Caterina Cuppari

TLR2 and TLR4 gene polymorphisms and atopic dermatitis in Italian children: a multicenter study.

Background Genetic factors have an important role in atopic dermatitis (AD) predisposition. Toll like receptor (TLR) are important mediators between environment and immune system. There are incosnsitent studies about TLSR polymorphisms in AD. Objective This study examined whether single nucleotide polimorphisms (SNPs) in the genes for TLR2 and TLR4 could be associated with the AD phenotypes and with its clinical severity in a large group of Italian children. Methods 187 children with Ad and 150 healthy children were recruited. AD severity was assessed by SCORAD. TLR2 (A-16934T and R753Q polymorphisms) and TLR4 (D299G and T399I SNPs) were genotyped by PCR-RFLP. Results The frequency of the R753Q was significantly higher in AD children (16.0%) compared with controls (6.0%, P=0.004; OR2.99,95%CI 1.39–6.41; RR 1.46,95%CI 1.14–1.69). AD patients a significantly different frequency of the D299G SNP (14.9%) in comparison with the controls (6.6%, P = 0.01; OR 2.46, 95%CI 1.17–5.17; RR 2.24; 95%CI 1.15–4.45). Conclusion Children with AD may have a distinct genotype and the TLR-2 R753Q SNP was prevalent in a subset of patients with AD characterized by a more severe clinical picture.

Nasal High-Mobility Group Box-1 Protein in Children with Allergic Rhinitis

Background: Allergic rhinitis (AR) is characterized by an inflammatory reaction. High-mobility group box-1 protein (HMGB1) has many characteristics similar to classic proinflammatory cytokines. No study has yet investigated its role in AR. The aim of this study was to measure HMGB1 levels in the fluid recovered from nasal lavage in children with untreated AR and in control subjects. Materials: The study was conducted on 104 AR subjects (48 males and 56 females, median age 10.3 ± 3.4 years) and 97 healthy children (42 males and 55 females) who were age-matched (median age 9.8 ± 4.1 years). Total serum immunoglobulin E, peripheral eosinophils and nasal symptoms assessed by visual analog scale (VAS) were considered. HMGB1 was measured using an ELISA assay. Results: HMGB1 levels in nasal lavage fluid were higher in AR children than in the control group (96.9 ± 19.3 vs. 9.27 ± 4.01 ng/ml; p < 0.001). There was a very strong relationship between HMGB1 levels and VAS values in AR children (r = 0.919). Considering the symptom severity assessed by VAS, there was a relationship between HMGB1 and VAS in all AR subgroups: more evident in the severe subgroup (r = 0.727). Conclusions: Nasal HMGB1 has significantly increased in children with AR and is significantly related to symptom severity.

Obesity and breastfeeding: The strength of association

UNLABELLED Obesity and attendant co-morbidities are an emergent problem in public health. Much attention has focused on prevention, especially during the perinatal period. Breastfeeding is considered a possible protective factor for obesity in childhood, influencing gene-neuroendocrine-environment-lifestyle interaction. Therefore, breastfeeding and its longer duration are probably associated with lower development of childhood obesity. Through human milk, but not formula, the child assumes greater bioactive factors contributing to immunological, endocrine, development, neural and psychological benefits. Contrarily, other studies did not confirm a critical role of breast milk. Confounding factors, especially maternal pre-pregnancy overweight, may influence breastfeeding effects. This review summarises what is known about the possible relationship between breastfeeding and prevention of obesity development. CONCLUSION Breastfeeding appears to represent a protective factor for obesity in childhood, although evidence is still controversial and underlying mechanisms unclear. Further research is needed to improve knowledge on overweight/obesity and breastfeeding.

Serum IL-23 strongly and inversely correlates with FEV1 in asthmatic children.

Background: Recently, Th17 cells have been found to participate in the pathogenesis of allergic asthma. IL-23 is a cytokine that may be implicated in modulating Th17 response. This study aimed at evaluating IL-23 and relating it to lung function in asthmatic children. Methods: Seventy-eight asthmatic children and 40 healthy children were evaluated. Spirometry and serum IL-23 measurement (ELISA kit) were performed in all asthmatic children. Results: IL-23 levels were higher in asthmatic than in healthy children (p < 0.001). There was a strong inverse relationship between FEV1 and IL-23 (r = –0.787). Conclusions: This preliminary study suggests that serum IL-23 could be a suitable marker of bronchial function impairment in allergic asthmatic children.

Role of the diet as a link between oxidative stress and liver diseases

Oxidative stress is caused by an imbalance between the production of reactive oxygen (free radicals) and the bodys ability (antioxidant capacity) to readily detoxify the reactive intermediates or easily repair the resulting damage. An adequate diet, characterized by daily intake of foods associated with improvements in the total antioxidant capacity of individuals and reduced incidence of diseases related to oxidation, can modulate the degree of oxidative stress. In fact, diet-derived micronutrients may be direct antioxidants, or are components of antioxidant enzymes, leading to improvement of some indicators of hepatic function. However, although their increased dietary intake might be beneficial, literature data are still controversial. This review summarizes what is known about the effects of diet nutrients on oxidative stress, inflammation and liver function. Moreover, we have analyzed: (1) the main nutritional components involved in the production and/or removal of free radicals; and (2) the role of free radicals in the pathogenesis of several hepatic diseases and related comorbidities.

Investigation of the eotaxin gene -426C-->T, -384A-->G and 67G-->a single-nucleotide polymorphisms and atopic dermatitis in Italian children using family-based association methods.

Background.  Eotaxin plays an important role in atopic dermatitis (AD) as a potent chemoattractant and activator of eosinophils and T‐helper 2 lymphocytes.

Identification of α-thalassemia mutations in subjects from Eastern Sicily (Italy) with abnormal hematological indices and normal Hb A2

We analyzed the prevalence of α-thalassemia mutations in 298 subjects from Eastern Sicily (Italy) with reduced mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH), normal HbA2 and HbF, and normal serum iron. In 131 subjects (43.9%) we found six different genotypes of α-thalassemia: -α3.7/αα (36.6%), -α3.7/-α3.7 (27.5%), –MED/αα (10.0%), -α20.5/αα (9.1%), αHphIα/αα (8.4%), αHphIα/αHphIα (6.1%), and -α3.7/αHphIα (2.3%). Our data underline that in Eastern Sicily populations, the molecular screening of α-thalassemia mutations and/or deletions may be useful to better characterize the clinically asymptomatic subjects with a slightly reduced MCV and MCH and normal iron status.

HMGB1 levels in children with atopic eczema/dermatitis syndrome (AEDS)

To the Editor, Atopic eczema/dermatitis syndrome (AEDS) is a chronic relapsing-remitting inflammatory skin disorder beginning usually in early childhood, characterized by a skin barrier dysfunction resulting in epidermal damage and altered permeability to allergens and microbes (1). Depending on whether there is an association with or without immunoglobulin (Ig)E sensitization, AEDS may be defined as atopic (aAEDS) or nonatopic (naAEDS), respectively. However, it is currently unclear whether aAEDS and naAEDS are really two different diseases or whether AEDS starts in early infancy as naAEDS phenotype without evidence of IgE sensitization and then progresses through allergic sensitization to the IgE-associated phenotype (aAEDS). Moreover, in infants, the progression from AEDS to other forms of allergic diseases (e.g., rhinitis and asthma), usually referred to as the ‘atopic march’, as well as their relationships with one other, seems more complicated than a simple evolution of one condition into another and one which does not always follow the classic sequential pattern of these illnesses (1). Although the exact etiology of AEDS remains unknown, both genetic and environmental factors have been proposed to play crucial pathogenetic roles. However, various factors including immunological abnormalities have been suggested to contribute to the pathogenesis and development of AEDS. In this regard, we recently studied serum interleukin (IL)-17, IL-23, and IL-10 levels in 181 children with AEDS (99 males, 82 females; mean age: 8.31 3.21 years), and we found significantly higher levels of IL-17 and IL-23 and significantly lower levels of IL-10 than in a healthy control group. Moreover, serum IL-17 and IL-23 levels, but not IL-10 levels, were significantly higher in aAEDS than in naAEDS subtypes. Additionally, this immune biomarker phenotype significantly correlated with score atopic dermatitis (SCORAD) values. Interestingly, in the aAEDS subjects, we found a concomitant association of atopic diseases such as asthma and rhinitis, and higher serum IL-17 and IL-23 levels than in children with nonallergic sensitization (naAEDS) (2). To add new data on a ‘double-face’ disease, we, firstly, investigated the levels of high-mobility box 1 (HMGB1), an inflammatory marker belonging to the alarmin family, in the patients’ sera frozen of our previous study (2). High-mobility group box (HMGB) 1, is implicated as a mediator of both infectious and non-infectious inflammatory conditions. Extracellular HMGB1 acts as an endogenous danger signal and binds to Toll-like receptor (TLR) 2, TLR4, receptor for advanced glycation end products (RAGE), and chemokine receptors. Recent studies suggest that the elevated levels of extracellular HMGB1 have been implicated in association with several disease states, including sepsis, and autoimmune disease such as arthritis, meningitis, ischemia– reperfusion injury, cancer, psoriasis, and local inflammation. Furthermore, although several studies have assessed the role of HMGB1 in immune-mediated tissue-damaging responses (3, 4) of some allergic diseases (asthma and rhinitis), to date, no data have been reported in children with AEDS (5, 6) and only a few data in mice (7, 8). In this report, we analyzed the HMGB1 levels in both patients with naAEDS and patients with aAEDS, the relationship between serum HMGB1 levels and clinical severity of the disease, and, finally, the HMGB1 levels in different allergic phenotypes such as aAEDS plus allergic sensitization, aAEDS plus rhinitis, aAEDS plus asthma, and aAEDS plus rhinitis and asthma. Moreover, we investigated the relationship between HMGB1 and IL-17/IL-23 axis and IL-10. HMGB1 levels (IBL Shino Test Corporation, Hamburg, Germany) were determined through ELISA according to the manufacturer’s instructions. The data collected were statistically analyzed using a statistical computer software SPSS, version 15.0 (IBM. Statistical Package for the Social Sciences. 2009). A p value of <0.05 was considered to be statistically significant. Statistical analysis was performed with ANOVA test and relative post hoc vs. control. Mean and standard deviations were calculated for the variables, and t-test was employed for the comparisons. For the attributes, percentages were calculated first, and then, v2 test was used for comparisons. Correlations between HMGB1 levels and serum total IgE levels and between SCORAD index and serum IL-17, IL-23, and IL-10 levels were calculated using Spearman’s correlation coefficient. Clinical and laboratory findings of all patients are shown in Table 1. Although no difference was found between aAEDS and naAEDS subtypes (serum HMGB1 levels 19.73 1.68 ng/ml vs. 19.27 3.16 ng/ml, respectively, p = 0.208), serum

Increase in the Level of Proinflammatory Cytokine HMGB1 in Nasal Fluids of Patients With Rhinitis and its Sequestration by Glycyrrhizin Induces Eosinophil Cell Death

Objectives The nuclear protein high mobility group protein box 1 (HMGB1) is a proinflammatory mediator that belongs to the alarmin family of proinflammatory mediators, and it has recently emerged as a key player in different acute and chronic immune disorders. Several lines of evidence demonstrate that HMGB1 is actively released extracellularly from immune cells or passively released from necrotic cells. Because of the ability of HMGB1 to sustain chronic inflammation, we investigated whether the protein is present in nasal fluids of patients with different forms of rhinitis. Methods HMGB1 levels were evaluated in nasal fluids of healthy subjects or rhinitis patients who were treated or not treated with different treatments. Results We report that the level of HMGB1 was significantly increased in nasal fluids of patients with allergic rhinitis, patients with NARES (nonallergic rhinitis with eosinophiliac syndrome), as well as patients with polyps. We also found that a formulation containing the HMGB1-binding compound glycyrrhizin (GLT) reduced the HMGB1 content in nasal fluids of rhinitis patients to an extent similar to that with nasal budesonide treatment. We also found that among the cultured human leukocyte populations, eosinophils released higher amounts of HMGB1. Based on the ability of HMGB1 to sustain eosinophil survival and the ability of GLT to inactivate HMGB1, we report that GLT selectively killed cultured eosinophils and had no effect on neutrophils, macrophages, and lymphocytes. Conclusion Collectively, these data underscore the role of HMGB1 in rhinitis pathogenesis and the therapeutic potential of GLT formulations in treatment of chronic inflammatory disorders of the nasal mucosa.

Breastfeeding and IL-10 levels in children affected by cow’s milk protein allergy: A restrospective study

AIM To assess the protective role of breast-feeding in infants with CMPA-related AEDS as well as IL-10 utility as marker of disease evolution. METHODS 64 breast-feeding children with CMPA-related AEDS (31 males and 33 females; mean age 5.56±2.41months; 21 mild AEDS; 25 moderate AEDS; 18 severe AEDS) and 60 artificial feeding babies (33 males and 27 females; mean age 6.01±2.08months; 26 mild AEDS; 19 moderate AEDS; 15 severe AEDS) were evaluated. In all patients serum IL-10 levels were detected. RESULTS Significant Score Atopic Dermatitis (SCORAD) index point differences between breastfed and not breastfed children (p<0.001) have been detected. The serum IL-10 levels were lower in children with CMPA-related AEDS as compared to the healthy control group (p<0.001). Moreover, a significant inverse correlation between serum IL-10 levels and SCORAD in both enrolled groups has been also noted. In particular, IL-10 levels, in both groups, were significantly lower in children with severe symptoms. Conversely, serum IL-10 levels were significantly increased in children with mild-severe symptoms in both groups. Furthermore, breastfed children, with lower severe symptoms, had higher serum IL-10 levels. Finally, serum total IgE levels were negatively correlated with serum IL-10 levels in both breastfed and non-breastfed children with CMPA-related AEDS (p<0.001). CONCLUSIONS We reported that exclusive breast-feeding induces hyposensitization in children with CMPA-related AEDS and it is associated with minor disease severity and higher serum IL-10 levels, resulting as useful disease-monitor marker.