing evidence suggests that the epithelial cells serve as the 'engine' which initiates an allergic reaction through the production of large quantities of cytokines, chemokines and growth factors. Because the epithelial cells cover the entire surface of the skin, the conjunctivae, the airways, and the digestive tract, and are positioned at the terminals of neurons and the blood supply, the connection between the primary site and the atopic site can not be easily understood by the current knowledge of anatomy and of the neuroendocrine immune network. What is the linkage between these huge vulnerable biologic surfaces? This article highlights selected frontiers in allergy research of atopic march, and focuses on recently attained insights into the cellular and molecular events of primary and atopic lesions in the allergy progress. Special attention is paid to the homogeneity of the cellular and molecular events on the huge vulnerable surface. Based on currently available data we conclude that the skin, conjunctivae, airways and digestive tract may join together to form the frontier 'commonwealth union' in order to fight the allergen. The epithelial cells are the 'engine' as well as the main target which initiates both primary and atopic inflammatory reactions. The atopic lesion may 'duplicate' the primary contacted site of cellular and molecular events. The atopic march may be due to the intrinsic 'social' involvements of the positioned epithelial cells, but may not be totally controlled by the anatomic connection or the circulating systemic factors involved in allergy pathogenesis.     

Vulvar Paget disease of urothelial origin: a report of three cases and a proposed classification of vulvar Paget disease

Extramammary Paget disease is generally considered a distinct entity that can involve the genital tract skin and may be associated with underlying adenocarcinoma. Evidence is presented that vulvar Paget disease represents a heterogeneous group of epithelial neoplasms that can be similar both clinically and histopathologically. Three cases of vulvar Paget-like disease that were manifestations of urothelial carcinoma are investigated. Vulvar Paget disease can be classified based on the origin of the neoplastic Paget cells as either primary (of cutaneous origin) or secondary (of noncutaneous origin). Each classification has 3 subtypes: primary, intraepithelial cutaneous Paget disease of the usual type; intraepithelial cutaneous Paget disease with invasion, and intraepithelial cutaneous Paget disease as a manifestation of underlying skin appendage adenocarcinoma; secondary, Paget disease of anorectal origin, Paget disease of urothelial origin, and Paget disease of other origin. This subclassification is based on a review of the literature and the current study of 3 patients with Paget-like disease of urothelial neoplastic origin. The 3 subtypes of vulvar Paget disease studied here can present similarly as eczematoid skin or vulvar mucosal lesions and may appear similar on routine hematoxylin and eosin-stained slides. Immunohistochemical studies can be used to help differentiate them. The distinction between these 3 types of Paget-like lesions is essential in that the specific diagnosis has a significant influence on current treatment. The difference in surgical approach to the subtypes of vulvar Paget disease justifies classifying them into distinct lesions to avoid potential confusion and unnecessary surgery.     

Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2007

This review highlights some of the research advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects that were reported primarily in the Journal in 2007. Advances in diagnosis include possible biomarkers for anaphylaxis, improved understanding of the relevance of food-specific serum IgE tests, identification of possibly discriminatory T-cell responses for drug allergy, and an elucidation of irritant responses for vaccine allergy diagnostic skin tests. Mechanistic studies are discerning T-cell and cytokine responses central to eosinophilic gastroenteropathies and food allergy, including the identification of multiple potential therapeutic targets. Regarding treatment, clinical studies of oral immunotherapy and allergen vaccination strategies show promise, whereas several clinical studies raise questions about whether oral allergen avoidance reduces atopic risks and whether probiotics can prevent or treat atopic disease. The importance of skin barrier dysfunction has been highlighted in the pathogenesis of atopic dermatitis (AD), particularly as it relates to allergen sensitization and eczema severity. Research has also continued to identify immunologic defects that contribute to the propensity of patients with AD to have viral and bacterial infections. New therapeutic approaches to AD, urticaria, and angioedema have been reported, including use of sublingual immunotherapy, anti-IgE, and a kallikrein inhibitor.     

The atopic march: current insights into skin barrier dysfunction and epithelial cell-derived cytokines

Atopic dermatitis often precedes the development of other atopic diseases. The atopic march describes this temporal relationship in the natural history of atopic diseases. Although the pathophysiological mechanisms that underlie this relationship are poorly understood, epidemiological and genetic data have suggested that the skin might be an important route of sensitization to allergens. Animal models have begun to elucidate how skin barrier defects can lead to systemic allergen sensitization. Emerging data now suggest that epithelial cell-derived cytokines such as thymic stromal lymphopoietin (TSLP), IL-33, and IL-25 may drive the progression from atopic dermatitis to asthma and food allergy. This review focuses on current concepts of the role of skin barrier defects and epithelial cell-derived cytokines in the initiation and maintenance of allergic inflammation and the atopic march.     

The genetics of asthma and allergic disease: a 21st century perspective

Asthma and allergy are common conditions with complex etiologies involving both genetic and environmental contributions. Recent genome-wide association studies (GWAS) and meta-analyses of GWAS have begun to shed light on both common and distinct pathways that contribute to asthma and allergic diseases. Associations with variation in genes encoding the epithelial cell-derived cytokines, interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP), and the IL1RL1 gene encoding the IL-33 receptor, ST2, highlight the central roles for innate immune response pathways that promote the activation and differentiation of T-helper 2 cells in the pathogenesis of both asthma and allergic diseases. In contrast, variation at the 17q21 asthma locus, encoding the ORMDL3 and GSDML genes, is specifically associated with risk for childhood onset asthma. These and other genetic findings are providing a list of well-validated asthma and allergy susceptibility genes that are expanding our understanding of the common and unique biological pathways that are dysregulated in these related conditions. Ongoing studies will continue to broaden our understanding of asthma and allergy and unravel the mechanisms for the development of these complex traits.     

The role of atopy patch tests in the diagnosis of allergy in atopic dermatitis

PURPOSE OF REVIEW: Recent literature on the atopy patch test, published since 2004, is reviewed to evaluate whether the pathomechanism of the test has become more evident and whether previous studies require standardization. RECENT FINDINGS: There is evidence accumulating that a smaller subset of patients with atopic dermatitis show only atopy patch test positivity while specific IgE to the same allergen remains negative. It is possible that local IgE-mediated reactions occur in the skin. New data bring us a step forward in understanding the role of the atopy patch test in diagnosis of allergy in atopic dermatitis but no comprehensive studies were published during the period reviewed. SUMMARY: Despite recent advances in determining the value and indication for use of the atopy patch test in atopic dermatitis, more objective studies are needed. The atopy patch test may be useful in understanding the mechanisms of atopic allergy, and in defining the clinical relevance of the airborne allergens in eliciting dermatitis. Regarding food allergy, the atopy patch test still requires standardization. To date, methodology differs in all published papers; even the gold standard, the challenge test itself, is not appropriately standardized, which makes the interpretation of results less reliable.     

The epithelial barrier and immunoglobulin A system in allergy

Airway and intestinal epithelial layers represent first‐line physical barriers, playing a key role in mucosal immunity. Barrier dysfunction, characterized by alterations such as disruption of cell–cell apical junctions and aberrant epithelial responses, probably constitutes early and key events for chronic immune responses to environmental antigens in the skin and in the gut. For instance, barrier dysfunction drives Th2 responses in atopic disorders or eosinophilic esophagitis. Such epithelial impairment is also a salient feature of allergic asthma and growing evidence indicates that barrier alterations probably play a driving role in this disease. IgA has been identified as the most abundant immunoglobulin in mucosa, where it acts as an active barrier through immune exclusion of inhaled or ingested antigens or pathogens. Historically, it has been thought to represent the serum factor underlying reaginic activity before IgE was discovered. Despite several studies about regulation and major functions of IgA at mucosal surfaces, its role in allergy remains largely unclear. This review aims at summarizing findings about epithelial functions and IgA biology that are relevant to allergy, and to integrate the emerging concepts and the recent developments in mucosal immunology, and how these could translate to clinical observations in allergy.     

IgE in the pathophysiology and therapy of food allergy

Food allergy is becoming a major public health issue, with no regulatory approved therapy to date. Food allergy symptoms range from skin rash and gastrointestinal symptoms to anaphylaxis, a potentially fatal systemic allergic shock reaction. IgE antibodies are thought to contribute importantly to key features of food allergy and anaphylaxis, and measurement of allergen-specific IgE is fundamental in diagnosing food allergy. This review will discuss recent advances in the regulation of IgE production and IgE repertoires in food allergy. We will describe the current understanding of the role of IgE and its high-affinity receptor FcεRI in food allergy and anaphylaxis, by reviewing insights gained from analyses of mouse models. Finally, we will review data derived from clinical studies of the effect of anti-IgE therapeutic monoclonal antibodies (mAbs) in food allergy, and recent insight on the efficiency and mechanisms through which these mAbs block IgE effector functions.     

Airway allergy and viral infection

There are complex interactions between airway allergy and viral infection. Available evidence suggests that viral respiratory infection can initiate, maintain and activate exacerbation of allergic conditions in respiratory tract. Innate and inflammatory responses to acute viral infection play important roles in its relationship to allergic reactions. On the other hand, biased immune responses toward Th2 caused by an allergic reaction may make the immune response ineffective in combating viral infection. It was previously shown that allergy can increase the expression level of rhinovirus receptors on mucosal epithelial cells. This suggests that airway allergy may increase the risk of rhinovirus infection. We have recently shown that allergy may also increase the expression level of influenza virus receptors. This suggests that airway allergy and viral infection may have a reciprocal interaction. The effect of allergy on the risk and outcome of viral infection needs to be further confirmed in clinical studies and its potential implication for clinical practice should be considered.     

The relationship between atopy and cystic fibrosis

The incidence and clinical significance of allergy in cystic fibrosis have been discussed. There is little evidence that the high prevalence of positive allergy skin tests in CF is a clinical manifestation of a hypersensitivity lung disease complicating the primary pulmonary disorder, except in the special case of allergic bronchopulmonary aspergillosis. The lung disease of CF appears to be caused by excessive bronchial secretions and recurrent infection that are the result of abnormal ion transport across the apical membrane of the respiratory epithelial cell. There are two important questions concerning the allergic reactions: Are they clinically significant, and, why do they occur? The former question is partly resolved by the data presented, although well-controlled studies of intervention would help to resolve it further. The cause of these reactions, which occur particularly in relationship to the moldAspergillus fumigatus, is unknown but the author is inclined to the view that they are the result of recurrent infection that induces heightened immunologic reactivity to inhaled allergens. The significance ofAF may be simply that this mold has a “predilection for diseased airways” or may be more complex; for example, owing to abnormal ion composition in respiratory secretions, abnormal lectin expression by CF respiratory epithelial cells, or selective filtration by the airways based on particle size.     

Prognostic value of asymptomatic skin sensitization to aeroallergens

PURPOSE OF REVIEW: Asymptomatic skin sensitization to aeroallergens is frequently encountered in epidemiological studies and in everyday clinical life. Correct management of the condition is essential to avoid both progression into allergic disease and unnecessary intervention. Understanding immunological mechanisms in asymptomatic skin sensitization might provide new insights into the natural history and treatment of respiratory allergy. RECENT FINDINGS: Research on asymptomatic skin sensitization is rare, and the present review unites previous studies with recent findings. It is a common condition affecting 8-30% of the population when using a local standard panel of aeroallergens. Clinically, immediate but not late-phase reactions are induced by allergen challenge. Absent eosinophil stimulation and migration and low IL-5 levels appear to be sentinel mechanisms. Prospective studies show that 30-60% become allergic, depending on allergens and follow-up period. No prospective intervention studies have been performed; however, allergen avoidance seems efficacious in reducing allergy development to occupational and domestic allergens. Asymptomatic skin sensitization due to an erroneously positive skin test must be ruled out before allergen avoidance measures are initiated. SUMMARY: Surprisingly few papers exist on asymptomatic skin sensitization epidemiology and immunology, despite the intriguing question as to why symptoms do not develop in IgE-sensitized patients. It is a common condition and a risk factor for later development of respiratory allergic disease. Cross-sectional intervention studies suggest that allergy development is reduced by allergen avoidance. Immunologically, control of eosinophil stimulation and migration seems to be pivotal. How this control is maintained remains to be elucidated.     

Pathogenesis of IgE‐mediated food allergy

Food allergy is a prevalent disease for which there is no current treatment beyond careful food avoidance. Accidental exposure to foods causes reactions in allergic individuals that can range in severity from mild skin reactions to severe and life‐threatening anaphylaxis, and there are no validated tools to predict severity of reactions. A greater understanding of the pathogenesis of food allergy is needed to develop prevention and treatment strategies for food allergy. In the last few years, there have been significant developments in the field of food allergy that have led to new ideas about food allergy prevention, diagnosis, and treatment. This review will discuss these recent advances in the food allergy field as well as identify gaps in our knowledge about the immune mechanisms of allergy and tolerance to foods.     

Penicillin allergy: prevalence of vague history in skin test-positive patients.

OBJECTIVE: Penicillin (PCN) skin testing is a reliable tool for predicting which patients can safely receive the antibiotic. Depending on the study, 7% to 76% of patients who have a history of PCN allergy have positive PCN skin tests. Many physicians approach patients who have a vague history of PCN allergy less cautiously than they approach those who have a convincing history suggestive of an IgE-mediated reaction. We reviewed the published literature to determine how many patients who had a history of PCN allergy and who were skin test-positive had a vague history of allergy. DATA SOURCES: By cross-referencing the keywords "penicillin" and "skin test," an Ovid MEDLINE search for English language studies published from 1966 to 1998 was performed. STUDY SELECTION: Studies in which history positive/skin test-positive patients were identified, and which contained documentation of the type of previous reaction in these patients, were included in the analysis. The MEDLINE search revealed 295 English language articles, of which 27 fulfilled the inclusion criteria. Three additional studies published prior to 1966 (and therefore not available through MEDLINE) also were found, bringing the total to 30. A "convincing" history was defined to be one likely to be IgE-mediated (such as anaphylaxis, urticaria, angioedema or pruritic rash). A "vague" history was one unlikely to be IgE-mediated (such as maculopapular rash, GI symptoms, or an unknown reaction). RESULTS: Overall, 347/1063, or 33%, of history positive/skin test-positive patients had a vague PCN allergy history, with a range of 0% to 70% among the 30 studies. CONCLUSION: A large proportion of patients who have PCN-specific IgE antibodies, as determined by skin testing, have vague PCN allergy histories. These results therefore, indicate that, like patients with convincing histories, patients with vague allergic histories should undergo PCN skin testing prior to PCN administration.     

Occupational respiratory allergy to roe deer.

BACKGROUND: Although scattered reports have been published on roe deer allergenicity, no systematic studies of allergenicity or possible cross-reactions have appeared. OBJECTIVES: To describe 2 patients with occupational roe deer allergy, demonstrated by positive skin and conjunctival provocation test results, and to note cross-reactions to other animal (mainly cow) allergens. METHODS: Two workers at animal rehabilitation centers were sensitized to roe deer. One patient had a history of rhinoconjunctivitis and the other a history of rhinoconjunctivitis and probable asthma. Both patients underwent skin testing with a standard battery of inhaled and epithelial allergens and with roe deer hair and dander extract and conjunctival provocation tests with roe deer hair extract. Immunodetection for IgE (both patients) and IgE immunoblot inhibition tests to determine inhibitory effect (1 patient) were also performed. RESULTS: The results of skin tests and conjunctival provocation tests showed that both patients were sensitized to roe deer allergens. In one patient specific IgE to roe deer extract was detected, and this extract completely inhibited IgE binding to cow hair and dander extract in immunoblotting tests. Specific IgE to roe deer proteins could not be demonstrated in the other patient. CONCLUSIONS: Our results suggest that roe deer epidermal derivatives can cause occupational respiratory disease in exposed workers and that allergy to this species should be considered in individuals who present with similar symptoms and exposure histories. Immunoblot inhibition studies suggested the possibility of cross-reaction between roe deer proteins and cow proteins.     

Genetic ablation of alphav integrins in epithelial cells of the eyelid skin and conjunctiva leads to squamous cell carcinoma

Integrin-mediated cell adhesion and signaling events are essential for the proper development and homeostasis of most epithelial tissues. Dysregulation of integrin expression and function can cause abnormal epithelial cell proliferation and/or differentiation, contributing to the pathogenesis of malignant epithelial cancers. Here we report on the use of a conditional knockout strategy exploiting the Cre/Lox technology to study the in vivo functions of alphav integrins during epithelial cell proliferation and differentiation. We show that genetic ablation of alphav integrin expression in basal epithelial cells of the eyelid skin and conjunctiva causes the formation of tumors that are strikingly similar to the malignant epithelial cancer, squamous cell carcinoma. These data suggest a mechanism whereby alphav integrins normally suppress epithelial cell proliferation, likely via adhesion to ECM ligands, as well as by the modulation of intracellular signaling cascades. We propose that alphav gene deletion eliminates normal integrin-mediated growth suppression, ultimately leading to cellular transformation and tumorigenesis. Hence, these studies reveal a novel tumor suppressor-like function of alphav integrins and provide a genetically tractable mouse model for studying the pathogenesis of squamous cell carcinoma and related cancers of epithelial origin, as well as to test and develop novel therapeutic compounds to treat or prevent squamous cell carcinoma of the skin.     

Skin testing and food challenges in allergy and immunology practice

Summary Skin tests by prick technique offer considerable guidance in the diagnosis of food allergy. Negative prick skin tests are powerful evidence against food allergy. Positive food skin tests are slightly to moderately predictive of reaction to a food on DBPCFC. Oral food challenge is necessary for confirmation of food allergy, except where the history is overwhelmingly convincing. Open, incremental food challenge as described is diagnostic if negative, but only 50% of all positive open challenges are confirmed on blinded challenge. DBPCFC can be designed for any food with simple blinding techniques. The technique of DBPCFC can be modified for investigation of atypical symptoms.     

Features of childhood atopic dermatitis

Eczema or atopic dermatitis (AD) is the most common skin disease in children, and recent data derived from several studies showed that the prevalence of AD is still increasing in most Asian countries. The role of allergic reactions in AD is still a matter of debate. In some children allergy is not involved, while in others allergic reactions can trigger and maintain the skin lesions. Therefore, AD is now considered as a group of skin diseases with as a common feature the existence of a chronic skin inflammation. The underlying mechanisms of AD are not uniform, but differ from patient to patient, and also differ in one patient in time, suggesting the existence of different subtypes of AD, in a complex interplay. From different studies it is now suggested that at least 4 different players are involved in AD. These 4 players are: congenital skin barrier defects, allergy, autoimmunity (i.e. the production of autoantibodies against skin cells), and microbial agent colonization, especially colonization with bacteria, mainly Staphylococcus aureus. Much more needs to be discovered on the mechanisms of AD and other "players" might be discovered soon, as the current "4-player-model" cannot explain all features of AD. Treatment of AD might change in the near future. Today's cornerstones of treatment are still moisturizers (from a young age to prevent further skin barrier dysfunctions and allergic sensitization), local corticosteroids, and antiseptics, but new future therapeutic approaches become very likely.     

Immunophysiology of experimental food allergy

Animal models of food allergy have been used to identify mechanisms involved in the development of sensitization to food proteins as well as immunologic mechanisms of adverse reactions to allergen reexposure. To counteract the normal tolerant responses to antigen generated in the gastrointestinal tract, investigators have used mucosal adjuvants or manipulated the mucosal barrier, taken advantage of endogenous adjuvanticity of some food allergens, or bypassed the oral route and sensitized through the skin. Site of antigen uptake in the gastrointestinal tract is a critical factor in both sensitization and anaphylaxis, and antigen uptake can be facilitated by immunoglobulin-E (IgE)–antigen complexes binding to CD23 on the epithelial cell surface. Studies on systemic anaphylaxis or local gastrointestinal manifestations of food allergy in mice have highlighted the contribution of IgE, mast cells, and pathogenic Th2 lymphocytes in experimental food allergy.