New insights into the mechanism and management of allergic diseases: atopic dermatitis

Rapidly increasing knowledge on the complex background of atopic dermatitis (AD) on the genetic, immunological and environmental level in combination with the continuous improvement in our diagnostic options has initiated an ongoing discussion on factors, which primarily promote the disease on one hand and mechanisms which emerge rather secondarily as a consequence of disease-specific modifications, on the other hand. Beside a sustained search for reliable and meaningful diagnostic tools for elicitors of the disease, novel therapeutic approaches are required, as most of the treatments of AD are limited to symptomatic therapies. In contrast, therapeutic approaches selectively regulating aberrant pathophysiological mechanisms in AD itself would be much more effective and promising.     

New insights into the role of T cells in atopic dermatitis and allergic contact dermatitis

Recently, studies on eczematous skin diseases, such as atopic dermatitis and allergic contact dermatitis, have concentrated on T-cell-mediated immune effector mechanisms. The apoptosis of keratinocytes induced by T cells and mediated by Fas is a crucial event in the transition from activation of the immune system to the manifestation of eczematous dermatitis. Here, we discuss the underlying mechanisms and molecular principles of the T-cell-induced formation of eczema and the focused targeting of these mechanisms by potential therapies.     

Recent insights into pathogenesis and control of asthma and atopic diseases

Inflammation Research -     

New insights into the phenotypes of 6q deletions

Deletions of chromosome 6q are rare. We report 3 new patients with 6q deletions. Case 1 is a male with an interstitial deletion [del(6)(q13q14.2)], hypotonia, speech delays, and minor anomalies. Case 2 is a male with an interstitial deletion [del(6)(q16.2q22.32)] and malformations, including truncus arteriosus and bilateral oligodactyly. Case 3 is a male with a terminal deletion [del(6)(q25.2)] with retinal pits, hydrocephalus, atrioventricular canal, and hydronephrosis. The findings in our patients and those from 57 previously reported cases demonstrated 3 phenotypic groups associated with 6q deletions. Group A [del(6)(q11–q16)] had a high incidence of hernias, upslanting palpebral fissures, and thin lips with lower frequency of microcephaly, micrognathia, and heart malformations. Group B [del(6)(q15–q25)] was associated with increased intrauterine growth retardation, abnormal respiration, hypertelorism, and upper limb malformations. Group C [del(6)(q25-qter)] was associated with retinal abnormalities, cleft palate, and genital hypoplasia. The only universal finding among all patients with 6q deletions was mental retardation. Other findings common to all 3 groups included ear anomalies (90%), hypotonia (82%), and postnatal growth retardation (68%). Am. J. Med. Genet. 70:377–386, 1997. © 1997 Wiley-Liss, Inc.     

Psychobiological aspects of atopic dermatitis: an overview

Atopic dermatitis (AD) is a chronic, pruritic inflammatory skin disease with increasing incidence characterized by eczematous inflammation of the skin, a chronically relapsing course and severe pruritus. In the last decade, there has been growing evidence indicating that psychological factors such as personality and stress may play an important role in the pathogenesis of AD. While there is only little consensus on an AD-specific personality profile and its etiological significance, a growing number of reports support the role of psychosocial stress in the onset and the course of AD symptomatology. However, although a close association between psychosocial stress and skin condition in AD patients has been demonstrated by several investigators, pathological models that integrate stress and its effect on atopy-relevant biological processes, e.g. immune processes, are still missing. This overview summarizes the role of immunological and psychological factors in AD pathogenesis and discusses potential psychobiological pathways of stress-related modulation of AD symptoms.     

New insights into asthma pathogenesis and treatment

Although national asthma guidelines help organize standards for asthma care, current asthma management is still primarily symptom based. Recent reports provide insights on how to improve asthma management through steps to better understand the natural history of asthma, individualize asthma care, reduce asthma exacerbations, manage inner city asthma, and some potential new ways to use available medications to improve asthma control. Despite many significant gains in managing asthma, we must now find improved strategies to prevent asthma exacerbations, alter the natural history of the disease, and to reduce health disparities in asthma care. Perhaps new directions in personalized medicine including a systems biology approach, along with improved health care access and communication will lead to better methods to alleviate the burden of asthma. This review will discuss the benefits and limitations of the current approach to asthma management, new studies that could impact new directions in asthma management, and new insights related to mechanisms of asthma and allergic airways inflammation that could eventually lead to improved asthma control.     

Atopic allergy: asthma and atopic dermatitis.

During the past 2 years much progress has been made in our understanding of allergic diseases: there is now increasing evidence for a direct causal relationship between exposure to allergen and the chronic diseases, asthma and atopic dermatitis; furthermore, it seems very likely that exposure to indoor allergens is the most common cause of the inflammation of the lungs that is characteristic of asthma.     

Increased risk of asthma and atopic dermatitis in perinatally HIV-infected children and adolescents

The incidence of asthma and atopic dermatitis (AD) was evaluated in HIV-infected (n = 451) compared to HIV-exposed (n = 227) but uninfected (HEU) children and adolescents by abstraction from clinical charts. Asthma was more common in HIV-infected compared to HEU children by clinical diagnosis (25% vs. 20%, p = 0.101), by asthma medication use, (31% vs. 22%, p = 0.012), and by clinical diagnosis and/or medication use, (34% vs. 25%, p = 0.012). HIV-infected children had a greater risk of asthma compared to HEU children (HR = 1.37, 95% CI: 1.01 to 1.86). AD was more common in HIV-infected than HEU children (20% vs. 12%, p = 0.009)) and children with AD were more likely to have asthma in both cohorts (41% vs. 29%, p = 0.010). HIV-infected children and adolescents in this study had an increased incidence of asthma and AD, a finding critical for millions of HIV-infected children worldwide.     

New insights into the role of cytokines in asthma

Asthma is a triad of intermittent airway obstruction, bronchial smooth muscle cell hyperreactivity to bronchoconstrictors, and chronic bronchial inflammation. From an aetiological standpoint, asthma is a heterogenous disease, but often appears as a form of immediate hypersensitivity. Many patients with asthma have other manifestations of atopy, such as rhinitis or eczema. Even among non-atopic patients with asthma, the pathophysiology of airway constriction is similar, raising the hypothesis that alternative mechanisms of mast cell degranulation may underlie the disease. The primary inflammatory lesion of asthma consists of accumulation of CD4⁺ T helper type 2 (TH2) lymphocytes and eosinophils in the airway mucosa. TH2 cells orchestrate the asthmatic inflammation through the secretion of a series of cytokines, particularly interleukin 4 (IL-4), IL-13, IL-5, and IL-9. IL-4 is the major factor regulating IgE production by B cells, and is required for optimal TH2 differentiation. However, blocking IL-4 is not sufficient to inhibit the development of asthma in experimental models. In contrast, inhibition of IL-13, another TH2 cytokine whose signal transduction pathway overlaps with that of IL-4, completely blocks airway hyperreactivity in mouse asthma models. IL-5 is a key factor for eosinophilia and could therefore be responsible for some of the tissue damage seen in chronic asthma. IL-9 has pleiotropic activities on allergic mediators such as mast cells, eosinophils, B cells and epithelial cells, and might be a good target for therapeutic interventions. Finally, chemokines, which can be produced by many cell types from inflamed lungs, play a major role in recruiting the mediators of asthmatic inflammation. Genetic studies have demonstrated that multiple genes are involved in asthma. Several genome wide screens point to chromosome 5q31–33 as a major susceptibility locus for asthma and high IgE values. This region includes a cluster of cytokine genes, and genes encoding IL-3, IL-4, IL-5, IL-9, IL-13, granulocyte macrophage colony stimulating factor, and the ß chain of IL-12. Interestingly, for some of these cytokines, a linkage was also established between asthma and their receptor. Another susceptibility locus has been mapped on chromosome 12 in a region that contains other potential candidate cytokine genes, including the gene encoding interferon γ, the prototypical TH1 cytokine with inhibitory activities for TH2 lymphocytes. Taken together, both experimental and genetic studies point to TH2 cytokines, such as IL-4, IL-13, IL-5, and IL-9, as important targets for therapeutic applications in patients with asthma.

Key Words: asthma • cytokines • interleukins • treatment of asthma • interferon γ

     

Anticardiolipin antibodies in children with atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disease with a multifactorial etiology. Immunological abnormalities (cell-mediated immune hyperactivity, elevated IgE serum levels and eosinophil-derived mediators) have been observed. In a recent issue, Szakos et al. describe, in children with extrinsic type of AD, an association between the occurrence of anticardiolipin (ACL) IgM and specific IgE against mite, and also in relation to the severity of the disease. We studied 51 children (35 males and 16 females, mean age 44 months) with AD, whose diagnosis was made on the basis of Hanifin and Rajka's criteria. The evaluation of the severity of the disease was made using the SCORAD index. Eleven children had intrinsic type AD (group A); 40 children had extrinsic type AD, 14 of them had specific IgE only against food allergens (group B); 26 children had specific IgE also against inhalant allergens (group C). Twelve children without allergy were designated as the control group. Specific IgEs were determined using the CAP-System (Pharmacia, Uppsala, Sweden) for food and inhalant allergens. The measurement of ACL IgG and IgM was carried out by ELISA (Orgentec Diagnostika, Mainz, Germany). An increase in serum levels of ACL was observed in 13 children (25.5%): 1 child (9%) from group A, 7 children (50%) from group B and 5 children (19.2%) from group C with a statistically significant difference (P=0.038). Our study shows the presence of ACL-IgG above all in extrinsic AD, but no association was found between high levels of ACL and increased severity scoring of AD. Increased levels of ACL were observed in younger children (mean age 26.5 months; P=0.025) especially if sensitized against food allergens.     

Allergic contact dermatitis to nickel in children with atopic dermatitis

We report two atopic boys with allergic contact dermatitis to nickel. Both children had early onset of atopic dermatitis and subsequently presented with infraumbilical dermatitis corresponding to the site of contact with metal snaps. A positive patch test response to 2.5% nickel sulfate in petrolatum was observed in both boys. Allergic contact dermatitis in patients with atopic dermatitis is not uncommon and probably occurs more often than recognized.     

Development of allergies and asthma in infants and young children with atopic dermatitis--a prospective follow-up to 7 years of age

BACKGROUND: The prognosis of atopic dermatitis is usually good, but the risk of developing asthma and allergic rhinitis is very high. The aim of this study was to follow children with atopic eczema up to school age to chart the course of sensitization and development of clinical allergy, as well as to study risk factors of sensitization. METHODS: Ninety-four children with atopic dermatitis were followed up to 7 years of age. The children were examined twice a year up to 3 years of age, and thereafter once yearly. At each visit, a clinical examination was performed, and a blood sample was taken. After 3 years of age, skin prick tests (SPTs) with inhalation allergens were performed at each visit. Information was obtained about atopy in the family, feeding patterns during infancy, symptoms of atopic disease, infections, and environmental factors. RESULTS: During the follow-up, the eczema improved in 82 of the 94 children, but 43% developed asthma and 45% allergic rhinitis. The risk of developing asthma was higher in children with a heredity of eczema. Presence of severe eczema at the time of inclusion in the study was associated with an increased tendency to produce food-specific IgE. An early onset of eczema was associated with an increased risk of sensitization to inhalant allergens, and development of urticaria. Early allergic reactions to food were associated with later reactions to food, allergic rhinitis, urticaria, and sensitization to both food and inhalant allergens. Early feeding patterns, time of weaning, and introduction of solid food did not influence the risk of development of allergic symptoms. A large number of periods or days with fever during the follow-up was associated with an increased risk of developing allergic rhinitis and urticaria. CONCLUSIONS: Our results confirm the good prognosis for the dermatitis and the increased risk of developing asthma and allergic rhinitis. Development of other allergic symptoms or sensitization was associated with the following factors: a family history of eczema, age at onset of eczema and its severity, early adverse reactions to foods, and proneness to infections.     

Environmental determinants of atopic eczema phenotypes in relation to asthma and atopic sensitization

BACKGROUND: There is still uncertainty about the determinants of atopic eczema (AE). To explain the heterogeneity of the disease, different phenotypes of AE have been suggested. METHODS: The cross-sectional PARSIFAL study included 14 893 school-age children of farmers or children attending Steiner schools and their respective reference groups. A detailed questionnaire was completed, and house dust was collected for the measurement of endotoxin and glucans. Atopic sensitization was defined by allergen-specific IgE levels in the serum. RESULTS: In multivariate analyses, helping with haying was the only variable related to a farming environment having a consistent inverse association with both current symptoms and a doctor's diagnosis of AE [aOR = 0.65 (95% CI: 0.46-0.93) and 0.73 (0.51-1.05)], respectively. Severe lower respiratory tract infections (LRTI) in the first 2 years of life and usage of antibiotics ever were found to be positively related only to asthma-associated AE, whereas the effect of LRTI on AE without asthma had an opposite effect. Levels of beta(1-->3)-glucans in mattress dust were inversely related to a doctor's diagnosis of asthma-associated AE [aOR = 0.75 (0.57-0.98)], and endotoxin levels to current symptoms of asthma-associated AE [aOR = 0.73 (0.57-0.94)]. CONCLUSIONS: The analyses of the PARSIFAL study revealed two different phenotypes of AE, depending on the association with asthma and wheezing ever. With regard to the hygiene hypothesis, help with haying, exposure to beta(1-->3)-glucans and endotoxin were found to be inversely associated with the AE phenotype associated with asthma and wheezing.     

The atopic march: progression from atopic dermatitis to allergic rhinitis and asthma

Atopic dermatitis (AD) is an inflammatory disease characterized by pruritic skin lesions. The pathogenesis of AD may include disrupted epidermal barrier function, immunodysregulation, and IgE-mediated sensitization to food and environmental allergens. AD is also part of a process called the atopic march, a progression from AD to allergic rhinitis and asthma. This has been supported by multiple cross-sectional and longitudinal studies and experimental data. Research on the mechanisms of AD has been centered on the adaptive immune system with an emphasis on the T-helper 1 (Th1)-Th2 paradigm. Recently, the conceptual focus has largely shifted to include a primary defect in the epithelial barrier as an initial event in AD providing a significant insight into the disease initiation and pointing to a complex secondary interplay of environmental and immunological sequelae with barrier disruption. Further understanding of AD will help the development of more effective treatment for AD and ultimately, preventative algorithms for the atopic march. In this review we highlight recent advances in our understanding of the pathogenesis of AD and the atopic march.     

Sleep and nighttime pruritus in children with atopic dermatitis

The number of scratching episodes and average frequency with which they started during each sleep stage as well as the effects of nighttime pruritus on objective sleep parameters in nine children with atopic dermatitis were assessed in the sleep laboratory. Scratching episodes occurred during rapid eye movement (REM) sleep and non-REM (NREM) sleep. The largest average frequency corresponded to stage 1, followed by stage 2, REM sleep, stage 4, and stage 3. Sleep maintenance was markedly altered. Total sleep time decrease was related mainly to smaller amounts of stage 4 NREM sleep. REM sleep percentage of total sleep time was increased as compared with normal children of the same age. Furthermore, in six of nine patients REM sleep latency was found to be decreased.