Interestingly we found reduced expression of pIgR in NPs Fig

Interestingly, we found reduced expression of pIgR in NPs (Fig 3), despite the fact that pIgR expression can be induced by local immunoglobulin production. Because pIgR is known to be expressed in glandular epithelium, its reduced expression in NPs might be due to the recently documented reduction of glands in NPs. Moreover, it is likely that antibody secretion from NPs constitutes only a small fraction of the total pi3k inhibitors recovered in nasal lavage fluid, and thus it is difficult to say with certainty that this is a good representation of NP-specific secretion. Nevertheless, the reduced pIgR expression fits well with the fact that we did not find significantly increased IgA or IgM levels in the nasal lavage fluid of patients with CRSwNP (Fig 4 and see Fig E3). In fact, the increased IgA and IgM levels in NP extracts might be a reflection of an inability of the pIgR system to upregulate its function and adequately accommodate the increased antibody production within the NP microenvironment. Accumulation of IgA in the tissue might further exacerbate inflammation through degranulation of eosinophils, and this could also be an important component of CRS pathogenesis. Although the antigen specificity of NP IgA is unknown, our previous studies have shown that at least some of the IgA in NPs is directed against autoantigens. Future studies will investigate whether antibodies derived from NPs are capable of activating innate effector cells, as well as assessing their specificities and the extent of clonal expansion within the tissues. In addition, although we have focused on antibody production as a key effector function of B cells in this work, it is possible that B cells and plasma cells within NPs play multiple roles during chronic inflammation (eg, T-cell costimulation, chemokine expression, cytokine expression, and regulatory roles), and further studies are needed to elucidate other mechanisms used by B cells during CRS pathogenesis. EBI2 is known to play a critical role in the induction of antibody responses in secondary lymphoid tissues.13, 14 However, little is known about the expression and function of EBI2 in human peripheral tissues. To our knowledge, this is the first report of increased EBI2 levels in peripheral tissues of a human pathological condition. We have found a significant increase in both EBI2 gene and protein expression in NPs in this study (Fig 5). Given the known role of EBI2 in facilitating plasmablast development and antibody production, and the striking enhancement of local production of antibodies in NPs, it is reasonable to speculate that EBI2 expression could be playing a role in this process in NPs. In addition, this work highlights EBI2 as a potential new therapeutic target that warrants further investigation. We have also shown that EBI2 levels correlate with markers of plasma cells in patients with CRS, lending further support to a potential role in disease pathogenesis, although future studies are needed to confirm whether EBI2 plays a role in activating local plasma cell responses in patients with CRS. The present studies suggest a potential importance of EBI2 expression in peripheral tissues in human subjects and extend our knowledge of the local mechanisms that promote B cells, plasma cells, and immunoglobulins in patients with CRSwNP-induced inflammation.