Elimination of Interface Energy Barriers Using Dendrimer Polyelectrolytes with Fractal Geometry.

In this work we study conjugated polyelectrolyte (CPE) films based on polyamidoamine (PAMAM) dendrimers of generations G1 and G3. These fractal macromolecules are compared to branched polyethylenimine (b-PEI) polymer using methanol as the solvent. All of these materials present a high density of amino groups, which protonated by methoxide counter-anions create strong dipolar interfaces. The vacuum level shift associated to these films on n-type silicon was 0.93 eV for b-PEI, 0.72 eV for PAMAM G1 and 1.07 eV for PAMAM G3. These surface potentials were enough to overcome Fermi level pinning, which is a typical limitation of aluminium contacts on n-type silicon. A specific contact resistance as low as 20 mΩ·cm2 was achieved with PAMAM G3, in agreement with the higher surface potential of this material. Good electron transport properties were also obtained for the other materials. Proof-of-concept silicon solar cells combining vanadium oxide as a hole-selective contact with these new electron transport layers have been fabricated and compared. The solar cell with PAMAM G3 surpassed 15% conversion efficiency with an overall increase of all the photovoltaic parameters. The performance of these devices correlates with compositional and nanostructural studies of the different CPE films. Particularly, a figure-of-merit (Vσ) for CPE films that considers the number of protonated amino groups per macromolecule has been introduced. The fractal geometry of dendrimers leads to a geometric increase in the number of amino groups per generation. Thus, investigation of dendrimer macromolecules seems a very good strategy to design CPE films with enhanced charge-carrier selectivity.

Dim artificial light at night alters gene expression rhythms and growth in a key seagrass species (Posidonia oceanica).

Artificial light at night (ALAN) is a globally spreading anthropogenic stressor, affecting more than 20% of coastal habitats. The alteration of the natural light/darkness cycle is expected to impact the physiology of organisms by acting on the complex circuits termed as circadian rhythms. Our understanding of the impact of ALAN on marine organisms is lagging behind that of terrestrial ones, and effects on marine primary producers are almost unexplored. Here, we investigated the molecular and physiological response of the Mediterranean seagrass, Posidonia oceanica (L.) Delile, as model to evaluate the effect of ALAN on seagrass populations established in shallow waters, by taking advantage of a decreasing gradient of dim nocturnal light intensity (from < 0.01 to 4 lx) along the NW Mediterranean coastline. We first monitored the fluctuations of putative circadian-clock genes over a period of 24 h along the ALAN gradient. We then investigated whether key physiological processes, known to be synchronized with day length by the circadian rhythm, were also affected by ALAN. ALAN influenced the light signalling at dusk/night in P. oceanica, including that of shorter blue wavelengths, through the ELF3-LUX1-ZTL regulatory network, and suggested that the daily perturbation of internal clock orthologs in seagrass might have caused the recruitment of PoSEND33 and PoPSBS genes to mitigate the repercussions of a nocturnal stress on photosynthesis during the day. A long-lasting impairment of gene fluctuations in sites characterised by ALAN could explain the reduced growth of the seagrass leaves when these were transferred into controlled conditions and without lighting during the night. Our results highlight the potential contribution of ALAN to the global loss of seagrass meadows, posing questions about key interactions with a variety of other human-related stressors in urban areas, in order to develop more efficient strategies to globally preserve these coastal foundation species.

Relationship between proinflammatory cytokines (Il-1beta, Il-18) and leukocyte telomere length in mild cognitive impairment and Alzheimer's disease.

Inflammation plays a crucial role in Alzheimer's disease (AD). AD neurodegeneration and concurrent involvement of the peripheral immune system may promote leukocyte division and telomere shortening. We examined genotypes and plasma levels of two proinflammatory cytokines, IL-1beta and IL-18, and leukocyte telomere length (LTL) in patients with mild cognitive impairment (MCI) and AD. We wanted to determine whether changes in plasma IL-1beta and IL-18 levels, together with LTL shortening, could be diagnostic for disease progression from MCI to AD. Median plasma IL-1beta levels were in the order MCI patients (2.2 pg/ml) < AD patients (4.0 pg/ml), both of which differed significantly from the controls (0.0 pg/ml). In the AD patients, the lowest IL-1beta levels were associated with the presence of the C allele of IL-1beta rs16944 SNP. Median plasma IL-18 levels were in the order MCI patients (116.3 pg/ml) > AD patients (85.8 pg/ml), both of which were significantly higher than in the controls (17.6 pg/ml). Analysis of LTL showed a progressive reduction in the order controls > MCI > AD patients (p < 0.0001). Overall LTL reduction was correlated with increased plasma IL-1beta levels, substantiating the hypothesis that inflammatory processes secondary to neuroinflammation may trigger telomere attrition. Changes in plasma IL-1beta and Il-18 levels, and LTL seem to reflect shifts in AD stage; they may have potential use as blood biomarkers to monitor disease onset and progression from MCI to AD.

Ecological feedback mechanisms and variable disturbance regimes: the uncertain future of Mediterranean macroalgal forests.

Loss of algal canopies can result in a shift towards a turf-dominated state, where variability in species life-history traits can determine new mechanisms of feedback, and influence the degraded system under variable regimes of disturbance. By focusing on rockpools dominated by Cystoseira brachycarpa, we tested the hypothesis that the alga Dictyopteris polypodioides could take advantage of extreme regimes of disturbance related to storms, and outcompete other turfs through a distinctive combination of life traits. Replacement of the canopy was initially driven by a mix of taxon-specific life-traits and resulting assemblages were susceptible to intense events of disturbance. Subsequently, D. polypodioides dominated removal quadrats, favored by density-dependent abilities to intercept more light and reach larger size than the rest of turf. These new positive feedbacks may contribute to maintain the modified state of the system and influence its ability to withstand extreme abiotic conditions.

IgG4 anti-infliximab in treated patients: Clinical impact and temporal evolution.

BACKGROUND: Infliximab (IFX) carries potential risk of immunogenicity with the production of anti-drug antibodies (ADA). ADA may belong to different isotypes and are usually measured by ELISA bridging assay. This test is not designed to detect IgG4 antibodies. The aim was to measure IgG4 anti-IFX antibodies in a cohort of IFX-treated patients and to evaluate their relationship with ADA and their clinical impact. METHODS: Anti-drug antibodies were detected using a bridging ELISA in the serum of 222 treated patients with different clinical outcomes to IFX. The same samples were analyzed for IgG4 anti-IFX antibodies using an experimental ImmunoCAP assay with reduced serum IgG4 background levels. A longitudinal evaluation was performed in a subgroup of 38 patients to define the temporal evolution of IgG4 anti-IFX. RESULTS: IgG4 anti-IFX was found in 26.6% of patients. Eighty of 222 patients were ADA+ (36%) and the majority (57/80, 71.3%) had IgG4 anti-IFX. Two IgG4-positive but ADA-negative patients were identified. IgG4 anti-IFX levels correlated with the serum levels of ADA. IgG4 anti-IFX was more common in both reactive and nonresponder patients than in tolerant/responder patients. Patients who had experienced IgE-mediated reactions displayed significantly higher IgG4 anti-IFX than IgE-negative reactive patients. The majority of patients tested positive for IgG4 anti-IFX after the first seven infusions. CONCLUSIONS: IgG4 anti-IFX is common in treated patients and a large part of ADA producing patients produce IgG4 antibodies. The IgG4 anti-IFX response does not prevent hypersensitivity reactions to IFX and correlates with the IgE anti-IFX response.

Preclinical evaluation of radiation and systemic, RGD-targeted, adeno-associated virus phage-TNF gene therapy in a mouse model of spontaneously metastatic melanoma.

The incidence of melanoma in the United States continues to rise, with metastatic lesions notoriously recalcitrant to therapy. There are limited effective treatment options available and a great need for more effective therapies that can be rapidly integrated in the clinic. In this study, we demonstrate that the combination of RGD-targeted adeno-associated virus phage (RGD-AAVP-TNF) with hypofractionated radiation therapy results in synergistic inhibition of primary syngeneic B16 melanoma in a C57 mouse model. Furthermore, this combination appeared to modify the tumor microenvironment, resulting in decreased Tregs in the draining LN and increased tumor-associated macrophages within the primary tumor. Finally, there appeared to be a reduction in metastatic potential and a prolongation of overall survival in the combined treatment group. These results indicate the use of targeted TNF gene therapy vector with radiation treatment could be a valuable treatment option for patients with metastatic melanoma.

Circulating T cells to infliximab are detectable mainly in treated patients developing anti-drug antibodies and hypersensitivity reactions.

Antibodies recognizing infliximab (IFX) may develop in a proportion of treated patients, leading to loss of response or hypersensitivity reactions (HRs). T cell response to IFX has been poorly investigated. This paper was addressed to detect IFX-specific T cells in treated patients with inflammatory diseases developing, or not, anti-drug antibodies (ADA) and to correlate the presence of specific T cells with the clinical outcomes of the treatment. A co-culture system of IFX-loaded dendritic cells and purified autologous CD4+ T cells was used to detect memory T cells in 32 ADA+ and 39 ADA- IFX-treated patients and control groups. The cytokine profile of IFX-specific T cells was also studied in culture supernatants. IFX-specific cell proliferation was detected mainly in cells from ADA+ patients, irrespective of their different diseases. HR patients displayed higher T cell proliferation than non-responder and tolerant patients. A mixed [interferon (IFN)-γ, interleukin (IL)-13, IL-10] cytokine profile was shown in cells from ADA+ patients, while IL-10 was the most frequently detected cytokine in the supernatants of cultures from ADA- patients. Immunoglobulin (Ig)E+ ADA+ patients with previous HRs exhibited a more pronounced type 2 profile than IgE- ADA+ patients. This work provides evidence that IFX-specific circulating T cells are detectable mainly in ADA+ patients with HRs, regardless of their disease. The IFX-induced cytokine pattern partially correlates with the ADA isotype.

Retinoblastoma-binding protein 2 (RBP2) is frequently expressed in neuroendocrine tumors and promotes the neoplastic phenotype.

Neuroendocrine tumors (NETs), which can have survival rates as low as 4%, currently have limited therapeutic interventions available highlighting the dire need for the identification of novel biological targets for use as new potential drug targets. One such potential target is retinoblastoma-binding protein 2 (RBP2), an H3K4 demethylase whose overexpression has been linked to cancer formation and metastasis in non-endocrine tumor types. We measured RBP2 mRNA and protein levels in enteropancreatic NETs by measuring RBP2 in matched human normal and NET tissue samples. Further, proliferation, migration, invasion and colony formation assays were performed in the physiologically relevant NET cell lines ßlox5, H727 and QGP-1 to understand the role of RBP2 and its demethylase activity on end points of tumorigenesis. Our data indicate a strong correlation between RBP2 mRNA and protein expression in NET specimens. RBP2 was overexpressed relative to tissue-matched normal controls in 80% of the human tumors measured. In vitro studies showed RBP2 overexpression significantly increased proliferation, migration, invasion and colony formation, whereas knockdown significantly decreases the same parameters in a demethylase-independent manner. The cell cycle inhibitors p21 and p57 decreased with RBP2 overexpression and increased upon its depletion, suggesting a regulatory role for RBP2 in cellular proliferation. Taken together, our results support the hypothesis that the aberrant overexpression of RBP2 is a frequent contributing factor to tumor formation and metastasis in enteropancreatic NETs.

Comparative transcriptomic analysis reveals the oncogenic fusion protein PAX3-FOXO1 globally alters mRNA and miRNA to enhance myoblast invasion.

Rhabdomyosarcoma, one of the most common childhood sarcomas, is comprised of two main subtypes, embryonal and alveolar (ARMS). ARMS, the more aggressive subtype, is primarily characterized by the t(2;13)(p35;p14) chromosomal translocation, which fuses two transcription factors, PAX3 and FOXO1 to generate the oncogenic fusion protein PAX3-FOXO1. Patients with PAX3-FOXO1-postitive tumors have a poor prognosis, in part due to the enhanced local invasive capacity of these cells, which leads to the increased metastatic potential for this tumor. Despite this knowledge, little is known about the role that the oncogenic fusion protein has in this increased invasive potential. In this report we use large-scale comparative transcriptomic analyses in physiologically relevant primary myoblasts to demonstrate that the presence of PAX3-FOXO1 is sufficient to alter the expression of 70 mRNA and 27 miRNA in a manner predicted to promote cellular invasion. In contrast the expression of PAX3 alters 60 mRNA and 23 miRNA in a manner predicted to inhibit invasion. We demonstrate that these alterations in mRNA and miRNA translate into changes in the invasive potential of primary myoblasts with PAX3-FOXO1 increasing invasion nearly 2-fold while PAX3 decreases invasion nearly 4-fold. Taken together, these results allow us to build off of previous reports and develop a more expansive molecular model by which the presence of PAX3-FOXO1 alters global gene regulatory networks to enhance the local invasiveness of cells. Further, the global nature of our observed changes highlights the fact that instead of focusing on a single-gene target, we must develop multi-faceted treatment regimens targeting multiple genes of a single oncogenic phenotype or multiple genes that target different oncogenic phenotypes for tumor progression.

Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals: recommendations of the Innovative Medicines Initiative ABIRISK consortium.

Biopharmaceuticals (BPs) represent a rapidly growing class of approved and investigational drug therapies that is contributing significantly to advancing treatment in multiple disease areas, including inflammatory and autoimmune diseases, genetic deficiencies and cancer. Unfortunately, unwanted immunogenic responses to BPs, in particular those affecting clinical safety or efficacy, remain among the most common negative effects associated with this important class of drugs. To manage and reduce risk of unwanted immunogenicity, diverse communities of clinicians, pharmaceutical industry and academic scientists are involved in: interpretation and management of clinical and biological outcomes of BP immunogenicity, improvement of methods for describing, predicting and mitigating immunogenicity risk and elucidation of underlying causes. Collaboration and alignment of efforts across these communities is made difficult due to lack of agreement on concepts, practices and standardized terms and definitions related to immunogenicity. The Innovative Medicines Initiative (IMI; www.imi-europe.org), ABIRISK consortium [Anti-Biopharmaceutical (BP) Immunization Prediction and Clinical Relevance to Reduce the Risk; www.abirisk.eu] was formed by leading clinicians, academic scientists and EFPIA (European Federation of Pharmaceutical Industries and Associations) members to elucidate underlying causes, improve methods for immunogenicity prediction and mitigation and establish common definitions around terms and concepts related to immunogenicity. These efforts are expected to facilitate broader collaborations and lead to new guidelines for managing immunogenicity. To support alignment, an overview of concepts behind the set of key terms and definitions adopted to date by ABIRISK is provided herein along with a link to access and download the ABIRISK terms and definitions and provide comments (http://www.abirisk.eu/index_t_and_d.asp).

Mesenchymal stem cells are enriched in head neck squamous cell carcinoma, correlates with tumour size and inhibit T-cell proliferation.

BACKGROUND: Cancer is a multifactorial disease not only restricted to transformed epithelium, but also involving cells of the immune system and cells of mesenchymal origin, particularly mesenchymal stem cells (MSCs). Mesenchymal stem cells contribute to blood- and lymph- neoangiogenesis, generate myofibroblasts, with pro-invasive activity and may suppress anti-tumour immunity. METHODS: In this paper, we evaluated the presence and features of MSCs isolated from human head neck squamous cell carcinoma (HNSCC). RESULTS: Fresh specimens of HNSCC showed higher proportions of CD90+ cells compared with normal tissue; these cells co-expressed CD29, CD105, and CD73, but not CD31, CD45, CD133, and human epithelial antigen similarly to bone marrow-derived MSCs (BM-MSCs). Adherent stromal cells isolated from tumour shared also differentiation potential with BM-MSCs, thus we named them as tumour-MSCs. Interestingly, tumour-MSCs showed a clear immunosuppressive activity on in vitro stimulated T lymphocytes, mainly mediated by indoelamine 2,3 dioxygenase activity, like BM-MSCs. To evaluate their possible role in tumour growth in vivo, we correlated tumour-MSC proportions with neoplasm size. Tumour-MSCs frequency directly correlated with tumour volume and inversely with the frequency of tumour-infiltrating leukocytes. CONCLUSIONS: These data support the concept that tumour-MSCs may favour tumour growth not only through their effect on stromal development, but also by inhibiting the anti-tumour immune response.

Molecular diagnosis and the Italian Board for ISAC.

The Component Resolved Diagnostic (CRD) approach has been developed when highly purified or recombinant allergen molecules have become available. These molecules are the allergenic proteins toward which the specific and clinically relevant IgE immune response is directed. So, the identification of protein families and cross-reactivity patterns of importance in allergy have been possible. The Italian advisory BOARD for ISAC was born: to evaluate the advantages, disadvantages and placement in diagnosis of CRD studying its application in allergic patients; to facilitate the interpretation of molecular diagnostics for clinical allergists; to evaluate the effectiveness of CRD in improving diagnostic risk assessment and early preventive treatment of allergic diseases. In the last years, its fields of interest have been: the evaluation of the performance of CRD on multi-sensitized allergic patients with respiratory symptoms and on poly-sensitized athletes; the evolution of IgE repertoire directed to single allergenic components by evaluating allergic patients with different age at a molecular level; the relevance of results obtained using allergen microarray technique for describing the IgE repertoire in allergic patients by reviewing the main articles focused on CRD published in the last 2 years; the need for an educational program focused on this new diagnostic tool also through the creation of an exhaustive and interactive explanation of the laboratory report molecular allergy; the investigation of the performance and potential additional diagnostic values of the ISAC microarray in a real-life clinical setting, taking into account also the economic values.

Potential pathogenetic role of Th17, Th0, and Th2 cells in erosive and reticular oral lichen planus.

OBJECTIVES: The role of Th17 cells and associated cytokines was investigated in oral lichen planus. MATERIAL AND METHODS: 14 consecutive patients with oral lichen planus were investigated. For biological studies, tissues were taken from reticular or erosive lesions and from normal oral mucosa (controls) of the same patient. mRNA expression for IL-17F, IL-17A, MCP-1, IL-13, IL-2, IL-10, IL-1ß, RANTES, IL-4, IL-12B, IL-8, IFN-γ, TNF-α, IL-1α, IL-18, TGF-ß1, IL-23R, IL-7, IL-15, IL-6, MIG, IP-10, LTB, VEGF, IL-5, IL-27, IL-23A, GAPDH, PPIB, Foxp3, GATA3, and RORC was measured using the QuantiGene 2.0. RESULTS: Results showed that Th17-type and Th0-type molecules' mRNAs, when compared with results obtained from tissue controls, were increased in biopsies of erosive lesions, whereas Th2-type molecules' mRNAs were increased in reticular lesions. When the CD4+ T-cell clones, derived from oral lichen planus tissues and tissue controls, were analyzed, a higher prevalence of Th17 (confirmed by an increased CD161 expression) and Th0 CD4+ T clones was found in erosive lesions, whereas a prevalence of Th2 clones was observed in reticular lesions. CONCLUSIONS: Our data suggest that Th17, Th0, and Th2 cells, respectively, may have a role in the pathogenesis of erosive and reticular oral lichen planus.

The additional values of microarray allergen assay in the management of polysensitized patients with respiratory allergy.

BACKGROUND: The IgE response is directed against specific components from an allergenic source. The traditional diagnostic methods use whole extracts, containing allergenic, nonallergenic and cross-reactive molecules. This may pose diagnostic challenges in polysensitized patients. Microarray techniques detect specific IgE against multiple molecules, but their value in term of additional information and economic saving has not been yet defined. OBJECTIVE: We assessed the additional diagnostic information provided by an allergen microarray in a large population of polysensitized subjects. METHODS: In this multicentre study, allergists were required to carefully record diagnosis and treatment of consecutive patients referred for asthma/rhinitis, using the standard methodology (history, skin prick test, IgE assay). Then, a microarray allergen assay was carried out. Clinicians were required to review their diagnosis/treatment according to microarray results. RESULTS: 318 allergic patients (30% reporting also nonrespiratory symptoms) and 91 controls were enrolled. The clinicians reported at least one additional information from the microarray in about 60% of patients, this resulting in therapeutic adjustments. In 66% of patients IgE to pan-allergens were detectable, being this clinically relevant in 38% of patients with polysensitization to pollens. CONCLUSION: Microarray IgE assay represents an advancement in allergy diagnosis, as a third-level approach in polysensitized subjects, when the traditional diagnosis may be problematic.

Allergological in vitro and in vivo evaluation of patients with hypersensitivity reactions to infliximab.

BACKGROUND: The administration of biological agents is potentially affected by IgE-mediated infusion reactions. OBJECTIVE: The aim of the study was to evaluate the utility of skin testing in patients who have experienced infliximab (IFX)-related reactions. METHODS: Thirty patients with previous immediate hypersensitivity reaction to IFX, 20 disease-matched non exposed subjects, 15 IFX-treated disease-matched tolerant patients and 15 IFX non-responder patients were enrolled. Non-isotype-specific and IgE anti-drug antibodies (ADAs) were measured by a double-capture ELISA kit and ImmunoCAP assay, respectively. Prick and intra-dermal tests were carried out with the commercial IFX preparation serially diluted. RESULTS: Skin testing, performed in 23 of 30 reactive patients, resulted positive in 7 of them (30.4%), whereas no positivity was found in other groups of patients. The majority of reactive patients displayed non-isotype-specific ADAs (23/30, 76.6%) and the presence of anti-IFX IgE antibodies was detected in 6 of them (26%). All 6 IgE-positive reactive patients showed skin testing positivity. One reactive ADAs-positive patient who resulted skin test positive, with no detectable serum IFX-specific IgE ADAs, was also found. Skin testing positivity was associated with severe and early reactions (within the 3rd dose). No unexpected adverse reactions to skin testing were recorded. CONCLUSIONS AND CLINICAL RELEVANCE: This study shows that about 30% of reactive patients display skin testing positivity. They usually develop severe reactions, mainly during the first administrations of IFX. The specificity and the safety of skin testing procedure for this biological agent are also confirmed.

Poly(I:C) promotes the production of IL-17A by murine CD1d-driven invariant NKT cells in airway inflammation.

BACKGROUND: IL-17A is associated with different asthma phenotypes as virus-associated or steroid-resistant asthma. Invariant natural killer T (iNKT) cells play an important role in the pathogenesis of asthma. The aim of the study was to evaluate the activity of polyinosinic-polycytidylic acid [poly(I:C)] on IL-17A production by CD1d-activated iNKT cells. METHODS: We analysed the in vitro effect of poly(I:C) on the release of IL-17A by spleen and lung CD1d-activated iNKT cells with α-galactosylceramide (α-GalCer). Its activity was also investigated in an α-GalCer-induced murine models, including lung inflammation. The inhibition of IL-17A by Toll-like receptor (TLR) 7 agonists in the same in vitro and in vivo models has been analysed. RESULTS: Poly(I:C) upregulated the in vitro IL-17A production by CD1d-activated NK1.1- CD4- iNKT subset, without modifying type 1 and type 2 cytokines. The two stimuli selectively upregulated IL-17A serum levels in vivo. Their intratracheal administration resulted in increased airway hyper-reactivity (AHR), neutrophilia in bronchoalveolar lavage and airway inflammation, which were inhibited by anti-IL-17A antibody. Poly(I:C) effects were attributable to IL1ß and IL-23 release from dendritic cells, as showed by inhibition with neutralizing antibodies. TLR7 agonists inhibited the IL-17A production by poly(I:C) plus α-GalCer in the same models. Such effect was associated with the increased production by DC of IL-17A-inhibiting cytokines and the dampening of IL-1ß and IL-23. CONCLUSIONS: Synthetic dsRNA selectively expand a CD1d-driven IL-17A-producing iNKT cell subset, thus explaining the worsening of airway inflammation by some viral infections. TLR3- and TLR7-triggering viral sequences can exert variable and opposite effects on adaptive immune response.

Connell and Slatyer's models of succession in the biodiversity era.

Understanding how species interactions drive succession is a key issue in ecology. In this study we show the utility of combining the concepts and methodologies developed within the biodiversity-ecosystem functioning research program with J. H. Connell and R. O. Slatyer's classic framework to understand succession in assemblages where multiple interactions between early and late colonists may include both inhibitory and facilitative effects. We assessed the net effect of multiple species interactions on successional changes by manipulating the richness, composition, and abundance of early colonists in a low-shore assemblage of algae and invertebrates of the northwestern Mediterranean. Results revealed how concomitant changes in species richness and abundance can strongly alter the net effect of inhibitory vs. facilitative interactions on succession. Increasing richness of early colonists inhibited succession, but only under high levels of initial abundance, probably reflecting the formation of a highly intricate matrix that prevented further colonization. In contrast, increasing initial abundance of early colonists tended to facilitate succession under low richness. Thus, changes in abundance of early colonists mediated the effects of richness on succession.

Th17 cells: new players in asthma pathogenesis.

CD4+ T effector lymphocytes are distinguished in different subsets on the basis of their patterns of cytokine secretion. Th1 cells, thank to IFN-γ production, are responsible for cell-mediated immunity against intracellular pathogens, Th2 cells, through the production of IL-4, provide some degree of protection against helminthes, and Th17 cells, via IL-17, promote neutrophils recruitment for the clearance of bacteria and fungi. However, beyond their protective role, these T-helper subsets can also be involved in the pathogenesis of several inflammatory diseases. Asthma is an inflammatory disease characterized by different clinical phenotypes. Allergic asthma is the result of an inflammatory process driven by allergen-specific Th2 lymphocytes, whereas Th17 cells are mainly involved in those forms of asthma, where neutrophils more than eosinophils, contribute to the inflammation. The identification in allergic asthma of Th17/Th2 cells, able to produce both IL-4 and IL-17, is in keeping with the observation that different clinical phenotypes can coexist in the same patient. In conclusion, a picture in which different T-cell subpopulations are active in different phase of bronchial asthma is emerging, and the wide spectrum of clinical phenotypes is probably the expression of different cellular characters playing a role in lung inflammation.