INTRODUCTION
Nasal polyps (NPs) are benign edematous outgrowth of the sinonasal mucosa characterized by persistent and exaggerated inflammation.1 Clinical management of NPs is largely unsatisfying,2, 3 reflecting our limited understanding of the pathogenesis of NPs. Emerging evidence highlight an important role of local immunoglobulin (Ig) hyperproduction in the pathogenesis of NPs. Local IgE, IgG, IgA and IgD may lead to the activation of mast cells, eosinophils and classic complement pathway in NPs, and associate with poor treatment outcome.4-7 Recently, it has been revealed that local immunoglobulin production is supported by ectopic lymphoid tissues (eLTs) in NPs, which are composed of T/B cell aggregation and germinal center (GC) like structure.8The eLT formation associates with refractory disease in patients with NPs as well.8, 9 Therefore, disrupting the formation of eLTs, which likely function as lymphoid organs in NPs, may hold significant clinical implications for NP treatment, particularly for the refractory type. However, little is known about what drives the appearance of eLTs in NPs.
The eLTs share morphological and functional similarities with secondary lymphoid organs (SLOs).10 In the development of SLOs, lymphotoxin (LT) α1β2-expressing lymphoid tissue inducer (LTi) cells induce the differentiation of the LTβ receptor (LTβR) positive stromal organizer cells and subsequent secretion of homeostatic chemokines, such as CXCL13, CCL21 and CXCL12, from those cells, which lead to the recruitment and compartmentalization of T and B cells.11, 12 In contrast to the well documented formation of SLOs, the mechanisms controlling the eLT development are limited understood. Although homeostatic chemokines have also been implicated in the eLT formation in inflamed tissues in response to infection, auto-immunity, cancer and transplantation,13-17 the involvement of specific homeostatic chemokines is highly tissue and disease-dependent. In addition, inflammatory cells may substitute for embryonic LTi cells to induce the production of lymphorganogenic chemokines during ectopic lymphoid neogenesis. For example, IL-17A has been implicated in driving microbial infection-induced lung eLT formation by inducing CXCL12 or CXCL13 production in murine models.18, 19
Previous studies have demonstrated elevated IL-17A levels and increased accumulation of IL-17A positive CD4+ and CD8+ T cells in NPs, especially in Asian patients.20, 21 We discovered that the presence of eLTs associated with elevated levels of IL-17A, LT and CXCL13 in NPs.8 IL-17A-producing cells have been identified inside and surrounding the eLTs in NPs.8 We therefore hypothesized that IL-17A, LT and CXCL13 may have a role in the development of eLTs in NPs. In this study, we determined the cellular sources of LT and CXCL13 as well as their receptors in NPs. We also performed mechanistic studies to explore the function of IL-17A, LT and CXCL13 in eLT formation in NPs by using nasal stromal cell and B cell culture, and a murine model with local IL-17A inflammation.