Amber Luong

IL-33–Responsive Innate Lymphoid Cells Are an Important Source of IL-13 in Chronic Rhinosinusitis with Nasal Polyps

RATIONALE Chronic rhinosinusitis (CRS) without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP) are associated with Th1 and Th2 cytokine polarization, respectively; however, the pathophysiology of CRS remains unclear. The importance of innate lymphoid cells in Th2-mediated inflammatory disease has not been clearly defined. OBJECTIVES The objective of this study was to investigate the role of the epithelial cell-derived cytokine IL-33 and IL-33-responsive innate lymphoid cells in the pathophysiology of CRS. METHODS Relative gene expression was evaluated using quantitative real-time polymerase chain reaction. Innate lymphoid cells in inflamed ethmoid sinus mucosa from patients with CRSsNP and CRSwNP were characterized using flow cytometry. Cytokine production from lymphoid cells isolated from inflamed mucosa of patients with CRS was examined using ELISA and intracellular cytokine staining. MEASUREMENTS AND MAIN RESULTS Elevated expression of ST2, the ligand-binding chain of the IL-33 receptor, was observed in inflamed sinonasal mucosa from CRSwNP compared with CRSsNP and healthy control subjects. An increased percentage of innate lymphoid cells was observed in inflamed sinonasal mucosa from CRSwNP compared with CRSsNP. ST2(+) innate lymphoid cells are a consistent source of IL-13 in response to IL-33 stimulation. Significant induction of IL-33 was observed in epithelial cells derived from patients with CRSwNP compared with patients with CRSsNP in response to stimulation with Aspergillus fumigatus extract. CONCLUSIONS These data suggest a role for sinonasal epithelial cell-derived IL-33 and an IL-33-responsive innate lymphoid cell population in the pathophysiology of CRSwNP demonstrating the functional importance of innate lymphoid cells in Th2-mediated inflammatory disease.

Cleavage of Fibrinogen by Proteinases Elicits Allergic Responses Through Toll-Like Receptor 4

Allergy Induction Proteinases found in fungi and other allergens elicit allergic inflammation, but how they do so is far from clear. It is also unclear how pattern recognition receptors, which detect invading microbes, drive allergic inflammation. Millien et al. (p. 792) shed light on this puzzle by showing that, in mice, induction of allergic inflammation requires proteinase-dependent cleavage of the clotting factor fibrinogen, leading to generation of a ligand that activates the pattern-recognition receptor, Toll-like receptor 4 (TLR4). Cleaved fibrinogen signals through TLR4 to activate the innate immune system and recruit cells to the airway, which drives both allergic responses and antifungal immunity. Allergic inflammation requires proteinase-dependent cleavage of fibrinogen that activates innate immunity through Toll-like receptor 4. Proteinases and the innate immune receptor Toll-like receptor 4 (TLR4) are essential for expression of allergic inflammation and diseases such as asthma. A mechanism that links these inflammatory mediators is essential for explaining the fundamental basis of allergic disease but has been elusive. Here, we demonstrate that TLR4 is activated by airway proteinase activity to initiate both allergic airway disease and antifungal immunity. These outcomes were induced by proteinase cleavage of the clotting protein fibrinogen, yielding fibrinogen cleavage products that acted as TLR4 ligands on airway epithelial cells and macrophages. Thus, allergic airway inflammation represents an antifungal defensive strategy that is driven by fibrinogen cleavage and TLR4 activation. These findings clarify the molecular basis of allergic disease and suggest new therapeutic strategies.

International Consensus Statement on Allergy and Rhinology: Rhinosinusitis

Isam Alobid, MD, PhD1, Nithin D. Adappa, MD2, Henry P. Barham, MD3, Thiago Bezerra, MD4, Nadieska Caballero, MD5, Eugene G. Chang, MD6, Gaurav Chawdhary, MD7, Philip Chen, MD8, John P. Dahl, MD, PhD9, Anthony Del Signore, MD10, Carrie Flanagan, MD11, Daniel N. Frank, PhD12, Kai Fruth, MD, PhD13, Anne Getz, MD14, Samuel Greig, MD15, Elisa A. Illing, MD16, David W. Jang, MD17, Yong Gi Jung, MD18, Sammy Khalili, MD, MSc19, Cristobal Langdon, MD20, Kent Lam, MD21, Stella Lee, MD22, Seth Lieberman, MD23, Patricia Loftus, MD24, Luis Macias‐Valle, MD25, R. Peter Manes, MD26, Jill Mazza, MD27, Leandra Mfuna, MD28, David Morrissey, MD29, Sue Jean Mun, MD30, Jonathan B. Overdevest, MD, PhD31, Jayant M. Pinto, MD32, Jain Ravi, MD33, Douglas Reh, MD34, Peta L. Sacks, MD35, Michael H. Saste, MD36, John Schneider, MD, MA37, Ahmad R. Sedaghat, MD, PhD38, Zachary M. Soler, MD39, Neville Teo, MD40, Kota Wada, MD41, Kevin Welch, MD42, Troy D. Woodard, MD43, Alan Workman44, Yi Chen Zhao, MD45, David Zopf, MD46

Antibiotic therapy for nontuberculous mycobacterial cervicofacial lymphadenitis

Objectives/Hypothesis: To evaluate the efficacy of antibiotic treatment of nontuberculous mycobacterial (NTM) cervicofacial lymphadenitis, both as an alternative and as adjuvant to surgical excision.

The Link Between Allergic Rhinitis and Chronic Otitis Media with Effusion in Atopic Patients

The significant incidence of atopy associated with otitis media with effusion (OME) has suggested a role of allergy in the pathogenesis of OME. Analysis of inflammatory mediators indicates that the mucosa of the middle ear can respond to antigen in the same way as does the mucosa of the lower respiratory tract. Recent characterization of the mucosa and effusion from atopic patients with OME reveals a Th2 cytokine and cellular profiles consistent with an allergic response, supporting the role of allergy in OME. In addition, animal studies demonstrate that inhibiting characteristic allergy cytokines can prevent the production of middle ear effusion. As the understanding of allergy and its role in the inflammation of OME continues to deepen, this will introduce focused treatments of OME in the atopic population.

Outcomes of minimally invasive endoscopic resection of anterior skull base neoplasms.

The objective of this study was to review clinical outcomes of minimally invasive endoscopic resection (MIER) for anterior skull base (ASB) neoplasms.

Cross talk between follicular Th cells and tumor cells in human follicular lymphoma promotes immune evasion in the tumor microenvironment.

The microenvironment of human follicular lymphoma (FL), an incurable B cell non-Hodgkin’s lymphoma, is thought to play a major role in its pathogenesis and course. Microenvironmental cells of likely importance include follicular Th cells (TFH) and regulatory T cells (Tregs), and understanding their interactions with FL tumor cells is necessary to develop novel therapeutic strategies. We found that IL-4 and CD40L are expressed by intratumoral TFH and induce production of CCL17 and CCL22 by FL tumor cells. IL-4 alone induces only CCL17 but enhances stimulation by CD40L of both CCL17 and CCL22. Consistent with our in vitro results, mRNA transcripts of IL-4 correlated with CCL17, but not CCL22, in gene expression profiling studies of FL biopsies, whereas CD40L correlated with both CCL17 and CCL22. Tumor supernatants induced preferential migration of Tregs and IL-4–producing T cells rather than IFN-γ–producing T cells, and Abs to CCR4 significantly abrogated the migration of Tregs. Our results suggest that through two distinct mechanisms, intratumoral TFH induce production of CCL17 and CCL22 by FL tumor cells and facilitate active recruitment of Tregs and IL-4–producing T cells, which, in turn, may stimulate more chemokine production in a feed-forward cycle. Thus, TFH appear to play a major role in generating an immunosuppressive tumor microenvironment that promotes immune escape and tumor survival and growth. Our results provide novel insights into the cross talk among TFH, tumor cells, and Tregs in FL, and offer potential targets for development of therapeutic strategies to overcome immune evasion.

Balloon catheter dilatation for frontal sinus ostium stenosis in the office setting

Background Frontal sinus ostium stenosis (FSOS) is problematic even for expert surgeons. Balloon catheter (BC) technology has been recently introduced to rhinology. The aim of this study is to assess technical feasibility and effectiveness of BC dilatation of FSOS in the office setting. Methods This retrospective, multi-institutional case series describes all patients who underwent BC dilatation of FSOS in the office setting in the year ending December 31, 2007. Results Six adult patients underwent a total of seven BC dilatations of FSOS in the clinical setting. The pretreatment ostium size was 1-2 mm. Four of the dilatations were performed with a 5-mm lacrimal BC (LacriCATH, Quest Medical, Allen, TX) and three dilatations were executed with a 7-mm sinus BC (SinuCATH, Quest Medical). All procedures were performed using topical anesthesia only. No complications occurred. Five of the six dilated FSOS dilatations were deemed successful after one BC dilatation. One ostium contracted >50% and required repeat BC dilatation. All ostia have remained patent with a follow-up range of 4-9 months. No subject has required formal surgical revision. Conclusion This preliminary report describes BC of FSOS in the office setting. The technique may serve as a safe and feasible alternative, potentially avoiding formal revision sinus surgery in select patients.

Airway surface mycosis in chronic TH2-associated airway disease

BACKGROUND Environmental fungi have been linked to TH2 cell-related airway inflammation and the TH2-associated chronic airway diseases asthma, chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), and allergic fungal rhinosinusitis (AFRS), but whether these organisms participate directly or indirectly in disease pathology remains unknown. OBJECTIVE To determine the frequency of fungus isolation and fungus-specific immunity in patients with TH2-associated and non-TH2-associated airway disease. METHODS Sinus lavage fluid and blood were collected from sinus surgery patients (n = 118) including patients with CRSwNP, patients with CRS without nasal polyps, patients with AFRS, and non-CRS/nonasthmatic control patients. Asthma status was determined from medical history. Sinus lavage fluids were cultured and directly examined for evidence of viable fungi. PBMCs were restimulated with fungal antigens in an enzyme-linked immunocell spot assay to determine total memory fungus-specific IL-4-secreting cells. These data were compared with fungus-specific IgE levels measured from plasma by ELISA. RESULTS Filamentous fungi were significantly more commonly cultured in patients with TH2-associated airway disease (asthma, CRSwNP, or AFRS: n = 68) than in control patients with non-TH2-associated disease (n = 31): 74% vs 16%, respectively (P < .001). Both fungus-specific IL-4 enzyme-linked immunocell spot (n = 48) and specific IgE (n = 70) data correlated with TH2-associated diseases (sensitivity 73% and specificity 100% vs 50% and 77%, respectively). CONCLUSIONS The frequent isolation of fungi growing directly within the airways accompanied by specific immunity to these organisms only in patients with TH2-associated chronic airway diseases suggests that fungi participate directly in the pathogenesis of these conditions. Efforts to eradicate airway fungi from the airways should be considered in selected patients.

Biofilm presence in humans with chronic suppurative otitis media

Objective: To study the presence of biofilm formation in humans with chronic suppurative otitis media (CSOM). Study Design: Cross-sectional study. Setting: Tertiary academic hospital. Subjects and Methods: Patients undergoing middle ear surgery between July 2006 and March 2008. Tissue samples were obtained from 25 patients, of which 20 specimens were successfully processed for this study. The remaining samples were not analyzed due to sample damage or loss during preparation. Of the 20 specimens studied, 10 were harvested as the experimental group from patients with CSOM and the other 10 harvested as controls from patients undergoing otologic surgery for acoustic neuroma, cochlear implant, or routine tympanoplasty. Ages ranged from 26 to 74 years (mean 45 yrs). Male-to-female ratio was 2:3. Scanning electron microscopy and confocal laser scanning microscopy were used to identify the presence of biofilms. Live-dead staining was used to assess whether bacteria present were viable. The outcome measured was the presence of adherent biofilms on middle ear mucosa. Results: Biofilms were present in six of 10 samples (60%) from the CSOM group, but only in one of 10 control samples (10%). Comparative analysis revealed a statistically significant difference (P < 0.05) in the presence of biofilms in specimens from the CSOM group versus the control group. Conclusion: Biofilms were statistically more common in patients with CSOM compared with control patients.