Gunda Herberth

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.

Chemerin as a mediator between obesity and vascular inflammation in children.

CONTEXT The chemoattractant protein chemerin has recently been shown to be expressed in adipose tissue. OBJECTIVE We aimed to evaluate the association of chemerin with obesity and early-onset metabolic and vascular sequelae in children. DESIGN We quantified chemerin serum levels in 69 lean and 105 obese children and assessed associations with metabolic and cardiovascular parameters. In addition, a potential direct effect of chemerin on the expression of endothelial adhesion molecules and cell viability was assessed in human coronary artery endothelial cells in vitro. RESULTS Chemerin concentrations were significantly higher in obese compared to lean children and correlated with obesity-related parameters such as body mass index sd score, leptin, and skinfold thickness. Moreover, we identified significant associations with the measures of inflammation high-sensitivity C-reactive protein and white blood cell count, as well as with the markers of endothelial activation intercellular adhesion molecule-1 (ICAM-1) and E-selectin. Multiple regression analyses confirmed chemerin as the strongest predictor of ICAM-1 and E-selectin independent of body mass index sd score. Likewise, on the cellular level, chemerin induced ICAM-1 and E-selectin expression in endothelial cells in vitro, whereas VCAM-1 and eNOS expression and endothelial cell viability were unaffected. CONCLUSION Our results suggest an association of chemerin with obesity and inflammatory and endothelial activation markers and support a role for chemerin as a molecular link between increasing fat mass and an early atherogenic risk profile in obese children.

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

Vaccination with hybrids of tumor and dendritic cells induces tumor-specific T-cell and clinical responses in melanoma stage III and IV patients.

Hybrid cell vaccination was developed as therapeutic approach that aims at stimulating tumor‐specific cytotoxic T‐cell responses in cancer patients using hybrids of autologous tumor and allogeneic dendritic cells. We tested this concept and the efficacy of the vaccines in inducing clinical and immunologic responses in a clinical trial with melanoma stage III and IV patients. Of the 17 patients evaluated, 1 experienced a complete response, 1 a partial response and 6 stable disease with remarkably long survival times. In 11 of 14 patients analyzed, high‐frequency T‐cell responses to various tumor‐associated T‐cell epitope were induced and detectable in the peripheral blood. These immune responses were detected in clinical response patients as well as nonresponders. Failures of clinical responses in all the cases investigated correlated with loss of antigen expression and presentation. Hybrid cell vaccination thus proves effective in inducing tumor‐specific T‐cell responses in cancer patients.

Maternal immune status in pregnancy is related to offspring's immune responses and atopy risk

To cite this article: Herberth G, Hinz D, Röder S, Schlink U, Sack U, Diez U, Borte M, Lehmann I. Maternal immune status in pregnancy is related to offspring’s immune responses and atopy risk. Allergy 2011; 66: 1065–1074.

Chlorobenzene induces oxidative stress in human lung epithelial cells in vitro

Chlorobenzene is a volatile organic compound (VOC) that is widely used as a solvent, degreasing agent and chemical intermediate in many industrial settings. Occupational studies have shown that acute and chronic exposure to chlorobenzene can cause irritation of the mucosa of the upper respiratory tract and eyes. Using in vitro assays, we have shown in a previous study that human bronchial epithelial cells release inflammatory mediators such as the cytokine monocyte chemoattractant protein-1 (MCP-1) in response to chlorobenzene. This response is mediated through the NF-kappaB signaling pathway. Here, we investigated the effects of monochlorobenzene on human lung cells, with emphasis on potential alterations of the redox equilibrium to clarify whether the chlorobenzene-induced inflammatory response in lung epithelial cells is caused via an oxidative stress-dependent mechanism. We found that expression of cellular markers for oxidative stress, such as heme oxygenase 1 (HO-1), glutathione S-transferase pi1 (GSTP1), superoxide dismutase 1 (SOD1), prostaglandin-endoperoxide synthase 2 (PTGS2) and dual specificity phosphatase 1 (DUSP1), were elevated in the presence of monochlorobenzene. Likewise, intracellular reactive oxygen species (ROS) were increased in response to exposure. However, in the presence of the antioxidants N-(2-mercaptopropionyl)-glycine (MPG) or bucillamine, chlorobenzene-induced upregulation of marker proteins and release of the inflammatory mediator MCP-1 are suppressed. These results complement our previous findings and point to an oxidative stress-mediated inflammatory response following chlorobenzene exposure.

SM5-1: a new monoclonal antibody which is highly sensitive and specific for melanocytic lesions.

Abstract Antibodies such as HMB-45 and anti-S100 protein have been widely used as markers of malignant melanoma despite evidence that HMB-45 has a sensitivity of only 67–93% and S100 is nonspecific for melanoma. Using a subtractive immunization protocol in a mouse model of human melanoma, we have generated several monoclonal antibodies with putative specificity for melanoma. After initial screenings, the antibody SM5-1 was chosen because of its intriguing reactivity with melanocytic tumors in both frozen and paraffin sections. The immunohistochemical staining of SM5-1 was studied in paraffin-embedded specimens of 401 melanomas ( n = 401; 250 primary melanomas, 151 metastases), melanocytic nevi of the skin ( n = 16), nonmelanocytic neoplasms ( n = 84). The results were compared with HMB-45 and anti-S100 staining. All antibodies reacted with nevi and 97–99% with primary melanomas. Whereas both SM5-1 and anti-S100 stained 96% (146/151) of melanoma metastases, HMB-45 correctly identified only 83% (126/151). All HMB-45-negative metastases were positive for SM5-1. Whereas neither SM5-1 nor HMB-45 stained any of 84 specimens from 40 different nonmelanocytic neoplasms, anti-S100 was positive in 21/84 (25%). While the staining pattern of SM5-1 was mostly homogeneous, small tumor areas in some metastases remained unstained. Staining with SM5-1 was also observed in perivascular dendritic cells, in plasma cells, some myofibroblasts and the secretion of eccrine sweat glands. Nonactivated epidermal melanocytes, keratinocytes, endothelial cells, smooth muscle cells and peripheral nerves were all negative for SM5-1. These results suggest that SM5-1 is highly specific, as well as sensitive, for melanocytic lesions and is useful in the immunohistochemical evaluation of melanoma.

Differential expression of MART-1, tyrosinase, and SM5-1 in primary and metastatic melanoma.

The new monoclonal antibody SM5-1 has been shown to have significant advantages in immunohistochemistry of melanoma over currently used antibodies such as HMB-45 or anti-S100. In this study we compared the immunohistological staining pattern of SM5-1 with that of the more recently described antibodies A103 (anti-MART-1) and T311 (anti-Tyrosinase) in 344 paraffin-embedded melanoma specimens, consisting of 101 primary melanomas (77 SSM, 16 NM, 6 ALM, 2 LMM) and 243 melanoma metastases. The overall reactivity of SM5-1 for all the specimens was 92% (318/344) compared with 83% (285/344) for MART-1 and 71% (245/344) for Tyrosinase. Staining of melanoma metastases with SM5-1 was found in 91% (222/243), but only in 77% (187/243) with A103 and 63% (154/243) with T311, respectively. Staining with SM5-1 was more homogenous with 196 of 243 (80%) of metastatic lesions showing 50% or more positively stained cells within the lesions, whereas A103 and T311 did so in 141 of 243 (58%) or 117 of 243 (48%) of the lesions. With regard to staining intensity of SM5-1, 157 of 243 (64%) showed a strong or very strong staining intensity, whereas A103 and T311 did so in 85 of 243 (35%) or 70 of 243 (29%) of the lesions. Staining intensity and percentage positivity correlated well for SM5-1, because from the 58 very strong positive metastases 55 showed staining in more than 75% of the cells within a lesion. Importantly, 52 of 56 MART-1-negative metastases and 81 of 89 Tyrosinase-negative metastases were positive for SM5-1. Thirty-eight metastases (15.6%) were negative for both A103 and T311. Of those, 35 (92.1%) were positive for SM5-1, demonstrating the value of SM5-1 in identifying melanoma-associated antigen-negative lesions. We conclude that SM5-1 could be of value in immunohistochemistry of melanoma.