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Cytotoxicity is the primary function of CD8 + T-cells, also called cytotoxic CD8 + T lymphocytes (or CTLs). Quantification of this capacity is of major importance in diagnostic and research tools. While phenotypic characterization of CTLs is frequent and easily performed, their function is indeed more difficult to assess. CTLs are responsible for the lysis of cells expressing foreign or modified antigen peptides on their MHC class I molecules. Here we describe the detailed protocol used for the in vitro specific lysis of target cells.

Background: Egg allergy is the second most prevalent form of food allergy in childhood. In spite of the evidence accumulated, inoculating egg allergy children with attenuated vaccines grown on chick embryo cell cultures, such as the measles, mumps, and rubella (MMR) vaccine, is regarded (erroneously) as potentially dangerous or even anaphylactogenic, by many. An issue perceived as particularly conflicting also by Health Professionals., Case Presentation: A 15-year-old boy, with a history of severe egg allergy in early infancy, who was still sensitized to egg allergens, including baked egg, had never received MMR vaccination, in fear of possible anaphylaxis, in spite of the fact that this vaccination is mandatory in the first year of life, in Italy. Because of that, he was not allowed to attend school, longer, and was referred to us in order to assess the potential risk of MMR vaccination. Upon thorough allergologic workup, sensitization to MMR vaccine components was excluded by an in vivo approach, consisting in skin prick tests, intradermal tests, and subcutaneous injection test, corroborated by vaccine-specific B-lymphocyte proliferation assay, ex vivo. T-cell proliferation in response to MMR vaccine was also excluded. Eventually, the boy was inoculated with MMR vaccine and was readmitted to school., Conclusions: The diagnostic strategy adopted appears feasible and easy-to-perform and may be adopted in controversial cases (as the one reported), characterized by previous severe allergic reactions to egg. The B-lymphocyte proliferation assay we developed may represent a useful and reliable tool not only in research but also in clinical practice.

In the last decade, an increasing number of randomized controlled trials (RCTs) on biologic therapy in patients with severe asthma have included patient-reported outcomes (PROs) as secondary efficacy measures. The majority of these RCTs showed a benefit in symptoms and quality of life. However, the magnitude of this benefit remains uncertain, because it rarely exceeded the minimal important difference (MID), owing to a significant improvement in the control group (placebo effect). Real-life studies on biologic therapies assessing PRO are scarce. They may support and integrate RCT results through their different experimental design. This real-life retrospective study provides data on 15 patients with difficult-to-treat severe eosinophilic asthma treated with benralizumab up to 6 months. Asthma quality of life questionnaire (AQLQ) and asthma control test (ACT) were assessed and administered at each visit to minimize the Hawthorne effect. Changes in general accepted efficacy measures, such as forced expiratory volume in 1 s (FEV 1 ), peak expiratory flux (PEF), exacerbation rate and blood eosinophils, from baseline were also assessed. AQLQ and ACT improved from 3.9 ± 0.4 to 5.2 ± 0.4 and from 15.6 ± 5.7 to 18.1 ± 5.6, respectively. FEV 1 increased of about 250 ml (+14%). PEF increased from 288 ± 107 to 333 ± 133 l/min. The number of exacerbations requiring OCS courses decreased from 2.8 ± 2.2 to 0.5 ± 0.8. Eosinophil counts dropped to 25.6 ± 15 cells/microliter. In conclusion, most patients reported improvements in AQLQ and ACT greater than MID, suggesting that these outcome represent a sensitive tool in real-life effectiveness studies. Our approach reduced the limitations of transition questions and the Hawthorne effect, increasing findings reliability., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Major scientific societies, such as the EAACI or the AAAAI, do not express any suggestion on which form of allergen immunotherapy (AIT) is to be preferred (subcutaneous immunotherapy, SCIT, vs sublingual immunotherapy, SLIT). This choice could depend on their relative pharmacoeconomic value., Objective: To assess the cost-effectiveness of AIT for grass pollen, administered as SCIT or SLIT., Methods: We created a Markovian Model, to evaluate, in a hypothetical cohort of adult patients suffering from moderate-to-severe rhino-conjunctivitis with or without allergic asthma, the cost-effectiveness of SLIT (tablets, Grazax ® and Oralair ® ) or SCIT (various currently available products, plus indirect nonmedical costs, such as travel and productivity costs) in addition to pharmacological therapy, assuming a 9-year horizon to capture AIT long-term effects. The incremental cost-effectiveness ratio (ICER) was calculated assuming pharmacological therapy as the reference comparator., Results: In the base case, SCIT was slightly more expensive, but more effective than SLIT, being the most cost-effective option (ICER for SCIT, €11 418; ICER for SLIT, €15 212). ICERs greater than €120 000 for both SCIT and SLIT were demonstrated in a scenario assuming that low treatment persistence rates, which are common in real-life, lead to absence of long-term AIT clinical benefit. Considering indirect nonmedical costs SLIT resulted more cost-effective than SCIT (ICER for SCIT, €17 318; ICER for SLIT, €15 212)., Conclusion: In daily practice, AIT for grass pollens may be a cost-effective option only in patients with low discontinuation rates. SCIT, which is less affected by this limitation than SLIT, seems the most cost-effective AIT form., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Aim: The purpose of this study is to describe the main chest radiological features (CXR) of COVID-19 and correlate them with clinical outcome., Materials and Methods: This is a retrospective study involving patients with clinical-epidemiological suspect of COVID-19 infection, who performed CXRs at the emergency department (ED) of our University Hospital from March 1 to March 31, 2020. All patients performed RT-PCR nasopharyngeal and throat swab, CXR at the ED and clinical-epidemiological data. RT-PCR results were considered the reference standard. The final outcome was expressed as discharged or hospitalized patients into a medicine department or intensive care unit (ICU)., Results: Patients that had a RT-PCR positive for COVID-19 infection were 234 in total: 153 males (65.4%) and 81 females (34.6%), with a mean age of 66.04 years (range 18-97 years). Thirteen CXRs were negative for radiological thoracic involvement (5.6%). The following alterations were more commonly observed: 135 patients with lung consolidations (57.7%), 147 (62.8%) with GGO, 55 (23.5%) with nodules and 156 (66.6%) with reticular-nodular opacities. Patients with consolidations and GGO coexistent in the same radiography were 35.5% of total. Peripheral (57.7%) and lower zone distribution (58.5%) were the most common predominance. Moreover, bilateral involvement (69.2%) was most frequent than unilateral one. Baseline CXR sensitivity in our experience is about 67.1%. The most affected patients were especially males in the age group 60-79 years old (45.95%, of which 71.57% males). RALE score was slightly higher in male than in female patients. ANOVA with Games-Howell post hoc showed significant differences of RALE scores for group 1 vs 3 (p < 0.001) and 2 vs 3 (p = 0.001). Inter-reader agreement in assigning RALE score was very good (ICC: 0.92-with 95% confidence interval 0.88-0.95)., Conclusion: In COVID-19, CXR shows patchy or diffuse reticular-nodular opacities and consolidation, with basal, peripheral and bilateral predominance. In our experience, baseline CXR had a sensitivity of 68.1%. The RALE score can be used in the emergency setting as a quantitative method of the extent of SARS-CoV-2 pneumonia, correlating with an increased risk of ICU admission.

Background: Safety and treatment compliance are still considered important shortcomings of subcutaneous immunotherapy (SCIT)., Objective: To assess the rate of side effects (SE) to SCIT and treatment compliance at a hospital medically supervised facility., Methods: A retrospective review of patients with allergic rhino-conjunctivitis (ARC) with or without asthma, who received SCIT to mites and pollens from 1988 to 2018, was performed. The information was collected from patient's allergen immunotherapy forms that had been prospectically filled in by expert physicians., Results: Two thousand two hundred patients (50.2% males; mean age 29.4 ± 11.7 years) received 3037 SCIT courses. A total of 91,187 injections were given, with a mean SCIT duration of 2.5 ± 1.9 years. Nine hundred fifty-seven patients (43.5%) were compliant as they completed the minimally required treatment duration of 3 years. A total of 1087 SE (1.2% of all injections; 76.8% local reactions) were reported in 513 patients (23.3%). There were 42 anaphylactic reactions (in 29 patients) during the study period; two of these were severe. Adrenalin was administered only once. No anaphylactic shock was reported. Only 39 patients (1.8%) discontinued SCIT because of SE, the majority of whom (24; 61.5%) because of systemic reactions (urticaria, asthma, anaphylaxis). Parietaria vaccines were the most frequently associated to SE. Female gender, number of vaccines administered (2 vaccine vs. 1 vaccine) and year of SCIT inception (1996-2018 vs. 1988-1995) were independently associated to SE., Conclusion: SCIT, although not absolutely free of risk, is safe and well tolerated. There is still room for improvement of treatment compliance., Competing Interests: Declaration of competing interest We declare that we have no conflict of interest., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Mast cells (MCs) are a potent proangiogenic factor in tumors, they product several pro-angiogenic factors such as fibroblast growth factor 2 (FGF-2), vascular epithelial growth factor (VEGF), tryptase and chymase. Tryptase is a serine protease classified as α-tryptase and β-tryptase, both produced by MCs. Tryptase degrades the tissues, playing an important role in angiogenesis and in the development of metastases. Serum tryptase increases with age, with increased damage to cells and risk of developing a malignancy and it could be considered the expression of a fundamental role of MCs in tumor growth or, on the contrary, in the antitumor response. Many biomarkers have been developed in clinical practice for improving diagnosis and prognosis of some neoplasms. Elevated tryptase levels are found in subgroups of patients with haematologic and solid cancers. In the current review, we want to update the perspectives of tryptase as a potential biomarker in daily practice in different neoplasms.

Purpose of Review: Although allergen immunotherapy (AIT) for fungi has been performed for many years, evidence clearly demonstrating its clinical benefit are still lacking. Here, we reviewed the available studies assessing efficacy and safety of AIT for molds., Recent Findings: Studies on AIT for fungi were performed only for the two predominating mold species in the external environment, namely Cladosporium and Alternaria. There is no evidence for other mold species. Recent finding in the literature are lacking; the 2 most recent studies on AIT for molds were published in 2011. Overall, 13 studies were identified (the first was published in 1986), but only nine of these compared AIT to placebo. The studies are small (median study sample size, 27 patients) and of low quality, owing to several defects leading to moderate-to-high risk of bias. Symptoms improvement and medication use reduction, which are the main outcome measures of the studies, were inconsistently demonstrated. There are some concerns about safety with Cladosporium extracts, whereas vaccines with Alternaria extracts seem to be safe and well tolerated., Summary: Low strength evidence suggests that mold AIT is efficacious for the treatment of respiratory allergies. High-quality studies with an adequate sample size are needed.

Introduction: Onion (Allium cepa) handling can induce contact dermatitis, rhinoconjunctivitis and asthma. However, only sporadic reports exist on allergic reactions to onion consumption., Aim: We describe herein a case of a 35-year-old man who had an episode of anaphylaxis following cooked onion ingestion. We evaluated onion-specific IgE, the possible cross-reactivity between onion and peach and lymphocyte proliferation in response to onion., Material and Methods: Specific IgE was evaluated using two techniques: skin test and ImmunoCAP technology. Cross-reactivity between onion and peach was evaluated by IgE-ELISA inhibition test. As for lymphocyte proliferation, blood mononuclear cells were stained with CFSE dye and cultured with an in-house onion extract. Proliferation and phenotype was assessed by flow-cytometry., Results: The skin test and ImmunoCAP confirmed the IgE-dependent response towards onion. The incubation of the patient serum with increasing concentrations of the peach extract reduced only scarcely (~30%) onion-specific IgE. Interestingly, B cells but not T cells showed proliferation in response to onion extract., Conclusions: In conclusion, our report shows that cooked onion can induce severe allergic reactions, suggesting the presence of thermostable components. Moreover, we applied for the first time a B-cell-based approach to the diagnosis of food allergy. This latter approach might also be applied to other allergic conditions., Competing Interests: The authors declare no conflict of interest.

Background: Allergen immunotherapy (AIT) with mould extracts has been performed for many years but the final demonstration of its clinical efficacy is still missing, due to the small number of studies and their inconsistent results., Objective: To systematically review efficacy and safety of AIT for the treatment of respiratory allergies to moulds., Design: The primary outcomes were safety and reduction of symptoms (Symptom Score, SS) and medication use (Medication Score, MS) in patients treated with AIT compared to controls. The strength of the evidence was graded based on the risk of bias, consistency and magnitude of effect, according to the GRADE Working Group's guide., Data Sources: Medline, Web of Science and the Cochrane Library (through September 2017) supplemented with manual searches of reference lists., Eligibility Criteria: Randomized studies of intervention comparing AIT to placebo/pharmacotherapy. Studies not reporting on our outcome of interest or without a control population were excluded., Results: Nine studies (168 children, 99 adults; median sample size, 27) met the inclusion criteria. The risk of bias was moderate-to-high in all but one study. Low strength evidence supports the assumption that AIT is effective in reducing symptoms and medication use, with only four of nine studies reporting higher benefit of AIT vs. comparators. The highest benefit of AIT compared to pharmacotherapy/placebo was reported in studies with a longer follow-up (SMD for MS from -3.96 to -3.97 in favour of AIT) and low risk of bias (VAS for SS: 66.3 ± 13 in AIT group; 186.6 ± 39 in comparators; P < 0.05). No difference was reported with respect to study sample size, route of administration, age of participants. Generalised adverse reactions were reported in 12.5% of participants treated with sublingual immunotherapy, and 37.2% of participants treated with subcutaneous immunotherapy., Conclusions: Low strength evidence suggests that mould AIT is efficacious for the treatment of respiratory allergies. High-quality studies with an adequate sample size are needed., (© 2018 John Wiley & Sons Ltd.)

Background: Hymenoptera venom immunotherapy (VIT) is a clinically effective treatment. However, little is known about its long-term clinical efficacy and biological effects. Several mechanisms have been proposed to account for VIT efficacy, including reduction of specific IgE and induction of allergen-specific IgG 4 , but the overall picture remains elusive. We investigated Vespula VIT clinical efficacy up to 8 years after discontinuation and the kinetics of Vespula -specific IgE and IgG 4 . Out of 686 consecutive patients we retrospectively selected and analysed a series of 23 patients with Vespula allergy that underwent a 5-year IT course, followed by a prolonged follow-up., Methods: Clinical efficacy of VIT was assessed as number and severity of reactions to Vespula re-stinging events. The presence of Vespula -specific IgE and IgG 4 was also monitored over time., Results: During the VIT treatment, patients were protected, reporting no reactions or mild reactions in occasion of re-stinging events. This protection was entirely maintained during the follow-up, up to 8 years. Skin reactivity (reflecting mast cell-bound Vespula -specific IgE) and circulating Vespula -specific IgE levels declined substantially during VIT. Notably, this reduction was maintained over time during the follow-up. Moreover, all the patients were analysed for IgG 4 . A robust induction of Vespula -specific IgG 4 was observed during the VIT course, with a substantial decline during the follow-up., Conclusions: We conclude that Vespula VIT is a clinically effective treatment, which induces long-term protection after discontinuation. The reduction of specific IgE, assessed by skin tests and RAST, closely matches the VIT- induced protection, while the IgG 4 induction seems not to be associated with VIT clinical efficacy in the long term.

Background: Randomized Controlled Trials showed that omalizumab exhibited a good safety and tolerability profile in patients with moderate-to-severe asthma. However, safety data of long-term treatment with omalizumab are scarce. Our aim was to assess the safety of omalizumab in patients under long-term treatment in a real-life setting., Methods: Difficult-to-control asthmatic patients treated with omalizumab up to 9 years were retrospectively evaluated. Mild to severe adverse events any and reasons for discontinuation were recorded., Results: Ninety-one patients (26.4% males, mean age 49.9 ± 14.9 years) were included: mean treatment length, 3.8 ± 2.6 years; mean individual monthly dose, 514.5 ± 345.7 mg (range, 150-1200 mg). A total of 10,472 single injections were given cumulatively to the 91 patients (115 single injections per patients, on average, over a treatment period up to 9 years). Fifty-nine patients (64.8%) were treated for a period of time from 3 to 9 years, 14 of whom from 6 to 9 years. A high proportion of patients who discontinued treatment dropped out within the first year (18, 39.1%), mainly for reasons unrelated to treatment. Six patients (6.6%) discontinued omalizumab for treatment-related adverse events: arthralgia/myalgia (3 patients); urticaria, angioedema (1 patients); metrorrhagia (1 patient); relapsing herpes labialis (1 patient). Four other patients complained of mild adverse events (rhinitis/conjunctivitis, injection site reaction, fatigue, thrombosis) but continued the treatment. Anaphylaxis was not reported., Conclusions: Long-term treatment with omalizumab appears remarkably safe and well tolerated in real-life setting. Prolonged omalizumab treatment for many consecutive years did not increase the risk of side effects, particularly anaphylaxis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Mastocytosis can be associated with other clonal or non-clonal hematologic diseases as well as a variety of non-hematologic malignancies. A 75-year-old Caucasian male patient was referred to us with a 5-month history of neutrophilic leukocytosis and mild splenomegaly. He had developed a cutaneous melanoma sixteen years ago. According to the clinical and pathological features, a final diagnosis of systemic mastocytosis was established. The patient started treatment with interferon-α at a dose of 3 MIU/day, combined with low doses of prednisone. We observed a rapid disappearance of symptoms. Unfortunately, after 3 months a diagnosis of pancreatic adenocarcinoma was established. A review of the literature suggests that mastocytes could have a pivotal role in several malignancies. Different chemokines, mitogenic factors, chemical mediators of inflammation, and specific gene mutations could explain the association between mastocytosis and other hematologic and non-hematologic disorders.

Allergic and autoimmune inflammation are associated with the activation of mast cells and basophils by antibodies against allergens or auto-antigens, respectively. Both cell types express several receptors for the Fc portion of antibodies, the engagement of which by antigen-antibody complexes controls their responses. When aggregated on the plasma membrane, high-affinity immunoglobulin E (IgE) receptors (FcεRI) and low-affinity IgG receptors (FcγRIIIA in mice, FcγRIIA in humans) induce these cells to release and secrete proinflammatory mediators, chemokines, and cytokines that account for clinical symptoms. When coaggregated with activating receptors on the same cells, other low-affinity IgG receptors (FcγRIIB in both species) inhibit mast cell and basophil activation. We found that FcγRIIB inhibited not only signals triggered by activating receptors with which they were coengaged (cis-inhibition), but also signals triggered by receptors engaged independently (trans-inhibition). Trans-inhibition acted upon the FcεRI-dependent activation of mouse mast cells, mouse basophils, and human basophils, and upon growth factor receptor (Kit)-dependent normal mouse mast cell proliferation, as well as the constitutive in vitro proliferation and the in vivo growth of oncogene (v-Abl)-transformed mastocytoma cells. Trans-inhibition was induced by receptors, whether inhibitory (FcγRIIB) or activating (FcεRI), which recruited the lipid phosphatase SHIP1. By hydrolyzing PI(3,4,5)P 3 , SHIP1 induced a global unresponsiveness that affected biological responses triggered by receptors that use phosphoinositide 3-kinase to signal. These data suggest that trans-inhibition controls numerous physiological and pathological processes, and that it may be used as a therapeutic tool in inflammation, especially but not exclusively, in allergy and autoimmunity., (Copyright © 2016, American Association for the Advancement of Science.)

Weight loss surgery (WLS) is efficacious for long-term weight reduction and decreases overall mortality in severely obese patients. The mechanisms implicated in long-term weight loss are not fully understood. Proposed mechanisms include changes in gut hormones and brain regulation of appetite and satiety. We aimed to investigate the long-term ghrelin and leptin profiles and changes in food preference and eating behavior after WLS in adolescent patients. Two obese females aged 15 years and 14 4/12 years, who did not respond to lifestyle changes, including dietary intervention and physical exercise in combination with medical therapy, underwent robotic-assisted gastroplication. Anthropometric measurements, food habits and eating behavior, as well as metabolic and hormonal changes during long-term post-surgical follow-up were monitored. Long-term weight reduction was obtained in both patients, with a significant decrease in waist circumference. Resting energy expenditure showed a decrease over time, with a respiratory quotient that increased showing a shift from oxidation of a high-fat diet before surgery to oxidation of a mixed diet two and three years later. Both subjects improved their eating habits and lifestyle. Co-morbidity resolution was also noted. Increased pre-prandial ghrelin levels as well as higher post-prandial ghrelin and a leptin drop compared with pre-surgery values were observed in both patients. Persistent weight loss after gastroplication is associated with a favorable change in gut hormones and food preferences. The role of hormonal and sensory components in long-term results seems crucial. Particularly in adolescent patients, a multidisciplinary approach and continuous nutritional care is mandatory for weight maintenance and consolidation of changes.

Aim of the Study: Turmer syndrome (TS) patients show increased morbidity due to metabolic, autoimmune and cardiovascular disorders. A risk of neoplasia is also reported. Here, we review the prevalence of neoplasia in a cohort of Turner patients., Methods: We retrospectively evaluated 87 TS women. Follow-up included periodic ultrasound of the neck, abdominal and pelvic organs, dermatologic evaluation and fecal occult blood test. Karyotype was 45,X in 46 patients. During follow-up, 63 girls were treated with growth hormone, 65 with estro-progestin replacement therapy and 20 with L-thyroxine. Autoimmune diseases were present in 29 TS., Results: A total of 17 neoplasms in 14 out of 87 patients were found. Six skin neoplasia, 3 central nervous system tumors, 3 gonadal neoplasia, 2 breast tumors, 1 hepatocarcinoma, 1 carcinoma of the pancreas and 1 follicular thyroid cancer were detected. Age at tumor diagnosis was higher in 45,X pts than in those with other karyotypes (p = 0.003). Adenomioma gallbladdder (AG) was detected in 15.3% of the patients, with a lower age in girls at diagnosis with an associated neoplasia in comparison with TS without tumors (p = 0.017). No correlation between genetic make up, treatment, associated autoimmune diseases and neoplastia was found., Conclusion: In our TS population an increased neoplasia prevalence was reported. A high prevalence of AG was also noted and it might be indicative of a predisposition to neoplasia. Further studies are needed to define the overall risk for neoplasia, and to determine the role of the loss of the X-chromosome and hormonal therapies., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Background/aims: Patients with type 1 diabetes mellitus (T1DM), autoimmune thyroiditis (ATD), and celiac disease (CD) are at increased risk for developing other autoimmune diseases. We evaluated zinc transporter 8 (ZnT8) prevalence in patients with ATD and/or CD in order to define the usefulness of ZnT8 autoantibodies for prediabetes screening., Methods: Eighty-one young patients with ATD and/or CD were included in the study; 32 subjects with clinical onset of T1DM were enrolled as a control group. GAD65, IA-2, and ZnT8 antibodies were measured. An intravenous glucose tolerance test, C-peptide, glycosylated hemoglobin levels, and genomic analysis of HLA-DQA1* and -DQB1* were also considered in patients positive for autoantibodies., Results: The ZnT8 prevalence was higher in T1DM patients than in patients with other autoimmune diseases (p < 0.001); positive ZnT8 detection was found in 2 ATD (p = 0.004) and 3 ATD + CD (p = 0.04) patients. Positive ZnT8 was associated with GAD65 (p = 0.01) but not with IA-2 positivity. No correlation between ZnT8 detection and the number of T1DM-susceptible HLA-DQ heterodimers was found. Pathological C-peptide levels and insulin response were found in subjects with islet autoimmunity and genetic susceptibility., Conclusion: ZnT8 autoantibodies detection in ATD and/or CD patients is low, and routine ZnT8 screening is not justified. ZnT8 evaluation may be recommended in subjects with autoimmune diseases as a marker for predicting compromised insulin secretion., (© 2016 S. Karger AG, Basel.)

To study gene functions specifically in NKp46+ cells we developed novel Cre mice allowing for conditional gene targeting in cells expressing Ncr1 (encoding NKp46). We generated transgenic Ncr1(greenCre) mice carrying an EGFPcre fusion under the control of a proximal Ncr1 promoter that faithfully directed EGFPcre expression to NKp46+ cells from lymphoid and nonlymphoid tissues. This approach allowed for direct detection of Cre-expressing NKp46+ cells via their GFP signature by flow cytometry and histology. Cre was functional as evidenced by the NKp46+ cell-specific expression of RFP in Ncr1(greenCre) Rosa-dtRFP reporter mice. We generated Ncr1(greenCre) Il2rg(fl/fl) mice that lack NKp46+ cells in an otherwise intact hematopoietic environment. Il2rg encodes the common gamma chain (γc ), which is an essential receptor subunit for cytokines (IL-2, -4, -7, -9, -15, and -21) that stimulate lymphocyte development and function. In Ncr1(greenCre) Il2rg(fl/fl) mice, NK cells are severely reduced and the few remaining NKp46+ cells escaping γc deletion failed to express GFP. Using this new NK-cell-deficient model, we demonstrate that the homeostasis of NKp46+ cells from all tissues (including the recently described intraepithelial ILC1 subset) requires Il2rg. Finally, Ncr1(greenCre) Il2rg(fl/fl) mice are unable to reject B16 lung metastases demonstrating the essential role of NKp46+ cells in antimelanoma immune responses., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: The concomitance of psoriasis and high IgE levels in the same patient, possibly associated to allergies, should not come as a surprise anymore, because both diseases are characterised by an immunological disorder, involving cytokines and other inflammatory mediators, with massive activation of the cell-mediated immunity., Materials and Methods: During a period of 18 months, using a radio-immunologic method, we assessed the level of IgE in patients with severe psoriasis who were not responding to the common therapy., Results: Patients with severe psoriasis had high levels of IgE., Conclusions: IgEs have an important role in pathogenesis of psoriasis and atopic dermatitis, but the mechanism is not yet clear.

Tumor engraftment followed by monoclonal antibody (mAb) therapy targeting tumor antigens represents a gold standard for assessing the efficiency of mAbs to eliminate tumor cells. Mouse models have demonstrated that receptors for the Fc portion of immunoglobulin G (FcγRs) are critical determinants of mAb therapeutic efficacy, but the FcγR-expressing cell populations responsible remain elusive. We show that neutrophils are responsible for mAb-induced therapy of both subcutaneous syngeneic melanoma and human breast cancer xenografts. mAb-induced tumor reduction, abolished in neutropenic mice, could be restored in FcγR-deficient hosts upon transfer of FcγR+ neutrophils or upon human FcγRIIA/CD32A transgenic expression. Finally, conditional knockout mice unable to perform FcγR-mediated activation and phagocytosis specifically in neutrophils were resistant to mAb-induced therapy. Our work suggests that neutrophils are necessary and sufficient for mAb-induced therapy of subcutaneous tumors, and represent a new and critical focal point for optimizing mAb-induced immunotherapies that will impact on human cancer treatment.

Neutrophils are notorious for their efficacy in microbial killing. Various mechanisms, such as phagocytosis, production of ROS, cytokines/chemokines and lipid mediators, degranulation of antimicrobials and enzymes, as well as NETosis contribute to this capacity. However, every incidence of neutrophil activation bears a risk to cause damage to the host. Several distinct steps, i.e., adhesion to endothelial cells, transmigration, chemotaxis, cytokine stimulation, and TLR signaling, are thought to control the extent of neutrophil activation. In the absence of a microbial stimulus, other pathways can induce neutrophil activation, among which FcR-induced activation when neutrophils encounter ICs. In these situations (inflammation, autoimmunity, allergy), neutrophils may act as primary or secondary effectors of immune reactions. In the presence of circulating ICs, neutrophils can indeed get stimulated directly in the bloodstream and trigger an immune response. Upon deposition of antibody complexes inside of tissues, neutrophils are first recruited and primed before being highly activated to amplify the ongoing inflammation. This review focuses on the engagement, activation, and responses of neutrophils to antibody ICs, inside of tissues or in the vasculature.

Receptors for the Fc portion of IgG (FcγRs) are mandatory for the induction of various IgG-dependent models of autoimmunity, inflammation, anaphylaxis, and cancer immunotherapy. A few FcγRs have the ability to bind monomeric IgG: high-affinity mouse mFcγRI, mFcγRIV, and human hFcγRI. All others bind IgG only when aggregated in complexes or bound to cells or surfaces: low-affinity mouse mFcγRIIB and mFcγRIII and human hFcγRIIA/B/C and hFcγRIIIA/B. Although it has been proposed that high-affinity FcγRs are occupied by circulating IgG, multiple roles for mFcγRI and mFcγRIV have been reported in vivo. However, the potential roles of hFcγRI that is expressed on monocytes, macrophages, and neutrophils have not been reported. In the present study, we therefore investigated the role of hFcγRI in antibody-mediated models of disease and therapy by generating hFcγRI-transgenic mice deficient for multiple endogenous FcRs. hFcγRI was sufficient to trigger autoimmune arthritis and thrombocytopenia, immune complex-induced airway inflammation, and active and passive systemic anaphylaxis. We found monocyte/macrophages to be responsible for thrombocytopenia, neutrophils to be responsible for systemic anaphylaxis, and both cell types to be responsible for arthritis induction. Finally, hFcγRI was capable of mediating antibody-induced immunotherapy of metastatic melanoma. Our results unravel novel capabilities of human FcγRI that confirm the role of high-affinity IgG receptors in vivo.

Introduction: Chronic Urticaria is a difficult to define condition from the nosographic standpoint, with complex pharmacological management, that heavily impacts the life of the patient. Some forms show not to be responsive to anti H1 anti-histaminic and require other treatments. One of these can be the treatment with Cyclosporine A (CsA)., Materials and Methods: This study, open and sequential, reports the results of short-term treatment over a sample of adults (21 patients) of both sexes, all suffering from chronic urticaria with IgE levels higher than 200 mU/ml treated with 4 mg/kg/die of CsA., Results: The results obtained show a reduction in the levels of total IgE and a significant improvement in symptoms; there were no adverse effects., Conclusions: Cyclosporine is an excellent treatment for chronic urticaria because it reduces the activity of T lymphocytes and reduction of the histamine release from the mast cells and basophils.

mAb therapy for experimental metastatic melanoma relies on activating receptors for the Fc portion of IgG (FcγR). Opposing results on the respective contribution of mouse FcγRI, FcγRIII, and FcγRIV have been reported using the gp75-expressing B16 melanoma and the protective anti-gp75 mAb TA99. We analyzed the contribution of FcγRs to this therapy model using bioluminescent measurement of lung metastases loads, novel mouse strains, and anti-FcγR blocking mAbs. We found that the TA99 mAb-mediated effects in a combination therapy using cyclophosphamide relied on activating FcγRs. The combination therapy, however, was not more efficient than mAb therapy alone. We demonstrate that FcγRI and, unexpectedly, FcγRIII contributed to TA99 mAb therapeutic effects, whereas FcγRIV did not. Therefore, FcγRIII and FcγRI are, together, responsible for anti-gp75 mAb therapy of B16 lung metastases. Our finding that mouse FcγRIII contributes to Ab-induced tumor reduction correlates with clinical data on its human functional equivalent human FcγRIIIA (CD16A).

During the last two decades, a rapidly increasing number of therapeutic antibodies have been generated and used in a variety of diseases. The rationale of passive immunotherapy is that, due to their unique specificity, antibodies can selectively target and act on molecules associated with pathological processes. However, how therapeutic antibodies actually act on target molecules and cells under specific conditions is poorly known. As a consequence, whether the efficacy of available antibodies could be increased and whether new antibodies could be tailored for specific purposes have not been thoroughly investigated. We discuss in this review how therapeutic antibodies interact with Fc receptors, what are the cellular responses induced by these interactions and how a better knowledge of these interactions and biological responses could improve antibody-based passive immunotherapy., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The aim of this review is to report recent findings and ongoing studies on the effects of acupuncture on endogenous biological mediators, in particular on neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). Acupuncture is a therapeutic technique and is a part of Traditional Chinese Medicine (TCM). Western descriptions of the clinical efficacy of acupuncture on pain, inflammation, motor dysfunction, mood disorders, and seizures are based on the stimulation of several classes of sensory afferent fibers and the consequent activation of physiological processes similar to those resulting from physical exercise or deep massage. The established research on the neuro-physiological correlates of acupuncture has pointed towards endogenous opioids as the principal biological mediators of the therapeutic actions of this ancient technique. More recently, several classes of molecules, such as neurotransmitters, cytokines and growth factors, have also been identified as possible mediators for specific acupuncture effects. This review will focus on the links between acupuncture and a class of growth factors known as neurotrophins (NTs), which are the main mediators of neural activity, plasticity and repair following neurodegeneration and/or traumatic injury. A special emphasis will be placed on the work of our laboratory investigating the role of nerve growth factor (NGF), the prototypical member of the neurotrophin family, as a mediator of acupuncture effects in the central nervous system (CNS) and as a modulator of sensory and autonomic activity., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The metabolic syndrome (MetS) is a common basis for the development of atherogenic cardiovascular disease. Adiponectin has been demonstrated to be insulin-sensitizing and an anti-atherogenic factor and is considered a key ofMetS. It was suggested that IL-10 may be involved in the inflammatory network of MetS in relation to adiponectin. We examined the relationship between adiponectin, IL-10 and MetS in pediatric obese patients. MetS components were assessed in 70 severely obese and 30 non-obese children and adolescents. Serum levels of adiponectin and IL-10 were measured in these subjects. Serum adiponectin levels were significantly lower (p < 0.001) and levels of IL-10 were significantly higher (p = 0.012) in obese subjects. MetS was present in 35.71% of obese patients. Patients with MetS showed a borderline significant decrease in serum adiponectin levels and significantly increased IL-10 levels when compared to those without MetS (p = 0.051 and p = 0.031, respectively); the differences in adiponectin and IL-10 values were controlled to the effect of BMI. No correlation between adiponectin and IL-10 levels was found. Our obese children showed hypoadiponectin and hyper-IL10 values. MetS was not associated with low IL-10. We probably observe a first phase of the complex mechanism implicated in the development of the MetS in children.