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.