Brunello Wüthrich

Role of interleukin 10 in specific immunotherapy.

The induction of allergen-specific anergy in peripheral T cells represents a key step in specific immunotherapy (SIT). Here we demonstrate that the anergic state results from increased IL-10 production. In bee venom (BV)-SIT the specific proliferative and cytokine responses against the main allergen, the phospholipase A2 (PLA), and T cell epitope-containing PLA peptides were significantly suppressed after 7 d of treatment. Simultaneously, the production of IL-10 increased during BV-SIT. After 28 d of BV-SIT the anergic state was established. Intracytoplasmic cytokine staining of PBMC combined with surface marker detection revealed that IL-10 was produced initially by activated CD4(+)CD25(+), allergen-specific T cells, and followed by B cells and monocytes. Neutralization of IL-10 in PBMC fully reconstituted the specific proliferative and cytokine responses. A similar state of IL-10-associated T cell anergy, as induced in BV-SIT, was found in hyperimmune individuals who recently had received multiple bee stings. The addition of IL-10 to soluble CD40 ligand IL-4-stimulated PBMC or purified B cells inhibited the PLA-specific and total IgE and enhanced the IgG4 formation. Accordingly, increased IL-10 production by SIT causes specific anergy in peripheral T cells, and regulates specific IgE and IgG4 production toward normal IgG4-related immunity.

Prevalence of hay fever and allergic sensitization in farmer's children and their peers living in the same rural community

Lower prevalence rates of allergic diseases in rural as compared with urban populations have been interpreted as indicating an effect of air pollution. However, little is known about other factors of the rural environment which may determine the development of atopic sensitization and related diseases.

Prevalence of Atopy and Pollinosis in the Adult Population of Switzerland (SAPALDIA Study)

The Swiss SAPALDIA study is a large multicenter cross-sectional study initiated in 1991 to evaluate the relationship between environment and respiratory symptoms and diseases in adults, and included subjects from eight areas in Switzerland with distinctive environmental characteristics. We present here prevalence data for atopy, pollinosis and atopic asthma obtained from a random sample of 8,357 adults (18-60 years) assessed by standardized computer-based interview as well as by allergy skin prick tests (SPTs) (performed with Phazet) to grass, birch and Parietaria pollen, house dust mite, cat and dog epithelia and the moulds Alternaria and Cladosporium and by an in vitro allergy screen test (Phadiatop CAP FEIA system). On the basis of a positive Phadiatop (total 28.9%; males 32.9%, females 25.0%; p < 0.001) and/or a positive SPT (total 23%; males 25.0%, females 20.8%; p < 0.001), 32.3% of the study population were considered atopic (males 35.7%, females 28.8%; p < 0.001). Concerning the prevalence of skin sensitization (SPT wheal > or = 3 mm), the highest rate was observed for grass (12.7%), followed by house dust mite (8.9%), silver birch (7.9%), cat (3.8%) and dog (2.8%), whereas moulds and Parietaria elicited less than 1% positive SPTs. The prevalence of atopic rhinitis (rhinitis symptoms associated with atopy) was 13.5% (males 14.3%, females 12.6%; p < 0.05) and the prevalence of current hay fever varied between 9.1% (questionnaire answer and a positive SPT to at least one pollen), 11.2% (questionnaire answer and presence of atopy) to 14.2% (questionnaire answer only) with no significant difference by sex.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of current and childhood exposure to cat and atopic sensitization

BACKGROUND Clinical and population studies have shown that exposure and sensitization to allergens derived from furred pets, particularly cats, represent an important risk factor of allergic respiratory disease and also a significant risk factor for asthma. OBJECTIVE In the framework of the multicenter European Community Respiratory Health Survey an analysis of the association of current and childhood exposure to cat with atopic sensitization to cat was conducted. METHODS This study included cross-sectional data from 35 centers representing 16 countries. Altogether, 18,097 subjects were included, of whom 13,509 (75%) provided a blood sample for the measurement of specific IgE. Exposure data and data for potential confounders were extracted from an interviewer-led questionnaire. RESULTS The prevalence of sensitization to cat (serum specific IgE >0.35 kU/L) was 9%. Among those who did not report allergic symptoms in the presence of pets or house dust, those who owned cats were significantly more likely to be sensitized to cats than were those who did not (odds ratio [95% confidence interval] 1.57 [1.20-2.06]. Childhood exposure to pets including cats was associated with lower sensitization to cats in adulthood, particularly among those with a positive family history of atopy (odds ratio [95% confidence interval] 0.68 [0.51-0.93]. Positive correlations were found between the community prevalence of cat and the prevalences of sensitization to cat, respiratory symptoms, physician-diagnosed asthma, and current asthma medication. CONCLUSIONS Current cat ownership represents a significant risk for sensitization to cat if cats are allowed indoors. Our results support the hypothesis that childhood exposure to pets, including cats, might modulate immunologic mechanisms and reduce sensitization to cat in adulthood. The significant correlation found between the community prevalence of cat ownership and community prevalence of specific sensitization to cat represents the first documentation of such a relationship.

Predictors of severe systemic anaphylactic reactions in patients with Hymenoptera venom allergy: Importance of baseline serum tryptase—a study of the European Academy of Allergology and Clinical Immunology Interest Group on Insect Venom Hypersensitivity

BACKGROUND Severe anaphylaxis to honeybee or vespid stings is associated with a variety of risk factors, which are poorly defined. OBJECTIVE Our aim was to evaluate the association of baseline serum tryptase concentrations and other variables routinely recorded during patient evaluation with the frequency of past severe anaphylaxis after a field sting. METHODS In this observational multicenter study, we enrolled 962 patients with established bee or vespid venom allergy who had a systemic reaction after a field sting. Data were collected on tryptase concentration, age, sex, culprit insect, cardiovascular medication, and the number of preceding minor systemic reactions before the index field sting. A severe reaction was defined as anaphylactic shock, loss of consciousness, or cardiopulmonary arrest. The index sting was defined as the hitherto first, most severe systemic field-sting reaction. Relative rates were calculated with generalized additive models. RESULTS Two hundred six (21.4%) patients had a severe anaphylactic reaction after a field sting. The frequency of this event increased significantly with higher tryptase concentrations (nonlinear association). Other factors significantly associated with severe reactions after a field sting were vespid venom allergy, older age, male sex, angiotensin-converting enzyme inhibitor medication, and 1 or more preceding field stings with a less severe systemic reaction. CONCLUSION In patients with honeybee or vespid venom allergy, baseline serum tryptase concentrations are associated with the risk for severe anaphylactic reactions. Preventive measures should include substitution of angiotensin-converting enzyme inhibitors.

Intralymphatic allergen administration renders specific immunotherapy faster and safer: A randomized controlled trial

The only causative treatment for IgE-mediated allergies is allergen-specific immunotherapy. However, fewer than 5% of allergy patients receive immunotherapy because of its long duration and risk of allergic side effects. We aimed at enhancing s.c. immunotherapy by direct administration of allergen into s.c. lymph nodes. The objective was to evaluate safety and efficacy compared with conventional s.c. immunotherapy. In a monocentric open-label trial, 165 patients with grass pollen-induced rhinoconjunctivitis were randomized to receive either 54 s.c. injections with pollen extract over 3 years [cumulative allergen dose 4,031,540 standardized quality units (SQ-U)] or 3 intralymphatic injections over 2 months (cumulative allergen dose 3,000 SQ-U). Patients were evaluated after 4 months, 1 year, and 3 years by nasal provocation, skin prick testing, IgE measurements, and symptom scores. Three low-dose intralymphatic allergen administrations increased tolerance to nasal provocation with pollen already within 4 months (P < 0.001). Tolerance was long lasting and equivalent to that achievable after standard s.c. immunotherapy (P = 0.291 after 3 years). Intralymphatic immunotherapy ameliorated hay fever symptoms (P < 0.001), reduced skin prick test reactivity (P < 0.001), decreased specific serum IgE (P < 0.001), caused fewer adverse events than s.c. immunotherapy (P = 0.001), enhanced compliance (P < 0.001), and was less painful than venous puncture (P = 0.018). In conclusion, intralymphatic allergen administration enhanced safety and efficacy of immunotherapy and reduced treatment time from 3 years to 8 weeks.

Epidemiology of the Allergic Diseases: Are They Really on the Increase?

Epidemiological studies on representative populations clearly demonstrate a significant general increase of atopic diseases during the last decades, mainly for pollinosis. For the manifestation of an atopic disease both allergen exposure, which leads to specific IgE antibody formation, and the presence of additional realization factors are required. The nature of the latter is still partially unknown. Careful interpretations of clinical and experimental observations show that besides indoor and outdoor pollution, increased exposure to allergens through changes in human way of living is an important cofactor responsible for the increased incidence of atopic diseases.

Eosinophils express functional IL-13 in eosinophilic inflammatory diseases.

IL-13 is an immunoregulatory and effector cytokine in allergic diseases such as bronchial asthma. A variety of immune and non-immune cells are known as IL-13 producers. In this study we investigated whether and under what conditions human eosinophils generate IL-13. Freshly isolated highly purified peripheral blood eosinophils from patients with several eosinophilic inflammatory diseases and from normal control individuals were investigated. We observed that blood eosinophils from patients suffering from bronchial asthma, atopic dermatitis, parasitic infections, hypereosinophilic syndrome, and idiopathic eosinophilic esophagitis expressed IL-13, as assessed by ELISA, ELISPOT assay, flow cytometry, and immunocytochemistry. By using nasal polyp tissues and immunohistochemistry, we demonstrated IL-13 expression in eosinophils under in vivo conditions. In contrast, blood eosinophils from control individuals as well as blood neutrophils from both eosinophilic and control patients did not produce detectable IL-13 levels. However, when blood eosinophils from control individuals were stimulated with GM-CSF or IL-5 in vitro, they generated IL-13 mRNA and protein, suggesting that IL-13 expression by eosinophils under inflammatory conditions is a cytokine-driven process. Stimulation of blood eosinophils containing IL-13 by eotaxin resulted in a rapid release of this cytokine. Eosinophil-derived IL-13 was functional, as it increased the surface expression of the low affinity IgE receptor (CD23) on purified B cells. In conclusion, human eosinophils are able to produce and release functional IL-13 in eosinophilic inflammatory responses.

Clinical aspects, epidemiology, and prognosis of atopic dermatitis.

OBJECTIVE This review article examines the clinical aspects, epidemiology, and prognosis of atopic dermatitis. DATA SOURCES These are studies and review articles from textbooks of dermatitis and allergy in general, as well as more recent epidemiologic surveys published in specialist journals of allergy and dermatology. STUDY SELECTION Included studies meet the criteria of being a survey of the prevalence of atopic dermatitis published recently in a respected peer-reviewed journal. Particular emphasis is placed on those that examine both the prevalence of the problem and significant causative and associated factors. RESULTS Atopic dermatitis is frequently a severe illness that develops in early infancy. It can persist beyond the childhood years and is often found in association with significant respiratory complications. The exact pathogenesis is unclear but it appears that it has a complex immunologic origin. Early surveys lack the methodologic refinements of more recent data from the mid-1990s, including the SCARPOL study. Collectively, these point to a high current prevalence rate of 10% to 15%, a figure that has risen steadily in the preceding decades. The most common associations of atopic dermatitis are a risk of developing respiratory disorders, such as allergic rhinitis and asthma (40% to 60%), and a persistence rate after puberty (40% to 60%), which is indeed much higher than previously suspected. CONCLUSIONS A clear recognition of the various disease subgroups along with intervention studies that evaluate reduction of risk are needed before more precise treatment strategies can be devised.

Exposure to motor vehicle traffic and allergic sensitization

We examined the association between the presence of an allergic sensitization and seasonal allergic diseases or symptoms and the exposure to road traffic in Basel, Switzerland. Traffic counts at the domiciles of subjects ranged from 24 to 32,504 cars per 24 hours, with a median of 1,624. To investigate the relation of road traffic and allergies, we matched the data of the traffic inventory of Basel with those of the 820 participants of the SAPALDIA study (Swiss Study on Air Pollution and Lung Diseases in Adults), ages 18-60 years, who had completed a detailed respiratory health questionnaire and had undergone allergy testing (skin prick tests and serologic examinations). We observed a positive association with a sensitization to pollen that was most pronounced among persons with a duration of residence of at least 10 years. The odds ratios (adjusted for educational level, smoking behavior, number of siblings, age, sex, and family history of atopy) for cars, contrasting four exposure categories with the lowest quartile as referent category, were 1.99 [95% confidence interval (CI) = 0.91-4.38], 2.47 (95% CI = 1.06-5.73), and 2.83 (95% CI = 1.26-6.31). These results suggest that living on busy roads is associated with a higher risk for a sensitization to pollen and could possibly be interpreted as an indication for interactions between pollen and air pollutants. We did not, however, find a similar relation between motor vehicle traffic and hay fever or seasonal allergic symptoms, and we saw no trend that increasing traffic exposure was associated with a rise in sensitization rates to indoor allergens.