Immunorhinology and rhinosinusitis: Where are we heading? O ver the past 2 decades, multiple etiologic options have been published as to the cause of chronic rhinosinusitis (CRS). We have had excellent documents that relate to microbiologic organisms, including viruses, bacteria, and fungi. These have taken the form of a multitude of different pathologic entities, including immunologic response to fungi and bacteria, staph exotoxin, and bacterial biofilm, and, more recently, the importance of the microbiome. However, we are still left without any single etiologic factor involved in the development of CRS. This edition of the American Journal of Rhinology and Allergy has a number of extremely fascinating themes.The first theme is aimed at highlighting the sinonasal microbiome in CRS and potential factors in the stimulation of the inflammatory process. Anderson et al. 1 performed a systematic review of the sinonasal microbiome in CRS, and their findings indicated that, in fact, there is no clear single causative microbe. There was significant heterogeneity throughout their studied articles, with firmicutes, Actinobacteria, and bacteroides being identified in both the controls and the patients with CRS. There is clearly much more research required to fully define the role that the microbiome plays in CRS. In terms of factors that influence the inflammatory cycle, Shimizu et al. 2 presented a fascinating article that looked at the role that alarmins play in the pathogenesis of upper airway inflammation. They specifically looked at alarmin protein high mobility group box 1 (HMGB1). With sound methodology, they found significantly higher concentrations of HMGB1 in nasal secretions from patients with CRSwNP or with allergic rhinitis (AR) compared with the control. They noted that TNF-␣ stimulated the production of HMGB1, which, in turn, upregulated the production and secretion of interleukins 6 and 8, which indicated that HMGB1 does in fact play an important role in the pathogenesis of upper airway inflammation.Lee et al. 3 looked at the role of a number of cytokines in the nasal epithelium of patients with AR, and they showed that a decreased expression of epithelial junctional protein was found in patients with AR, with disruption of epithelial integrity via interleukins 4 and 5, and TNF-␣, which indicated a possible role in the pathogenesis of AR. There also are valuable data from Shun et al., 4 who evaluated the role that hypoxia plays in the formation of nasal polyposis by promoting autophagy in nasal polyp fibroblasts. The autophagy seems to be suppressed in hypoxia through the antiglycolytic activity of SIRT6, which is shown to be beneficial to nasal polyp formation. There are significant potential therapeutic benefits in the management of nasal polyposis if glucose metabolism through a SIRT6-based strategy can be found to be modulated.AR has long fascinated researchers and clinicians. The relationship between AR and asthma is well known. It, therefore, was interesting to see the article from Dogru 5 that showed ...