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Abstract Rationale The mechanisms that underlie the pathogenesis of chronic rhinosinusitis without nasal polyps (CRSsNP), chronic rhinosinusitis with nasal polyps (CRSwNP), and aspirin-exacerbated respiratory disease (AERD) are not clear. Objectives To first evaluate the inflammatory profiles of CRSsNP and CRSwNP tissues and then to investigate whether clinical differences observed between CRSwNP and AERD are in part secondary to differences in inflammatory mediator expression within nasal polyp (NP) tissues. Methods Expression levels of numerous inflammatory mediators were determined by quantitative real-time polymerase chain reaction, ELISA, and multiplex immunoassay. Measurements and Main Results CRSwNP NP had increased levels of type 2 mediators, including IL-5 (P < 0.001), IL-13 (P < 0.001), eotaxin-2 (P  < 0.001), and monocyte chemoattractant protein (MCP)-4 (P < 0.01), compared with sinonasal tissue from subjects with CRSsNP and control subjects. Expression of IFN-γ messenger RNA or protein was low and not different among the chronic rhinosinusitis subtypes examined. Compared with CRSwNP, AERD NP had elevated protein levels of eosinophil cationic protein (ECP) (P < 0.001), granulocyte–macrophage colony–stimulating factor (GM-CSF) (P < 0.01), and MCP-1 (P = 0.01), as well as decreased gene expression of tissue plasminogen activator (tPA) (P = 0.02). Despite the higher eosinophilia in AERD, there was no associated increase in type 2 mediator protein levels observed. Conclusions CRSwNP was characterized by a predominant type 2 inflammatory environment, whereas CRSsNP did not reflect a classic type 1 milieu, as has been suggested previously. AERD can be distinguished from CRSwNP by elevated ECP levels, but this enhanced eosinophilia is not associated with elevations in traditional type 2 inflammatory mediators associated with eosinophil proliferation and recruitment. However, other factors, including GM-CSF, MCP-1, and tPA, may be important contributors to AERD pathogenesis.

Elevated numbers of antibody-secreting cells (ASCs) and anti–double-stranded DNA (anti-dsDNA) antibodies are found in nasal polyp (NP) tissue. The presence of anti-dsDNA IgG in tissue prospectively predicts recurrent NP but the characteristics of the source ASCs are unknown. Here, we investigated whether NP B cells expressing the extrafollicular marker EBI2 have increased propensity for autoantibody production and evaluated the molecular characteristics of NP ASCs. NPs showed increased frequencies of anti-dsDNA IgG and total IgG ASCs compared with tonsils, with more pronounced differences among EBI2 + cells. In NPs, EBI2 + cells were frequently double negative (IgD – CD27 – ) and ASCs. Single-cell RNA-Seq analysis of tonsils and NPs revealed substantial differences in B lineage composition, including differences in percentages of ASCs, germinal centers, proliferative cells, and non-ASCs. NPs exhibited higher expression of specific isotypes ( IGHE , IGHA1 , IGHA2 , and IGHG4 ) and mature plasma genes, including SDC1 and XBP1 , than tonsils. Gene Ontology biological processes indicated upregulated NF-κB and downregulated apoptosis pathways in NP ASCs. Together, these data indicate that NP EBI2 + ASCs secret increased total and anti-dsDNA IgG compared with those from tonsils and had molecular features of mature plasma cell differentiation.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by type 2 inflammation with accumulation of activated group 2 innate lymphoid cells (ILC2s) and elevation of thymic stromal lymphopoietin (TSLP). A member of the TNF superfamily (TNFSF), TNFSF15, is known to induce the production of type 2 cytokines in ILC2s. Although ILC2s have been implicated in CRSwNP, the presence and role of TNFSFs in ILC2-mediated type 2 inflammation in CRSwNP has not been elucidated. Here, we investigate the involvement of TNFSFs in ILC2-mediated type 2 inflammation in CRSwNP. We found that receptor activator of NF-κB (RANK) ligand (RANK-L (TNFSF11)) was significantly elevated in nasal polyps (NPs), and that the receptor of RANK-L, RANK, was expressed on ILC2s in human peripheral blood and NPs. An agonistic antibody against RANK induced production of type 2 cytokines in human ILC2s, and TSLP significantly enhanced this reaction. The membrane-bound RANK-L was detected mainly on CD45 + immune cells, including TH2 cells in NPs. The co-culture of NP-derived ILC2s and TH2 cells significantly enhanced production of type 2 cytokines, and anti-RANK-L monoclonal antibody suppressed this enhancement. In conclusion, RANK-L, together with TSLP, may play an inductive role in the ILC2-mediated type 2 inflammation in CRSwNP.

Background Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is characterized by type 2 inflammation with high levels of Th2 cytokines. Although T helper cytokines are released from T cells, innate lymphoid cells (ILC) are also known to produce high levels of the same cytokines. However, the presence of various types of ILC in CRS is poorly understood. Objective The objective of this study was to fully characterize the presence of all ILC subsets in CRS and to identify phenotypical differences of group 2 ILC (ILC2) in CRSwNP compared to ILC2 from non‐type 2 inflamed areas. Methods We investigated the presence of ILC subsets in peripheral blood mononuclear cells (PBMC) from healthy subjects, tonsil tissue, ethmoid tissue from control subjects and patients with non‐polypoid CRS (CRSsNP) and CRSwNP, as well as nasal polyp (NP) tissue from CRSwNP by flow cytometry. Sorted ILC2 were cultured in the presence and absence of IL‐33 and production of IL‐5 and IL‐13 was assessed by Luminex. Results We found that all ILC subsets were present in NP but ILC2 were dominant and significantly elevated compared to PBMC, tonsil, CRSsNP, and normal sinus tissue. We also found that inducible T‐cell co‐stimulator (ICOS) and side scatter were increased and CD127 was down‐regulated in ILC2 from NP compared to blood or tonsil ILC2. Thymic stromal lymphopoietin, IL‐7, and IL‐33 were able to down‐regulate expression of CD127 and increase side scatter in blood ILC2. Furthermore, sorted NP ILC2 but not blood ILC2 spontaneously released type 2 cytokines including IL‐5 and IL‐13. Conclusions and Clinical Relevance These results suggest that ILC2 are not only elevated but also activated in CRSwNP in vivo and that ILC2 may play important roles in the type 2 inflammation in CRSwNP. ILC2s were elevated in CRSwNP and expressions of inducible T‐cell co‐stimulator (ICOS) and CD127 in ILC2s were altered in CRSwNP compared to blood or tonsil ILC2. In addition, sorted CRSwNP ILC2 but not blood ILC2 spontaneously released type 2 cytokines including IL‐5 and IL‐13. These results suggest that ILC2s are not only elevated but also activated in CRSwNP in vivo.

Occupational rhinitis is characterized by nasal congestion, rhinorrhea, nasal itching, and/or sneezing that occur secondary to exposures in the workplace. This disease can be classified into allergic or nonallergic subgroups based upon the underlying disease pathogenesis as well as the type of causative agent. While the true prevalence of occupational rhinitis is unknown, there are certain professions and occupational exposures that place workers at a higher risk for developing the disease. Additionally, occupational rhinitis can be associated with occupational asthma and upper airway symptoms may precede those of the lower respiratory tract. Taken together, occupational rhinitis is an important disease for study given its medical as well as socioeconomic implications. This review will focus on the classification of occupational rhinitis as well the prevalence, diagnosis, and treatment strategies.

Up to 50% of patients with chronic rhinosinusitis (CRS) have comorbid asthma, and we have reported that a subset of CRS patients who have nasal polyps (CRSwNP) have elevated autoantigen‐specific antibodies within their nasal polyps (NP). While increases in the prevalence and/or severity of both asthma and autoimmunity in women are well characterized, it is not known whether CRSwNP is more severe or frequent in women than men. We sought to determine whether CRSwNP demonstrated sex‐specific differences in frequency and/or severity. Using a retrospectively collected database of tertiary care patients (n = 1393), we evaluated the distribution of sex in patients with CRSwNP with or without comorbid asthma or aspirin hypersensitivity. We further compared the severity of sinus disease between men and women with CRSwNP. Although women comprised 55% of CRS patients without NP (CRSsNP), a significantly smaller proportion of CRSwNP patients were female (38%, P < 0.001). Interestingly, women with CRSwNP were significantly more likely than men to have comorbid asthma (P < 0.001), and 61% of patients with the most severe form of disease (aspirin‐exacerbated respiratory disease (CRSwNP plus asthma plus aspirin sensitivity)) were women (P < 0.05). Women with CRSwNP were significantly more likely to have taken oral steroids, and were more likely to have a history of revision surgeries (P < 0.05) compared to men. These data suggest that women with CRSwNP have more severe disease than men in a tertiary care setting. Future studies are needed to elucidate the mechanisms that drive disease severity in men and women, paving the way for the development of personalized treatment strategies for CRSwNP based on sex.

Vaccination with formalin-inactivated respiratory syncytial virus (RSV) vaccine results in enhanced respiratory tract inflammation and injury following subsequent RSV infection. RSV vaccine-enhanced disease can also be produced in mice by prior vaccination with a vaccinia virus vector containing the RSV G protein, followed by intranasal infectious RSV challenge, a process characterized by induction of a potent memory CD4+ T-cell response to challenge infection with some features characteristic of Th-2 CD4+ T-cell responses, including increased eosinophil accumulation in pulmonary inflammatory infiltrates. The adaptive immune response to the RSV G protein in immunized BALB/c mice is characterized by a weak or absent primary and secondary recall CD8+ T-cell response. These and related results have led to the hypothesis that the failure of the infected animals to mount an effective CD8+ memory T-cell (CD8+ Tm) response in this model could account for the pulmonary eosinophilia associated with the development of enhanced disease, and that CD8+ T cells may control the development of eosinophilia. In this study, we investigated how and when the generation of a CD8+ Tm response to RSV infection might affect the development of pulmonary eosinophilia in this model of vaccine-enhanced disease. By defining the CD8+ T-cell response kinetics and monitoring lung parenchymal eosinophil accumulation, we show that the establishment of an RSV-specific CD8+ Tm response in the infected lungs early after challenge infection (i.e., within the first 3 d of RSV infection) is necessary and sufficient to control pulmonary eosinophilia development. Additionally, our work suggests that the mechanism by which CD8+ T cells regulate this process is not by modulating the differentiation or development of the CD4+ Tm response. Rather, we demonstrate that IL-10 produced by early responding CD8+ Tm cells may regulate the pulmonary eosinophilia development observed in RSV vaccine-enhanced disease.

THE SIXTH INTERNATIONAL RESPIRATORY SYNCYTIAL VIRUS (RSV) SYMPOSIUM was held from October 25 through October 28, 2007 in Marco Island, Florida. During this conference, over 200 students and investigators representing 16 countries convened to present and discuss recent advancements in RSV research. Presentations ranged from bench to bedside studies encompassing aspects of basic virology, pathogenesis, and immunology, as well as therapeutic and vaccine designs. In total, there were 12 invited speakers and 36 oral presentations divided into six sessions. Additionally, there were two posters sessions displaying more than one hundred abstracts. The following summary provides a review of the proceedings from each session.