The role of the intestinal microbiota in the development of atopic disorders

The prevalence of atopic diseases, including eczema, allergic rhinoconjunctivitis and asthma, has increased worldwide, predominantly in westernized countries. Recent epidemiological studies and experimental research suggest that microbial stimulation of the immune system influences the development of tolerance to innocuous allergens. The gastrointestinal microbiota composition may be of particular interest, as it provides an early and major source of immune stimulation and seems to be a prerequisite for the development of oral tolerance. In this review the observational studies of the association between the gut microbiota and atopic diseases are discussed. Although most studies indicated an association between the gut microbiota composition and atopic sensitization or symptoms, no specific harmful or protective microbes can be identified yet. Some important methodological issues that have to be considered are the microbiological methods used (traditional culture vs molecular techniques), the timing of examining the gut microbiota, the definition of atopic outcomes, confounding and reverse causation. In conclusion, the microbiota hypothesis in atopic diseases is promising and deserves further attention. To gain more insight into the role of the gut microbiota in the etiology of atopy, large-scale prospective birth cohort studies using molecular methods to study the gut microbiota are needed.     

Oral cow milk challenge abolishes antigen-specific interferon-γ production in the peripheral blood of children with atopic dermatitis and cow milk allergy

Background A major feature of atopic dermatitis (AD) is the propensity to generate IgE to environmental antigens. Despite extensive information on IgE dysregulation in AD, the nature of immune responses to ingested allergens is poorly characterized. Objective To determine the clinical and immunological responses to food in AD patients. Methods To characterize the type and timing of clinical reactions to oral cow milk, 83 AD patients aged 2 to 60 months were subjected to double-blind placebo-controlled food challenge (DBPCFC). IFN-γ and IL-4 production by their peripheral blood mononuclear cells (PBMC) was determined before and after DBPCFC. Results Of 50 patients positive to DBPCFC, 46% manifested exanthematous-type immediate-onset reactions and 54% eczematous-type late-onset reactions. In either group, the production of lL-4 and IFN-γ by Concanavalin A-stimulated FBMC was comparable before and after DBPCFC. For immediate-reacting patients, the median IFN-γ production by milk-stimulated PBMC was 11.5 (4.2–17.2) pg/mL as against 2.3 (0.2–5.7) pg/mL by unstimulated PBMC, P = 0.0008 before DBPCFC, and 4.6 (2.8–10.3) pg/mL vs 4.2 (1.7–9.0) pg/mL, P = 0.40, correspondingly after DBPCFC. Conclusion Before DBPCFC, immediate-reacting but not late-reacting patients were found to be capable of allergen-specific IFN-γ production in vitro, indicating the heterogeneity in AD patients. After DBPCFC, the IFN-γ generation abolished, indicating the effect of oral allergen exposure on IFN-γ-producing responses of AD patients.     

Atopic dermatitis, extrinsic atopic dermatitis and the hygiene hypothesis: results from a cross-sectional study

BACKGROUND: Atopic Dermatitis (AD), hayfever and asthma are commonly summarized as atopic diseases. The spatial distribution of AD differs from that of asthma and hayfever, suggesting that AD might follow a different risk pattern than these diseases. AD can be differentiated into an allergic extrinsic form (EAD) and a non-allergic intrinsic form (IAD). Only EAD might follow the distribution and risk pattern that have been ascribed to asthma and hayfever. OBJECTIVE: To investigate the distribution and risk factor profile of AD and EAD focusing on environmental factors relating to the hygiene hypothesis. METHODS: Population-based cross-sectional study on 12,601 children aged 5-7 and 9-11 years from Dresden (Eastern Germany) and Munich (Western Germany). Information was obtained by International Study of Asthma and Allergic Childhood questionnaires, dermatological examinations and skin prick testing. AD-diagnosis ever, current AD-symptoms and visible eczema were investigated with their respective extrinsic forms. RESULTS: Maternal and paternal history of AD were equally strong determinants of the child's AD status. Factors related to the hygiene hypothesis like day-care attendance and number of older siblings were not associated with a decreased risk of AD. The proportion of EAD within AD was higher in Eastern than in Western Germany. The determinants of the diseases appeared to be similar for both EAD and IAD. CONCLUSIONS: There was no evidence of the hygiene hypothesis holding true for AD or EAD. AD might be a separate entity than respiratory atopic diseases. Little is known about the risk factors of AD and factors different from those of respiratory allergic diseases should be considered in future research.     

Sclareol attenuates the development of atopic dermatitis induced by 2,4-dinitrochlorobenzene in mice

Context: Atopic dermatitis is a common chronic inflammatory skin disease affecting up to 20% of children and 1% of adults worldwide. Treatment of atopic dermatitis include corticosteroids and immunosuppressants, such as calcineurin inhibitors and methotrexate. However, these treatments often bring about adverse effects including skin atrophy, osteoporosis, skin cancer, and metabolic syndrome.

Objective: In this study, we evaluated the therapeutic effects and mechanisms of sclareol, a natural diterpene, on atopic dermatitis (AD)-like skin lesions induced by 2,4-dinitrochlorobenzene (DNCB) in mice.

Materials and methods: To evaluate the effect of sclareol in vivo model, BALB/c mice were repeatedly injected intraperitoneally with sclareol (50 and 100?mg/kg) in 2,4-dinitrochlorobenzene (DNCB)-induced AD-like murine model. Major assays were enzyme-linked immunosorbent assay, histological analysis, flow cytometry, western blot analysis.

Results: Intraperitoneal administration of sclareol (50 and 100?mg/kg) significantly attenuated AD-like symptoms, such as serum IgE levels, epidermal/dermal hyperplasia, and the numbers of infiltrated mast cells. In addition, systemic sclareol treatments reduced local pro-inflammatory cytokine concentrations, including IL-6, IL-1b, TNF-a, IL-4, IFN-g, and IL-17A, on AD-like lesions. Furthermore, we demonstrated that sclareol also suppressed T cell activation and the capability of cytokine productions (IFN-g, IL-4 and IL-17A) in response to DNCB stimulation. By examining the skin homogenate, we found that sclareol inhibited the AD-like severity likely through suppressions of both NF-kB translocation and phosphorylation of the MAP kinase pathway.

Discussion and conclusions: Cumulatively, our results indicate that sclareol induced anti-inflammatory effects against the atopic dermatitis elicited by DNCB. Thus, sclareol is worth of being further evaluated for its potential therapeutic benefits for the clinical treatment of AD.     

IgE on Langerhans cells in the skin of patients with atopic dermatitis and birch allergy

Epidermal cell suspensions from the skin of seven patients with atopic dermatitis (AD) and seven healthy non-atopic controls were investigated for the presence of surface HLA-DR and CD1 antigen, and IgE using indirect and double-staining immunofluorescence techniques. Fifty-seven percent of all CDI + and 68% of all HLA-DR + cells from the patients demonstrated IgE on their surface, indicating that Langerhans cells (Lc) in AD may be a heterogeneous population with regard to surface characteristics. No IgE + cells were found in the epidermal cell suspensions from the healthy non-atopic controls. An attempt lo demonstrate birch pollen antigen on the surface of Lc from the same patients all strongly allergic to birch pollen, using indirect immunofluorescence techniques, was unsuccessful, also after in vitro incubation of the Lc with high concentration of the birch antigen.     

Mechanism of HBD-3 deficiency in atopic dermatitis

Extrinsic atopic dermatitis (EAD) and intrinsic atopic dermatitis (IAD) patients suffer from recurrent bacterial and viral infections. In this study, we demonstrate significantly decreased expression of human beta defensin (HBD)-3, a potent antimicrobial peptide (AMP), in lesional skin of both IAD (p<0.01) and EAD patients (p<0.01), as compared to psoriasis patients. Using primary keratinocytes from EAD and IAD patients, we determined that the deficiency in HBD-3 expression is an acquired rather than a constitutive defect. Furthermore, we demonstrate the down-regulatory effect of IL-4, IL-10, and IL-13 - which are over-expressed in the skin of AD patients - on HBD-3 expression in keratinocytes. Additionally, treatment of EAD skin explants with antibodies against IL-4, IL-10, and IL-13 augmented the expression of HBD-3. These studies suggest that neutralizing the Th2 cytokine milieu in AD skin may augment the innate immune response against bacterial and viral pathogens.     

Interleukin 2 therapy in severe atopic dermatitis

Interleukin 2 (IL-2) at a dose of 10,000 to 20,000 U/kg/q 8 hr was given for 9–12 days to six patients with cases of severe atopic dermatitis (AD) which were refractory to conventional therapy. After IL-2 therapy, the clinical symptoms and signs of eczema including pruritus, scratching, papulovesicles, and lichenification were much improved, but all of them recurred 2–6 weeks after stopping treatment. Adverse reactions were similar to those reported previously, but all of them subsided after discontinuation of therapy. Laboratory findings showed decreased T-cell subsets, especially CD4+ cells, and increased IL-2R+ (CD25) cells, but there was no significant change in serum IL-2, serum IgE, orin vitro IgE production. Immunopathological studies of the skin biopsies showed decreased mononuclear-cell infiltration, depletion of CD4+ cells, and enhanced expression of CD25 and HLA-DR antigens. As lymphokine-activated killer (LAK)-cell activity against cultured fibroblasts was similar in patients with AD and in normals and CD1+ Langerhans cells were not decreased after IL-2 therapy, we speculate that the depletion of helper/inducer CD4+ cells and hence abrogation of the exaggerated antigen processing and cellular activation in diseased skin are the explanation for the transient efficacy of IL-2 in the treatment of atopic dermatitis.     

Outcome of double-blind, placebo-controlled food challenge tests in 107 children with atopic dermatitis

BACKGROUND AND OBJECTIVE: Little is known about late phase clinical reactions during oral food challenges and the value of specific IgE in terms of sensitivity and specificity. METHODS: We therefore analysed retrospectively the clinical outcome of 387 oral provocations during double-blind, placebo-controlled food challenge tests in 107 children with atopic dermatitis. RESULTS: Eighty-seven (81%) children showed a positive clinical reaction to at least one challenge. The vast majority of children (94%) showed clinical symptoms to one or two allergens. One hundred and thirty-one of 259 (51%) of verum challenges and 1/128 (0.8%) placebo challenge were assessed as positive. Oral provocations with hen's egg showed the highest percentage of positive reactions (70%). Sensitivity of specific IgE to the four allergens tested was 90%, specificity 30%. Sensitivity of the parental history as a predictive factor was 48%, specificity 72%. Ninety-two of 131 (70%) children with positive verum provocations showed early reactions, 33 (25%) late and six (5%) combined early and late reactions. In 84/131 (64%) positive provocations one organ system was involved, while in 44 (34%) provocations two and in three (2%) challenges three organ systems were involved. Skin reactions were the most frequent clinical manifestation leading to positive reactions followed by gastro-intestinal and respiratory symptoms. There was no correlation between titration dose and specific IgE. The subgroup of non-sensitized children did not differ in terms of sex, age or titration dose from the total study population. CONCLUSION: Double-blind, placebo-controlled oral food challenges are helpful in distinguishing children with clinically manifested symptoms from those with food sensitization. Accurately identifying children with a clinical relevant food allergy may help to prescribe specific diets on a scientific basis, avoiding dietary limitations which may be unnecessary or even harmful.     

The exposome in atopic dermatitis

Atopic dermatitis (AD) is a complex inflammatory disorder with multiple interactions between genetic, immune and external factors. The sum of external factors that an individual is exposed to throughout their lifetime is termed the exposome. The exposome spans multiple domains from population to molecular levels and, in combination with genetic factors, holds the key to understanding the phenotypic diversity seen in AD patients. Exposomal domains are categorized into nonspecific (human and natural factors affecting populations), specific (eg humidity, ultraviolet radiation, diet, pollution, allergens, water hardness) and internal (cutaneous and gut microbiota and host cell interaction) exposures. The skin, as the organ that most directly interacts with and adapts to the external environment, is a prime target for exploration of exposomal influences on disease. Given the well-recognized physical environmental influences on AD, this condition could be much better understood through insightful exposomal research. In this narrative review, we examine each domain in turn, highlighting current understanding of the mechanisms by which exposomal influences modulate AD pathogenesis at distinct points in time. We highlight current approaches to exposome modification in AD and other allergic disease and propose future directions for exposome characterization and modification using novel research techniques.     

Efficacy and tolerance of tacrolimus and pimecrolimus for atopic dermatitis: a meta-analysis

Tacrolimus ointment and pimecrolimus cream have proved to be suitable for the treatment of atopic dermatitis. We conducted a meta-analysis of the efficacy, adverse events/withdrawal of tacrolimus versus pimecrolimus in the treatment of atopic dermatitis. According to our meta-analysis, 0.1% tacrolimus was more effective than 1% pimecrolimus in the treatment of adult patients and moderate to very severe pediatric patients, and more 0.1% mild pediatric patients treatal with pimecrolimus withdrew from the trials because of a lack of efficacy or the occurrence of adverse events, compared with mild pediatric patients treated with 0.03% tacrolimus. The combined analyses of tacrolimus with pimecrolimus showed that tacrolimus was more effective than pimecrolimus (week 3: RR=0.67, 95% CI=0.56-0.80; week 6/end of study: RR=0.65, 95% CI=0.57-0.75), and fewer tacrolimus-treated patients withdrew because of a lack of efficacy (RR=0.32, 95CI%=0.19-0.53) or the occurrence of adverse events (RR=0.43, 95% CI=0.24-0.75), compared with pimecrolimus-treated patients. In conclusion, tacrolimus has higher efficacy and better tolerance than pimecrolimus in the treatment of atopic dermatitis.