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1.  The microbiome of the upper airways: focus on chronic rhinosinusitis 
Upper airway diseases including allergic rhinitis, chronic rhinosinusitis with or without polyps, and cystic fibrosis are characterized by substantially different inflammatory profiles. Traditionally, studies on the association of specific bacterial patterns with inflammatory profiles of diseases had been dependent on bacterial culturing. In the past 30 years, molecular biology methods have allowed bacterial culture free studies of microbial communities, revealing microbiota much more diverse than previously recognized including those found in the upper airway.
At presence, the study of the pathophysiology of upper airway diseases is necessary to establish the relationship between the microbiome and inflammatory patterns to find their clinical reflections and also their possible causal relationships. Such investigations may elucidate the path to therapeutic approaches in correcting an imbalanced microbiome.
In the review we summarized techniques used and the current knowledge on the microbiome of upper airway diseases, the limitations and pitfalls, and identified areas of interest for further research.
Electronic supplementary material
The online version of this article (doi:10.1186/s40413-014-0048-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4306241  PMID: 25624972
2.  Clinical significance of plasmacytoid dendritic cells and myeloid-derived suppressor cells in melanoma 
Immune markers in the peripheral blood of melanoma patients could provide prognostic information. However, there is currently no consensus on which circulating cell types have more clinical impact. We therefore evaluated myeloid-derived suppressor cells (MDSC), dendritic cells (DC), cytotoxic T-cells and regulatory T-cells (Treg) in a series of blood samples of melanoma patients in different stages of disease.
Flow cytometry was performed on peripheral blood mononuclear cells of 69 stage I to IV melanoma patients with a median follow-up of 39 months after diagnosis to measure the percentage of monocytic MDSCs (mMDSCs), polymorphonuclear MDSCs (pmnMDSCs), myeloid DCs (mDCs), plasmacytoid DCs (pDCs), cytotoxic T-cells and Tregs. We also assessed the expression of PD-L1 and CTLA-4 in cytotoxic T-cells and Tregs respectively. The impact of cell frequencies on prognosis was tested with multivariate Cox regression modelling.
Circulating pDC levels were decreased in patients with advanced (P = 0.001) or active (P = 0.002) disease. Low pDC levels conferred an independent negative impact on overall (P = 0.025) and progression-free survival (P = 0.036). Even before relapse, a decrease in pDC levels was observed (P = 0.002, correlation coefficient 0.898). High levels of circulating MDSCs (>4.13%) have an independent negative prognostic impact on OS (P = 0.012). MDSC levels were associated with decreased CD3+ (P < 0.001) and CD3 + CD8+ (P = 0.017) T-cell levels. Conversely, patients with high MDSC levels had more PD-L1+ T-cells (P = 0.033) and more CTLA-4 expression by Tregs (P = 0.003). pDCs and MDSCs were inversely correlated (P = 0.004). The impact of pDC levels on prognosis and prediction of the presence of systemic disease was stronger than that of MDSC levels.
We demonstrated that circulating pDC and MDSC levels are inversely correlated but have an independent prognostic value in melanoma patients. These cell types represent a single immunologic system and should be evaluated together. Both are key players in the immunological climate in melanoma patients, as they are correlated with circulating cytotoxic and regulatory T-cells. Circulating pDC and MDSC levels should be considered in future immunoprofiling efforts as they could impact disease management.
PMCID: PMC4326397  PMID: 25592374
Melanoma; Plasmacytoid dendritic cell (pDC); Myeloid-derived suppressor cell (MDSC); Myeloid differentiation; Prognosis; Immunoprofiling
3.  ICON: chronic rhinosinusitis 
Chronic rhinosinusitis (CRS) is a public health problem that has a significant socio-economic impact. Moreover, the complexity of this disease due to its heterogeneous nature based on the underlying pathophysiology - leading to different disease variants - further complicates our understanding and directions for the most appropriate targeted treatment strategies. Several International/national guidelines/position papers and/or consensus documents are available that present the current knowledge and treatment strategies for CRS. Yet there are many challenges to the management of CRS especially in the case of the more severe and refractory forms of disease. Therefore, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), a collaboration between EAACI, AAAAI, ACAAI, and WAO, has decided to propose an International Consensus (ICON) on Chronic Rhinosinusitis. The purpose of this ICON on CRS is to highlight the key common messages from the existing guidelines, the differences in recommendations as well as the gaps in our current knowledge of CRS, thus providing a concise reference. In this document we discuss the definition of the disease, its relevance, pharmacoeconomics, pathophysiology, phenotypes and endotypes, genetics and risk factors, natural history and co-morbidities as well as clinical manifestations and treatment options in both adults and children comprising pharmacotherapy, surgical interventions and more recent biological approaches. Finally, we have also highlighted the unmet needs that wait to be addressed through future research.
PMCID: PMC4213581  PMID: 25379119
Chronic rhinosinusitis; Pharmacoeconomics; Pathophysiology; Phenotypes; Genetics; Co-morbidities; Treatment; Biologicals; Unmet needs
4.  Endotypes and phenotypes of chronic rhinosinusitis: A PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology 
Chronic rhinosinusitis (CRS) is a complex disease consisting of several disease variants with different underlying pathophysiologies. Limited knowledge of the mechanisms of these disease subgroups is possibly the greatest obstacle in understanding the causes of CRS and improving treatment. It is generally agreed that there are clinically relevant CRS phenotypes defined by an observable characteristic or trait, such as the presence or absence of nasal polyps. Defining the phenotype of the patient is useful in making therapeutic decisions. However, clinical phenotypes do not provide full insight into all underlying cellular and molecular pathophysiologic mechanisms of CRS. Recognition of the heterogeneity of CRS has promoted the concept that CRS consists of multiple groups of biological subtypes, or “endotypes,” which are defined by distinct pathophysiologic mechanisms that might be identified by corresponding biomarkers. Different CRS endotypes can be characterized by differences in responsiveness to different treatments, including topical intranasal corticosteroids and biological agents, such as anti–IL-5 and anti-IgE mAb, and can be based on different biomarkers that are linked to underlying mechanisms. CRS has been regarded as a single disease entity in clinical and genetic studies in the past, which can explain the failure to identify consistent genetic and environmental correlations. In addition, better identification of endotypes might permit individualization of therapy that can be targeted against the pathophysiologic processes of a patient's endotype, with potential for more effective treatment and better patient outcomes.
PMCID: PMC4161279  PMID: 23587334
Chronic rhinosinusitis; endotypes; phenotypes; cytokines; biological agents; treatment; diagnosis; IgE; nasal polyps; pathophysiology
5.  Mixed T Helper Cell Signatures In Chronic Rhinosinusitis with and without Polyps 
PLoS ONE  2014;9(6):e97581.
In chronic rhinosinusitis (CRS) different phenotypes have been reported based on cytokine profile and inflammatory cell patterns. The aim of this study was to characterize the intracytoplasmatic cytokines ofTcells infiltrating theinflamed sinonasal mucosa.
Infiltrated T cells and tissue homogenates from sinonasal mucosal samples of 7 healthy subjects, 9 patients with CRS without nasal polyp (CRSsNP), 15 with CRS with nasal polyps (CRSwNP) and 5cystic fibrosis patients (CF-NP) were analyzed for cytokine expression using flow cytometry and multiplex analysis respectively. Intracytoplasmic cytokinesin T cells were analyzed after stimulation of nasal polyps with Staphylococcus aureus enterotoxin B for 24 hours.
The number of T cellsper total living cells was significantly higher in patients with CRSwNP vs. CRSsNP and controls. 85% of the CD4+ Tcells showed to be memory T cells. The effector T cells present in all tissues have apredominantTh1 phenotype. Only in CRSwNP, a significantfraction of T cellsproduced the Th2 cytokinesIL-4 and IL-5, while nasal polyps from CF patients were characterized by a higher CD4/CD8 T cell ratio and an increased number of Th17 cells. 24 h stimulation with SEB resulted in a significant induction of CD4+ T cells producing IL-10 (Tr1 cells).
T cell cytokine patternsin healthy and inflamed sinonasal mucosa revealed that Th2 cells (IL-4 and IL-5 producing cells) are significantly increased in CRSwNP mucosal inflammation. Exposure to SEB stimulates Tr1 cellsthat may contribute to the Th2 bias in CRSwNP.
PMCID: PMC4049589  PMID: 24911279
6.  Suppression of Cytokine Release by Fluticasone Furoate vs. Mometasone Furoate in Human Nasal Tissue Ex-Vivo 
PLoS ONE  2014;9(4):e93754.
Topical glucocorticosteroids are the first line therapy for airway inflammation. Modern compounds with higher efficacy have been developed, but head-to-head comparison studies are sparse.
To compare the activity of two intranasal glucocorticoids, fluticasone furoate (FF) and mometasone furoate (MF) with respect to the inhibition of T helper (Th)1, Th2 and Th17 cytokine release in airway mucosa.
We used an ex-vivo human nasal mucosal tissue model and employed pre- and post- Staphylococcus aureus enterotoxin B (SEB)-challenge incubations with various time intervals and drug concentrations to mimic typical clinical situations of preventive or therapeutic use.
At a fixed concentration of 10−10 M, FF had significantly higher suppressive effects on interferon (IFN)-γ, interleukin (IL)-2 and IL-17 release, but not IL-5 or tumor necrosis factor (TNF)-α, vs. MF. While the maximal suppressive activity was maintained when FF was added before or after tissue stimulation, the cytokine suppression capacity of MF appeared to be compromised when SEB-induced cell activation preceded the addition of the drug. In a pre-challenge incubation setting with removal of excess drug concentrations, MF approached inhibition of IL-5 and TNF-α after 6 and 24 hours while FF maximally blocked the release of these cytokines right after pre-incubation. Furthermore, FF suppressed a wider range of T helper cytokines compared to MF.
The study demonstrates the potential of our human mucosal model and shows marked differences in the ability to suppress the release of various cytokines in pre- and post-challenge settings between FF and MF mimicking typical clinical situations of preventive or therapeutic use.
PMCID: PMC3977874  PMID: 24710117
8.  Immunoregulatory Effects of Bone Marrow-Derived Mesenchymal Stem Cells in the Nasal Polyp Microenvironment 
Mediators of Inflammation  2014;2014:583409.
Nasal polyposis is a severe, chronic inflammatory condition of the paranasal sinuses and is frequently associated with asthma and aspirin sensitivity. Mesenchymal stem cells exhibit a potent immunosuppressive effect in several inflammatory conditions, and their role in nasal polyposis remains little explored. Hence, we investigated whether bone marrow-derived mesenchymal stem cells could modulate cell phenotype in the nasal polyp milieu. After coculture with mesenchymal stem cells, the frequency of these inflammatory cells was found to decrease. Furthermore, mesenchymal stem cells promoted strong inhibition of CD4+ and CD8+ T cell proliferation, increased the frequency of CD4+CD25+Foxp3 T cells, and changed the global cytokine profile from an inflammatory to an anti-inflammatory response. We believe that mesenchymal stem cells may be a very useful adjunct for investigation of the inflammatory process in nasal polyposis, contributing to better understanding of the inflammatory course of this condition.
PMCID: PMC3943259  PMID: 24707116
11.  Asthma in the elderly: what we know and what we have yet to know 
In the past, asthma was considered mainly as a childhood disease. However, asthma is an important cause of morbidity and mortality in the elderly nowadays. In addition, the burden of asthma is more significant in the elderly than in their younger counterparts, particularly with regard to mortality, hospitalization, medical costs or health-related quality of life. Nevertheless, asthma in the elderly is still been underdiagnosed and undertreated. Therefore, it is an imperative task to recognize our current challenges and to set future directions. This project aims to review the current literature and identify unmet needs in the fields of research and practice for asthma in the elderly. This will enable us to find new research directions, propose new therapeutic strategies, and ultimately improve outcomes for elderly people with asthma. There are data to suggest that asthma in older adults is phenotypically different from young patients, with potential impact on the diagnosis, assessment and management in this population. The diagnosis of AIE in older populations relies on the same clinical findings and diagnostic tests used in younger populations, but the interpretation of the clinical data is more difficult. The challenge today is to encourage new research in AIE but to use the existing knowledge we have to make the diagnosis of AIE, educate the patient, develop a therapeutic approach to control the disease, and ultimately provide a better quality of life to our elderly patients.
PMCID: PMC4137434  PMID: 25152804
12.  Staphylococcal enterotoxin B influences the DNA methylation pattern in nasal polyp tissue: a preliminary study 
Staphylococcal enterotoxins may influence the pro-inflammatory pattern of chronic sinus diseases via epigenetic events. This work intended to investigate the potential of staphylococcal enterotoxin B (SEB) to induce changes in the DNA methylation pattern. Nasal polyp tissue explants were cultured in the presence and absence of SEB; genomic DNA was then isolated and used for whole genome methylation analysis. Results showed that SEB stimulation altered the methylation pattern of gene regions when compared with non stimulated tissue. Data enrichment analysis highlighted two genes: the IKBKB and STAT-5B, both playing a crucial role in T- cell maturation/activation and immune response.
PMCID: PMC3867657  PMID: 24341752
Staphylococcus aureus enterotoxin B; Chronic rhinosinusitis and nasal polyps; DNA methylation; MBD2; Whole genome methylation analysis; Hypermethylation
13.  The Development of Nasal Polyp Disease Involves Early Nasal Mucosal Inflammation and Remodelling 
PLoS ONE  2013;8(12):e82373.
Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by both a chronic inflammation and tissue remodelling; as indicated by extracellular matrix protein deposition, basement membrane thickening, goblet cell hyperplasia and subepithelial edema, with reduced vessels and glands. Although remodelling is generally considered to be consequence of persistent inflammation, the chronological order and relationship between inflammation and remodelling in polyp development is still not clear. The aim of our study was therefore to investigate the pathological features prevalent in the development of nasal polyps and to elucidate the chronological order and relationship between inflammation and remodelling, by comparing specific markers of inflammation and remodelling in early stage nasal polyps confined to the middle turbinate (refer to as middle turbinate CRSwNP) obtained from 5 CRSwNP patients with bilateral polyposis, mature ethmoidal polyps from 6 CRSwNP patients, and normal nasal mucosal tissue from 6 control subjects. Middle turbinate CRSwNP demonstrated significantly more severe epithelial loss compared to mature ethmoidal polyps and normal nasal mucosa. The epithelial cell junction molecules E-cadherin, ZO-1 and occludin were also expressed in significantly lower amounts in mature ethmoidal polyps compared to healthy mucosa. Middle turbinate CRSwNP were further characterized by significantly increased numbers of subepithelial eosinophils and M2 type macrophages, with a distinct lack of collagen and deposition of fibronectin in polyp part. In contrast, the turbinate area of the middle turbinate CRSwNP was characterized by an increase in TGF-β activated myofibroblasts expressing α-SMA and vimentin, an increase in the number of pSmad2 positive cells, as well as increased deposition of collagen. These findings suggest a complex network of processes in the formation of CRSwNP; including gross epithelial damage and repair reactions, eosinophil and macrophage cell infiltration, and tissue remodelling. Furthermore, remodelling appears to occur in parallel, rather than subsequent to inflammation.
PMCID: PMC3858290  PMID: 24340021
14.  Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses 
Purinergic Signalling  2013;9(3):285-306.
Extracellular ATP and related nucleotides promote a wide range of pathophysiological responses via activation of cell surface purinergic P2 receptors. Almost every cell type expresses P2 receptors and/or exhibit regulated release of ATP. In this review, we focus on the purinergic receptor distribution in inflammatory cells and their implication in diverse immune responses by providing an overview of the current knowledge in the literature related to purinergic signaling in neutrophils, macrophages, dendritic cells, lymphocytes, eosinophils, and mast cells. The pathophysiological role of purinergic signaling in these cells include among others calcium mobilization, actin polymerization, chemotaxis, release of mediators, cell maturation, cytotoxicity, and cell death. We finally discuss the therapeutic potential of P2 receptor subtype selective drugs in inflammatory conditions.
PMCID: PMC3757148  PMID: 23404828
ATP; Extracellular nucleotides; P2 receptors; Inflammatory cells; Regulation of immune responses
24.  Immunopathology features of chronic rhinosinusitis in high-altitude dwelling Tibetans 
Allergy & Rhinology  2013;4(2):e69-e76.
Chronic rhinosinusitis (CRS) presents distinct inflammatory and remodeling patterns in different populations and environments. Tibetan ethnic groups live at high altitudes and in cold weather conditions. We sought to examine whether Tibetans exhibit distinct CRS pathology or characteristics. Sinonasal polyps and mucosal tissue were obtained from 14 Tibetan patients with CRS and nasal polyps (CRSwNPs), 13 patients with CRS without nasal polyps (CRSsNPs), and 12 Tibetan controls. Tissue homogenates and serum samples were assayed for several T-helper (TH) cell cytokines and mediators using enzyme linked immunosorbent assay profiles were measured using quantity polymerase chain reaction. Several key inflammatory cells were examined for immunohistochemical markers. CRSwNPs were characterized by increased mediator promoting eosinophilic inflammation (interleukin [IL]-5, eosinophil cationic protein, and total immunoglobulin E) and slight synergism with expression of IL-8, IL-2sRa, IL-1beta, IL-6, and myeloperoxidase, and a predominance of eosinophils, mast cells, and neutrophils. GATA-3 transcription factor was significantly increased and Foxp3 showed a tendency to be impaired in CRSwNPs compared with controls. CRSsNPs were characterized by significantly high levels of transforming growth factor beta1, increased interferon γ, and a significant enhancement of Foxp3 and T-beta compared with CRSwNPs. There were reduced numbers of inflammatory cells but increased levels of macrophages in CRSsNPs. Compared with CRSsNPs, CRSwNPs present a severe inflammatory reaction and show a TH2 milieu with apparently impaired regulatory T cells (Treg) function and increased inflammatory cells infiltration predominated by eosinophilic and mast cells. In contrast, TH1 polarization with enhanced Treg function and increased levels of macrophages appear in CRSsNPs.
PMCID: PMC3793116  PMID: 24124640
Chronic rhinosinusitis; eosinophils; high altitude; interleukin-5; nasal polyps; neutrophils; T-cell subsets; Tibetan patients; transcription factor
25.  Epithelium and stroma from nasal polyp mucosa exhibits inverse expression of TGF-β1 as compared with healthy nasal mucosa 
To evaluate TGF-β1 expression in polypoid mucosa (epithelium and stroma) of patients with chronic rhinosinusitis with nasal polyposis (CRSwNP).
Cross-sectional study with two groups: 17 patients with nasal polyposis and 11 controls. Polyps and normal nasal mucosa were processed by immunohistochemical methods for TGF-β1 visualization. Then, the percentage of TGF-β1 expression in stroma and epithelium was objectively quantified using UT Morph software.
A lower percentage of positive expression was found in the epithelium of CRSwNP patients (32.44%) versus normal controls (55.91%) (p < 0.05), and a higher percentage of positive expression in the stroma of CRSwNP patients (23.24%) versus controls (5.88%) (p < 0.05).
The lower percentage of TGF-β1 expression in the nasal epithelium of CRSwNP patients may have an impact on epithelium-directed topical treatments employed in this patient population.
PMCID: PMC3651223  PMID: 23663486
TGF-β1; Nasal polyps; Rhinosinusitis; Mucosa

Results 1-25 (42)