ICH3, a selective alpha7 nicotinic acetylcholine receptor agonist, modulates adipocyte inflammation associated with obesity.

PURPOSE: The alpha7 nicotinic acetylcholine receptor (α7nAChR), involved in the modulation of inflammation and insulin sensitivity, is downregulated in white adipose tissue (WAT) of obese patients. This study aims to test the ability of a selective synthetic α7nAChR agonist, the spirocyclic Δ2-isoxazoline derivative (R)-(-)-ICH3 (ICH3), to counteract acute inflammation and obesity-associated modifications in WAT. METHODS: We employed the LPS-septic shock murine model, human primary adipocytes and diet-induced obese (DIO) mice. Inflammatory factor expression was assessed by ELISA and quantitative real-time PCR. Flow cytometry was employed to define WAT inflammatory infiltrate. Insulin signaling was monitored by quantification of AKT phosphorylation. RESULTS: In the septic shock model, ICH3 revealed antipyretic action and reduced the surge of circulating cytokines. In vitro, ICH3 stimulation (10 µM) preserved viability of human adipocytes, decreased IL-6 mRNA (P < 0.05) and blunted LPS-induced peak of TNFα (P < 0.05) and IL-6 (P < 0.01). Chronic administration of ICH3 to DIO mice was associated with lower numbers of CD8+ T cells (P < 0.05) and to changed WAT expression of inflammatory factors (Hp, P < 0.05; CD301/MGL1, P < 0.01; Arg-1, P < 0.05). As compared to untreated, ICH3 DIO mice exhibited improved insulin signaling in the skeletal muscle (P < 0.01) mirrored by an improved response to glucose load (ipGTT: P < 0.05 at 120 min). CONCLUSIONS: We proved that ICH3 is an anti-inflammatory drug, able to reduce inflammatory cytokines in human adipocytes and to blunt the effects of obesity on WAT inflammatory profile, on glucose tolerance and on tissue insulin sensitivity.

Profiles of Birch Sensitization (Bet v 1, Bet v 2, and Bet v 4) and Oral Allergy Syndrome Across Italy.

BACKGROUND: Birch allergy (BA) is a common pollinosis caused by the allergens Bet v 1, Bet v 2, and Bet v 4. Oral allergy syndrome (OAS) is frequently associated with BA. A gradient of sensitization to birch allergen across Europe has been reported. Therefore, this study aimed to investigate the birch sensitization profile, including OAS, across Italy. METHODS: We performed a retrospective study of 854 patients (391 males, mean age 35.9 years, range 18-93 years): 196 patients were recruited in Genoa, 188 in northern Italy, 359 in central Italy, and 111 in southern Italy. Serum IgE to Bet v 1, Bet v 2, and Bet v 4 was assessed, and OAS was analyzed. RESULTS: With respect to the geographical path Genoa-North-Center-South, the frequency of sensitization to Bet v 1 decreased significantly (P<.0001) from Genoa (95.41%) to southern Italy (58.56%). The frequency of sensitization to Bet v 2 increased significantly (P<.0001) from Genoa (6.12%) to southern Italy (52.25%). The frequency of Bet v 4 also increased significantly (P=.0002) from Genoa (6.12%) to southern Italy (14.41%). The distribution of patients with OAS differed significantly across the areas (P<.0001), the most marked difference ranging between 33.5% in Genoa and 76.9% in northern Italy. The frequency of birch allergens correlated with OAS in central Italy only. CONCLUSIONS: The present study demonstrated a significant difference between sensitization to birch and its clinical expression across Italy.

-295 T-to-C promoter region IL-16 gene polymorphism is associated with Whipple's disease.

Whipple's disease (WD) is a rare systemic condition caused, in genetically predisposed subjects, by Tropheryma whipplei, a common bacterium widespread in the environment. The relevance of genetic predisposition in WD is shown by the association with HLA alleles DRB1*13 and DQB1*06 and by the demonstration that, in patients with WD, the cytokine genetic profile is skewed toward a Th2 and Treg response. Since IL-16 is involved in hampering the development of a protective macrophagic response against Tropheryma whipplei, we investigated whether the genetic background of IL-16 is different between patients with WD and controls. The -295 T-to-C polymorphism of the promoter region of the IL-16 gene was studied in 90 patients with WD and 152 healthy controls. Levels of serum IL-16 protein were also tested. The frequency of the wild type T allele was significantly higher in patients with WD compared to the controls (155/180 vs. 235/304; p = 0.02 for the Chi(2) test), odds ratio 1.82 [95 % confidence interval (CI) 1.07-3.10]. The TT genotype was found in 65/90 patients with WD and 88/152 controls (p = 0.026). No relationship was found between serum levels of IL-16 and genotypes. Although the functional consequences of this genetic background on levels of IL-16 and on the course of the disease are still unknown, we found, for the first time, that the wild type T allele and the TT genotype of the -295 polymorphism are associated with WD.

TRYPTASE AND HISTAMINE MAY SUPPORT ORAL FOOD CHALLENGE IN THE DIAGNOSIS OF ALLERGY.

Allergen-specific immunoglobulin E (IgE) reactions lead to acute degranulation of mast cells and basophils and release of stored mediators, particularly tryptase and histamine, which can be measured in vitro after reactions. The aim of this study was to investigate the utility of serum tryptase and plasma histamine during oral food challenge (OFC) in 103 children with suspected food allergy, in order to support the diagnosis of a IgE-mediated reaction. Blood samples for serum tryptase and plasma histamine were collected before the OFC and after the onset of allergic symptoms or after 60 minutes from test completion. Serum tryptase and plasma histamine were measured by a fluoroenzyme immunoassay (ImmunoCAP; ThermoFisher, Uppsala, Sweden) according to the manufacturer’s instructions. A correlation between serum tryptase and plasma histamine distributions was observed after OFC (p=0.0035). A correlation was also observed for both serum tryptase and plasma histamine before and after OFC (p less than0.0001). Subjects with positive response to OFC had significantly higher values (p = 0.0375) of serum tryptase compared to subjects with negative response. The plasma histamine distribution showed a significant difference between measurements before and after OFC, both in the complete population (p less than 0.0001), and considering the response (negative OFC: p less than 0.0001; positive OFC: p=0.0181). The diagnostic work-up of IgE- mediated food allergy may include determination of serum tryptase and plasma histamine, in order to support the results of OFC. These markers are strongly related to the same IgE-mediated mechanism and, as they can be both easily measured, can confirm the allergic nature of a reaction in the real-life setting of food allergy.

WALNUT SENSITIZATION IN PEDIATRIC AGE: A PRELIMINARY STUDY.

Walnut consumption has recently become a healthy dietary habit worldwide, due to its positive benefits in reducing cholesterol levels and oxidative stress; this has resulted in an increase in individual consumption, global production and risk of developing sensitization and allergy. In general, clinical manifestations of walnut allergy are frequently severe and systemic potentially life-threatening, leading to anaphylaxis both in the pediatric and adult populations. In light of these findings, we performed a preliminary study considering the walnut native allergen and the recombinant Jug r1 in order to evaluate their role in atopic diseases.

SERUM IMMUNOGLOBULIN IgE IN A PEDIATRIC POPULATION: A RETROSPECTIVE ANALYSIS.

UNLABELLED: Allergic sensitization is mediated by immunoglobulin E (IgE) and an increase of their total value is frequently used to complete a correct diagnosis of atopy. Serum IgE may be considered a typical biomarker for the allergic phenotype. The aim of this study was to evaluate total serum IgE, according to sensitizations and to find a cut off to discriminate between atopic and non-atopic subjects. Seven hundred and ninety-five patients were enrolled in this study. Serum levels of total IgE were measured by a fluorescence immunoassay (ImmunoCAP; ThermoFisher, Uppsala, Sweden) while specific IgE levels were measured by immunofluorometric assay (ImmunoCAP; ThermoFisher, Uppsala, Sweden). Both tests were expressed in kU/L, according to manufacturer’s instructions. RESULTS: A difference for total IgE, according to the gender, has been found (p = 0,0012 ) with higher values for males than for females. A correlation has been found between total IgE and specific IgE, even distinguishing the population in sensitized and non-sensitized. A statistically significant difference has been found according to the presence or the absence of sensitization (p less than 0.0001) and also considering mono-sensitized and polysensitized patients (p less than 0.0001). ROC analysis has been performed to define a cut off for total serum IgE, according to sensitization and to the type of sensitization (mono-sensitization or poly-sensitization). Finally multiple regression models have been performed to describe total IgE response (positive or negative) and to predict total IgE values. Since clinical limitations are well known, total IgE provide a useful aid to define atopy, allowing the clinician to carry out further investigations in patients with total IgE values beyond normal limits.

Impact of individual molecular components in determining primary sensitization to latex.

Allergy to natural rubber latex emerged as one of the main allergies at the beginning among some professional groups and the general population. Sensitization and development of latex allergy have been attributed to exposure to products containing residual latex proteins. The prevailing cross-reactivity of latex proteins with other food allergens is of great concern. Numerous purified allergens are currently available, which greatly help in patient management, thus determining their specific profile. We conducted a multicenter study to investigate changes, from the ROC analysis, in the characteristics of patients with latex allergy by measuring its major protein components. Sensitization to latex proteins is crucial because it highlights the cross reactivity to inhalants (pollen) and food (fruit). It is very essential in an accurate and specific clinical setting.

Adenoid hypetrophy: definition of some risk factors.

Adenoids removed for airway obstruction and-or recurrent infections have been studied to identify a possible mechanism to explain chronicity. In this regard, macrophages may play a relevant pathogenic role as well as neutrophils during bacterial infections and eosinophils in allergic inflammation. Therefore, this study aimed at investigating some mediators as surrogate markers of inflammation in children who had to undergo to adenoidectomy. Globally, 67 children (25 females, 42 males, mean age 4.9 years), affected by persistent obstruction caused by adenoid hypertrophy were consecutively enrolled into the study. Blood samples were collected from patients and controls to determine serum CD163, Myeloperoxidase (MPO) and ECP. There were significant differences between patients and controls for serum CD163 (p less than 0.0001); MPO (p less than 0.0001); serum ECP (p less than 0.0001). This study demonstrated some risk factors for severe AH: apnoea, recurrent respiratory infections, and high serum CD163 levels.

Pentraxin 3 serum levels in children with atopic dermatitis.

PTX3 behaves as an acute-phase response protein as its blood levels rapidly and dramatically increase during endotoxic shock, sepsis, and other inflammatory and infectious conditions. Therefore, this study was designed to investigate a possible role of PTX3 in children with Atopic Dermatitis (AD). One-hundred-and-thirty-six patients (37 females, 99 males, mean age 10.4 years) were enrolled in the study. One hundred patients (74%) had only respiratory symptoms (allergic rhinitis and/or bronchial asthma); thirty-six patients (26%) showed dermatitis associated with respiratory allergy (allergic rhinitis and/or bronchial asthma). PTX3 levels were higher in children with AD and there was a significant correlation between serum PTX3 levels and SCORAD index (p-value=0.0001, rho=0.658). Therefore, this study may show that PTX3 might be a reliable marker for the severity of AD in children with respiratory allergy.

Pentraxin 3 in children suffering from allergic rhinitis.

Allergic disorders are typically characterized by an inflammatory response to allergen exposure. PTX3 behaves as an acute-phase response protein as there is a relationship between PTX3 plasma levels and disease severity. Therefore, this study was designed to investigate a possible role of PTX3 in children with allergic rhinitis. One hundred patients (28 females, 72 males, median age 11 years) were enrolled in the study. All patients were monosensitized: 43 (43%) to seasonal allergens (Graminaceae), 57 (57%) to perennial allergens (house dust mites, cat and dog epithelium, alternaria tenuis). Patients' blood samples for assessing serum PTX3 levels were performed during the spring. Children with rhinitis had higher PTX3 levels and there was a significant relationship between symptom severity and serum levels. Therefore, this study shows that PTX3 serum levels could be a reliable marker for symptom severity in children with allergic rhinitis.

Patients with oral allergic syndrome to apple have intense proliferative response to BET V 1.

Patients with pollen allergy may frequently present an additional food-related allergy (Oral Allergic Syndrome, OAS), as consequence of cross-reactivity between pollen allergens (mainly birch, hazelnut, alder, mugwort) and vegetable allergens. The aim of this study was to evaluate the effect on Bet v 1-induced T cell proliferation exerted by the presence of OAS in birch patients. Fourteen allergic patients were evaluated (6 males, mean age 35.8 years). All of them were monosensitized to birch and suffered from allergic rhinitis: 4 had also OAS to apple. Proliferation of peripheral mononuclear cells was evaluated using Bet v 1 and non-specific stimuli. OAS had higher proliferation than non-OAS patients. In addition, there were significant relationships between immunological and clinical parameters in OAS patients. This study evidences that OAS characterizes a more severe form of birch allergy: as OAS patients had higher SI, circulating eosinophils, and IgE levels. Thus, this study confirms the previous report and underlines the relevance of measuring recombinant birch allergen as higher values may suggest a reliable prediction of OAS.

Tetanus toxoid IgE may be useful in predicting allergy during childhood.

Hypersensitivity reactions after immunization with tetanus toxoid are occasionally observed in atopic and non-atopic individuals. High IgE levels in infancy may predict subsequent allergy. The aims of this study were: i) to evaluate the role of specific IgE to tetanus toxoid in children in response to tetanus immunization and the possible factors associated with specific IgE levels, and ii) to investigate the correlation between specific IgE levels to tetanus toxoid and the late development of allergy (up to 12 years). Initially, 278 healthy infants (152 males and 126 females, aged 12 months) living in an urban city were screened for serum total IgE and specific IgE to tetanus toxoid, after having obtained informed consent from parents. After 12 years, 151 children could be evaluated. Total IgE summed with tetanus specific IgE were significantly associated with allergy at 12 years. In conclusion, this study demonstrates that serum total IgE and tetanus specific IgE may be predictive of subsequent allergy onset.

Serum IL-9 levels and sublingual immunotherapy: preliminary report.

Th9 is a new T cell subset characterized by IL-9 production. It has been reported that serum IL-9 levels are related with symptom severity in patients with allergic rhinitis (AR). This study is aimed at investigating whether serum IL-9 may be modulated by sublingual immunotherapy (SLIT) in patients with persistent AR due to Parietaria allergy. Twenty-one AR patients (9 males, median age 41 years) successfully treated with SLIT and 52 AR patients (25 males, median age 34 years) treated only with drugs were evaluated during the pollen season. Serum IL-9 was dosed in all patients. SLIT-treated patients showed significantly lower serum IL-9 levels than untreated AR patients (p <0.0001). In conclusion, this preliminary study shows that a single pre-seasonal SLIT course might modulate serum IL-9.

Serum neopterin levels in spontaneous urticaria and atopic dermatitis.

Serum neopterin may be considered a diagnostic marker of the degree of activation of the immune system. This preliminary study was performed to measure serum neopterin levels in patients with acute spontaneous urticaria (ASU), chronic spontaneous urticaria (CSU) and atopic dermatitis (AD). In total, 180 patients [96 men, 84 women; mean age 23.1 years; 41 with spontaneous urticaria (13 ASU and 28 CSU), 48 with AD] and 96 healthy controls were enrolled in the study. Patients with ASU had the highest neopterin levels, and all three groups of patients (ASU, CSU and AD) had higher values than normal subjects. This preliminary study demonstrates that serum neopterin could be a biomarker of immune activation in patients with SU or AD.

Comparison of serum specific IgE and skin prick test in polysensitized patients.

The aim of this study is to evaluate serum specific-IgE in a large group of polysensitized patients with the same SPT result (such as ++++) comparing two diagnostic methods. Six hundred ten patients (310 females; median age 32 years) suffering from allergic rhinitis were studied. Serum specific-IgE were measured by ImmunoCap assay. Skin prick test was also performed. There was a significant difference between serum specific-IgE values in these polysensitized patients. In conclusion, the serum specific-IgE measurement in polysensitized patients seems to be more appropriate than SPT.

Allergen-specific Ig classes in non-allergic individuals.

Allergic rhinitis (AR) is characterized by Th2 polarized immune response, such as increased IL-4 and reduced IFN-gamma production, and by a functional defect of T regulatory cells. This impaired immune response profile influences the pattern of immunoglobulin production in allergic patients. However, there is no study that has explored the pattern of allergen-specific Immunoglobulin (Ig) classes in normal subjects. Therefore, the aim of this study is to investigate the allergen-specific IgE, IgG, IgG4, and IgA serum level pattern in a group of non-allergic individuals. Forty healthy non-allergic subjects were enrolled. Serum allergen-specific IgE, IgG, IgG4, and IgA for mites, cat, Parietaria, grasses, and birch were quantitatively determined by ELISA method. Allergen-specific IgE, IgG, IgG4, and IgA serum levels were significantly different for each tested allergen (p=0.0001 for each class). In conclusion, the present study provides the first evidence that immunoglobulin production pattern depends on the specificity of the allergenic response in non-allergic subjects as well as in allergic patients. In addition, this study is the first that quantitatively evaluates the Ig classes.

Soluble serum HLA-G in children with allergic rhinitis and asthma.

Allergic rhinitis (AR) and asthma are characterized by Th2 polarized immune response. Soluble HLA (sHLA) molecules play an immunomodulatory activity. It has been reported that both molecules are increased in sera of patients with pollen-induced allergic rhinitis studied outside the pollen season. To date, however, no study has investigated them in AR children. The aim of this preliminary study is to evaluate serum sHLA-G levels in children with AR or asthma patients and in a group of healthy controls. Forty-seven symptomatic allergic patients were enrolled. A group of 50 healthy subjects was considered as control. Serum sHLA-G levels were determined by the immunoenzymatic method. Children with AR had significantly higher levels of sHLA-G molecules than normal controls or children with allergic asthma. However, there is no difference between children with AR and asthmatics. In conclusion, the present study provides the preliminary evidence that serum sHLA-G molecules are significantly increased in children with AR.