Irina Lehmann

An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor

Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology. TDO-derived Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO–AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival. Because Kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, these results provide evidence for a previously unidentified pathophysiological function of the AHR with profound implications for cancer and immune biology.

Mode of delivery and development of atopic disease during the first 2 years of life.

It has been hypothesized that cesarean delivery might have an impact on the development of atopic diseases because of its gut flora modulating properties. In the present study, we analysed the association between cesarean delivery and atopic diseases using data of 2500 infants enrolled in the LISA‐Study, a German prospective multicenter birth cohort study. Data on symptoms and physician‐diagnosed atopic diseases were gathered by questionnaires shortly after birth and at infants age 6, 12, 18, and 24 months. In addition, sensitization to common food and inhalant allergens was assessed by measuring specific immunoglobulin E (IgE) using the CAP‐RAST FEIA method at the age of 2 yr. Confounder‐adjusted odds ratios (aOR) with 95% confidence intervals (CI) were calculated by multiple logistic regression. We found a positive association between cesarean delivery and occurrence of at least one episode of wheezing [aOR 1.31 (95% CI 1.02–1.68)] and of recurrent wheezing [1.41 (1.02–1.96)] during the first 2 yr of life. Furthermore, effect estimates for allergic sensitization defined as at least one specific IgE ≥0.70 kU/l against any allergen [1.48 (0.98–2.24)], against food allergens [1.64 (1.03–2.63)], and against inhalant allergens [1.75 (0.98–3.12)] were increased. Symptoms of atopic dermatitis [1.21 (0.92–1.59)], physician‐diagnosed atopic dermatitis [1.04 (0.79–1.39)], and symptoms of allergic rhinoconjunctivitis [1.40 (0.80–2.44)] were only marginally increased in children delivered by cesarean section. In conclusion, our results suggest that cesarean delivery may be an additional risk factor for wheezing and allergic sensitization at least to food allergens up to the age of 2 yr. This should be considered when cesarean section is done for other than medical reasons.

Maternal and newborn vitamin D status and its impact on food allergy development in the German LINA cohort study

Vitamin D levels are known to be associated with atopic disease development; however, existing data are controversial. The aim of this study was to investigate whether corresponding maternal and cord blood vitamin D levels are associated with atopic outcomes in early infancy.

Cord blood Tregs with stable FOXP3 expression are influenced by prenatal environment and associated with atopic dermatitis at the age of one year

Regulatory T cells (Tregs) with stable FOXP3 expression are characterized by a specific demethylated region in the FOXP3 gene (Treg‐specific demethylated region, TSDR). The aim of this study was to analyse the influence of prenatal factors on cord blood Treg numbers, as detected by changes in the TSDR demethylation, and the subsequent risk for allergic diseases.

Early endotoxin exposure and atopy development in infants: results of a birth cohort study

Background Exposure to endotoxin in childhood is currently discussed to protect from the development of allergic diseases.

Infant eczema, infant sleeping problems, and mental health at 10 years of age: the prospective birth cohort study LISAplus

To cite this article: Schmitt J, Chen C‐M, Apfelbacher C, Romanos M, Lehmann I, Herbarth O, Schaaf B, Kraemer U, von Berg A, Wichmann H‐E, Heinrich J, the LISA‐plus Study Group. Infant eczema, infant sleeping problems, and mental health at 10 years of age: the prospective birth cohort study LISAplus. Allergy 2011; 66: 404–411.

The capacity to produce IFN-gamma rather than the presence of interleukin-4 determines the resistance and the degree of susceptibility to Leishmania donovani infection in mice.

The immune response against Leishmania donovani infection has been investigated in one resistant mouse strain (C3H/HeJ) and three susceptible mouse strains (C57BL/6, BALB/c, and B10D2/n). In order to correlate the strain-specific course of infection with the individual T cell response phenotype, the ex vivo cytokine secretion patterns of splenic lymphocytes were assessed by ELISA (interferon-y [IFN-gamma], interleukin-4 [IL-4], IL-10) or by bioassay (IL-2). The strain-dependent differences in the course of infection correlated closely with the potency of T cells to produce IFN-gamma. C3H/HeJ mice produced high amounts of IFN-gamma before and during infection, whereas susceptible mice produced low amounts of IFN-gamma early during L. donovani infection. However, C57BL/6 mice, which recovered from the infection rapidly after the acute stage, developed marked IFN-gamma response within the first 30 days of infection. In contrast, in BALB/c and B10D2/n mice, the IFN-gamma production diminished during the acute stage, and this was associated with a delay in recovery and with subsequent switching into the chronic stage. Interestingly, CD8+ T cells contributed significantly to IFN-gamma production during this phase. In contrast to IFN-y, the levels of IL-4 in response to antigen or mitogen ex vivo were always very low. Moreover, neutralization of endogenous IL-4 in vivo by treatment with soluble murine IL-4 receptor did not result in significant decreases in the parasite burdens in spleen and liver but did cause a decrease in the serum IgE level of L. donovani-infected BALB/c mice. These results confirm that in visceral leishmaniasis a Thl-dominated immune response is protective against the L. donovani parasites and, furthermore, that the capacity to produce IFN-gamma rather than the presence of IL-4 determines the efficacy of the immune response in susceptible mice. The data show that CD8+ T cells represent an important source of IFN-gamma during L. donovani infection in susceptible mice, implying a role for this cell type in healing and development of protective immunity.

Respiratory effects of indoor particles in young children are size dependent

BACKGROUND Extensive epidemiological studies have provided evidence of an association between elevated outdoor particulate air pollution and adverse health effects. However, while people typically spend majority of time indoors, there is limited knowledge on airborne indoor particles and on the correlation between the concentrations of indoor particles and health effects. Even insights into the influence of differently sized indoor particles on human health are still rare. OBJECTIVE The association between differentially sized indoor air particles and the development of respiratory diseases was studied for three year aged children. METHODS Short-term measurements of particle mass and number concentrations were carried out in childrens rooms. Information on possible particle sources (smoking habits, type of heating, and traffic) and respiratory outcomes were obtained from questionnaires. Measured indoor particle concentrations were correlated with possible sources of indoor particles and with respiratory health impacts. RESULTS Daily smoking, smoking more than 5 cigarettes per day at home and traffic density in front of the window of childrens room were found to be related to indoor exposure by particles of different diameters. High indoor particle exposures were associated with an increased risk for the development of obstructive bronchitis and in some extent of non-obstructive bronchitis. The strongest impact was observed for the mass concentration of particles <1 μm and the number concentration of particles >0.5 μm. The risk increases still remain significant if tested for stability changing the number of adjustment variables or omitting randomly selected cases, respectively. CONCLUSION Our results show significant associations between indoor particle concentrations and the risks for respiratory diseases in young children. The applied short-term measurements can help to assess the health risks of indoor particles with different sizes within epidemiological studies.

Maternal and cord blood miR-223 expression associates with prenatal tobacco smoke exposure and low regulatory T-cell numbers

BACKGROUND There is evidence that microRNAs (miRNAs) are sensitive to environmental stressors, including tobacco smoke. On the other hand, miRNAs are involved in immune regulation, such as regulatory T (Treg) cell differentiation. The aim of the present study was to investigate the association between prenatal tobacco smoke exposure, miRNAs, and Treg cell numbers. METHODS Within a prospective mother-child study (Lifestyle and Environmental Factors and Their Influence on Newborns Allergy Risk), we analyzed the expression of miR-155 and miR-223 together with Treg cell numbers in maternal blood during pregnancy, as well as in cord blood (n = 441). Tobacco smoke exposure was assessed based on questionnaire answers and maternal urine cotinine levels. Additionally, the concentration of smoking-related volatile organic compounds was measured in dwellings of study participants. RESULTS Both maternal and cord blood miR-223 expressions were positively correlated with maternal urine cotinine levels. An association was also found between maternal miR-223 expression and indoor concentrations of benzene and toluene. High miR-223 expression was associated with lower Treg cell numbers in maternal and cord blood. Furthermore, children with lower Treg cell numbers at birth had a higher risk of atopic dermatitis during the first 3 years of life. The concentration of the toluene metabolite S-benzylmercapturic acid in maternal urine was associated with decreased cord blood, but not maternal blood, miR-155 expression. A relationship between miR-155 expression and Treg cell numbers was not found. CONCLUSIONS For the first time, we show that maternal tobacco smoke exposure during pregnancy correlates with the level of miRNA-223 expression in blood, with an effect on childrens cord blood Treg cell numbers and subsequent allergy risk.

Reduced IFN-γ- and enhanced IL-4-producing CD4+ cord blood T cells are associated with a higher risk for atopic dermatitis during the first 2 yr of life

Herberth G, Heinrich J, Röder S, Figl A, Weiss M, Diez U, Borte M, Herbarth O and Lehmann I, for the LISA study group. Reduced IFN‐γ‐ and enhanced IL‐4‐producing CD4+ cord blood T cells are associated with a higher risk for atopic dermatitis during the first 2 yr of life.
Pediatr Allergy Immunol 2010: 21: 5–13.
© 2009 John Wiley & Sons A/S