Joachim Kuehr

Intrinsic Defect in T Cell Production of Interleukin (IL)-13 in the Absence of Both IL-5 and Eotaxin Precludes the Development of Eosinophilia and Airways Hyperreactivity in Experimental Asthma

Interleukin (IL)-5 and IL-13 are thought to play key roles in the pathogenesis of asthma. Although both cytokines use eotaxin to regulate eosinophilia, IL-13 is thought to operate a separate pathway to IL-5 to induce airways hyperreactivity (AHR) in the allergic lung. However, identification of the key pathway(s) used by IL-5 and IL-13 in the disease process is confounded by the failure of anti–IL-5 or anti–IL-13 treatments to completely inhibit the accumulation of eosinophils in lung tissue. By using mice deficient in both IL-5 and eotaxin (IL-5/eotaxin−/−) we have abolished tissue eosinophilia and the induction of AHR in the allergic lung. Notably, in mice deficient in IL-5/eotaxin the ability of CD4+ T helper cell (Th)2 lymphocytes to produce IL-13, a critical regulator of airways smooth muscle constriction and obstruction, was significantly impaired. Moreover, the transfer of eosinophils to IL-5/eotaxin−/− mice overcame the intrinsic defect in T cell IL-13 production. Thus, factors produced by eosinophils may either directly or indirectly modulate the production of IL-13 during Th2 cell development. Our data show that IL-5 and eotaxin intrinsically modulate IL-13 production from Th2 cells and that these signaling systems are not necessarily independent effector pathways and may also be integrated to regulate aspects of allergic disease.

Linkage and allelic association of atopy and markers flanking the IL4-receptor gene

Atopy, a clinical syndrome characterized by heightened IgE responsiveness, is largely determined by genetic factors. The disease may well be heterogeneous but the mode of inheritance is unknown. Several genes have been named which affected IgE responsiveness. However, results are conflicting reflecting heterogeneity and a complicated inheritance pattern of the atopic syndrome. In 1994 linkage of the 5q32 gene region and elevated total IgE levels were reported, leaving the IL4 gene as a prominent candidate.

The co-seasonal application of anti-IgE after preseasonal specific immunotherapy decreases ocular and nasal symptom scores and rescue medication use in grass pollen allergic children

Background: Specific immunotherapy (SIT) and treatment with anti‐immunoglobulin (Ig)E antibody are complementary approaches to treat allergic rhinoconjunctivitis, which may be used for single or combined treatment.

Study on the Prevention of Allergy in Children in Europe (SPACE): allergic sensitization in children at 1 year of age in a controlled trial of allergen avoidance from birth

Several studies have demonstrated that early intervention may modulate the natural course of atopic disease. Our objective was to prevent sensitization to house‐dust mite and food allergens, as well as the development of atopic symptoms during infancy, by the combination of an educational package and the use of mite allergen‐impermeable mattress encasings. A multicentre European, population‐based, randomized, controlled study of children at increased atopic risk [Study on the Prevention of Allergy in Children in Europe (SPACE)] was performed in five countries (Austria, Germany, Greece, the UK, and Lithuania), and included three cohorts – schoolchildren, toddlers, and newborns. We report on the newborn cohort. A total of 696 newborns were included from Austria, the UK, and Germany. Inclusion criteria were: a positive history of parental allergy; and a positive skin‐prick test or specific immunoglobulin E (IgE) (IgE ≥ 1.43 kU/L) against at least one out of a panel of common aeroallergens in one or both parents. At 1 year of age, the overall sensitization rate against the tested allergens [dust‐mite allergens: Dermatophagoides pteronyssinus and Dermatophagoides farinae (Der p and Der f)] and food allergens (egg, milk) in the prophylactic group was 6.21% vs. 10.67% in the control group. The prevalence of sensitization against Der p was 1.86% in the prophylactic group vs. 5% in the control group. In conclusion, we were able to demonstrate, in a group of newborns at risk for atopic diseases, that the sensitization rate to a panel of aero‐ and food allergens could be effectively decreased through the use of impermeable mattress encasings and the implementation of easy‐to‐perform preventive measures.

Sensitization to mite allergens is a risk factor for early and late onset of asthma and for persistence of asthmatic signs in children

BACKGROUND To describe the natural history of asthma between the ages of 7 and 10 years and to analyze risk factors for prevalences, as well as new onset of asthma-like symptoms, a longitudinal study of 1812 children was conducted. METHODS In four surveys, each 1 year apart, four asthma-like symptoms and several hypothetical risk factors were ascertained through standardized questionnaires. Sensitization to seven common inhalant allergens was measured by skin prick testing. Exposure to mite allergens (Der p I, Der f I) was assessed by measuring the antigen concentrations in the dust of each childs mattress. Occurrence of more than one asthma-like symptom closely related to the practioners diagnoses of bronchial asthma and recurrent wheezy bronchitis was used as the outcome variable. RESULTS After an initial prevalence of 14.5%, new onset of symptoms in children unaffected at the beginning was reported in 7.2% during the 3 years. Of the factors explaining prevalence and persistence of asthma-like symptoms (sensitization to mite allergens and animal danders, history of hay fever and eczema, low gestational age, male gender, parental atopy), only sensitization to mite allergens (odds ratio = 2.3, 95% confidence interval = 1.1-4.7) and parental atopy (odds ratio = 2.1, 95% confidence interval = 1.2-3.7) were also significantly associated with new onset. In a relatively small number of sensitized subjects with new onset of symptoms (n = 31), mite antigen concentration did not appear to be associated with incidence of symptoms. CONCLUSION Sensitization to mite allergens antedated the onset of asthma-like symptoms, and no strong effect of allergen exposure on clinical development could be found. Thus the primary focus should be on preventing sensitization to mite allergens by implementing avoidance measures in infancy or at early school age in order to reduce the onset of asthma at a later stage.

Effect of mite‐impermeable mattress encasings and an educational package on the development of allergies in a multinational randomized, controlled birth‐cohort study – 24 months results of the Study of Prevention of Allergy in Children in Europe

Background Sensitization to house dust mite (HDM) is an important risk factor for the development of asthma and allergic disease in childhood. Higher levels of HDM allergen are linked to increased sensitization to HDM.

Modulation of Ca2+-activated Cl- secretion by basolateral K+ channels in human normal and cystic fibrosis airway epithelia.

Human airway epithelia express Ca2+-activated Cl− channels (CaCC) that are activated by extracellular nucleotides (ATP and UTP). CaCC is preserved and seems to be up-regulated in the airways of cystic fibrosis (CF) patients. In the present study, we examined the role of basolateral K+ channels in CaCC-mediated Cl− secretion in native nasal tissues from normal individuals and CF patients by measuring ion transport in perfused micro Ussing chambers. In the presence of amiloride, UTP-mediated peak secretory responses were increased in CF compared with normal nasal tissues. Activation of the cAMP pathway further increased CaCC-mediated secretion in CF but not in normal nasal mucosa. CaCC-dependent ion transport was inhibited by the chromanol 293B, an inhibitor of cAMP-activated hKvLQT1 K+ channels, and by clotrimazole, an inhibitor of Ca2+-activated hSK4 K+ channels. The K+ channel opener 1-ethyl-2-benzimidazolinone further increased CaCC-mediated Cl− secretion in normal and CF tissues. Expression of hSK4 as well as hCACC-2 and hCACC-3 but not hCACC-1 was demonstrated by reverse transcriptase PCR on native nasal tissues. We conclude that Ca2+-activated Cl− secretion in native human airway epithelia requires activation of Ca2+-dependent basolateral K+ channels (hSK4). Co-activation of hKvLQT1 improves CaCC-mediated Cl− secretion in native CF airway epithelia, and may have a therapeutic effect in the treatment of CF lung disease.

Infections and atopic disorders in childhood and organochlorine exposure

Abstract The authors investigated whether organochlorine exposure is associated with prevalence of otitis media, pneumonia, pertussis, asthma, and increased immunoglobulin E levels in children. Organochlorine concentrations and histories of infection and atopic manifestation were available for 343 children, and immunoglobulin E levels were available for 340 children. The authors applied logistic and linear regressions and controlled for confounders. In general, the prevalence of infections in children was not related to organochlorine exposure. However, for the combined effect of dichlorodiphenyldichloroethene with polychlorinated biphenyls or hexachlorobenzene, a significantly increased relative risk (odds ratios = 3.70 and 2.38, respectively) was found for otitis media. Exposure to dichlorodiphenyldichloroethene resulted in a significantly higher odds ratio for asthma (odds ratio = 3.71; 95% confidence interval = 1.10, 12.56) and in immunoglobulin E concentrations above 200 kU/l (odds ratio = 2.28; 95% confidence interval = 1.20, 4.31). This is the first study in which dichlorodiphenyldichloroethene has been identified as a substantial risk factor for asthma and for increased immunoglobulin E blood levels.

Natural variation in mite antigen density in house dust and relationship to residential factors

To investigate the year‐to‐year variation of mite antigen density (Der p I, Der f1) in dust from mattresses and the relevance of residential factors for antigen load, information derived from an epidemiologic study including two surveys carried out in the households of a cohort of elementary school children (n= 1291) was analysed.

Maternal smoking in early childhood: A risk factor for bronchial responsiveness to exercise in primary-school children

The relationship between maternal smoking and bronchial hyperresponsiveness as assessed by a standardized free running test was investigated in a cohort of 1812 primary-school children in first grade. A childs exposure to maternal smoking during pregnancy, the first year of life, and the study year was recorded. Current exposure was not positively associated with bronchial hyperresponsiveness. The prevalence of this disorder was higher when maternal smoking during the childs first year of life was reported (9%) than when it was not (5.9%). The odds of being hyperresponsive were significantly higher in children exposed to maternal smoking in their first year of life (odds ratio, 2.82; 95% confidence interval, 1.25 to 6.34; p less than 0.01), especially in children with asthma (odds ratio, 20.55; 95% confidence interval, 2.5 to 168.9; p less than 0.01). Current exposure to maternal smoking was associated with less hyperresponsiveness. The effect of current maternal smoking might reflect changes in smoking habits by mothers of children with symptoms, whereas exposure to tobacco smoke in early life might be causally related to bronchial hyperresponsiveness. Our findings support the general hypothesis that early lung injuries have an impact on the later respiratory health of children.